Researcher Profile and Settings

Master

Affiliation (Master)

• Faculty of Medicine　Internal Medicine　Internal Medicine

Affiliation (Master)

• Faculty of Medicine　Internal Medicine　Internal Medicine

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Profile and Settings

Profile and Settings

• Name (Japanese)

  SAKAMOTO

• Name (Kana)

  NAOYA

• Name

  200901002125524070

Achievement

Research Interests

• 肝疾患   ウイルス肝炎   

Research Areas

• Life sciences / Gastroenterology

Published Papers

• Preoperative risk factors for skeletal muscle mass loss in patients with biliary tract cancer

  Ryo Sugiura, Masaki Kuwatani, Kazumichi Kawakubo, Kazuma Kishi, Hiroki Yonemura, Shunichiro Nozawa, Masatsugu Ohara, Takehiro Noji, Satoshi Hirano, Naoya Sakamoto

  Journal of Hepato-Biliary-Pancreatic Sciences 1868-6974 2024/06/06 

  Abstract Background Endoscopic retrograde cholangiography (ERC)‐related procedures, usually performed before biliary tract cancer (BTC) surgery, are associated with increased risk for various complications, which can cause sarcopenia. No study has previously elucidated the relationship between preoperative ERC‐related procedures and sarcopenia/skeletal muscle mass loss. Methods Patients with BTC who underwent radical surgical resection following ERC‐related procedures were included. Skeletal muscle mass was evaluated using the psoas muscle mass index (PMI), which was determined using computed tomography images, and the change in PMI before the initial pre‐ERC and surgery (ΔPMI) was calculated. Risk factors for advanced skeletal muscle mass loss, defined as a large ΔPMI, were evaluated. Results The study cohort included 90 patients with a median age of 72 (interquartile range, 65–75) years. The median PMI pre‐ERC and surgery was 4.40 and 4.15 cm²/m², respectively (p < .01). The median ΔPMI was −6.2% (interquartile range, −10.9% to 0.5%). By multivariate analysis, post‐ERC pancreatitis and cholangitis before surgery were independent predictive factors for large PMI loss (odds ratio, 4.57 and 3.18, respectively; p = .03 and p = .02, respectively). Conclusions Skeletal muscle mass decreases preoperatively in most patients with BTC undergoing ERC. Post‐ERC pancreatitis and cholangitis before surgery were independent risk factors for large skeletal muscle mass loss.
• Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

  Margherita Rimini, Bernardo Stefanini, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Fabian Finkelmeier, Changhoon Yoo, José Presa, Elisabeth Amadeo, Virginia Genovesi, Maria Caterina De Grandis, Massimo Iavarone, Fabio Marra, Francesco Foschi, Emiliano Tamburini, Federico Rossari, Francesco Vitiello, Linda Bartalini, Caterina Soldà, Francesco Tovoli, Caterina Vivaldi, Sara Lonardi, Marianna Silletta, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Vera Himmelsbach, Margarida Montes, Atsushi Hiraoka, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Mara Persano, Silvia Camera, Silvia Foti, Luca Aldrighetti, Stefano Cascinu, Andrea Casadei-Gardini, Fabio Piscaglia

  Liver international : official journal of the International Association for the Study of the Liver 44 (5) 1108 - 1125 2024/05 

  INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.
• Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab.

  Mara Persano, Margherita Rimini, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Federico Rossari, Changhoon Yoo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Francesca Bergamo, Elisabeth Amadeo, Francesco Vitiello, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Massimo Alberto Iavarone, Giuseppe Cabibbo, Margarida Montes, Francesco Giuseppe Foschi, Caterina Vivaldi, Caterina Soldà, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Mariangela Bruccoleri, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Atsushi Hiraoka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Silvia Foti, Silvia Camera, Fabio Piscaglia, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini

  Targeted oncology 2024/04/30 

  BACKGROUND: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors. OBJECTIVE: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting. PATIENTS AND METHODS: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea). RESULTS: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival. CONCLUSIONS: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.
• 食道胃静脈瘤に対し経皮経脾静脈瘤塞栓術を施行した1例

  保浦 直弘, 大原 正嗣, めの 晃光, 甲谷 理紗子, 佐々木 貴志, 吉田 苑永, 細田 峻一, 北潟谷 隆, 中井 正人, 荘 拓也, 須田 剛生, 小川 浩司, 阿保 大介, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 134回・128回 46 - 46 2024/03
• Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.

  Silvia Camera, Margherita Rimini, Federico Rossari, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Changhoon Yoo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Francesca Bergamo, Francesca Salani, Mariarosaria Marseglia, Elisabeth Amadeo, Francesco Vitiello, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Massimo Iavarone, Giuseppe Cabibbo, Margarida Montes, Francesco Giuseppe Foschi, Caterina Vivaldi, Sara Lonardi, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Atsushi Hiraoka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Mara Persano, Silvia Foti, Fabio Piscaglia, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini

  Targeted oncology 19 (1) 29 - 39 2024/01/22 

  BACKGROUND: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. OBJECTIVE: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC. PATIENTS AND METHODS: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years). RESULTS: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). CONCLUSIONS: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.
• 【チーム医療で取り組む肝胆膵疾患の栄養マネジメント】肝胆膵疾患に最適な栄養アセスメント法とは

  中井 正人, 大原 正嗣, 坂本 直哉

  肝胆膵 (株)アークメディア 88 (1) 7 - 13 0389-4991 2024/01
• α-FAtE: A new predictive score of response to atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.

  Federico Rossari, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Changhoon Yoo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Francesca Bergamo, Elisabeth Amadeo, Francesco Vitiello, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Massimo Iavarone, Giuseppe Cabibbo, Margarida Montes, Francesco Giuseppe Foschi, Caterina Vivaldi, Caterina Soldà, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Atsushi Hiraoka, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Mara Persano, Valentina Burgio, Fabio Piscaglia, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini, Margherita Rimini

  International journal of cancer 2023/11/23 

  Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.
• 【胆膵の画像・内視鏡診断の進歩-早期診断と正確な診断のために】閉塞性黄疸に対する内視鏡的診断アプローチ EUS/ERCP

  桑谷 将城, 米村 洋輝, 野澤 俊一郎, 岸 法磨, 杉浦 諒, 川久保 和道, 坂本 直哉

  臨床消化器内科 (株)日本メディカルセンター 38 (13) 1625 - 1631 0911-601X 2023/11 

  ＜文献概要＞閉塞性黄疸の原因には,遠位胆管狭窄と肝門部胆管狭窄がある.狭窄部位診断のためにまず簡便に施行可能なUS/CTを行う.MRCPも有用であるが,設備や時間的制約に縛られることが多いため,バイタルサインの異常を伴う場合には向いていない.狭窄部位診断の後に行うのは,病変の詳細な局在診断である.遠位胆管狭窄においては,診断精度が高く侵襲性の低い,EUSが第一に推奨される.US/CT/MRCPによっても胆道病変,膵病変,それ以外の病変(リンパ節病変や後腹膜病変など)がある程度診断可能ではあるが,画像分解能で最も優れるEUSを行うことで診断が変わったり確証が得られたりする.病変の主座に加えて遠隔リンパ節腫大の有無や病変と血管との位置関係も観察でき,癌のステージ診断にも寄与する.胆道病変の場合には,胆管ドレナージも同時に可能なERCPを行い,胆管造影による狭窄の範囲診断,IDUSによる胆管壁構造の詳細な観察と生検や細胞診による病理学的診断を行う.胆道病変以外の場合,可能であればEUS-FNAにより病理学的診断を行ったのち,必要に応じてERCPを行って胆道病変診断と同様の順を踏む.肝門部胆管狭窄においても上記同様にEUSが第一に推奨される.胆道病変とそれ以外の病変(リンパ節病変や後腹膜病変など)の区別により,前者であればERCPによる診断を遠位胆管狭窄と同様に進めるが,胆道癌の場合の肝葉切除の要否の判断のため,さらに近接する右肝動脈と病変との関係性を十分に観察する.後者であれば,EUS-FNAにより病理学的診断を行ったのち,ERCPを行って胆道病変診断と同様の順を踏む.
• Application of polyglycolic acid sheets and basic fibroblast growth factor to prevent esophageal stricture after endoscopic submucosal dissection in pigs.

  Yusuke Nishimura, Masayoshi Ono, Naoto Okubo, Takayuki Sone, Masayuki Higashino, Shogo Matsumoto, Marina Kubo, Keiko Yamamoto, Shoko Ono, Shunsuke Ohnishi, Naoya Sakamoto

  Journal of gastroenterology 58 (11) 1094 - 1104 2023/11 

  BACKGROUND: Endoscopic submucosal dissection (ESD) has been the first-line treatment for early-stage esophageal cancer. However, it often causes postoperative stricture in cases requiring wide dissection. Basic fibroblast growth factor (bFGF) reportedly has anti-scarring effects during cutaneous wound healing. We hypothesized that suppressing myofibroblast activation will prevent stricture after esophageal ESD. METHODS: We resected a complete porcine esophagus circumference section by ESD. To investigate the preventive effect of bFGF on esophageal stricture formation after ESD, we endoscopically applied bFGF-soaked poly-glycolic acid (PGA) sheets onto the wound bed after ESD and fixed them by spraying fibrin glue (PGA + bFGF group), PGA sheets alone onto the wound bed and fixed them by spraying fibrin glue (PGA group), or nothing (control group). After removing the esophagus on day 22, we evaluated the mucosal constriction rate. RESULTS: Compared with those in the control group, esophageal stricture was significantly reduced in the PGA + bFGF group, and the areas stained with α-SMA and calponin-1 antibodies were significantly inhibited in the PGA + bFGF and PGA groups. The thickness of the fibrous layer in the PGA + bFGF group was uniform compared to that of the other groups. Thus, PGA + bFGF inhibited the development of unregulated fibroblasts in the acute phase, leading to uniform wound healing. CONCLUSIONS: Stenosis after esophageal ESD is related to fibrosis in the acute phase. Administration of PGA and bFGF suppresses myofibroblast activation in the acute phase, thereby preventing esophageal constriction in pigs.
• 【薬物療法によって変貌する肝細胞癌治療:2023 Update】Advanced stage肝細胞癌 Phase 3 HIMALAYA試験の結果とその解釈

  荘 拓也, 須田 剛生, 北潟谷 隆, 大原 正嗣, 中井 正人, 小川 浩司, 坂本 直哉

  肝胆膵 (株)アークメディア 87 (4) 439 - 446 0389-4991 2023/10
• IMbrave150基準外進行肝細胞癌に対するアテゾリズマブ+ベバシズマブ併用療法の治療効果と肝予備能変化

  荘 拓也, 須田 剛生, 大原 正嗣, 中井 正人, 小川 浩司, 出水 孝章, 目黒 高志, 中村 晃久, 高木 智史, 馬場 英, 古家 乾, 鈴木 和治, 山本 義也, 伊藤 淳, 山田 錬, 宮城島 拓人, 坂本 直哉

  肝胆膵 (株)アークメディア 87 (4) 508 - 509 0389-4991 2023/10
• 北海道における肝炎医療コーディネーター養成研修会の実施状況の変遷に関する検討

  大原 正嗣, 小川 浩司, 長谷川 智子, 櫻井 菜々子, 中井 正人, 荘 拓也, 須田 剛生, 坂本 直哉

  肝臓 (一社)日本肝臓学会 64 (Suppl.3) A808 - A808 0451-4203 2023/10
• IMbrave150基準外症例におけるアテゾリズマブ+ベバシズマブ併用療法の生存に寄与する因子の検討 多施設共同研究

  荘 拓也, 須田 剛生, 大原 正嗣, 中井 正人, 小川 浩司, 出水 孝章, 目黒 高志, 中村 晃久, 高木 智史, 馬場 英, 古家 乾, 山本 義也, 伊藤 淳, 山田 錬, 宮城島 拓人, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 120 (臨増大会) A813 - A813 0446-6586 2023/10
• 【薬物療法によって変貌する肝細胞癌治療:2023 Update】Advanced stage肝細胞癌 Phase 3 HIMALAYA試験の結果とその解釈

  荘 拓也, 須田 剛生, 北潟谷 隆, 大原 正嗣, 中井 正人, 小川 浩司, 坂本 直哉

  肝胆膵 (株)アークメディア 87 (4) 439 - 446 0389-4991 2023/10
• IMbrave150基準外進行肝細胞癌に対するアテゾリズマブ+ベバシズマブ併用療法の治療効果と肝予備能変化

  荘 拓也, 須田 剛生, 大原 正嗣, 中井 正人, 小川 浩司, 出水 孝章, 目黒 高志, 中村 晃久, 高木 智史, 馬場 英, 古家 乾, 鈴木 和治, 山本 義也, 伊藤 淳, 山田 錬, 宮城島 拓人, 坂本 直哉

  肝胆膵 (株)アークメディア 87 (4) 508 - 509 0389-4991 2023/10
• 肝肺症候群を合併したBudd-Chiari症候群の1例

  保浦 直弘, 目野 晃光, 甲谷 理紗子, 佐々木 貴志, 細田 峻一, 吉田 苑永, 大原 正嗣, 中井 正人, 荘 拓也, 須田 剛生, 小川 浩司, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 133回・127回 40 - 40 2023/09
• 腹腔鏡下横隔膜縫合術、腹腔静脈シャント術により体液コントロールされた肝硬変の1例

  目野 晃光, 小川 浩司, 保浦 直弘, 甲谷 理紗子, 佐々木 貴志, 細田 峻一, 吉田 苑永, 得地 祐匡, 大原 正嗣, 中井 正人, 荘 拓也, 須田 剛生, 坂本 直哉, 武藤 潤

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 133回・127回 40 - 40 2023/09
• 消化器癌に対する免疫療法の現状と課題 非切除肝細胞癌患者における複合的がん免疫療法における治療後獲得薬剤耐性化に伴ってみられる血清増殖因子変化の検討

  須田 剛生, 大原 正嗣, 坂本 直哉

  肝臓 (一社)日本肝臓学会 64 (Suppl.2) A558 - A558 0451-4203 2023/09
• 肝癌患者におけるマニュアルトレース法による筋肉量と皮下脂肪CT値評価の有用性の検討

  大原 正嗣, 須田 剛生, 佐々木 貴志, 甲谷 理紗子, 細田 峻一, 吉田 苑永, 得地 祐匡, 中井 正人, 荘 拓也, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 64 (Suppl.2) A644 - A644 0451-4203 2023/09
• Metabolomics of Duodenal Juice for Biliary Tract Cancer Diagnosis

  Kazuma Kishi, Masaki Kuwatani, Yuki Ohnishi, Yasuhiro Kumaki, Hiroyuki Kumeta, Hajime Hirata, Yunosuke Takishin, Ryutaro Furukawa, Kosuke Nagai, Hiroki Yonemura, Shunichiro Nozawa, Ryo Sugiura, Kazumichi Kawakubo, Tomoyasu Aizawa, Naoya Sakamoto

  Cancers 15 (17) 4370 - 4370 2023/09/01 

  The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field.
• Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives.

  Masaki Kuwatani, Naoya Sakamoto

  Cancers 15 (14) 2023/07/20 

  To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, "staphylococcal enterotoxin A-MUC1 antibody" and "anti-GPC1 antibody-monomethyl auristatin F" conjugates showed anticancer activity. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. Currently, new forms of photosensitizers with nanotechnology and novel irradiation catheters are being developed. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called "IR700" conjugated with an antibody specific for cancer cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT.
• Novel endoscopic management of gastroenterological anastomosis leakage by injecting gel-forming solutions: an experimental animal study.

  Yusuke Watanabe, Keiko Yamamoto, Zijian Yang, Haruna Tsuchibora, Masakazu Fujii, Masayoshi Ono, Shoko Ono, Takayuki Kurokawa, Naoya Sakamoto

  Surgical endoscopy 2023/07/19 

  BACKGROUND: Anastomotic leakage (AL) after gastrointestinal surgery remains a challenging complication that requires surgical or non-surgical treatment. Although various therapeutic endoscopic techniques are available, no definitive interventions exist. We developed a therapeutic endoscopic submucosal injection method using novel gel-forming mixed solutions to close AL and evaluated the elasticity of the developed hydrogel. The safety and efficacy of the injection method were explored in porcine AL models. METHODS: We developed a novel gel-forming solution, and the formed gel lasted approximately one week within the gastrointestinal wall. An indentation test evaluated the elasticity of the novel hydrogel. After the confirmation of AL on porcine anterior gastric walls, sodium alginate was endoscopically injected into the submucosal layer around the leakage site circularly, followed by a calcium lactate/chitosan-based solution. After that, the outcomes data were collected, and histopathological effectiveness was evaluated. RESULTS: The increased sodium alginate elasticity with the addition of calcium lactate/chitosan-based solution facilitated long-lasting gel formation. Four pigs with AL underwent this intervention consecutively. Each endoscopic injection was completed in less than 5 min. No significant complications were observed for 3 weeks after the intervention. All AL sites were macroscopically healed. Histopathologic findings at 3 weeks showed that the wall defect was filled with collagen fibers that had grown around the site of the muscle layer tear. No tissue necrosis was observed. CONCLUSION: This preclinical study demonstrated that the therapeutic injection method for gastroenterological AL using gel-forming solutions could be an alternative endoscopic treatment, especially in patients with severe conditions or comorbidities. The optimal target of this treatment is small size and early AL without poor blood flow or intense hypertrophic scar lesions.
• 【ウイルス性肝炎学2023-最新の病態・診断・治療情報-】B型肝炎 日本におけるB型肝炎の疫学 国際比較

  小川 浩司, 大原 正嗣, 坂本 直哉

  日本臨床 (株)日本臨床社 81 (増刊7 ウイルス性肝炎学2023) 203 - 208 0047-1852 2023/07
• Neutrophil gelatinase-associated lipocalin predicts the efficacy of tolvaptan for ascites in patients with liver cirrhosis.

  Masato Nakai, Kenichi Morikawa, Takashi Sasaki, Risako Kohya, Sonoe Yoshida, Shunichi Hosoda, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Masatsugu Ohara, Takuya Sho, Goki Suda, Koji Ogawa, Naoya Sakamoto

  Journal of gastroenterology 58 (7) 656 - 667 2023/07 

  BACKGROUND: Acute kidney injury (AKI) is associated with liver cirrhosis (LC), water retention, diuretics to treat water retention, and a poor prognosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) reportedly predicts a poor prognosis in decompensated LC. This study investigated the usefulness of uNGAL in predicting the short- and long-term effects of tolvaptan (TVP) and the incidence of AKI post-TVP administration. METHODS: Of the LC cases with water retention, 86 with available pre-treatment uNGAL were analyzed. A short-term response was defined as weight loss of ≥ 1.5 kg within the first week; a long-term response was defined as a short-term response without early recurrence. The uNGAL usefulness in predicting the short- and long-term effects of TVP and AKI incidence post-TVP administration was investigated. RESULTS: Short-term effects of TVP were observed in 52 patients. Of these, 15 patients had an early recurrence. In multivariate analysis, significant short-term predictive factors were C-reactive protein (CRP) < 1.4 mg/dl, uNa/K ratio ≥ 3.51, and uNGAL < 50.2 ng/ml. Patients were classified according to these three cut-off values, with short-term response rates of 92.9%, 68.8%, 26.7%, and 0% for 0, 1, 2, and 3 points, respectively. CRP < 0.94 mg/dl and uNGAL < 50.2 ng/ml were significant factors for predicting the long-term response of TVP. The AKI incidence post-TVP was 8.1% (n = 7) and was significantly higher among those with uNGAL ≥ 38.1 ng/mL. CONCLUSION: uNGAL is a useful predictor of the short- and long-term efficacy of TVP and can be useful in predicting AKI incidence post-TVP administration.
• Potential Correlation between Changes in Serum FGF21 Levels and Lenvatinib-Induced Appetite Loss in Patients with Unresectable Hepatocellular Carcinoma.

  Risako Kohya, Goki Suda, Masatsugu Ohara, Takashi Sasaki, Tomoka Yoda, Naofumi Sakurai, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Osamu Maehara, Shunsuke Ohnishi, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  Cancers 15 (12) 2023/06/20 

  Lenvatinib, used for unresectable hepatocellular carcinoma (HCC), causes appetite loss, but the underlying mechanisms, clinical impact, and predictive factors have been unclear. The endocrine factor FGF21 modulates appetite and is involved in cachexia. We evaluated the association between FGF21 level changes during lenvatinib treatment for unresectable HCC and appetite loss. Sixty-three eligible unresectable HCC patients who started lenvatinib treatment between 2018 and 2021 were included. We analyzed FGF21 levels at baseline; 1, 2, and 4 weeks after lenvatinib initiation, and before the onset of appetite loss. Grade ≥ 2 lenvatinib-induced appetite loss led to liver functional reserve deterioration at disease progression and a poor prognosis. Baseline characteristics and serum FGF21 levels were similar between patients with and without appetite loss. However, the serum FGF21 change rate increased significantly at 4 weeks post-lenvatinib initiation in patients with grade ≥ 2 appetite loss, as compared to those without appetite loss. Similar significant increases in the serum FGF21 level change rate were observed prior to grade ≥ 2 appetite loss onset. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC.
• Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan.

  Takashi Sasaki, Goki Suda, Masatsugu Ohara, Shunichi Hosoda, Naoki Kawagishi, Risako Kohya, Tomoka Yoda, Osamu Maehara, Shunsuke Ohnishi, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Sho Komukai, Koji Ogawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 2023/06/18 

  AIM: Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan. METHODS: We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age. RESULTS: After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests. CONCLUSIONS: The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.
• 【肝疾患-診療のチェックポイント2023】(第I部)診断のチェックポイント(第5章) 肝疾患鑑別診断のチェックポイント 肝炎ウイルス以外のウイルス性肝障害が疑われるとき

  大原 正嗣, 須田 剛生, 坂本 直哉

  臨床消化器内科 (株)日本メディカルセンター 38 (7) 807 - 811 0911-601X 2023/06 

  ＜文献概要＞▼肝炎ウイルス以外のウイルスでも肝障害の原因となることを念頭に,鑑別診断として,とくにEBウイルス,サイトメガロウイルスを想起する.▼COVID-19患者の肝障害については今後の研究報告により対応が変わってくる可能性がある.
• 眼科外来への肝炎医療コーディネーターの配置による肝炎ウイルス陽性者対策の推進

  大原 正嗣, 小川 浩司, 長谷川 智子, 新明 康弘, 坂本 直哉, 是永 匡紹

  肝臓 (一社)日本肝臓学会 64 (6) 289 - 291 0451-4203 2023/06 

  当院肝疾患相談センターでは、院内非専門診療科での肝炎ウイルス陽性者(陽性者)の肝臓専門医(消化器内科)への紹介対策として、電子カルテアラートシステムによる陽性者対応を行っているが、アラートが通知された後に、必ずしも肝臓専門医への紹介や問診に至らず、未対応のままの患者が存在していることが判明した。そこで、院内非専門診療科で陽性者数が最も多かった眼科の外来看護師3名を肝炎医療コーディネーター(肝Co)として新たに養成・配置し、令和2年から要対応者には肝Coが個別対応を行っている。今回、肝Co配置前後(平成31年～令和3年)の眼科における陽性者数(B型肝炎ウイルス、C型肝炎ウイルス合算)、紹介率、要対応率の推移について検討、報告した。その結果、陽性者数は、39名(平成31年)、29名(令和2年)、30名(令和3年)で、紹介率は、肝Coの介入(肝Coが設置された令和2年は、平成31年まで遡って対応)により、アラート通知による平成31年の18.0%が25.6%まで改善し、以後、令和2年27.6%、令和3年26.7%と推移している。未対応者の指標となる要対応率については、アラート通知のみの28.2%(平成31年)、34.5%(令和2年)、20.0%(令和3年)が、肝Coの介入により2.6%(平成31年)、3.4%(令和2年)、6.7%(令和3年)と大幅に低下、改善した。
• Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment.

  Shunichi Hosoda, Goki Suda, Takuya Sho, Koji Ogawa, Megumi Kimura, Zijian Yang, Sonoe Yoshida, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Takuto Miyagishima, Naoya Sakamoto

  Liver cancer 12 (2) 156 - 170 2023/06 

  INTRODUCTION: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. METHODS: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib. RESULTS: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. CONCLUSION: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.
• Significance of Shear Wave Dispersion Slope Values Before Versus After Biliary Drainage in Patients With Obstructive Jaundice

  Ryo Sugiura, Masaki Kuwatani, Mutsumi Nishida, Megumi Satoh, Kazumichi Kawakubo, Shin Kato, Koji Hirata, Masahito Nakajima, Hajime Hirata, Yunosuke Takishin, Naoya Sakamoto

  Ultrasound Quarterly Publish Ahead of Print 2023/05/22
• Quantitative diagnostic algorithm using endocytoscopy for superficial nonampullary duodenal epithelial tumors.

  Marina Kubo, Shoko Ono, Isao Yokota, Shogo Matsumoto, Yusuke Nishimura, Masayoshi Ono, Keiko Yamamoto, Naoya Sakamoto

  Journal of gastroenterology and hepatology 38 (9) 1496 - 1502 2023/05/02 

  BACKGROUND AND AIM: Optical biopsy using endocytoscopy for superficial nonampullary duodenal epithelial tumors (SNADETs) is practical; however, a diagnostic algorithm has not been established. The aim of this study was to determine correlations of endocytoscopic findings of SNADETs with histology using computer analysis and to establish an algorithm. METHODS: Endocytoscopic images and histological images of duodenal lesions from 70 patients were retrospectively collected. The numbers of glands and densely stained areas with methylene blue (DSMs) per 1 mm2 and the percentage of DSMs per screen in endocytoscopy were determined. Moreover, correlations in DSMs and glands between endocytoscopy and histological images were analyzed. Histopathological diagnoses were assessed according to the revised Vienna classification. The primary outcome was correlation between the number of glands in endocytoscopy and that in histology. Finally, a diagnostic algorithm for endoscopic intervention of SNADETs with a statistical program command was established. RESULTS: The number of glands in endocytoscopic images was correlated with that in histopathological images (ρ 0.64, P < 0.001). There were significant differences in the mean number of glands between category 4/5 and category 3 (P = 0.03) and the mean percentage of DSMs between category 4/5 and category 1 (P < 0.001). When the cutoffs for the number of glands and percentage of DSMs were set at 47 per 1 mm2 and 20.8% in one screen, respectively, the area under the ROC curve was 0.89. CONCLUSIONS: Endocytoscopic images of SNADETs reflect histopathological atypia, and computer analysis provides a practical diagnostic algorithm for endoscopic intervention.
• Improvement of detection sensitivity of upper gastrointestinal epithelial neoplasia in linked color imaging based on data of eye tracking.

  Masayuki Higashino, Shoko Ono, Shogo Matsumoto, Marina Kubo, Naohiro Yasuura, Shuhei Hayasaka, Ikko Tanaka, Yoshihiko Shimoda, Yusuke Nishimura, Masayoshi Ono, Keiko Yamamoto, Yuji Ono, Naoya Sakamoto

  Journal of gastroenterology and hepatology 38 (5) 710 - 715 2023/05 

  BACKGROUND AND AIM: Linked color imaging (LCI) is useful for screening in the gastrointestinal tract; however, its true clinical benefit has not been determined. The aim of this study was to determine the objective advantage of LCI for detection of upper gastrointestinal neoplasms. METHODS: Nine endoscopists, including three novices, three trainees, and three experts, prospectively performed eye tracking. From 30 cases of esophageal or gastric neoplasm and 30 normal cases without neoplasms, a total of 120 images, including 60 pair images of white light imaging (WLI) and LCI taken at the same positions and angles, were randomly shown for 10 s. The sensitivity of tumor detection as a primary endpoint was evaluated and sensitivities by organ, size, and visual gaze pattern were also assessed. Color differences (ΔE using CIE1976 [L*a*b*]) between lesions and surrounding mucosa were measured and compared with detectability. RESULTS: A total of 1080 experiments were completed. The sensitivities of tumor detection in WLI and LCI were 53.7% (50.1-56.8%) and 68.1% (64.8-70.8%), respectively (P = 0.002). LCI provided higher sensitivity than WLI for the novice and trainee groups (novice: 42.2% [WLI] vs 65.6% [LCI], P = 0.003; trainee: 54.4% vs 70.0%, P = 0.045). No significant correlations were found between sensitivity and visual gaze patterns. LCI significantly increased ΔE, and the diagnostic accuracy with WLI depended on ΔE. CONCLUSIONS: In conclusion, LCI significantly improved sensitivity in the detection of epithelial neoplasia and enabled epithelial neoplasia detection that is not possible with the small color difference in WLI. (UMIN000047944).
• 肝疾患におけるサルコペニア診断と栄養・運動介入の課題 マニュアルトレース法による筋肉量評価及び皮下脂肪CT値と肝疾患患者の予後の検討

  大原 正嗣, 須田 剛生, 坂本 直哉

  肝臓 (一社)日本肝臓学会 64 (Suppl.1) A231 - A231 0451-4203 2023/04
• A病院における肝炎検査陽性者拾い上げの取り組み 眼科・整形外科外来との協働

  長谷川 智子, 小川 浩司, 大原 正嗣, 櫻井 菜々子, 中野 政子, 坂本 直哉

  肝臓 (一社)日本肝臓学会 64 (Suppl.1) A281 - A281 0451-4203 2023/04
• Clinical significance of dispersion imaging by shear wave elastography in the treatment and diagnosis of pancreatic cancer.

  Yunosuke Takishin, Masaki Kuwatani, Mutsumi Nishida, Tomoko Mitsuhashi, Kazuma Kishi, Kosuke Nagai, Ryutaro Furukawa, Hajime Hirata, Koji Hirata, Shin Kato, Kazumichi Kawakubo, Naoya Sakamoto

  Journal of gastroenterology and hepatology 38 (4) 656 - 663 2023/04 

  BACKGROUND AND AIM: Recently, dispersion imaging by shear wave elastography has been developed to visualize a tissue viscosity-related factor by measuring the dispersion slope. However, clinical significance of dispersion imaging in the field of pancreatic cancer is unknown. This study aimed to investigate the clinical significance of dispersion imaging in the treatment and diagnosis of pancreatic cancer. METHODS: We measured shear wave dispersion slope (SWD) (m/s/kHz) and shear wave elasticity (SWE) (kPa) in patients with pancreatic ductal adenocarcinoma (PDA). The primary endpoint was the relationship between the changes in SWD and SWE values before and after chemotherapy and the response to chemotherapy. Secondary endpoints included SWD and SWE values in relation to differences between PDA and non-PDA sites and histopathological scores of stroma, inflammation, fibrosis, and necrosis in endoscopic ultrasound-guided fine-needle aspiration specimens. RESULTS: Fifty-six patients were included, 30 of whom underwent chemotherapy. There was no relationship between the changes of SWD and SWE values and chemotherapy responses. In 56 patients, the median SWD value was 12.20 m/s/kHz (interquartile range [IQR]: 10.88-13.61) at PDA sites and 13.57 m/s/kHz (IQR: 12.28-16.20) at non-PDA sites (P = 0.005). The median SWE value was 8.18 kPa (IQR: 7.00-9.74) at PDA sites and 6.14 kPa (IQR: 5.40-6.77) at non-PDA sites (P < 0.001). Histopathological evaluation revealed that inflammation scores were correlated with SWD values (rs  = 0.42, P < 0.001). CONCLUSIONS: Dispersion imaging in pancreatic cancer would be useful for diagnosis and assessing inflammation.
• Effects of activation of an alcohol metabolic gene, cigarette smoking, and alcohol intake on the incidence of metachronous gastric cancer in patients who underwent endoscopic resection for gastric cancer: A multicenter retrospective pilot study

  Satoshi Abiko, Yuichi Shimizu, Marin Ishikawa, Masaki Inoue, Katsuma Nakajima, Risako Kohya, Koji Hirata, Kazuharu Suzuki, Ryo Sugiura, Shuichi Miyamoto, Kenji Kinoshita, Kazuteru Hatanaka, Yoshiya Yamamoto, Hirohito Naruse, Takuto Miyagishima, Naoya Sakamoto

  JGH Open 2397-9070 2023/03/31
• Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients.

  Margherita Rimini, Mara Persano, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Francesca Salani, Sara Lonardi, Fabio Piscaglia, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Marta Schirripa, Margarida Montes, Caterina Vivaldi, Caterina Soldà, Atsushi Hiraoka, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Valentina Burgio, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini

  Journal of cancer research and clinical oncology 149 (10) 7565 - 7577 2023/03/28 [Refereed][Not invited]
   

  INTRODUCTION: The best first-line treatment for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class B remains unknown. The aim of the present study was to perform a real-world analysis on a large sample of patients with unresectable HCC with CP B treated with atezolizumab plus bevacizumab Vs Lenvatinib. METHODS: The study population included patients affected by advanced (BCLC-C) or intermediate (BCLC-B) HCC patients not suitable for locoregional therapies from both the Western and Eastern world (Italy, Germany, Republic of Korea and Japan), who received atezolizumab plus bevacizumab or Lenvatinib as first-line treatment. All the study population presented a CP class of B. The primary endpoint of the study was the overall survival (OS) of CP B patients treated with Lenvatinib compared to atezolizumab plus bevacizumab. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analyzed with log-rank tests. Finally, an interaction test was performed for the main baseline clinical characteristics. RESULTS: 217 CP B HCC patients were enrolled in the study: 65 (30%) received atezolizumab plus bevacizumab, and 152 (70%) received lenvatinib. The mOS for patients receiving Lenvatinib was 13.8 months (95% CI: 11.6-16.0), compared to 8.2 months (95% CI 6.3-10.2) for patients receiving atezolizumab plus bevacizumab as first-line treatment (atezolizumab plus bevacizumab Vs Lenvatinib: HR 1.9, 95% CI 1.2-3.0, p = 0.0050). No statistically significant differences were highlighted in terms of mPFS. The multivariate analysis confirmed that patients receiving Lenvatinib as first-line treatment have a significantly longer OS compared to patients receiving atezolizumab plus bevacizumab (HR 2.01; 95% CI 1.29-3.25, p = 0.0023). By evaluating the cohort of patients who received atezolizumab plus bevacizumab, we found that Child B patients with ECOG PS 0, or BCLC B stage or ALBI grade 1 were those who had benefited from the treatment thus showing survival outcomes no significantly different compared to those receiving Lenvatinib. CONCLUSION: The present study suggests for the first time a major benefit from Lenvatinib compared to atezolizumab plus bevacizumab in a large cohort of patients with CP B class HCC.
• Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight.

  Yoshimasa Tokuchi, Goki Suda, Naoki Kawagishi, Masatsugu Ohara, Risako Kohya, Takashi Sasaki, Tomoka Yoda, Osamu Maehara, Shunsuke Ohnishi, Akinori Kubo, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Takashi Kitagataya, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 53 (7) 595 - 606 2023/03/21 

  AIM: Hepatitis C virus (HCV) infection has been reported to cause liver steatosis. Thus, eradicating HCV with direct-acting antivirals (DAAs) is expected to reduce liver steatosis. We aimed to clarify long-term changes in the prevalence of fatty liver and hyper-low-density lipoprotein (LDL) cholesterolemia and their associations in patients who achieve successful HCV eradication using DAAs. METHODS: This retrospective study included patients with HCV who achieved sustained virologic response after interferon-free DAA and analyzed the changes in the prevalence of fatty liver diagnosed with controlled attenuation parameter (CAP), hyper-LDL cholesterolemia, and their relationships at baseline (n = 100) and 24 weeks (SVR24, n = 100), 96 weeks (SVR96, n = 100), and 144 weeks (SVR144, n = 90) after DAA. RESULTS: In 100 participants, the prevalence of fatty liver (19% vs. 32%, p = 0.0349) and hyper-LDL cholesterolemia (6% vs. 15%, p = 0.0379) significantly increased without changes in body weight at SVR96. Median total cholesterol, low-density lipoprotein cholesterol (LDL-C), and small-dense-LDL (sdLDL) levels and CAP values were significantly greater at SVR24, SVR96, and SVR144 than at baseline. Baseline CAP values and changes in CAP values were significantly negatively correlated at every observation point: r = -0.5305, p < 0.0001 at SVR24; r = -0.3617, p = 0.0005 at SVR96; and r = -0.4735, p < 0.0001 at SVR144. A similar relationship was observed in cholesterol levels. Unlike at baseline, CAP values were significantly positively correlated with LDL-C and sdLDL-C levels at all observation points after DAAs. CONCLUSIONS: Direct-acting antivirals may cause an increased prevalence of fatty liver accompanying hyper-LDL cholesterolemia without increased body weight. As post-SVR liver steatosis could cause HCC, careful follow-up may be required.
• Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis?

  Margherita Rimini, Mara Persano, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, José Presa, Gianluca Masi, Changhoon Yoo, Sara Lonardi, Fabio Piscaglia, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Tiziana Pressiani, Margarida Montes, Caterina Vivaldi, Caterina Soldà, Atsushi Hiraoka, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Valentina Burgio, Lorenza Rimassa, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini

  Targeted oncology 18 (2) 221 - 233 2023/03/15 

  BACKGROUND: Atezolizumab plus bevacizumab has recently been approved as a new first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). OBJECTIVE: We performed a real-world study to evaluate the impact of the IMbrave150 trial inclusion criteria on the safety and efficacy of treatment outside of clinical trials. METHODS: We analyzed patients treated with atezolizumab plus bevacizumab for unresectable HCC from four different countries. No specific inclusion and exclusion criteria were applied, except for the absence of previous systemic therapies for HCC. The entire population was split into two groups according to concordance with the inclusion criteria as reported in the IMbrave150 trial in 'IMbrave150-in' and 'IMbrave150-out' patients, and safety and efficacy in the two groups of patients were evaluated. RESULTS: Overall, 766 patients were included in the analysis: 561/766 (73%) in the 'IMbrave150-in' group and 205/766 (27%) in the 'IMbrave150-out' group. Median overall survival (OS) and median progression-free survival (PFS) were 16.3 versus 14.3 months (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.35-0.65; p < 0.0001] and 8.3 versus 6.0 months (HR 0.79, 95% CI 0.63-0.99; p = 0.0431) in 'IMbrave150-in' and 'IMbrave150-out' patients, respectively. Multivariate analysis confirmed that patients included in the 'IMbrave150-in' group had significantly longer OS compared with patients included in the 'IMbrave150-out' group (HR 0.76, 95% CI 0.47-0.97; p = 0.0195). In 'IMbrave150-in' patients, the albumin-bilirubin (ALBI) grade was not associated with OS, whereas in 'IMbrave150-out' patients, those with ALBI grade 1 reported a significant benefit in terms of OS compared with those with ALBI grade 2 (16.7 vs. 5.9 months; HR 4.40, 95% CI 2.40-8.08; p > 0.0001). No statistically significant differences were reported in the 'IMbrave150-in' and 'IMbrave150-out' groups in terms of safety profile. CONCLUSION: Adherence to the IMbrave150 trial inclusion criteria favorably impacts the prognosis of patients receiving atezolizumab plus bevacizumab. Among patients who did not meet the IMbrave150 inclusion criteria, those with ALBI grade 1 could benefit from the treatment.
• 肝細胞腺腫との鑑別が困難であった限局性結節性過形成の1例

  吉田 苑永, 小川 浩司, 佐々木 貴志, 甲谷 理紗子, 細田 峻一, 久保 彰則, 得地 祐匡, 大原 正嗣, 中井 正人, 荘 拓也, 須田 剛生, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 132回・126回 42 - 42 2023/03
• BCLCステージB2肝癌に対してアテゾリズマブ+ベバシズマブ併用療法と焼灼療法にてCancer Freeが得られた1症例

  細田 峻一, 荘 拓也, 佐々木 貴志, 甲谷 理紗子, 吉田 苑永, 得地 祐匡, 大原 正嗣, 中井 正人, 須田 剛生, 小川 浩司, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 132回・126回 46 - 46 2023/03
• BavenoVI分類とYerdel分類を用いた肝疾患に伴う門脈血栓症に対するアンチトロンビンIII製剤の治療効果の検討

  中井 正人, 小川 浩司, 佐々木 貴志, 甲谷 理紗子, 吉田 苑永, 細田 俊一, 得地 祐匡, 北潟谷 隆, 大原 正嗣, 荘 拓也, 須田 剛生, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 120 (臨増総会) A417 - A417 0446-6586 2023/03
• Novel usage of one nasobiliary drainage tube for cholecystitis with cholangitis from external to internal drainage.

  Kazuma Kishi, Masaki Kuwatani, Naoya Sakamoto

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 2023/02/20
• Correlation of UGT1A1 Gene Polymorphisms or Prior Irinotecan Treatment and Treatment Outcomes of Nanoliposomal-Irinotecan plus 5-Fluorouracil/Leucovorin for Pancreatic Ductal Adenocarcinoma: A Multicenter, Retrospective Cohort Study (HGCSG2101).

  Kazuaki Harada, Takahiro Yamamura, Osamu Muto, Michio Nakamura, Susumu Sogabe, Kentaro Sawada, Shintaro Nakano, Masataka Yagisawa, Tetsuhito Muranaka, Masayoshi Dazai, Miki Tateyama, Yoshimitsu Kobayashi, Sosuke Kato, Kazuteru Hatanaka, Yasuyuki Kawamoto, Satoshi Yuki, Yuh Sakata, Naoya Sakamoto, Yoshito Komatsu

  Journal of clinical medicine 12 (4) 2023/02/17 

  The effects of UGT1A1 gene polymorphisms or prior irinotecan treatment on treatment outcomes of nanoliposomal-irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) are not established. This multicenter, retrospective cohort study compared treatment outcomes in patients with UGT1A1*1/*1 and those with UGT1A1*1/*6 or *1/*28 genotypes. We also analyzed the impact of prior irinotecan treatment on survival outcomes in 54 patients treated with nal-IRI+5-FU/LV. Comparable effectiveness was found regardless of the UGT1A1 genotypes. While no significant differences were found, grade ≥3 neutropenia and febrile neutropenia were more frequent in patients with UGT1A1*1/*6 or *1/*28 than in those with UGT1A1*1/*1 genotypes (grade ≥3 neutropenia, 50.0% vs. 30.8%, p = 0.24; febrile neutropenia, 9.1% vs. 0.0%, p = 0.20, respectively). No significant difference in progression-free survival (PFS) and overall survival (OS) was observed between irinotecan-naïve-patients and other patients. However, irinotecan-resistant patients showed significantly shorter PFS (hazard ratio (HR) 2.83, p = 0.017) and OS (HR 2.58, p = 0.033) than other patients. Our study indicated that patients with UGT1A1*1/*6 or *1/*28 may be prone to neutropenia, though further study is needed. The survival benefit of nal-IRI+5-FU/LV could be maintained in patients without disease progression after irinotecan therapy.
• Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma.

  Zijian Yang, Goki Suda, Osamu Maehara, Masatsugu Ohara, Tomoka Yoda, Takashi Sasaki, Risako Kohya, Sonoe Yoshida, Shunichi Hosoda, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  Cancers 15 (3) 2023/01/18 

  The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies.
• Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C.

  Naoki Kawagishi, Goki Suda, Yoshiya Yamamoto, Masaru Baba, Ken Furuya, Osamu Maehara, Shunsuke Ohnishi, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Yoshimasa Tokuchi, Takashi Kitagataya, Masatsugu Ohara, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  Viruses 15 (1) 2023/01/07 

  Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014-2020 were screened and evaluated for HCC occurrence or recurrence every three-six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34-6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18-6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs.
• Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation-related hepatitis.

  Goki Suda, Masaru Baba, Yoshiya Yamamoto, Takuya Sho, Koji Ogawa, Megumi Kimura, Shunichi Hosoda, Sonoe Yoshida, Akinori Kubo, Qingjie Fu, Zijian Yang, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Tomoe Kobayashi, Izumi Tsunematsu, Naoya Sakamoto

  Journal of medical virology 95 (2) e28452  2023/01/04 

  BACKGROUND: No prospective study on the efficacy of tenofovir alafenamide (TAF), a novel tenofovir prodrug, in preventing HBV reactivation has yet been reported. METHODS: This multicenter prospective study enrolled HBV-carriers who received TAF to prevent HBV reactivation before antitumor or immunosuppressive therapy, and patients with resolved HBV infection who experienced HBV-reactivation and received TAF to prevent HBV reactivation-related hepatitis. The efficacy of prophylactic TAF in preventing HBV reactivation and HBV reactivation-related hepatitis was evaluated at 6 and 12 months after initiating TAF. RESULTS: Overall, 110 patients were administered TAF to prevent HBV reactivation or HBV reactivation-related hepatitis. Three patients died owing to primary disease, whereas one patient was transferred to another hospital within 6 months after initiating TAF. Seven patients died due to primary disease, and five patients were transferred to another hospital within 12 months after initiating TAF. Therefore, 106 and 94 (77 patients with HBV infection, 17 with previous-HBV infection) patients were evaluated at 6 and 12 months after initiating TAF, respectively. No patient experienced HBV reactivation, HBV reactivation-related hepatitis, or treatment discontinuation due to HBV reactivation or adverse events of TAF after 6 and 12 months. CONCLUSION: TAF could effectively prevent HBV reactivation and HBV reactivation-related hepatitis. This article is protected by copyright. All rights reserved.
• Anti-epidermal growth factor receptor treatment for patients with NeoRAS wild-type metastatic colorectal cancer: a case report of two cases.

  Kazuaki Harada, Satoshi Yuki, Yasuyuki Kawamoto, Takeaki Nakamura, Shiho Kaneko, Koichi Ishida, Naoya Sakamoto, Yoshito Komatsu

  Therapeutic advances in medical oncology 15 17588359231216090 - 17588359231216090 2023 

  The NeoRAS phenomenon is defined as the conversion of tumor RAS status from mutant-type (MT) to wild-type (WT) after systemic chemotherapy in metastatic colorectal cancer (mCRC). Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, is effective in patients with RAS WT mCRC but ineffective in those with RAS MT mCRC; however, its outcome in patients with NeoRAS WT mCRC is unclear. Herein, we report two cases of NeoRAS WT mCRC that responded clinically to anti-EGFR treatment. The first was a 40-year-old man with synchronous peritoneal metastatic rectosigmoid cancer. The first RAS testing on tumor tissue revealed a KRAS G12C mutation, which was converted to RAS WT after two lines of chemotherapy, as assessed by liquid biopsy. After initiating irinotecan plus cetuximab treatment, a computed tomography (CT) scan revealed that malignant ascites had resolved. The treatment was discontinued after 4 months because of disease progression. The second was a 68-year-old male patient with synchronous liver metastasis from sigmoid colon cancer. The KRAS G12D mutation, initially detected in tumor tissue, was not detected by liquid biopsy after six lines of chemotherapy. Cetuximab monotherapy was initiated, and the liver metastases shrank significantly. The patient continued cetuximab monotherapy for 8 months without disease progression. Our cases demonstrate the efficacy of anti-EGFR therapy for NeoRAS WT mCRC and highlight the importance of capturing the gene mutation profile throughout the clinical course for optimal treatment selection.
• Characteristics and usefulness of transabdominal ultrasonography in immune-mediated colitis.

  Kensuke Sakurai, Takehiko Katsurada, Mutsumi Nishida, Satomi Omotehara, Shinya Fukushima, Shinsuke Otagiri, Kazunori Nagashima, Reizo Onishi, Ryo Takagi, Yoshito Komatsu, Naoya Sakamoto

  Intestinal research 21 (1) 126 - 136 2023/01 

  BACKGROUND/AIMS: The usefulness of ultrasonography (US) in diseases of the gastrointestinal tract has been reported recently. This prospective study aimed to determine the features of US findings in immune-mediated colitis (IMC), an adverse event induced by immune checkpoint inhibitor, and examine the correlation between US findings, colonoscopy (CS) findings, and severity of colitis. METHODS: We studied patients examined using CS and US upon suspicion of IMC in Hokkaido University Hospital between April 2018 and February 2021. Endoscopic findings of IMC were assessed using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The severity of US findings in IMC was evaluated using US grade, which is the ultrasonographic grading scale in ulcerative colitis. Bowel wall thickness and the intensity of the color Doppler signal were also analyzed. Severity of colitis was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) grade version 5. RESULTS: Fourteen patients with IMC were enrolled. The US findings were bowel wall thickening, loss of stratification, ulceration and increased blood flow signal. The US grade was moderately correlated with the UCEIS (r=0.687, p=0.009) and CTCAE grade (r=0.628, p=0.035). Bowel wall thickness and UCEIS (r=0.628, p=0.020), as well as color Doppler signal grade and CTCAE grade (r=0.724, p=0.008), were significantly correlated. CONCLUSIONS: US findings in IMC were mainly similar to those of ulcerative colitis, but there were some findings that were characteristic only of IMC. Significant correlation was found between US findings, CS findings, and severity of colitis. Hence, US could be useful for the evaluation of IMC.
• Coexistence of muscle atrophy and high subcutaneous adipose tissue radiodensity predicts poor prognosis in hepatocellular carcinoma.

  Masatsugu Ohara, Goki Suda, Risako Kohya, Takashi Sasaki, Tomoka Yoda, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Osamu Maehara, Shunsuke Ohnishi, Yoshimasa Tokuchi, Takashi Kitagataya, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  Frontiers in nutrition 10 1272728 - 1272728 2023 

  INTRODUCTION: We aimed to assess the prognostic implications of muscle atrophy and high subcutaneous adipose tissue (SAT) radiodensity in patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective study, muscle atrophy was assessed using the psoas muscle index (PMI) obtained from computed tomography. SAT radiodensity was evaluated based on radiodensity measurements. Survival and multivariate analyses were performed to identify factors associated with prognosis. The impact of muscle atrophy and high SAT radiodensity on prognosis was determined through survival analysis. RESULTS: A total of 201 patients (median age: 71 years; 76.6% male) with HCC were included. Liver cirrhosis was observed in 72.6% of patients, and the predominant Child-Pugh grade was A (77.1%). A total of 33.3% of patients exhibited muscle atrophy based on PMI values, whereas 12.9% had high SAT radiodensity. Kaplan-Meier survival analysis demonstrated that patients with muscle atrophy had significantly poorer prognosis than those without muscle atrophy. Patients with high SAT radiodensity had a significantly worse prognosis than those without it. Muscle atrophy, high SAT radiodensity, the Barcelona Clinic Liver Cancer class B, C, or D, and Child-Pugh score ≥ 6 were significantly associated with overall survival. Further classification of patients into four groups based on the presence or absence of muscle atrophy and high SAT radiodensity revealed that patients with both muscle atrophy and high SAT radiodensity had the poorest prognosis. CONCLUSION: Muscle atrophy and high SAT radiodensity are significantly associated with poor prognosis in patients with HCC. Identifying this high-risk subgroup may facilitate the implementation of targeted interventions, including nutritional therapy and exercise, to potentially improve clinical outcomes.
• Simultaneous determination of heparan sulfate, chondroitin/dermatan sulfates, and hyaluronan glycosaminoglycan disaccharides by high-performance liquid chromatography using a reverse-phase column with adamantyl groups.

  Hisatoshi Hanamatsu, Satoshi Makino, Masatsugu Ohara, Goki Suda, Ikuko Yokota, Shoko Nishihara, Naoya Sakamoto, Jun-Ichi Furukawa

  Journal of chromatography. A 1689 463748 - 463748 2022/12/23 

  Glycosaminoglycans (GAGs), which are one of the major components of proteoglycans, play a pivotal role in physiological processes such as signal transduction, cell adhesion, growth, and differentiation. Characterization of GAGs is challenging due to the tremendous structural diversity of heteropolysaccharides with numerous sulfate or carboxyl groups. In this present study, we examined the analysis of 2-aminobenzamide (2-AB) labeled GAG disaccharides by high-performance liquid chromatography (HPLC) using a reverse-phase (RP)-column with adamantyl groups. Under the analytical conditions, 17 types of 2-AB labeled GAG disaccharides derived from heparan sulfate, chondroitin/dermatan sulfates, and hyaluronan were sequentially separated in a single analysis. The analysis time was fast with high retention time reproducibility. Moreover, the RP-HPLC column with adamantyl groups allowed the quantification of GAGs in various biological samples, such as serum, cultured cells, and culture medium.
• Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study.

  Andrea Casadei-Gardini, Margherita Rimini, Masatoshi Kudo, Shigeo Shimose, Toshifumi Tada, Goki Suda, Myung Ji Goh, Andre Jefremow, Mario Scartozzi, Giuseppe Cabibbo, Claudia Campani, Emiliano Tamburini, Francesco Tovoli, Kazuomi Ueshima, Tomoko Aoki, Hideki Iwamoto, Takuji Torimura, Takashi Kumada, Atsushi Hiraoka, Masanori Atsukawa, Ei Itobayashi, Hidenori Toyoda, Naoya Sakamoto, Takuya Sho, Wonseok Kang, Jürgen Siebler, Markus Friedrich Neurath, Valentina Burgio, Stefano Cascinu

  Liver cancer 11 (6) 527 - 539 2022/12 

  INTRODUCTION: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. METHODS: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. RESULTS: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). CONCLUSIONS: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.
• Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population.

  Andrea Casadei-Gardini, Margherita Rimini, Toshifumi Tada, Goki Suda, Shigeo Shimose, Masatoshi Kudo, Jaekyung Cheon, Fabian Finkelmeier, Ho Yeong Lim, Lorenza Rimassa, José Presa, Gianluca Masi, Changhoon Yoo, Sara Lonardi, Francesco Tovoli, Takashi Kumada, Naoya Sakamoto, Hideki Iwamoto, Tomoko Aoki, Hong Jae Chon, Vera Himmelsbach, Tiziana Pressiani, Margarida Montes, Caterina Vivaldi, Caterina Soldà, Fabio Piscaglia, Atsushi Hiraoka, Takuya Sho, Takashi Niizeki, Naoshi Nishida, Christoph Steup, Massimo Iavarone, Giovanni Di Costanzo, Fabio Marra, Mario Scartozzi, Emiliano Tamburini, Giuseppe Cabibbo, Francesco Giuseppe Foschi, Marianna Silletta, Masashi Hirooka, Kazuya Kariyama, Joji Tani, Masanori Atsukawa, Koichi Takaguchi, Ei Itobayashi, Shinya Fukunishi, Kunihiko Tsuji, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Chikara Ogawa, Takashi Nishimura, Takeshi Hatanaka, Satoru Kakizaki, Noritomo Shimada, Kazuhito Kawata, Fujimasa Tada, Hideko Ohama, Kazuhiro Nouso, Asahiro Morishita, Akemi Tsutsui, Takuya Nagano, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Hisashi Kosaka, Atsushi Naganuma, Yohei Koizumi, Shinichiro Nakamura, Masaki Kaibori, Hiroko Iijima, Yoichi Hiasa, Valentina Burgio, Mara Persano, Angelo Della Corte, Francesca Ratti, Francesco De Cobelli, Luca Aldrighetti, Stefano Cascinu, Alessandro Cucchetti

  European journal of cancer (Oxford, England : 1990) 180 9 - 20 2022/11/25 [Refereed][Not invited]
   

  BACKGROUND AND AIMS: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. METHODS: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point. RESULTS: The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. CONCLUSION: Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.
• Genetic Analyses of Cell-Free DNA in Pancreatic Juice or Bile for Diagnosing Pancreatic Duct and Biliary Tract Strictures

  Kosuke Nagai, Masaki Kuwatani, Koji Hirata, Goki Suda, Hajime Hirata, Yunosuke Takishin, Ryutaro Furukawa, Kazuma Kishi, Hiroki Yonemura, Shunichiro Nozawa, Ryo Sugiura, Kazumichi Kawakubo, Naoya Sakamoto

  Diagnostics 12 (11) 2704 - 2704 2022/11/05 

  Poor prognosis of pancreaticobiliary malignancies is attributed to intrinsic biological aggressiveness and the lack of reliable methods for early diagnosis. This study aimed to evaluate the feasibility and availability of pancreatic juice- and bile-derived cell-free DNA (cfDNA) for diagnosing pancreaticobiliary strictures. From October 2020 to February 2022, pancreatic juice or bile was obtained from 50 patients with pancreaticobiliary strictures during endoscopic retrograde cholangiopancreatography. cfDNAs extracted from the samples were analyzed using next-generation sequencing and a cancer gene panel. The obtained cfDNAs, genetic data and clinical information were analyzed for diagnosis. cfDNA concentrations in pancreatic juice were higher in the intraductal papillary mucinous neoplasm group than in the other groups, whereas those in bile were similar in all groups. In pancreatic juice, the sensitivity, specificity and positive and negative predictive values of cfDNA analyses were 33%, 100%, 100% and 71.4%, respectively, whereas those of cytological analyses were 0%, 100%, 0% and 62.5%, respectively. In bile, those of cell-free DNA analyses were 53%, 75%, 89.5% and 28.6%, respectively, whereas those of cytological analyses were 19%, 100%, 100% and 16%, respectively. In conclusion, pancreatic juice- and bile-derived cfDNA is a novel liquid biopsy tool that can diagnose pancreaticobiliary strictures.
• Incidence of post-transplant hepatitis B virus reactivation with the use of kidneys from donors with resolved hepatitis B virus infection.

  Ren Yamada, Kenichi Morikawa, Kiyohiko Hotta, Daiki Iwami, Tatsu Tanabe, Sachiyo Murai, Nobuo Shinohara, Sonoe Yoshida, Shunichi Hosoda, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Megumi Kimura, Koji Yamamoto, Masato Nakai, Takuya Sho, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  Journal of viral hepatitis 29 (11) 976 - 985 2022/11 

  Donors with resolved hepatitis B virus (HBV) infection may be a solution for the organ shortage for kidney transplantation (KT). The purpose of this study was to clarify the current state of HBV markers after KT from donors with resolved HBV infection to HBV naïve recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Furthermore, we investigated HBV covalently closed circular DNA (cccDNA) in transplanted organs from donors with resolved HBV infection and the capability of HBV replication in kidney cell lines. We retrospectively analysed the HBV status of 340 consecutive donors and recipients who underwent KT in a single centre. We prospectively measured cccDNA by real-time polymerase chain reaction in kidney biopsy specimens of 32 donors with resolved HBV infection. HBV reactivation was found in three recipients with resolved HBV infection (4.8%, 3/63) after KT. We analysed 45 cases of transplantation from donors with resolved HBV infection to HBV-naive recipients. One case (2.2%, 1/45) became seropositive for hepatitis B core antibody (anti-HBc) and in another case (2.2%, 1/45), HBV-DNA was detected qualitatively in an HBV naive recipient with a donor with resolved HBV infection. In the latter case, cccDNA was measured in the donor kidney during KT. HBV replication was observed in kidney cell lines with HBV plasmid transfection. In conclusion, the risk of reactivation in anti-HBc-positive donors is relatively low. However, post-transplant HBV monitoring should be conducted in all at-risk cases.
• Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy

  Naoki Kawagishi, Goki Suda, Ryotaro Sakamori, Takeshi Matsui, Masahiro Onozawa, Zijian Yang, Sonoe Yoshida, Masatsugu Ohara, Megumi Kimura, Akinori Kubo, Osamu Maehara, Qingjie Fu, Shunichi Hosoda, Yoshimasa Tokuchi, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Hajime Sakai, Shunsuke Ohnishi, Masaru Baba, Tetsuo Takehara, Naoya Sakamoto

  Scientific Reports 12 (1) 2022/10/07 

  Abstract De novo hepatitis B virus (HBV) reactivation occurs during direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-infected patients with resolved HBV infection. We evaluated the predictive factors, mechanical insight, and differences of cytokine levels during anti-cancer/immunosuppressive and DAA. Eleven, 35, and 19 HCV-infected patients with previous HBV infection with HBV reactivation during DAA treatment, previous HBV infection without HBV reactivation during DAA treatment, and without HBV infection resolution receiving DAA treatment, respectively, were enrolled. Clinical data and baseline cytokine levels were analyzed. Low baseline serum interleukin (IL)-1β levels predicted de novo HBV reactivation during DAA treatment (odds ratio: 47.6, 95% confidence interval: 6.94–333.3). HCV-infected patients with the IL-1β gene single nucleotide polymorphism rs16944 AA allele had significantly higher IL-1β levels; no HCV-infected patient with the IL-1β AA allele experienced HBV reactivation during DAA treatment. Compared to HCV-infected patients with HBV infection resolution, non-HCV infected patients with or without HBV reactivation during anti-cancer/immunosuppressive therapy or bone marrow transplantation had remarkably lower baseline IL-1β levels. Low IL-1β levels were not associated with HBV reactivation. IL-1β levels before DAA for HCV-infected patients with resolved HBV infection could predict HBV reactivation during DAA treatment.
• 肝疾患病態解明のための細胞生物学的アプローチ 肝細胞癌幹細胞維持機構の解析

  須田 剛生, 大原 正嗣, 坂本 直哉

  肝臓 (一社)日本肝臓学会 63 (Suppl.3) A691 - A691 0451-4203 2022/10
• 【進化する肝細胞癌の薬物療法:2022 update】免疫療法の基礎と臨床 免疫療法(単剤・複合療法)の効果は肝細胞癌のetiologyと関係するか

  小川 浩司, 大原 正嗣, 中井 正人, 荘 拓也, 須田 剛生, 坂本 直哉

  肝胆膵 (株)アークメディア 85 (3) 393 - 398 0389-4991 2022/09
• 切除不能進行肝細胞癌に対するアテゾリズマブ+ベバシズマブ併用療法の治療効果と肝予備能変化

  荘 拓也, 出水 孝章, 目黒 高志, 中村 晃久, 上林 実, 高木 智史, 馬場 英, 古家 乾, 鈴木 和治, 山本 義也, 伊藤 淳, 山田 錬, 宮城島 拓人, 須田 剛生, 大原 正嗣, 中井 正人, 小川 浩司, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 131回・125回 39 - 39 2022/09
• 肝血管筋脂肪腫の1切除例

  佐々木 貴志, 甲谷 理紗子, 細田 峻一, 吉田 苑永, 得地 祐匡, 久保 彰則, 大原 正嗣, 須田 剛生, 中井 正人, 荘 拓也, 小川 浩司, 坂本 直哉, 相山 健, 武冨 紹信, 岡崎 ななせ, 松野 吉宏

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 131回・125回 40 - 40 2022/09
• 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝と膵β細胞機能に及ぼす効果 前向きコホート研究

  大江 悠希, 中村 昭伸, 曹 圭龍, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 吉川 仁人, 西田 睦, 宮 愛香, 野本 博司, 亀田 啓, 荘 拓也, 須田 剛生, 倉島 庸, 阿保 大介, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病合併症 (一社)日本糖尿病合併症学会 36 (Suppl.1) 172 - 172 2022/09
• 肝硬変体液貯留に対するトルバプタン投与症例における尿NGAL測定の有用性

  中井 正人, 森川 賢一, 吉田 苑永, 細田 峻一, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 大原 正嗣, 荘 拓也, 須田 剛生, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 63 (Suppl.2) A592 - A592 0451-4203 2022/09
• Assessment of postoperative common bile duct stones after endoscopic extraction and subsequent cholecystectomy

  Ryo Sugiura, Hideaki Nakamura, Shoichi Horita, Takashi Meguro, Kiyotaka Sasaki, Hidetoshi Kagaya, Tatsuya Yoshida, Hironori Aoki, Takayuki Morita, Miyoshi Fujita, Eiji Tamoto, Masayuki Fukushima, Yoshitomo Ashitate, Takashi Ueno, Akio Tsutaho, Masaki Kuwatani, Naoya Sakamoto

  Surgical Endoscopy 36 (9) 6535 - 6542 0930-2794 2022/09
• No increased risk of hepatocellular carcinoma after eradication of hepatitis C virus by direct-acting antivirals, compared with interferon-based therapy.

  Masaaki Korenaga, Kazumoto Murata, Namiki Izumi, Nobuharu Tamaki, Osamu Yokosuka, Tetsuo Takehara, Naoya Sakamoto, Goki Suda, Shuhei Nishiguchi, Hirayuki Enomoto, Fusao Ikeda, Mikio Yanase, Hidenori Toyoda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Kazumi Yamasaki, Tatsuya Ide, Nobuo Toda, Tatsuo Kanda, Kazushige Nirei, Yoshiyuki Ueno, Hiroaki Haga, Yoichi Nishigaki, Kunio Nakane, Masao Omata, Hitoshi Mochizuki, Yoshihiko Aoki, Masatoshi Imamura, Tatsuya Kanto, Masashi Mizokami

  Global health & medicine 4 (4) 216 - 224 2022/08/31 

  It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.
• Usefulness of ultrasonography and elastography in diagnosing oxaliplatin-induced sinusoidal obstruction syndrome.

  Rika Saito, Yasuyuki Kawamoto, Mutsumi Nishida, Takahito Iwai, Yasuka Kikuchi, Isao Yokota, Ryo Takagi, Takahiro Yamamura, Ken Ito, Kazuaki Harada, Satoshi Yuki, Yoshito Komatsu, Naoya Sakamoto

  International journal of clinical oncology 27 (11) 1780 - 1790 2022/08/30 

  BACKGROUND: Sinusoidal obstruction syndrome (SOS) refers to liver injury caused by hematopoietic stem cell transplantation (HSCT) and anticancer drugs including oxaliplatin. Increased splenic volume (SV) on computed tomography (CT) indicates oxaliplatin-induced SOS. Similarly, ultrasonography and liver stiffness measurement (LSM) by shear-wave elastography (SWE) can help diagnose SOS after HSCT; however, their usefulness for diagnosing oxaliplatin-induced SOS remains unclear. We investigated the usefulness of the Hokkaido ultrasonography-based scoring system with 10 ultrasonographic parameters (HokUS-10) and SWE in diagnosing oxaliplatin-induced SOS early. METHODS: In this prospective observational study, ultrasonography and SWE were performed before and at 2, 4, and 6 months after oxaliplatin-based chemotherapy. HokUS-10 was used for assessment. CT volumetry of the SV was performed in clinical practice, and an SV increase ≥ 30% was considered the diagnostic indicator of oxaliplatin-induced SOS. We assessed whether HokUS-10 and SWE can lead to an early detection of oxaliplatin-induced SOS before an increased SV on CT. RESULTS: Of the 30 enrolled patients with gastrointestinal cancers, 12 (40.0%) with an SV increase  ≥ 30% on CT were diagnosed with SOS. The HokUS-10 score was not correlated with an SV increase ≥ 30% (r = 0.18). The change in rate of three HokUS-10 parameters were correlated with an SV increase ≥ 30% (r = 0.32-0.41). The change in rate of LSM by SWE was correlated with an SV increase  ≥ 30% (r = 0.40). CONCLUSIONS: The usefulness of HokUS-10 score was not demonstrated; however, some HokUS-10 parameters and SWE could be useful for the early diagnosis of oxaliplatin-induced SOS.
• Efficacy and Effect on Liver Functional Reserve of Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma in Patients Who Do Not Meet Eligibility Criteria of IMbrave150

  Takuya Sho, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Koji Ogawa, Akinori Kubo, Yoshimasa Tokuchi, Qingjie Fu, Zijian Yang, Megumi Kimura, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Tomofumi Takagi, Jun Ito, Tomoe Kobayashi, Takuto Miyagishima, Naoya Sakamoto

  Cancers 14 (16) 3938 - 3938 2022/08/15 

  The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 109/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.
• VALIDATION OF THE EASY-TO-USE LENVATINIB PROGNOSTIC (LEP) INDEX TO PREDICT PROGNOSIS IN ADVANCED HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH LENVATINIB.

  Margherita Rimini, Wonseok Kang, Valentina Burgio, Mara Persano, Tamoko Aoki, Shigeo Shimose, Toshifumi Tada, Takashi Kumada, Takuya Sho, Eleonora Lai, Ciro Celsa, Claudia Campani, Matteo Tonnini, Emiliano Tamburini, Atsushi Hiraoka, Koichi Takaguchi, Naoshi Nishida, Hideki Iwamoto, Ei Itobayashi, Kunihiko Tsuji, Naoya Sakamoto, Toru Ishikawa, Hidenori Toyoda, Masatoshi Kudo, Takumi Kawaguchi, Takeshi Hatanaka, Kazugiro Nouso, Goki Suda, Giuseppe Cabibbo, Fabio Marra, Angelo Della Corte, Francesca Ratti, Federica Pedica, Francesco De Cobelli, Luca Aldrighetti, Mario Scartozzi, Stefano Cascinu, Andrea Casadei-Gardini

  Hepatology research : the official journal of the Japan Society of Hepatology 2022/08/12 

  BACKGROUND: The identification of new prognostic factors able to stratify HCC patients candidate to first line therapy is an urgent. In the present work we validated the prognostic value of the LEP index. MATHERIALS AND METHODS: Data of Eastern and Western patients treated with lenvatinib as first-line for BCLC stage B or C HCC were recollected. LEP index was composed by three class of risk according with our previously study. The 'low risk'group includes patients with PNI >43.3 and with previous TACE. The 'medium risk' group includes patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, ALBI grade 1 and BCLC-B. The 'high risk'group includes patients with PNI <43.3, ALBI grade 2 and patients with PNI <43.3, ALBI grade 1 and BCLC-C. RESULTS: 717 patients were included. Median OS was 20.7 months (95% CI 16.1-51.6) in patients with low risk (n = 223), 16.7 months (95% CI 13.3-47.0) in medium risk (n = 264) and 10.7 months (95% CI 9.3-12.2) in high risk (n = 230) [HR 1, 1.29 and 1.92 respectively; p < 0.0001]. Median PFS was 7.3 months (95% CI 6.3-46.5) in patients with low risk, 6.4 months (95% CI 5.3-8.0) in medium and 4.9 months (95% CI 4.3-5.5) in high risk [HR 1, 1.07, 1.47 respectively; p = 0.0009]. CONCLUSION: The LEP index confirms its prognostic value on an external cohort of HCC patients treated with Lenvatinib. This article is protected by copyright. All rights reserved.
• Long-term changes in aberrant DNA methylation and gastritis after Helicobacter pylori eradication focused on metachronous gastric cancer.

  Ikko Tanaka, Shoko Ono, Yoshiyuki Watanabe, Hiroyuki Yamamoto, Ritsuko Oikawa, Shogo Matsumoto, Marina Kubo, Yusuke Nishimura, Yoshihiko Shimoda, Masayoshi Ono, Keiko Yamamoto, Naoya Sakamoto

  Helicobacter e12915  2022/08/08 

  BACKGROUND: A persistently high methylation level in gastric mucosa after Helicobacter pylori (H. pylori) eradication is presumed to be a risk for metachronous gastric cancer (MGC); however, long-term changes in aberrant DNA methylation and histological gastritis have been unclear. Our aim was to examine changes in DNA methylation and histological gastritis according to the occurrence of MGC. METHODS: Subjects were classified into three groups: 25 patients in whom MGCs occurred after the initial endoscopic resection (ER) for early gastric cancer and H. pylori eradication (MGC group), 17 patients in whom MGC did not occur for more than 5 years after the initial ER and H. pylori eradication (non-MGC group) and 29 patients without a history of gastric cancer who succeeded in eradication more than 5 years ago (HP group). Aberrance of DNA methylation in three genes (miR-124a-3, EMX1, NKX6-1) and histological score of atrophy and intestinal metaplasia (IM) were evaluated using biopsy samples before and more than a mean of 5 years after H. pylori eradication. Also, the mean Z-score was calculated using Z-score values of the three genes. RESULTS: The methylation level of miR-124a-3 in the HP group and non-MGC group and that of EMX1 in the HP group significantly decreased in the long term after eradication. In the MGC group, H. pylori eradication did not improve aberrant methylation, and the mean Z-score significantly increased. There were significant positive correlations between methylation levels in miR-124a-3 and EMX1 and histological findings after eradication. CONCLUSIONS: A persistently high methylation level after H. pylori eradication reflected precancerous mucosal conditions and led to long-term MGC.
• Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603.

  Yasuyuki Kawamoto, Satoshi Yuki, Kentaro Sawada, Michio Nakamura, Osamu Muto, Susumu Sogabe, Yoshiaki Shindo, Atsushi Ishiguro, Atsushi Sato, Yasushi Tsuji, Masayoshi Dazai, Hiroyuki Okuda, Takashi Meguro, Kazuaki Harada, Mari Sekiguchi, Kazufumi Okada, Yoichi M Ito, Yuh Sakata, Naoya Sakamoto, Yoshito Komatsu

  The oncologist 27 (8) e642-e649  2022/08/05 

  BACKGROUND: Ramucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug. RESULTS: Thirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%-41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed. CONCLUSION: Although the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.
• Pre-sarcopenia and Mac-2 binding protein glycosylation isomer as predictors of recurrence and prognosis of early-stage hepatocellular carcinoma.

  Masato Nakai, Kenichi Morikawa, Shunichi Hosoda, Sonoe Yoshida, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Masatsugu Ohara, Takuya Sho, Goki Suda, Koji Ogawa, Naoya Sakamoto

  World journal of hepatology 14 (7) 1480 - 1494 2022/07/27 

  BACKGROUND: The Mac-2 binding protein glycosylation isomer (M2BPGi), a fibrosis marker in various liver diseases, is reportedly a prognostic marker in patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. AIM: To evaluate whether the M2BPGi value, M2BP, and pre-sarcopenia before radiofrequency ablation (RFA) could be useful recurrence and prognostic markers in patients with early-stage HCC. METHODS: In total, 160 patients with early-stage primary HCC treated with RFA were separately analyzed as hepatitis C virus (HCV)-positive and HCV-negative. Factors contributing to recurrence and liver-related death, including M2BP, M2BPGi, and skeletal muscle mass index, were statistically analyzed. Eighty-three patients were HCV-positive and 77 were HCV-negative. RESULTS: In HCV-positive patients, only des-γ-carboxy-prothrombin ≥ 23 mAU/mL was a significant poor prognostic factor affecting survival after RFA. In HCV-negative patients, M2BPGi ≥ 1.86 cutoff index was significantly associated with tumor recurrence, while M2BP was not. M2BPGi ≥ 1.86 cutoff index (hazard ratio, 4.89; 95% confidence interval: 1.97-12.18; P < 0.001) and pre-sarcopenia (hazard ratio, 3.34, 95% confidence interval: 1.19-9.37; P = 0.022) were independent significant poor prognostic factors in HCV-negative patients. CONCLUSION: In HCV-negative patients with primary HCC treated with RFA, lower M2BPGi contributed to a lower tumor recurrence rate and longer survival period. Pre-sarcopenia contributed to the poor prognosis independently in HCV-negative patients. These factors might be useful recurrence and prognostic markers for early-stage primary HCC.
• Effects of nucleos(t)ide analogs on hepatitis B surface antigen reduction with interferon-lambda 3 induction in chronic hepatitis B patients.

  Machiko Umemura, Koji Ogawa, Kenichi Morikawa, Akinori Kubo, Yoshimasa Tokuchi, Ren Yamada, Takashi Kitagataya, Taku Shigesawa, Tomoe Shimazaki, Megumi Kimura, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Masato Nakai, Takuya Sho, Goki Suda, Mitsuteru Natsuizaka, Kota Ono, Kazumoto Murata, Masaya Sugiyama, Masashi Mizokami, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 52 (7) 586 - 596 2022/07 

  BACKGROUND & AIMS: Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN-λ3 levels in chronic hepatitis B (CHB) patients. METHODS: A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN-λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post-therapy. RESULTS: The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was -0.38 ± 0.46 and -0.84 ± 0.64 log10 IU/ml in ETV and ADV/TDF groups, respectively (p = 0.0004). Higher serum IFN-λ3 levels were observed in ADV/TDF group compared with ETV group during treatment (p < 0.001). Serum IFN-λ3 levels showed negative correlation with HBsAg reduction in ADV/TDF group (r = -0.386, p = 0.038) at week 48. Nucleotide analogs (ADV/TDF) treatment has associated factors with -0.3 log HBsAg decline at 1 year, -0.5 log HBsAg decline at 3 years, and -0.8 log HBsAg decline at 5 years after NAs treatment on multivariate analysis. CONCLUSIONS: Nucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN-λ3 induction.
• Small-molecule inhibitor cocktail promotes the proliferation of pre-existing liver progenitor cells.

  Qingjie Fu, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto

  Stem cell reports 17 (7) 1589 - 1603 2022/06/13 

  A recent study showed that a cocktail of three small molecules, Y-27632, A83-01, and CHIR99021 (YAC), converts mature hepatocytes (MHs) into proliferative bipotent cells that can be induced into MHs and cholangiocytes in rats. However, when we reproduced these experiments, it was found that bipotent cells may be derived from resident liver progenitor cells (LPCs), whose proliferative activity was promoted by YAC. A simple and efficient sorting scheme was also developed in this study to harvest high-purity and high-yield LPCs. The inducible bipotency of purified LPCs was verified; in addition, they were found to spontaneously differentiate into hepatocytes and cholangiocytes due to changes in proliferative status even without induction. Moreover, during the differentiation process, some hepatocytes spontaneously reconverted to LPCs under certain conditions, such as the release of contact inhibition. These findings may improve our understanding of LPCs and provide a cell source for regenerative medicine.
• Analysis of the Pancreatic Cancer Microbiome Using Endoscopic Ultrasound–Guided Fine-Needle Aspiration–Derived Samples

  Shintaro Nakano, Yasuyuki Kawamoto, Yoshito Komatsu, Rika Saito, Ken Ito, Takahiro Yamamura, Kazuaki Harada, Satoshi Yuki, Kazumichi Kawakubo, Ryo Sugiura, Shin Kato, Koji Hirata, Hajime Hirata, Masahito Nakajima, Ryutaro Furukawa, Yunosuke Takishin, Kousuke Nagai, Isao Yokota, Keisuke H. Ota, Shinji Nakaoka, Masaki Kuwatani, Naoya Sakamoto

  Pancreas Publish Ahead of Print (4) 351 - 357 0885-3177 2022/06/13
• 【臓器線維化へのアプローチ-肝臓・膵臓のアンチエイジングを見据えて-】臓器線維化治療のニューウェーブ

  小川 浩司, 中井 正人, 坂本 直哉

  アンチ・エイジング医学 (株)メディカルレビュー社 18 (3) 182 - 185 1880-1579 2022/06
• Multicenter, prospective, observational study of chemotherapy-induced dysgeusia in gastrointestinal cancer.

  Ken Ito, Satoshi Yuki, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Kazuaki Harada, Shintaro Nakano, Rika Saito, Takayuki Ando, Kentaro Sawada, Masataka Yagisawa, Atsushi Ishiguro, Masayoshi Dazai, Ichiro Iwanaga, Kazuteru Hatanaka, Atsushi Sato, Ryusuke Matsumoto, Yoshiaki Shindo, Miki Tateyama, Tetsuhito Muranaka, Masaki Katagiri, Isao Yokota, Yuh Sakata, Naoya Sakamoto, Yoshito Komatsu

  Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 30 (6) 5351 - 5359 2022/06 

  PURPOSE: Dysgeusia is an adverse event caused by chemotherapy. Although retrospective studies have shown zinc administration improves dysgeusia, there have been no prospective studies. The present study examined effects of zinc therapy on dysgeusia in patients with gastrointestinal cancer. METHODS: This multicenter, prospective, observational study enrolled patients with dysgeusia during chemotherapy treatment. Patients received no intervention (control), polaprezinc p.o., or zinc acetate hydrate p.o., and serum zinc levels were measured at 0 (baseline), 6, and 12 weeks. Dysgeusia was assessed using CTCAE v5.0 and subjective total taste acuity (STTA) criteria using questionnaires at baseline and 12 weeks. RESULTS: From February 2020 to June 2021, 180 patients were enrolled from 17 institutes. There were no differences in mean baseline serum zinc levels among the groups (67.3, 66.6, and 67.5 μg/dL in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. P = 0.846). The changes in mean serum zinc levels after 12 weeks were - 3.8, + 14.3, and + 46.6 μg/dL, and the efficacy rates of dysgeusia were 33.3%, 36.8%, and 34.6% using CTCAE and 33.3%, 52.6%, 32.7% using STTA in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. The STTA scores improved in all groups, with significant improvement observed in the polaprezinc group compared with the no intervention group (P = 0.045). CONCLUSION: There was no significant correlation between the degree of serum zinc elevation and improvement in dysgeusia, suggesting that polaprezinc, but not zinc acetate hydrate, was effective in improving chemotherapy-induced dysgeusia. TRIAL REGISTRATION: UMIN000039653. Date of registration: March 2, 2020.
• Optical biopsy for esophageal squamous cell neoplasia by using endocytoscopy.

  Yoshihiko Shimoda, Yuichi Shimizu, Hiroaki Takahashi, Satoshi Okahara, Takakazu Miyake, Shin Ichihara, Ikko Tanaka, Masaki Inoue, Sayoko Kinowaki, Masayoshi Ono, Keiko Yamamoto, Shoko Ono, Naoya Sakamoto

  BMC gastroenterology 22 (1) 259 - 259 2022/05/21 

  BACKGROUND: Endocytoscopy (ECS) enables microscopic observation in vivo for the gastrointestinal mucosa; however, there has been no prospective study in which the diagnostic accuracy of ECS for lesions that have not yet undergone histological diagnosis was evaluated. We conducted a surveillance study for patients in a high-risk group of esophageal squamous cell carcinoma (ESCC) and evaluated the in vivo histological diagnostic accuracy of ECS. METHODS: This study was a multicenter prospective study. We enrolled 197 patients in the study between September 1, 2019 and November 30, 2020. The patients first underwent white light imaging and narrow band imaging, and ultra-high magnifying observation was performed if there was a lesion suspected to be an esophageal tumor. Endoscopic submucosal dissection (ESD) was later performed for lesions that were diagnosed to be ESCC by ECS without biopsy. We evaluated the diagnostic accuracy of ECS for esophageal tumorous lesions. RESULTS: ESD was performed for 37 patients (41 lesions) who were diagnosed as having ESCC by ECS, and all of them were histopathologically diagnosed as having ESCC. The sensitivity [95% confidence interval (CI)] was 97.6% (87.7-99.7%), specificity (95% CI) was 100% (92.7-100%), diagnostic accuracy (95% CI) was 98.9% (94.0-99.8%), positive predictive value (PPV) (95% CI) was 100% (91.4-100%) and negative predictive value (NPV) (95% CI) was 98.0% (89.5-99.7%). CONCLUSIONS: ECS has a high diagnostic accuracy and there were no false positives in cases diagnosed and resected as ESCC. Optical biopsy by using ECS for esophageal lesions that are suspected to be tumorous is considered to be sufficient in clinical practice.
• Study protocol of the HGCSG1803: a phase II multicentre, non-randomised, single-arm, prospective trial of combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) as first-line treatment for metastatic or relapsed pancreatic cancer.

  Shintaro Nakano, Yasuyuki Kawamoto, Satoshi Yuki, Kazuaki Harada, Takuto Miyagishima, Susumu Sogabe, Masayoshi Dazai, Atsushi Sato, Atsushi Ishiguro, Michio Nakamura, Shinya Kajiura, Yasuo Takahashi, Miki Tateyama, Kazuteru Hatanaka, Yasushi Tsuji, Takahide Sasaki, Yoshiaki Shindo, Tomoe Kobayashi, Isao Yokota, Naoya Sakamoto, Yuh Sakata, Yoshito Komatsu

  BMJ open 12 (5) e048833  2022/05/09 

  INTRODUCTION: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) has become one of the standard treatments for metastatic pancreatic cancer. However, the use of FOLFIRINOX requires prolonged infusion. Therefore, we planned to develop a new combination chemotherapy regimen with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. In the phase Ⅰ study that was conducted previously, the safety and recommended dose of OX-IRIS were assessed. In this study, we will evaluate the efficacy and safety of OX-IRIS. METHODS AND ANALYSIS: The HGCSG1803 study started as a multicentre, non-randomised, single-arm, prospective, phase II study in December 2019. Eligible subjects were patients with untreated metastatic or relapsed pancreatic cancer. OX-IRIS is administered as follows: 30 min infusion of antiemetic; 2-hour infusion of oxaliplatin (65 mg/m2); 1.5-hour infusion of irinotecan (100 mg/m2) on day 1 and 15 of each 4-week cycle; and oral S-1 (40 mg/m2) twice daily from after dinner on day one to after breakfast on day 15, followed by a 14-day rest, to be repeated every 2 weeks until disease progression, unacceptable toxicity or patient refusal. The primary endpoint is response rate. The secondary endpoints are overall and progression-free survival, safety and dose for each drug. Using a binomial test, a sample size of 40 patients was set with a threshold value of 10% and expected value of 30%. Registration of 40 cases is planned from 18 institutions in Japan. ETHICS AND DISSEMINATION: All the procedures will be conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1964 and its later versions. All the patients will receive written information about the trial and will provide informed consent before enrolment. This trial was approved by the Hokkaido University Certified Review Board (approval No: 018-037). TRIAL REGISTRATION NUMBER: jRCTs011190008.
• Phase II Study of Continued Trastuzumab Plus Irinotecan in Patients with HER2-positive Gastric Cancer Previously Treated with Trastuzumab (HGCSG 1201).

  Yasuyuki Kawamoto, Satoshi Yuki, Takashi Meguro, Kazuteru Hatanaka, Minoru Uebayashi, Michio Nakamura, Hiroyuki Okuda, Ichiro Iwanaga, Takashi Kato, Shintaro Nakano, Atsushi Sato, Kazuaki Harada, Koji Oba, Yuh Sakata, Naoya Sakamoto, Yoshito Komatsu

  The oncologist 27 (5) 340-e374  2022/05/06 

  BACKGROUND: The efficacy of irinotecan plus continuous trastuzumab beyond progression in patients with gastric cancer previously treated with trastuzumab plus standard first-line chemotherapy has not been reported. METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer who were previously treated with trastuzumab received trastuzumab every 3 weeks and irinotecan every 2 weeks. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), 6-month survival rates, safety, and subgroup analysis by HER2 status. RESULTS: Sixteen patients were enrolled in a 3-year pre-planned registration period. This study was prematurely closed due to poor patient accrual. The ORR and disease control rate were 6.7% (95% CI, 0.2-32.0) and 53.3% (95% CI, 26.6-78.7). The median PFS and overall survival (OS) were 2.4 months (95% CI, 0.0-5.2) and 9.7 months (95% CI, 8.2-11.2), respectively. The most frequently reported grades 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%). CONCLUSION: With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier: UMIN000007636.
• Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia

  Michiko Takimoto-Sato, Toshinari Miyauchi, Masaru Suzuki, Hideyuki Ujiie, Toshifumi Nomura, Tomoo Ikari, Tomohiko Nakamura, Kei Takahashi, Machiko Matsumoto-Sasaki, Hirokazu Kimura, Hiroki Kimura, Yuichiro Matsui, Takashi Kitagataya, Ren Yamada, Kazuharu Suzuki, Akihisa Nakamura, Masato Nakai, Takuya Sho, Koji Ogawa, Naoya Sakamoto, Naoko Yamaguchi, Noriyuki Otsuka, Utano Tomaru, Satoshi Konno

  Frontiers in Genetics 13 2022/05/05 

  Background: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is an extremely rare disease caused by mutations in FAM111B, and only approximately 30 cases have been reported worldwide. Some patients develop interstitial pneumonia, which may lead to progressive pulmonary fibrosis and poor prognosis. However, no effective treatment for interstitial pneumonia associated with POIKTMP has been reported. Here, we report an autopsy case of POIKTMP, wherein interstitial pneumonia was improved by corticosteroids. Case Presentation: A 44-year-old Japanese man was referred to our hospital due to poikiloderma, hypotrichosis, and interstitial pneumonia. He developed progressive poikiloderma and muscle weakness since infancy. He also had tendon contractures, short stature, liver cirrhosis, and interstitial pneumonia. Mutation analysis of FAM111B revealed a novel and de novo heterozygous missense mutation, c.1886T &gt; G (p(Phe629Cys)), through which we were able to diagnose the patient with POIKTMP. 3 years after the POIKTMP diagnosis, interstitial pneumonia had worsened. After 2 weeks of administrating 40 mg/day of prednisolone, his symptoms and lung shadows improved. However, he subsequently developed severe hepatic encephalopathy and eventually died of respiratory failure due to bacterial pneumonia and pulmonary edema. Autopsy revealed an unclassifiable pattern of interstitial pneumonia, as well as the presence of fibrosis and fatty degeneration in several organs, including the liver, kidney, skeletal muscle, heart, pancreas, and thyroid. Conclusions: We report a case of POIKTMP in which interstitial pneumonia was improved by corticosteroids, suggesting that corticosteroids could be an option for the treatment of interstitial pneumonia associated with this disease.
• Promising Genomic Testing for Biliary Tract Cancer Using Endoscopic Ultrasound-Guided Fine-Needle Aspiration/Biopsy Specimens.

  Masaki Kuwatani, Kazumichi Kawakubo, Naoya Sakamoto

  Diagnostics (Basel, Switzerland) 12 (4) 2022/04/05 

  The undesired prognosis of biliary tract cancer is mainly attributed to the difficult detection of cancer lesions, including intraepithelial neoplasia and no standard examination for screening. In addition, pathological diagnosis of biliary stricture, whether it is malignant or benign, is not so easy, because of difficult optimal sampling by forceps biopsy and brush cytology, although various devices and methods for pathological diagnosis have been reported. Furthermore, we have to be careful about post-endoscopic retrograde cholangiography pancreatitis when we approach the biliary tract lesion via a transpapillary route. In order to improve the diagnostic accuracy, there have been several studies that indicate the feasibility and efficacy of genomic analysis for accurate diagnosis of biliary tract cancer by using pathological specimens, including endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) samples. For efficient and precision medicine for patients with biliary tract cancer, future diagnosis and treatment should also be based on molecular and genetic analyses. In this article, we review and summarize the past knowledge and cutting edge of genomic testing for biliary tract cancer, using EUS-FNA/FNB specimens, and indicate some ingenuities in sample processing to promote effective clinical practice and future perspectives.
• ウイルス肝炎研究-ウイルスゲノム・ホストゲノム・免疫 腎臓移植後のB型肝炎ウイルス再活性化の検討

  山田 錬, 森川 賢一, 坂本 直哉

  肝臓 (一社)日本肝臓学会 63 (Suppl.1) A108 - A108 0451-4203 2022/04
• 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝に及ぼす効果 前向きコホート研究

  大江 悠希, 高瀬 崇宏, 曹 圭龍, 小川 浩司, 海老原 裕磨, 吉川 仁人, 西田 睦, 宮 愛香, 野本 博司, 亀田 啓, 荘 拓也, 須田 剛生, 中村 昭伸, 倉島 庸, 阿保 大介, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 (一社)日本糖尿病学会 65 (Suppl.1) S - 139 0021-437X 2022/04
• 非アルコール性脂肪肝炎、非代償性肝硬変のhigh MELD例に実施した脳死肝移植の一例

  中村 恒星, 後藤 了一, 巖築 慶一, 川村 典生, 渡辺 正明, 森川 賢一, 小川 浩司, 坂本 直哉, 嶋村 剛, 武冨 紹信

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 122回 RS - 2 2022/04
• Image findings of malignant lymphoma of the gallbladder

  Kuwatani Masaki, Takishin Yunosuke, Mitsuhashi Tomoko, Sakamoto Naoya

  Tando 一般社団法人 日本胆道学会 36 (1) 82 - 90 0914-0077 2022/03/31
• Overestimated Renal Function in Patients with Liver Cirrhosis Predicts Poor Prognosis.

  Sonoe Yoshida, Goki Suda, Masatsugu Ohara, Megumi Kimura, Zijian Yang, Osamu Maehara, Qingjie Fu, Shunichi Hosoda, Kubo Akinori, Yoshimasa Tokuchi, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 52 (7) 603 - 613 2022/03/30 

  AIM: A high prevalence of overestimated renal function in patients with liver cirrhosis (LC) has been reported; nonetheless, its impact on prognosis remains unclear. We aimed to evaluate the impact of overestimated renal function on prognosis in patients with LC. METHODS: An overestimated renal function was defined as a >20% increase in the creatinine-based estimated glomerular filtration rate (eGFR), compared with cystatin C-based eGFR. LC patients with conserved serum, who were evaluated for muscle atrophy and had proper clinical information were included, and their prognostic factors were analyzed. RESULTS: A total of 215 consecutive patients with LC were included. The prevalence of overestimated renal function was 29.8% (64/215). Kaplan-Meier survival analysis revealed that patients with overestimated renal function had a poorer prognosis than those without overestimated renal function (hazard ratio [HR]: 2.217 95% confidence interval [CI]: 1.290-3.810; P=0.001). Subgroup analysis showed that overestimated renal function was a significant prognostic factor, irrespective of sex and the presence of hepatocellular carcinoma (HCC). Multivariate Cox regression analyses revealed that overestimated renal function was a significant and independent factor predictive of poor prognosis in the entire cohort (HR: 2.050; 95% CI: 1.041-4.037; P=0.038) and in subgroups classified by Child-Pugh class A (HR: 2.131; 95% CI: 1.019-4.458; P=0.044), Model for End-Stage Liver Disease score <9 (HR: 2.303; 95% CI: 1.038-5.109; P=0.04), and presence of HCC (HR: 2.290; 95% CI: 1.128-4.651; P=0.022). CONCLUSION: Overestimated renal function is a significant and independent prognostic factor in patients with LC. This article is protected by copyright. All rights reserved.
• Bleeding After Gastric Endoscopic Submucosal Dissection Focused on Management of Xa Inhibitors.

  Shoko Ono, Masahiro Ieko, Ikko Tanaka, Yoshihiko Shimoda, Masayoshi Ono, Keiko Yamamoto, Naoya Sakamoto

  Journal of gastric cancer 22 (1) 47 - 55 2022/03 

  PURPOSE: The use of direct oral Xa inhibitors (DXaIs) to prevent venothrombotic events is increasing. However, gastrointestinal bleeding, including that related to endoscopic resection, is a concern. In this study, we evaluated bleeding and coagulation times during the perioperative period of gastric endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: Patients who consecutively underwent gastric ESD from August 2016 to December 2018 were analyzed. Bleeding rates were compared among the 3 groups (antiplatelet, DXaIs, and control). DXaI administration was discontinued on the day of the procedure. Prothrombin time (PT), activated partial thromboplastin time, and the ratio of inhibited thrombin generation (RITG), which was based on dilute PT, were determined before and after ESD. RESULTS: During the study period, 265 gastric ESDs were performed in 239 patients, where 23 and 50 patients received DXaIs and antiplatelets, respectively. Delayed bleeding occurred in 17 patients (7.4%) and 21 lesions (7.1%). The bleeding rate in the DXaI group was significantly higher than that in the other groups (30.4%, P<0.01), and the adjusted odds ratio of bleeding was 5.7 (95% confidence interval, 1.4-23.7; P=0.016). In patients using DXaIs, there was a significant (P=0.046) difference in the median RITG between bleeding cases (18.6%) and non-bleeding cases (3.8%). CONCLUSIONS: A one-day cessation of DXaIs was related to a high incidence of bleeding after gastric ESD, and monitoring of residual coagulation activity at trough levels might enable the predicted risk of delayed bleeding in patients using DXaIs.
• 個別化医療を見据えた消化器診療の現状 超音波内視鏡下穿刺吸引法で得られた検体を用いた膵腫瘍内細菌叢の検討

  中野 真太郎, 川本 泰之, 小松 嘉人, 伊藤 憲, 原田 一顕, 結城 敏志, 川久保 和道, 杉浦 諒, 加藤 新, 平田 幸司, 平田 甫, 中島 正人, 古川 龍太郎, 滝新 悠之介, 永井 孝輔, 横田 勲, 太田 圭祐, 中岡 慎治, 桑谷 将城, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 130回・124回 36 - 36 2022/03
• 再活性化が疑われた急性E型肝炎の1例

  久保 彰則, 小川 浩司, 吉田 苑永, 細田 峻一, 得地 祐匡, 山田 錬, 北潟谷 隆, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 石田 勢津子, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 130回・124回 55 - 55 2022/03
• 肝癌に対する新世代マイクロ波凝固療法の治療成績

  中井 正人, 吉田 苑永, 細田 峻一, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 130回・124回 70 - 70 2022/03
• The potential of soluble CD14 in discriminating nonalcoholic steatohepatitis from nonalcoholic fatty liver disease.

  Akihisa Nakamura, Koji Yamamoto, Rei Takeda, Ren Yamada, Akinori Kubo, Kenichi Morikawa, Sayaka Ando, Tomoe Shimazaki, Takaaki Izumi, Machiko Umemura, Takashi Kitagataya, Taku Shigesawa, Kazuharu Suzuki, Megumi Kimura, Masato Nakai, Takuya Sho, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Toshiro Sugiyama, Hiroshi Takeda, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 52 (6) 508 - 521 2022/02/07 

  BACKGROUND AND AIMS: Although various noninvasive markers and prediction formulas for nonalcoholic steatohepatitis (NASH) have been reported, they are of value only in the diagnosis of the advanced fibrosis stage of NASH. In this study, we evaluated soluble CD14 (sCD14) as a diagnostic marker for discriminating NASH from nonalcoholic fatty liver disease (NAFLD) using an animal model and clinical specimens. METHODS: Serum sCD14 levels were measured in samples derived from mice with diet-induced NASH and patients using an enzyme-linked immunosorbent assay. Our cohort enrolled 126 patients with liver needle biopsy-proven NAFLD. RESULTS: The intestinal defense mechanism in NASH model mice was altered as a consequence of the unique gut environment. Elevated serum levels of sCD14 were observed in mice with diet-induced NASH, and the condition of the liver was exacerbated as a result of exposure to gut-derived endotoxin. We confirmed that the serum sCD14 levels in NAFL patients significantly differed from those in NASH patients. The area under the curve for distinguishing between NAFL and NASH was 0.891. Moreover, we found that serum sCD14 levels were weakly correlated with the inflammation grade based on the NAFLD activity score (NAS), the grade of fibrosis according to the Brunt fibrosis classification, and a positive correlation with the grade of ballooning based on NAS in patients with NAFLD. CONCLUSION: sCD14 could be a useful pathophysiological marker and diagnostic adjunct distinguishing NASH from NAFLD. The use of sCD14 may allow the screening and identification of high-risk groups for NASH development and support early therapeutic interventions.
• 腎移植後のB型肝炎ウイルス(HBV)再活性化の検討

  堀田 記世彦, 山田 錬, 森川 賢一, 田邉 起, 坂本 直哉, 篠原 信雄

  日本臨床腎移植学会プログラム・抄録集 (一社)日本臨床腎移植学会 55回 260 - 260 2022/02
• Prediction of hepatocellular carcinoma using age and liver stiffness on transient elastography after hepatitis C virus eradication.

  Masato Nakai, Yoshiya Yamamoto, Masaru Baba, Goki Suda, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Ken Furuya, Naoya Sakamoto

  Scientific reports 12 (1) 1449 - 1449 2022/01/27 

  Liver stiffness measurement (LSM) is a useful tool for assessing advanced liver fibrosis, an important risk factor for hepatocellular carcinoma (HCC) following hepatitis C (HCV) eradication. This study aimed to clarify the non-invasive factors associated with HCC following sustained virological response (SVR) and to identify the low-risk group. 567 patients without history of HCC who achieved SVR at 24 weeks (SVR24) after IFN-free treatment were retrospectively analyzed. The cumulative incidence of HCC and the risk factors were examined using pre-treatment and SVR24 data. The median observation period was 50.2 months. Thirty cases of HCC were observed, and the 4-year cumulative incidence of HCC was 5.9%. In multivariate analysis, significant pre-treatment factors were age ≥ 71 years (hazard ratio [HR]: 3.402) and LSM ≥ 9.2 kPa (HR: 6.328); SVR24 factors were age ≥ 71 years (HR: 2.689) and LSM ≥ 8.4 kPa (HR: 6.642). In cases with age < 71 years and LSM < 8.4 kPa at the time of SVR24, the 4-year cumulative incidence of HCC was as low as 1.1%. Both pre-treatment LSM (≥ 9.2 kPa) and SVR24 LSM (≥ 8.4 kPa) and age (≥ 71 years) are useful in predicting the risk of HCC after SVR with IFN-free treatment. Identification of low-risk individuals may improve the efficiency of follow-up.
• Changes in Serum Growth Factors during Lenvatinib Predict the Post Progressive Survival in Patients with Unresectable Hepatocellular Carcinoma.

  Zijian Yang, Goki Suda, Osamu Maehara, Masatsugu Ohara, Sonoe Yoshida, Shunichi Hosoda, Megumi Kimura, Akinori Kubo, Yoshimasa Tokuchi, Qingjie Fu, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  Cancers 14 (1) 2022/01/04 

  Serum growth factor changes and their effect on prognosis during lenvatinib for unresectable hepatocellular carcinoma (HCC) remain underexplored. The sequential changes in serum growth factors during lenvatinib for unresectable HCC were evaluated in 58 patients using complete clinical data, and preserved serum was used to investigate changes in FGF-19, ANG-2, HGF, VEGF, and EGF. Patients with a complete response (CR), partial response (PR), and stable disease (SD) were evaluated for growth factor changes between the best response and progressive disease (PD) points, classified based on these changes, and evaluated by post progression survival (PPS). A total of 8, 24, 18, and 8 patients showed CR, PR, SD, and PD, respectively. Multivariate analysis revealed that age, relative dose intensity, and baseline ANG-2 were significantly associated with treatment response. Growth factor changes between the best response and PD points revealed that patients could be classified into four groups based on the EGF, ANG-2, and HGF changes. Although patient characteristics at baseline and PD, their response to lenvatinib, and PFS were similar among those groups, patients with an increase in all growth factors had significantly shorter PPS (median PPS was 553, 323, and 316 versus 173 days in groups 1-4 p = 0.032). We revealed that the evaluation of the changes in growth factors during lenvatinib could predict PPS.
• 【肝硬変症の診断治療の最新知見】肝硬変に対する次世代治療法 薬剤・再生療法の開発・治験状況

  小川 浩司, 中井 正人, 坂本 直哉

  日本内科学会雑誌 (一社)日本内科学会 111 (1) 74 - 81 0021-5384 2022/01
• Study protocol for HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer refractory to anti-EGFR antibodies.

  Hiroshi Nakatsumi, Yoshito Komatsu, Tetsuhito Muranaka, Satoshi Yuki, Yasuyuki Kawamoto, Kazuaki Harada, Masayoshi Dazai, Miki Tateyama, Yusuke Sasaki, Takuto Miyagishima, Yasushi Tsuji, Masaki Katagiri, Michio Nakamura, Susumu Sogabe, Kazuteru Hatanaka, Takashi Meguro, Tomoe Kobayashi, Atsushi Ishiguro, Osamu Muto, Yoshiaki Shindo, Masahito Kotaka, Takayuki Ando, Ryo Takagi, Naoya Sakamoto, Yu Sakata

  Frontiers in oncology 12 939425 - 939425 2022 

  BACKGROUND: The first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies. METHODS: FOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi. DISCUSSION: There is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.
• Efficacy of rifaximin against covert hepatic encephalopathy and hyperammonemia in Japanese patients.

  Masato Nakai, Goki Suda, Koji Ogawa, Sonoe Yoshida, Shunichi Hosoda, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Taku Shigesawa, Masatsugu Ohara, Takuya Sho, Kenichi Morikawa, Naoya Sakamoto

  PloS one 17 (7) e0270786  2022 

  Covert hepatic encephalopathy (CHE) impairs patient quality of life and occurs in approximately 30% of liver cirrhosis (LC) cases. Japanese clinical practice guidelines recommend rifaximin to treat overt HE (OHE). However, the usefulness of rifaximin against CHE is not thoroughly investigated in Japanese patients. We aimed to investigate the efficacy of rifaximin against hyperammonemia and CHE in Japan. We observed 102 patients with HE showing hyperammonemia secondary to LC and examined various biochemical and behavioral parameters following rifaximin treatment. CHE was diagnosed when the patients exhibited two or more abnormal neuropsychological test (NPT) scores but did not indicate OHE symptoms. In the 102 cases, a significant therapeutic effect of rifaximin on hyperammonemia was observed from 2 to 48 weeks after starting treatment. Excluding 10 patients diagnosed with OHE upon starting rifaximin treatment, 12 of the 92 remaining patients (11.8%) transitioned to OHE within 1 year. The 1 year cumulative OHE transition rate was 14.5%. Among the 24 patients with CHE diagnosed by the NPT for whom NPT results could be evaluated at 4 and 12 weeks after starting treatment, 10 (41.6%) had recovered from CHE at 12 weeks. When the factors contributing to recovery from CHE were examined by multivariate analysis, an ammonia level <129 μg/dL was a significant factor. Rifaximin was thus significantly effective against both hyperammonemia and CHE in Japanese patients.
• Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on lipid profiles in patients with hepatitis B.

  Kazuharu Suzuki, Goki Suda, Yoshiya Yamamoto, Satoshi Abiko, Kenji Kinoshita, Shuichi Miyamoto, Ryo Sugiura, Megumi Kimura, Osamu Maehara, Ren Yamada, Takashi Kitagataya, Taku Shigesawa, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  PloS one 17 (1) e0261760  2022 

  For long-term treatment of hepatitis B virus (HBV) infection, switching from tenofovir-disoproxil-fumarate (TDF) to tenofovir-alafenamide (TAF) may prevent renal dysfunction and bone loss. However, the precise effects of this switch on the blood lipid profile remain to be clarified. This is an important issue as TDF is known to have effects on both low- and high-density lipids. Therefore, our retrospective multi-center study aimed to evaluate the effects of switching from TDF to TAF on the lipid profile of patients with HBV infection. Samples were obtained prior to the switch from TDF to TAF and at 6-12 months after TAF initiation. In some cases, additional samples obtained pre- and post-TDF administration were available for analysis. Serum cholesterol levels, including oxidized-low-density lipoprotein (LDL) and non-high-density lipoprotein-cholesterol (HDL-c), and the rate of dyslipidemia, according to the NCEP-ATP III lipid risk classification, were analyzed. The data from 69 patients were analyzed, including 33 patients with pre- and post-TDF-initiation serum samples. Total cholesterol (T-chol), HDL-c, LDL-c, non-HDL-c, and oxidized LDL levels increased significantly after switching to TAF. With regard to sequential changes pre- to post-TAF, TDF was associated with significantly lower serum T-chol, HDL-c, and oxidized LDL-c levels, with T-chol, HDL-c, LDL-c, and oxidized LDL-c levels increasing significantly after the switch. The switch from TDF to TAF was also associated with an increase in the rate of dyslipidemia, from 33% to 39%, with an increase in the rate of severe dyslipidemia of 1.4% and 5.8%, based on T-chol and LDL-c levels. Of note, no cases of severe dyslipidemia were detected pre-TAF treatment. As oxidized LDL-c and non-HDL-c are strongly associated with atherosclerosis development, careful monitoring of lipid is needed after switching from TDF to TAF in this clinical population.
• Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy.

  Takuya Sho, Kenichi Morikawa, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Taku Shigesawa, Mugumi Kimura, Masato Nakai, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  World journal of gastrointestinal oncology 13 (12) 2076 - 2087 2021/12/15 

  The phase III clinical trial of the novel molecular targeted agent (MTA) lenvatinib for patients with advanced hepatocellular carcinoma (HCC) (REFLECT trial) found that lenvatinib was non-inferior to sorafenib in overall survival. Recently, the efficacy of multiple MTAs, including lenvatinib, in practice has been reported, and therapeutic strategies for Barcelona Clinic Liver Cancer (BCLC) intermediate stage HCC are undergoing major changes. Based on these results, lenvatinib could be recommended for patients with transcatheter arterial chemoembolization (TACE)-refractory, ALBI grade 1, within the up-to-seven criteria in the BCLC intermediate stage. Lenvatinib provides a more favorable outcome than TACE, even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A. When patients meet the definitions of TACE-refractory or TACE-unsuitable, switching to systemic chemotherapy, including lenvatinib, is for favorable for preserving liver function. If initial treatment, including MTA, has a significant therapeutic effect and downstaging of HCC is obtained, additional TACE or surgical resection should be considered. Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug. Furthermore, a significant therapeutic effect is expected in tumors with more than 50% liver involvement or main portal vein invasion, which have traditionally been considered to have a poor prognosis in patients. This suggests that at the start of lenvatinib treatment, HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.
• Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals

  Yoshimasa Tokuchi, Goki Suda, Megumi Kimura, Osamu Maehara, Takashi Kitagataya, Akinori Kubo, Sonoe Yoshida, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Masatsugu Ohara, Ren Yamada, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  Scientific Reports 11 (1) 2021/12 

  We aimed to evaluate factors associated with changes in skeletal muscle mass in hepatitis C virus (HCV)-infected patients after treatment with direct-acting antivirals (DAAs). Consecutive HCV-infected patients after treatment with DAA were recruited into the study. Patients who achieved sustained virological response (SVR); and had complete clinical information, preserved serum samples at baseline and SVR48, and skeletal muscle mass evaluations based on the psoas muscle mass index (PMI) on computed tomography at baseline and ≥ 12 months were included. Altogether, 70.7% of patients (41/58) showed increased PMI after DAA therapy, and mean relative PMI was significantly higher after DAA therapy than at baseline. There were no significant associations between baseline clinical factors routinely examined in clinical practice and increased PMI. Among factors reported to be associated with skeletal muscle loss in patients with chronic liver disease, serum zinc levels and total and free carnitine levels increased significantly after DAA therapy and only changes in serum free carnitine levels were significantly associated with an increased PMI (r = 0305, P = 0.020). In conclusion, increased skeletal muscle mass after successful HCV eradication by DAAs was significantly associated with increased serum-free carnitine levels. l-carnitine supplementation may be beneficial in patients with low skeletal muscle mass after DAA.
• Eradication of Helicobacter pylori may improve dyspepsia in the elderly for the long term.

  Ikko Tanaka, Shoko Ono, Yoshihiko Shimoda, Masaki Inoue, Sayoko Kinowaki, Momoko Tsuda, Masayoshi Ono, Keiko Yamamoto, Yuichi Shimizu, Mototsugu Kato, Naoya Sakamoto

  BMC gastroenterology 21 (1) 445 - 445 2021/11/25 

  BACKGROUND: Therapy for eradication of Helicobacter pylori (H. pylori) improves symptoms of H. pylori-associated dyspepsia (HPD), but the effects of eradication in elderly patients are unclear. The aim of our study was to investigate dyspepsia symptoms and long-term effects of eradication in elderly patients. METHODS: This retrospective study included 496 patients who received H. pylori eradication therapy. The patients were divided into a group of elderly patients (group E: ≧ 65 years old) and a group of non-elderly patients (group N: < 65 years old). Abdominal symptoms were evaluated using a questionnaire about abdominal symptoms before eradication and after eradication (1-2 months and more than one year). Dyspepsia was defined as a score of 4 points or more for at least one of 4 items (postprandial fullness, early satiety, epigastric pain, and hunger pain). Improvement of symptoms was defined on the basis of changes in Global Overall Systems scores. RESULTS: There were no differences in abdominal symptoms before eradication between the two groups. Successful eradication improved symptoms in patients with dyspepsia within 2 months (in 75.6% (56/74) of the patients in group N and in 64.5% (20/31) of the patients in group E). The questionnaire showed that 80% (32/40) of the patients in group N and 60% (12/20) of the patients in group E had long-term relief of dyspepsia. The scores for abdominal symptoms in group E continued to improve for a mean period of 54.8 months after eradication. CONCLUSIONS: Eradication of H. pylori age-independently improved dyspepsia symptoms for the long term.
• 特集 肝不全･肝硬変に対する再生療法-最先端の今 4.開発中の肝再生医療(7)肝星細胞に対するビタミンAを介した肝線維化改善療法の開発

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  臨床消化器内科 日本メディカルセンター 36 (13) 1690 - 1694 0911-601X 2021/11/20
• 治療法の再整理とアップデートのために 専門家による私の治療 C型肝炎

  森川 賢一, 坂本 直哉

  日本医事新報 (株)日本医事新報社 (5092) 40 - 40 0385-9215 2021/11
• Establishment of oxaliplatin-resistant gastric cancer organoids: importance of myoferlin in the acquisition of oxaliplatin resistance.

  Kenji Harada, Naoya Sakamoto, Shoichi Ukai, Yusuke Yamamoto, Quoc Thang Pham, Daiki Taniyama, Ririno Honma, Ryota Maruyama, Tsuyoshi Takashima, Hiroshi Ota, Yuki Takemoto, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui

  Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 24 (6) 1264 - 1277 2021/11 

  BACKGROUND: The attainment of drug resistance in gastric cancer (GC) is a problematic issue. Although many studies have shown that cancer stem cells (CSCs) play an important role in the acquisition of drug resistance, there is no clinically available biomarker for predicting oxaliplatin (L-OHP) resistance in relation to CSCs. Organoid technology, a novel 3D cell culture system, allows harboring of patient-derived cancer cells containing abundant CSCs using niche factors in a dish. METHODS: In this study, we established L-OHP-resistant gastric cancer organoids (GCOs) and evaluated their gene expression profile using microarray analysis. We validated the upregulated genes in the L-OHP-resistant GCOs compared to their parental GCOs to find a gene responsible for L-OHP resistance by qRT-PCR, immunohistochemistry, in vitro, and in vivo experiments. RESULTS: We found myoferlin (MYOF) to be a candidate gene through microarray analysis. The results from cell viability assays and qRT-PCR showed that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry of MYOF in GC tissue samples revealed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown of MYOF repressed L-OHP resistance, cell growth, stem cell features, migration, invasion, and in vivo tumor growth. CONCLUSIONS: Our results suggest that MYOF is highly involved in L-OHP resistance and tumor progression in GC. MYOF could be a promising biomarker and therapeutic target for L-OHP-resistant GC cases.
• 【肝胆膵疾患におけるバイオマーカーの意義を探る】肝疾患のバイオマーカー NASHにおける新規糖鎖バイオマーカー(AAT-A3F)

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 83 (4) 527 - 533 0389-4991 2021/10
• HGCSG2101 実臨床における進行膵癌に対するnal/IRI+5-FU/LVの治療成績

  山村 貴洋, 原田 一顕, 曽我部 進, 澤田 憲太郎, 八木澤 允貴, 中野 真太郎, 太宰 昌佳, 舘山 美樹, 伊藤 憲, 斎藤 里佳, 川本 泰之, 結城 敏志, 坂本 直哉, 坂田 優, 小松 嘉人

  日本癌治療学会学術集会抄録集 59回 O43 - 2 2021/10
• Endoscopic treatment for hepaticojejunostomy anastomotic stricture: Advantages and disadvantages of balloon dilatation with stenting.

  Masaki Kuwatani, Naoya Sakamoto

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 2021/09/29
• The TLR4-TRIF-type 1 IFN-IFN-γ pathway is crucial for gastric MALT lymphoma formation after Helicobacter suis infection.

  Koji Yamamoto, Yasuyuki Kondo, Shunsuke Ohnishi, Masaru Yoshida, Toshiro Sugiyama, Naoya Sakamoto

  iScience 24 (9) 103064 - 103064 2021/09/24 

  Helicobacter suis, a zoonotic infection-related bacterium, can induce gastric mucosa-associated lymphoid tissue (MALT) lymphoma in humans and animals. Recently, we reported that the formation of gastric MALT lymphoma after H. suis infection is induced by interferon (IFN)-γ activation. Here, we revealed that activation of the Toll-like receptor (TLR) 4-Toll/IL-1 receptor domain-containing adapter-inducing interferon-β (TRIF) pathway after H. suis infection is associated with the production of type 1 IFNs (IFN-α, IFN-β) by gastric epithelial cells. Additionally, these type 1 IFNs interact with type 1 IFN receptors on gastric B cells, facilitating the secretion of IFN-γ and the activation of which is enhanced by positive feedback regulation in B cells. These results suggest that the TLR4-TRIF-type 1 IFN-IFN-γ pathway is crucial in the development of gastric MALT lymphoma after H. suis infection and may, therefore, represent a therapeutic target for the prevention of this condition.
• Immunoglobulin G4-related cholecystitis mimicking gallbladder cancer diagnosed by EUS-guided biopsy.

  Kosuke Nagai, Masaki Kuwatani, Yunosuke Takishin, Ryutaro Furukawa, Hajime Hirata, Kazumichi Kawakubo, Tomoko Mitsuhashi, Naoya Sakamoto

  Endoscopic ultrasound 2021/09/03
• 当院における切除不能肝細胞癌に対するAtezolizumab+Bevacizumab併用療法の使用経験

  吉田 苑永, 荘 拓也, 久保 彰則, 得地 祐匡, 細田 峻一, 北潟谷 隆, 山田 錬, 中井 正人, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 129回・123回 40 - 40 2021/09
• Lenvatinib加療後にCRに至りconversion surgeryを施行した肝内多発転移を伴う肝細胞癌の1例

  細田 峻一, 中井 正人, 吉田 苑永, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉, 岡崎 ななせ, 大塚 拓也, 三橋 智子

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 129回・123回 42 - 42 2021/09
• Transient elastographyによるLSMと年齢を用いたSVR後肝発癌低リスク群の囲い込み

  中井 正人, 山本 義也, 馬場 英, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 重沢 拓, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 古家 乾, 坂本 直哉

  肝臓 (一社)日本肝臓学会 62 (Suppl.2) A543 - A543 0451-4203 2021/09
• 除不能進行肝細胞癌に対するアテゾリズマブ+ベバシズマブ併用療法の初期治療経験:多施設共同研究

  荘 拓也, 須田 剛生, 久保 彰則, 北潟谷 隆, 山田 錬, 重沢 拓, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 62 (Suppl.2) A550 - A550 0451-4203 2021/09
• 巨大大腸腫瘍ESD後の狭窄に対するバルーン拡張で穿孔をきたした1例

  西村 友佑, 大野 正芳, 松本 将吾, 久保 茉理奈, 霜田 佳彦, 田中 一光, 山本 桂子, 小野 尚子, 市川 伸樹, 本間 重紀, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 129回・123回 62 - 62 2021/09
• 肝細胞癌において血清中表皮型脂肪酸結合タンパク質は組織中発現レベルとは独立した予後不良因子である

  大平 将史, 横尾 英樹, 小川 浩司, 深井 原, 神山 俊哉, 坂本 直哉, 武冨 紹信

  日本癌学会総会記事 80回 [J14 - 4] 0546-0476 2021/09
• Genomic profiling of intestinal/mixed-type superficial non-ampullary duodenal epithelial tumors.

  Shuichi Miyamoto, Goki Suda, Marin Ishikawa, Hideyuki Hayashi, Satoshi Nimura, Yoshihiro Matsuno, Ryo Mori, Shigeki Tanishima, Takahiko Kudo, Tomofumi Takagi, Yoshiya Yamamoto, Shoko Ono, Yuichi Shimizu, Naoya Sakamoto

  JGH open : an open access journal of gastroenterology and hepatology 5 (9) 1071 - 1077 2021/09 

  Background and Aim: The mechanism underlying carcinogenesis and the genomic features of superficial non-ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next-generation sequencing (NGS). Methods: Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a panel of 160 cancer-related genes. Furthermore, the alteration/mutation frequencies in SNADETs were examined. Results: The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low-grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high-grade dysplasia tumors. Only one carcinoma in situ was detected. NGS data for 16 samples were obtained. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. Conclusion: We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD exhibited KRAS and BRAF alterations.
• Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria.

  Takuya Sho, Goki Suda, Koji Ogawa, Megumi Kimura, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Osamu Maehara, Shunsuke Ohnishi, Taku Shigesawa, Akihisa Nakamura, Ren Yamada, Masatsugu Ohara, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Kazuharu Suzuki, Takaaki Izumi, Takashi Meguro, Katsumi Terashita, Jun Ito, Takuto Miyagishima, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 51 (9) 979 - 989 2021/09 

  AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS: In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.
• 【ここまできた肝細胞癌の薬物療法:2021 update】免疫療法の動向 アテゾリズマブ+ベバシズマブによるCR例の特徴

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 83 (2) 259 - 263 0389-4991 2021/08
• 著明な隆起を伴った下咽頭上皮内癌の1例

  西村 友佑, 清水 勇一, 久保 茉理奈, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 小野 尚子, 三橋 智子, 鈴木 崇祥, 坂本 直哉

  耳鼻咽喉科展望 耳鼻咽喉科展望会 64 (4) 255 - 256 0386-9687 2021/08
• 【ここまできた肝細胞癌の薬物療法:2021 update】免疫療法の動向 アテゾリズマブ+ベバシズマブによるCR例の特徴

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 83 (2) 259 - 263 0389-4991 2021/08
• Clinical and Image Characteristics of IgG4-Related Sclerosing Cholecystitis.

  Masaki Kuwatani, Naoya Sakamoto

  Diagnostics (Basel, Switzerland) 11 (8) 2021/07/28 

  Since autoimmune pancreatitis (AIP) was established as a new disease entity, sclerosing change with abundant immunoglobulin-4 (IgG4)-positive plasma cells, storiform fibrosis, and obliterative phlebitis are main pathological features in IgG4-related diseases. Regarding IgG4-related sclerosing cholecystitis (IgG4-CC), which is occasionally associated with AIP cases and is rarely isolated, there are no diagnostic criteria and insufficient perceptions of the image findings. Although there have been some reports on IgG4-CC, differentiation between IgG4-CC and gallbladder cancer is very difficult in some cases with a localized lesion. In this review, we especially focused on image findings of IgG4-CC and summarized its image features for diagnostic assistance. The ultrasonography and CT findings of IgG4-CC could be classified into diffuse and localized types. Based on these findings, the presence of wall thickening with an intact or smooth mucosal layer, followed by a homogenously thickened outer layer, would be a helpful morphological finding to distinguish IgG4-CC from gallbladder cancer.
• Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI.

  Akinori Kubo, Goki Suda, Megumi Kimura, Osamu Maehara, Yoshimasa Tokuchi, Takashi Kitagataya, Masatsugu Ohara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  Cancers 13 (14) 2021/07/20 

  In hepatocellular carcinoma (HCC), CTNNB-1 mutations, which cause resistance to immune checkpoint inhibitors, are associated with HCC with iso-high intensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in resectable HCC; however, analyses on unresectable HCC are lacking. This study analyzed the prevalence, characteristics, response to lenvatinib, and CTNNB-1 mutation frequency in unresectable HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI. In 52 patients with unresectable HCC treated with lenvatinib, the prevalence of iso-high intensity in the hepatobiliary phase of EOB-MRI was 13%. All patients had multiple HCCs, and 3 patients had multiple HCCs with iso-high intensity in the hepatobiliary phase of EOB-MRI. Lenvatinib response to progression-free survival and overall survival were similar between patients with or without iso-high intensity in the hepatobiliary phase of EOB-MRI. Seven patients (three and four patients who had unresectable HCC with or without iso-high intensity in the hepatobiliary phase of EOB-MRI, respectively) underwent genetic analyses. Among these, two (67%, 2/3) who had HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI carried a CTNNB-1 mutation, while all four patients who had HCC without iso-high intensity in the hepatobiliary phase of EOB-MRI did not carry the CTNNB-1 mutation. This study's findings have clinical implications for the detection and treatment of HCC with iso-high intensity in the hepatobiliary phase of EOB-MRI.
• Frequency and Characteristics of Overestimated Renal Function in Japanese Patients with Chronic Liver Disease and Its Relation to Sarcopenia.

  Sonoe Yoshida, Goki Suda, Masatsugu Ohara, Qingjie Fu, Zijian Yang, Shunichi Hosoda, Megumi Kimura, Kubo Akinori, Yoshimasa Tokuchi, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Osamu Maehara, Shunsuke Ohnishi, Naoya Sakamoto

  Nutrients 13 (7) 2021/07/14 

  Renal dysfunction and sarcopenia are important prognostic factors in patients with chronic liver disease (CLD). Muscle atrophy can cause the overestimation of renal function based on serum creatinine. However, the frequency of overestimated renal function in Japanese patients with CLD and its relationship with sarcopenia are unclear. In present study, we evaluated the frequency of overestimated renal function, defined as a >20% higher eGFR using creatinine than using cystatin C, in 307 patients with CLD as well as its relationship with indicators of sarcopenia. In total, 24.8% of patients had overestimated renal function. In a multivariate regression analysis, liver cirrhosis (p = 0.004) and psoas muscle mass index (p = 0.049) were significantly associated with overestimated renal function. Loss of skeletal muscle mass was significantly more frequent in both male and female patients with overestimated renal function than without. In males, the loss of muscle strength and rate of sarcopenia, defined as loss of muscle mass and strength, were significantly higher in patients with than without overestimated renal function. The high frequency of overestimated renal function in Japanese patients suggests that indicators of renal function should be carefully considered; furthermore, monitoring and interventions for both renal function and sarcopenia are needed in patients with CLD.
• Trial protocol: a randomised controlled trial to verify the non-inferiority of a partially covered self-expandable metal stent to an uncovered self-expandable metal stent for biliary drainage during neoadjuvant therapy in patients with pancreatic cancer with obstructive jaundice (PUN-NAC trial).

  Masaki Kuwatani, Kazumichi Kawakubo, Kazuya Sugimori, Hiroyuki Inoue, Hideki Kamada, Hirotoshi Ishiwatari, Shin Kato, Takuji Iwashita, Makoto Yoshida, Shinichi Hashimoto, Masahiro Itonaga, Yusuke Mizukami, Yusuke Nomura, Akio Katanuma, Naoya Sakamoto

  BMJ open 11 (7) e045698  2021/07/08 

  INTRODUCTION: Neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (NAC/NACRT) for resectable/borderline resectable pancreatic cancers was recently performed to improve clinical outcomes and led to good results, although it remains controversial whether NAC/NACRT is beneficial for resectable pancreatic cancer. A few recent studies revealed longer patency and lower cost related to the stent occlusion of a metal stent than those of a plastic stent during NAC/NACRT. It also remains controversial which type of self-expandable metal stent (SEMS) is the most suitable for patients with resectable/borderline resectable pancreatic cancer during NAC/NACRT: an uncovered SEMS (USEMS), a fully covered SEMS (FCSEMS) or a partially covered SEMS (PCSEMS). So far, two randomised controlled trials indicated that a USEMS and an FCSEMS were similar in preoperative stent dysfunction and adverse event rate. Thus, we aimed to verify the non-inferiority of a PCSEMS to a USEMS in this multicentre randomised controlled trial. METHODS AND ANALYSIS: We designed a multicentre randomised controlled trial, for which we will recruit 100 patients with resectable/borderline resectable pancreatic cancer and distal biliary obstruction scheduled for NAC/NACRT from 13 high-volume institutions. Patients will be randomly allocated to the PCSEMS group or USEMS group. The primary outcome measure is the preoperative biliary event rate. Data will be analysed after completion of the study. We will calculate the 95% CIs of the incidence of preoperative biliary events in each group and analyse whether the difference between them is within the non-inferiority margin (10%). ETHICS AND DISSEMINATION: This study has been approved by the institutional review board of Hokkaido University Hospital. The results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000041737; jRCT1012200002.
• 【ガイドライン2020から読み解くNAFLD/NASH】診断 NAFLD/NASHの超音波診断

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 83 (1) 67 - 73 0389-4991 2021/07
• 特集 消化器ステント術のすべて II. 臓器別各論 4. 胆･膵 2)術前胆道ドレナージにおけるステント留置-適応と臨床成績

  桒谷 将城, 永井 孝輔, 平田 甫, 瀧新 悠之介, 古川 龍太郎, 川久保 和道, 坂本 直哉, 平野 聡

  外科 南江堂 83 (8) 917 - 927 0016-593X 2021/07/01
• 【ガイドライン2020から読み解くNAFLD/NASH】診断 NAFLD/NASHの超音波診断

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 83 (1) 67 - 73 0389-4991 2021/07
• Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers.

  Tsuyoshi Takashima, Daiki Taniyama, Naoya Sakamoto, Maika Yasumoto, Ryuichi Asai, Takuya Hattori, Ririno Honma, Pham Quoc Thang, Shoichi Ukai, Ryota Maruyama, Kenji Harada, Kazuya Kuraoka, Kazuaki Tanabe, Atsuo T Sasaki, Hideki Ohdan, Eiichi Morii, Junko Murai, Wataru Yasui

  British journal of cancer 125 (1) 65 - 77 2021/07 

  BACKGROUND: Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC. METHODS: We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids. RESULTS: GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs. CONCLUSIONS: This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.
• FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma.

  Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Taku Shigesawa, Gouki Kanbe, Megumi Kimura, Masaya Sugiyama, Masashi Mizokami, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Naoto Okubo, Shunsuke Ohnishi, Hiroshi Takeda, Naoya Sakamoto

  Cancer biology & therapy 22 (5-6) 372 - 380 2021/06/03 

  Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial-mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.
• Topical Application of Conditioned Medium from Hypoxically Cultured Amnion-Derived Mesenchymal Stem Cells Promotes Wound Healing in Diabetic Mice.

  Hiroko Takahashi, Shunsuke Ohnishi, Yuhei Yamamoto, Toshihiko Hayashi, Naoki Murao, Masayuki Osawa, Taku Maeda, Kosuke Ishikawa, Naoya Sakamoto, Emi Funayama

  Plastic and reconstructive surgery 147 (6) 1342 - 1352 2021/06/01 

  BACKGROUND: Mesenchymal stem cells or their conditioned medium improve chronic wound healing, and their effect is enhanced by hypoxia. Diabetic foot ulcers are chronic wounds characterized by abnormal and delayed healing, which frequently require amputation. The authors evaluated the effect of topical application of conditioned medium from hypoxically cultured amnion-derived mesenchymal stem cells on wound healing in diabetic mice. METHODS: Amnion-derived mesenchymal stem cells were cultured under 21% oxygen to prepare normoxic conditioned medium and under 1% oxygen to prepare hypoxic conditioned medium. Hydrogels containing standard medium, normoxic conditioned medium, or hypoxic conditioned medium were topically applied to excisional wounds of mice with streptozotocin-induced diabetes. Ulcer tissues were harvested on day 9; immunohistochemical and quantitative polymerase chain reaction analyses were performed to analyze angiogenesis, inflammatory cell infiltration, and expression levels of inflammation-related genes. RESULTS: Hypoxic conditioned medium significantly enhanced wound closure, increased capillary density and epithelization, and reduced macrophage infiltration. It also tended to reduce the infiltration of neutrophils and enhance the infiltration of regulatory T cells; it showed a tendency to downregulate the expression of the inflammation-related genes interleukin-1β, interleukin-6, chemokine ligand 1, and chemokine ligand 2. Normoxic conditioned medium exhibited similar effects, although they were of lesser magnitude than those of hypoxic conditioned medium. CONCLUSIONS: Hydrogels containing hypoxically cultured, amnion-derived mesenchymal stem cell conditioned medium accelerated wound healing in diabetic mice by enhancing angiogenesis, accelerating epithelization, and suppressing inflammation. Therefore, topical application of amnion mesenchymal stem cell-derived hypoxic conditioned medium could be a novel treatment for diabetic foot ulcers.
• Prognostic Value and Molecular Landscape of HER2 Low-Expressing Metastatic Colorectal Cancer.

  Masataka Yagisawa, Kentaro Sawada, Yoshiaki Nakamura, Satoshi Fujii, Satoshi Yuki, Yoshito Komatsu, Takayuki Yoshino, Naoya Sakamoto, Hiroya Taniguchi

  Clinical colorectal cancer 20 (2) 113 - 120 2021/06 

  BACKGROUND: The prognostic value and molecular landscape of human epidermal growth factor receptor 2 (HER2) low-expressing (HER2-L) metastatic colorectal cancer (mCRC) remain unclear. PATIENTS AND METHODS: This study enrolled patients with mCRC who had undergone surgical resection of primary tumor. Using the specimen, we evaluated HER2 expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 positivity was defined as follows: HER2 positivity (HER2-Pos) as IHC 3 + or IHC 2+/FISH positive, HER2-L as IHC 2+/FISH negative or IHC 1+, and HER2 negativity (HER2-Neg) as IHC 0+. Gene alterations were determined by next-generation sequencing. RESULTS: Between 2005 and 2015, a total of 370 patients were analyzed, comprising 15 patients (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg disease. The clinicopathologic characteristics among groups had no differences. HER2-L had a significantly higher proportion of coaltered RAS mutation than HER2-Pos (P = .037). With a median follow-up of 101.8 months, HER2-L had a significantly better median overall survival than HER2-Pos (P = .029) (18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 patients harboring wild-type RAS and receiving anti-EGFR antibody therapy, HER2-L had a better median progression-free survival tendency than HER2-Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.1 in HER2-Neg (P = .036). CONCLUSION: HER2-L mCRC showed a better prognosis than HER2-Pos mCRC, and it is similar to HER2-Neg mCRC. Hence, HER2-L mCRC might have different biologic behavior in terms of prognostic value and molecular landscape of mCRC, suggesting the possibility of implementation of HER2-guided clinical development against HER2-expressing mCRC.
• Experiment on endoscopic balloon dilation for esophageal stenosis after endoscopic submucosal dissection in pigs.

  Sayoko Kinowaki, Yuichi Shimizu, Masayoshi Ono, Yang ZiJian, Ikko Tanaka, Yoshihiko Shimoda, Masaki Inoue, Marin Ishikawa, Keiko Yamamoto, Shoko Ono, Shunsuke Ohnishi, Naoya Sakamoto

  Journal of gastroenterology 56 (6) 527 - 536 2021/06 

  BACKGROUND AND AIM: Endoscopic balloon dilation (EBD) is effective for esophageal stenosis caused by ESD. However, an efficient EBD method has not been established. We, therefore, conducted EBD experiments on porcine esophageal stenosis models. METHODS: Study 1: in dilation models (day 22 after ESD), the thickness of the outer muscle layer (as an index of the extension effect) and the area of muscle fiber bundle necrosis in the inner muscle layer (as an index of thermal damage) were evaluated. Study 2: in restenosis models (day 43 after ESD), the thickness of the fibrous plexus (as an index of restenosis) was evaluated. In total, 12 porcine models were created. RESULTS: Study 1: the thickness of the outer muscle layer was 1243 ± 322 μm in surrounding locations and it was 803 ± 145 μm beneath the laceration (p = 0.005). In cases of muscular layer injury, the area of necrosis was 15,500 ± 10400 μm2 in surrounding locations and it was 40,200 ± 12900 μm2 at the laceration site (p < 0.001). Study 2: the thickness of the fibrous plexus was 1359 ± 196 μm in surrounding locations and it was 1322 ± 136 μm2 in the laceration scar site (p = 0.74). CONCLUSION: Since thermal damage persists until the completion of stenosis, EBD in the initial stage should be carefully performed. An extension effect was observed only at the laceration site and it later returned to a status similar to that of surrounding locations. Additional intervention would be required for preventing restenosis.
• A Phase I Trial of Oxaliplatin, Irinotecan, and S-1 Combination Therapy (OX-IRIS) as Chemotherapy for Unresectable Pancreatic Cancer (HGCSG 1403).

  Yasuyuki Kawamoto, Hiroshi Nakatsumi, Kazuaki Harada, Tetsuhito Muranaka, Atsushi Ishiguro, Yoshimitsu Kobayashi, Hideyuki Hayashi, Satoshi Yuki, Kentaro Sawada, Masataka Yagisawa, Shintar Nakano, Naoya Sakamoto, Yoshito Komatsu

  The oncologist 26 (10) e1675-e1682  2021/05/28 

  LESSONS LEARNED: Because S-1 is orally administered, OX-IRIS does not necessitate the continuous infusion of 5-FU and is more convenient. The recommended dose of OX-IRIS was determined to be level - 1 (oxaliplatin, 65 mg/m2 ; irinotecan, 100 mg/m2 ; S-1, 80 mg/m2 ), which has manageable safety and promising anticancer activities. BACKGROUND: OX-IRIS is a new combination therapy of oxaliplatin, irinotecan, and S-1 for unresectable pancreatic ductal adenocarcinoma (PDAC), which may be beneficial because S-1 is administered orally and continuous infusion of 5-fluorouracil (5-FU) is not needed. METHODS: Patients who had not received prior therapy for unresectable PDAC were enrolled. Adenocarcinoma or adenosquamous histology was required. Oxaliplatin and irinotecan were administered on days 1 and 15; S-1 was administered orally twice a day on days 1-14, followed by 14 days of rest (one cycle). Primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: In level 0 (oxaliplatin, 85 mg/m2 ; irinotecan, 100 mg/m2 ; S-1, 80 mg/m2 ), two of five patients experienced DLT. In level - 1 (oxaliplatin, 65 mg/m2 ; irinotecan, 100 mg/m2 ; S-1, 80 mg/m2 ), DLT could not be evaluated in two of eight patients because one cycle was not completed; one of the remaining six patients experienced DLT. Anemia, thrombocytopenia, fatigue, nausea, anorexia, diarrhea, and peripheral sensory neuropathy were seen frequently in levels 0 and - 1. ORR was 30% in levels 0 and - 1. Median progression-free survival and median overall survival were 4.1 months (95% confidence interval [CI], 0.0-8.9 months) and 13.7 months (95% CI, 4.8-22.6 months), respectively. CONCLUSION: MTD of OX-IRIS therapy was estimated to be level 0, and the recommended dose (RD) for future trial was level - 1.
• Comprehensive Glycomic Approach Reveals Novel Low-Molecular-Weight Blood Group-Specific Glycans in Serum and Cerebrospinal Fluid.

  Jun-Ichi Furukawa, Hisatoshi Hanamatsu, Ikuko Yokota, Megumi Hirayama, Tomohiro Ando, Hiroyuki Kobayashi, Shunsuke Ohnishi, Nobuaki Miura, Kazue Okada, Shota Sakai, Kohei Yuyama, Yasuyuki Igarashi, Makoto Ito, Yasuro Shinohara, Naoya Sakamoto

  Journal of proteome research 20 (5) 2812 - 2822 2021/05/07 

  ABO blood antigens on the human red blood cell membrane as well as different cells in various human tissues have been thoroughly studied. Anti-A and -B antibodies of IgM are present in serum/plasma, but blood group-specific glyco-antigens have not been extensively described. In this study, we performed comprehensive and quantitative serum glycomic analyses of various glycoconjugates and free oligosaccharides in all blood groups. Our comprehensive glycomic approach revealed that blood group-specific antigens in serum/plasma are predominantly present on glycosphingolipids on lipoproteins rather than glycoproteins. Expression of the ABO antigens on glycosphingolipids depends not only on blood type but also on secretor status. Blood group-specific glycans in serum/plasma were classified as type I, whereas those on RBCs had different structures including hexose and hexosamine residues. Analysis of free oligosaccharides revealed that low-molecular-weight blood group-specific glycans, commonly containing lacto-N-difucotetraose, were expressed in serum/plasma according to blood group. Furthermore, comprehensive glycomic analysis in human cerebrospinal fluid showed that many kinds of free oligosaccharides were highly expressed, and low-molecular-weight blood group-specific glycans, which existed in plasma from the same individuals, were present. Our findings provide the first evidence for low-molecular-weight blood group-specific glycans in both serum/plasma and cerebrospinal fluid.
• Very urgent endoscopic retrograde cholangiopancreatography is associated with early discharge in patients with non-severe acute cholangitis.

  Ryo Sugiura, Hirohito Naruse, Yoshiya Yamamoto, Kazuteru Hatanaka, Kenji Kinoshita, Satoshi Abiko, Shuichi Miyamoto, Kazuharu Suzuki, Masayuki Higashino, Risako Kohya, Naoya Sakamoto

  Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva 114 (3) 133 - 139 2021/05/05 

  BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a first-line procedure for biliary drainage in patients with acute cholangitis, and no study focused very urgent ERCP within several hours of hospital arrival. We aimed to elucidate the utility of very urgent ERCP for non-severe acute cholangitis. METHODS: This retrospective observational study included patients with non-severe acute cholangitis who underwent ERCP between April 2011 and June 2020 in the study institution. Patients were stratified into three groups based on the time to ERCP after hospital arrival: very urgent (≤3hours), urgent (3-24hours), and elective (>24hours). The primary outcome was length of hospital stay (LOS). RESULTS: In the study cohort of 291 patients, including 168 males (57.7%), with a median age of 76 (interquartile range, 70-83) years, 47, 196, and 48 patients underwent very urgent, urgent, and elective ERCP, respectively. The median LOSs in the very urgent, urgent, and elective groups were 12, 14, and, 15 days, respectively (Kaplan-Meier method). A shorter LOS was associated with earlier ERCP (log-rank trend test, P=0.04). The rates of readmission within 30 days of discharge and adverse events were not significantly different among the three groups. By multivariate analysis, very urgent ERCP was associated with a significantly earlier discharge than urgent and elective ERCP (HR 0.71, P=0.04 and HR 0.47, P<0.01, respectively). In addition, age≥75years, pancreatitis, albumin≤2.8g/dL, and two or more ERCP procedures were associated with significantly longer LOS (HRs <1, P<0.05). CONCLUSIONS: Very urgent ERCP for non-severe acute cholangitis was associated with early discharge.
• Possible reasons for the regrettable results of patency of an inside stent in endoscopic transpapillary biliary stenting.

  Masaki Kuwatani, Kazumichi Kawakubo, Naoya Sakamoto

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 2021/05/04 

  Endoscopic biliary decompression is a minimally invasive procedure for cholestasis since the first endoscopic retrograde cholangiopancreatography-guided biliary stenting performed by Soehendra and Reynders-Frederix. Among the endoscopic biliary decompression, endoscopic transpapillary biliary stenting (EBS), is a mainstream choice and presently has two methods of placement: stenting above the sphincter of Oddi (SO) (suprapapillary) and stenting across the SO (transpapillary). Stent patency is the most important concern for patients, endoscopists and physicians because it can affect both the life prognosis and treatment schedule of patients. Biliary stent occlusion can occur because of several factors. Among them, direct food impaction, biofilm formation, and sludge formation play important roles and are presumed to be theoretically overcome by EBS above the SO. Thus, EBS above the SO is expected to result in a longer patency than EBS across the SO. In the literature, there have been six comparative studies on EBS for distal biliary obstruction in which the stent was placed above or across the SO, including two randomized controlled trials (RCTs) with negative results of stenting above the SO. With respect to EBS for hilar biliary obstruction, there have been no RCTs, whereas four retrospective comparative studies with negative results and four retrospective comparative studies showing positive results of stenting above the SO have been reported. In this review, we focused on EBS above and across the SO, and summarized the positive and negative results of the two types of stenting to promote effective clinical practice and to provide a basis for future studies.
• Recent advances in the treatment of hepatitis C virus infection for special populations and remaining problems.

  Goki Suda, Naoya Sakamoto

  Journal of gastroenterology and hepatology 36 (5) 1152 - 1158 2021/05 

  Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation (LT). The rate of HCV infection is high in patients on hemodialysis and in patients infected with human immunodeficiency virus (HIV). In liver transplant patients with HCV infection, recurrent HCV infection of the transplanted liver is universal and results in rapid liver fibrosis progression. In patients with HCV/HIV coinfection as well, liver fibrosis advances rapidly. Thus, there is an urgent need for prompt HCV infection treatment in these special populations (i.e. HIV/HCV coinfection, HCV infection after LT, and dialysis patients). Interferon (IFN)-based therapy for HCV infection could not achieve a high rate of sustained viral response and could cause severe adverse events in the aforementioned special populations. Direct-acting antivirals (DAAs) have recently been developed, and clinical trials have shown that IFN-free DAA-based therapies are associated with a significantly better safety and therapeutic profile than IFN-based therapies. However, the majority of the initial DAA trials excluded special populations; thus, the efficacy and safety of IFN-free DAA-based therapy in special populations remained to be clearly established. Although recent clinical trials and clinical studies have shown the high efficacy and safety of this therapy even in special populations, several unresolved problems, including emergence of resistance-associated variants after failure to respond to DAAs and HCC occurrence after DAA therapy, still exist. Hence, in this review, we discuss the recent advances in anti-HCV therapy for special populations and the remaining problems regarding this therapy.
• Changes in the estimated renal function after hepatitis C virus eradication with direct-acting antiviral agents: Impact of changes in skeletal muscle mass.

  Yoshimasa Tokuchi, Goki Suda, Megumi Kimura, Osamu Maehara, Takashi Kitagataya, Masatsugu Ohara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Journal of viral hepatitis 28 (5) 755 - 763 2021/05 

  Hepatitis C virus (HCV) infection can cause renal dysfunction, expected to improve upon HCV eradication. However, adverse effects of HCV eradication using direct-acting antiviral agents (DAAs) on renal function have been recently reported. This retrospective study aimed to evaluate renal function with glomerular filtration rate (eGFR) estimated using creatinine (eGFRcre) and cystatin C (eGFRcys). Complete clinical information and preserved serum samples were collected from 207 patients with HCV infection treated with interferon-free DAA at baseline and SVR48 (SVR48). Patients who underwent paired computed tomography (CT) at baseline and ≥12 months after DAA were evaluated for changes in skeletal muscle mass using the psoas muscle mass index (PMI). eGFRcre significantly worsened at SVR48, while eGFRcys was similar at baseline and SVR48. At baseline, eGFRcre was significantly higher than eGFRcys; eGFRcre and eGFRcys were similar at SVR48. Multivariate analysis revealed that the presence of liver cirrhosis and low-albumin level, as well as cirrhosis and age, was significantly associated with the overestimation of renal function by eGFRcre at baseline and SVR48, respectively. In the 57 patients who underwent paired CT at baseline and ≥12 months after DAA, relative values of PMI significantly increased after DAA. After DAA, in patients with increased PMI (65% 37/57), eGFRcre significantly worsened but did not change in patients without increased PMI. eGFRcre significantly worsened after DAAs; however, this might not reflect accurate changes in renal function, partially because of changes in skeletal muscle mass. eGFRcys did not change after DAAs, and it is a potential alternative to eGFRcre.
• Applicability of APRI and FIB-4 as a transition indicator of liver fibrosis in patients with chronic viral hepatitis.

  Jun Itakura, Masayuki Kurosaki, Hiroko Setoyama, Tetsuro Simakami, Noriko Oza, Masaaki Korenaga, Motohiko Tanaka, Takuji Torimura, Naoya Sakamoto, Nobuyuki Enomoto, Yoshiyuki Ueno, Norifumi Kawada, Shuichi Kaneko, Shuhei Nishiguchi, Kazuaki Chayama, Junko Tanaka, Namiki Izumi, Tatsuya Kanto

  Journal of gastroenterology 56 (5) 470 - 478 2021/05 

  BACKGROUND AND AIMS: The usefulness of APRI or FIB-4 is well established as a non-invasive liver fibrosis marker at a point of diagnosis in patients with chronic liver disease. However, their applicability for the monitoring of progression of liver fibrosis over time is yet to be determined. We aimed to clarify the feasibility of APRI and FIB-4 for the longitudinal evaluation of liver fibrosis in patients with chronic hepatitis B and C. METHODS: This is a multi-center retrospective and prospective cohort study, enrolling 1029 patients with HCV and 384 patients with HBV who were histologically diagnosed by liver biopsy. The observation period of retrospective and prospective study was 14 and 12 years, respectively. The APRI and FIB-4 were traced back in cases of histologically diagnosed cirrhosis, and those were prospectively analyzed after biopsy in cases diagnosed as F3 of METAVIR score, respectively. RESULTS: The averaged APRI and FIB-4 exhibited time-dependent increase in the retrospective study of hepatitis C patients (increase by 0.09/year in APRI and 0.29/year in FIB-4). In the prospective study of untreated hepatitis C patients, such increases were 0.14/year in APRI and 0.40/year in FIB-4, respectively. Neither the average of APRI nor FIB-4 showed a specific tendency with hepatitis B patients and treatment-experienced hepatitis C patients. CONCLUSION: The APRI and FIB-4 may serve as a transition indicator of liver fibrosis in anti-viral treatment-naïve patients with chronic hepatitis C.
• Spiral stent placement for bile leakage after hepatobiliary surgery.

  Yunosuke Takishin, Masaki Kuwatani, Naoya Sakamoto

  Endoscopy 2021/04/28
• Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C.

  Naoki Kawagishi, Goki Suda, Megumi Kimura, Osamu Maehara, Ren Yamada, Yoshimasa Tokuchi, Akinori Kubo, Takashi Kitagataya, Taku Shigesawa, Kazuharu Suzuki, Masatsugu Ohara, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Yusuke Kudo, Mutsumi Nishida, Naoya Sakamoto

  Scientific reports 11 (1) 9207 - 9207 2021/04/28 

  We previously revealed that Angiopoietin-2 (Ang2) predicts non-regression of liver fibrosis based on liver stiffness measurement (LSM) at 24 weeks after anti-hepatitis C virus (HCV) treatment. In this study, we extended the observational period to 96 weeks to investigate the factors associated with non-regression after treatment with direct-acting-antivirals (DAAs). Patients treated with DAAs who underwent transient elastography at baseline and 24 and 96 weeks after DAA therapy were included. Baseline and post-treatment serum Ang2 levels were measured. Liver fibrosis stages were defined based on LSM. Multivariate regression was used to evaluate factors associated with non-regression of liver fibrosis between various time points. In total, 110 patients were included. Of these, 11% showed non-regression of LSM-based fibrosis stage at 96 weeks after DAA therapy. In multivariate analysis, advanced liver fibrosis stage and high baseline Ang2 levels were significantly associated with non-regression at 96 weeks. In patients with advanced liver fibrosis (F3/4), baseline Ang2 levels were associated with non-regression of liver fibrosis stage. Between SVR24 and SVR96, post-treatment Ang2 levels and controlled attenuation parameter values at SVR24 were significantly associated with non-regression of liver fibrosis stage in patients with F3/4. Thus, serum Ang2 levels are an important target for monitoring and therapy.
• Successful treatment by on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in patients with diffuse large B-cell lymphoma: a case report.

  Machiko Umemura, Goki Suda, Shihori Tsukamoto, Ko Ebata, Shinjiro Takahash, Takashi Sasaki, Sae Nakajima, Koji Hirata, Mariko Ozasa, Masatoshi Takano, Masaki Katagiri, Naoya Sakamoto

  BMC infectious diseases 21 (1) 389 - 389 2021/04/27 

  BACKGROUND: In patients with hepatitis C virus (HCV) and malignant lymphoma, hepatitis C flare during R-CHOP can result in discontinuation of treatment. However, appropriate therapeutic strategies for managing hepatitis C flare during R-CHOP have not been established, and this issue is complicated by conflicting results regarding the use of direct-acting antivirals in patients with uncontrolled malignancies. CASE PRESENTATION: We report the first case of effective and safe treatment with on-demand 8-week glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in a patient with diffuse large B-cell lymphoma (DLBCL). The patient completed five additional courses of R-CHOP without hepatic toxicity. A complete response of DLBCL and a sustained virological response were observed at 24 weeks after glecaprevir and pibrentasvir completion. CONCLUSION: On-demand, direct-acting antivirals could be a novel strategy for managing hepatitis C flare during R-CHOP.
• Chronic Diarrhea as the Presenting Feature of Amyloidosis with Multiple Myeloma: A Case Report Diagnosed by a Myocardial Biopsy.

  Shinsuke Otagiri, Sae Nakajima, Takehiko Katsurada, Kensuke Sakurai, Kana Yamanashi, Takahide Ara, Emi Takakuwa, Tomoko Mitsuhashi, Naoya Sakamoto

  Internal medicine (Tokyo, Japan) 60 (8) 1197 - 1203 2021/04/15 

  A 73-year-old woman with a history of diarrhea for one year and other various symptoms was admitted to our hospital. Gastrointestinal endoscopy that included enteroscopy with multiple biopsies was performed. However, no significant findings were observed. Electrocardiography showed low voltage in all limb leads, and an echocardiogram showed thickened cardiac walls with granular sparkling pattern. A myocardial biopsy revealed amyloidosis, and a bone marrow biopsy showed multiple myeloma. This case suggests that we should suspect the possibility of amyloidosis in a patient with diarrhea and various symptoms involving multiple organ systems. Additionally, electrocardiograms and echocardiograms should be performed even when gastrointestinal biopsies reveal negative results.
• Asymptomatic Choledocholithiasis that Causes a Dilemma between Treatment and Observation.

  Masaki Kuwatani, Naoya Sakamoto

  JMA journal 4 (2) 176 - 177 2021/04/15
• IL28B遺伝子多型の発見から臨床応用 : 臨床応用

  須田 剛生, 小川 浩司, 坂本 直哉

  Kanzo 一般社団法人 日本肝臓学会 62 (4) 209 - 211 0451-4203 2021/04/01 [Not refereed]
  
• 【実地医家のためのNAFLD/NASH診療のポイント】実地医家のためのNAFLD/NASH診療のポイント 我が国における脂肪性肝疾患(NAFLD/NASH)の現状

  坂本 直哉, 森川 賢一

  Vita (株)ビー・エム・エル 38 (2) 2 - 7 0915-1028 2021/04
• H.pylori除菌後異時性胃癌症例の臨床病理学的特徴

  田中 一光, 小野 尚子, 坂本 直哉, 西村 友佑, 久保 茉理奈, 霜田 佳彦, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 清水 勇一

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 63 (Suppl.1) 894 - 894 0387-1207 2021/04
• IBD診療における超音波の有用性 免疫チェックポイント阻害薬誘発性大腸炎における体外式超音波検査の有用性

  桜井 健介, 西田 睦, 表原 里実, 小田切 信介, 長島 一哲, 桂田 武彦, 小松 嘉人, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 48 (Suppl.) S306 - S306 1346-1176 2021/04
• 肝疾患移行期医療の現状と問題点 フォンタン術後肝合併症の現状と5年経過からみえてくること

  荘 拓也, 森川 賢一, 坂本 直哉

  肝臓 (一社)日本肝臓学会 62 (Suppl.1) A167 - A167 0451-4203 2021/04
• 部分的脾動脈塞栓術(PSE)、バルーン閉塞下逆行性経静脈的塞栓術(B-RTO)の肝予備能、線維化マーカー、予後への影響

  中井 正人, 小川 浩司, 坂本 直哉, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 重沢 拓, 荘 拓也, 須田 剛生, 森川 賢一

  肝臓 (一社)日本肝臓学会 62 (Suppl.1) A332 - A332 0451-4203 2021/04
• 肝疾患患者における筋肉量の経時変化の評価はBIA法に比べCT画像を用いた方法が有用である

  大原 正嗣, 須田 剛生, 重沢 拓, 鈴木 和治, 中村 晃久, 川岸 直樹, 中井 正人, 荘 拓也, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 62 (Suppl.1) A335 - A335 0451-4203 2021/04
• Endoscopic ultrasonography-guided pancreaticoduodenostomy with a lumen-apposing metal stent to treat main pancreatic duct dilatation.

  Masaki Kuwatani, Kosuke Nagai, Yunosuke Takishin, Ryutaro Furukawa, Hajime Hirata, Kazumichi Kawakubo, Naoya Sakamoto

  Endoscopy 2021/03/30
• Serum fatty acid-binding protein 5 is a significant factor in hepatocellular carcinoma progression independent of tissue expression level.

  Masafumi Ohira, Hideki Yokoo, Koji Ogawa, Moto Fukai, Toshiya Kamiyama, Naoya Sakamoto, Akinobu Taketomi

  Carcinogenesis 42 (6) 794 - 803 2021/03/23 

  Fatty acid-binding protein 5 (FABP5) is highly expressed in hepatocellular carcinoma (HCC) tissues and is related to HCC progression. In this study, we analyzed the potential of serum FABP5 (sFABP5) as a tumor marker in HCC and its clinical significance in HCC progression. We compared the sFABP5 concentration in patients with HCC (HCC group) with that of patients with hepatitis without HCC (hepatitis group). Moreover, we measured the FABP5 expression levels in resected HCC tissues (tFABP5) and analyzed their relationship with sFABP5. We also performed cell-based assays using FABP5 knockout and overexpressing HCC cell lines to analyze the effect of extrinsic FABP5 on HCC cells. We showed that sFABP5 was not a useful tumor marker for HCC, as HCC and sFABP5 were not correlated. However, sFABP5 and tFABP5 significantly correlated with survival after surgery for HCC, while sFABP5 and tFABP5 were independent of each other. In cell-based assays, extrinsic FABP5 was taken up by HCC cell lines and positively affected cell survival under glucose-depleted conditions by complementing the endogenous FABP5 function. In conclusion, sFABP5 had a significant impact on HCC progression irrespective of tFABP5 by augmenting cell viability under glucose-depleted conditions. As tFABP5 and sFABP5 are important factors that are independent of each other in HCC progression, both of them should be considered independently in improving the prognosis of patients with HCC.
• Angiogenic Dreaded Killer: Cholesterol Crystal Embolization.

  Masaki Kuwatani, Naoya Sakamoto

  Internal medicine (Tokyo, Japan) 60 (6) 825 - 826 2021/03/15
• Endoscopic Papillectomy for Adenocarcinoma at the Duodenal Papilla- Will it Still Open a Pandora's Box?

  Kuwatani Masaki, Sakamoto Naoya

  Internal medicine (Tokyo, Japan) 60 (16) 2523 - 2524 2021/03/15
• A spontaneous rupture of lung metastasis from hepatocellular carcinoma after the introduction of lenvatinib.

  Masayuki Higashino, Ryo Sugiura, Yoshiya Yamamoto, Hirohito Naruse, Naoya Sakamoto

  Journal of gastrointestinal and liver diseases : JGLD 30 (1) 169 - 170 2021/03/13
• 著明な隆起を伴った下咽頭上皮内癌の一例

  西村 友佑, 清水 勇一, 久保 茉理奈, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 小野 尚子, 三橋 智子, 鈴木 崇祥, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 128回・122回 47 - 47 2021/03
• 若年発症した食道間葉系腫瘍の1例

  霜田 佳彦, 山本 桂子, 西村 友佑, 久保 茉理奈, 田中 一光, 井上 雅貴, 木脇 佐代子, 大野 正芳, 小野 尚子, 清水 勇一, 村上 壮一, 三橋 智子, 岡田 宏美, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 128回・122回 48 - 48 2021/03
• 胆嚢転移を来した原発性肝細胞癌再発の1例

  得地 祐匡, 須田 剛生, 久保 彰則, 北潟谷 隆, 山田 錬, 重沢 拓, 中井 正人, 荘 拓也, 小川 浩司, 森川 賢一, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 128回・122回 57 - 57 2021/03
• 経過観察中に増大傾向がみられ、肝切除術に至った肝原発神経内分泌腫瘍の1例

  久保 彰則, 小川 浩司, 得地 祐匡, 山田 錬, 北潟谷 隆, 重沢 拓, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 128回・122回 58 - 58 2021/03
• 肝機能障害を契機に診断された肝ヘモクロマトーシスの一例

  吉田 苑永, 中井 正人, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 重沢 拓, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 128回・122回 67 - 67 2021/03
• KHDRBS3 promotes multi-drug resistance and anchorage-independent growth in colorectal cancer.

  Shoichi Ukai, Naoya Sakamoto, Daiki Taniyama, Kenji Harada, Ririno Honma, Ryota Maruyama, Kazuhito Naka, Takao Hinoi, Yuji Takakura, Wataru Shimizu, Hideki Ohdan, Wataru Yasui

  Cancer science 112 (3) 1196 - 1208 2021/03 

  5-Fluorouracil (5-FU) is one of the most frequently used pharmacological agents in the treatment of colorectal cancer (CRC). Resistance to chemotherapy is a major cause of treatment failure of CRC, and it is a well known fact that cancer stem cells play a significant role in the acquisition of drug resistance. In this study, we focused on the KHDRBS3 gene that encodes KH RNA Binding Domain Containing, Signal Transduction Associated 3. We first clarified the relationship between KHDRBS3 and 5-FU resistance. We then observed higher expression levels of KHDRBS3 in KRAS-mutant organoids and cell lines in comparison with KRAS wild-type organoids and cell lines. Immunohistochemical analysis using CRC cases revealed that the prognosis of KHDRBS3-positive patients was significantly worse compared with that of KHDRBS3-negative patients. Univariate and multivariate Cox proportional hazards analyses showed that KHDRBS3 was an independent prognostic factor in patients with CRC. We determined that KHDRBS3 might play a crucial role in the acquisition of stem cell properties, such as drug resistance and spheroid/organoid formation, by regulating CD44 variant expression and the Wnt signaling pathway. In an immunodeficient mouse model, KHDRBS3-positive cells showed efficient tumor formation and formed metastatic lesions in the lungs. These results indicated that KHDRBS3 plays a crucial role in drug resistance and anchorage-independent growth by maintaining stem cell-like features in CRC cells. KHDRBS3 could be a promising candidate marker for predicting chemotherapeutic effect and prognosis in CRC patients.
• Optical effect of spraying l-menthol on gastric intestinal metaplasia visualized by linked color imaging.

  Shoko Ono, Yoshihiko Shimoda, Ikko Tanaka, Sayoko Kinowaki, Masaki Inoue, Masayoshi Ono, Keiko Yamamoto, Yuichi Shimizu, Naoya Sakamoto

  European journal of gastroenterology & hepatology 33 (3) 358 - 363 2021/03/01 

  OBJECTIVE: Linked color imaging (LCI) enables noninvasive detection of gastric intestinal metaplasia (GIM) as a lavender color sign (LCS), and there has been a recent report that l-menthol enhanced GIM with LCI. We measured color values of GIM and surrounding mucosa with white light imaging (WLI), LCI and LCI after spraying l-menthol (Mint-LCI) and investigated the effect of l-menthol on gastric mucosa. METHODS: Endoscopic images of the antrum with WLI, LCI and Mint-LCI from 18 patients were prepared. Each of six regions of interest (three points of GIM and three points of surrounding mucosa) was selected for each modality, and CIE1976 (L*a*b*) color space was used to measure the color values. The primary endpoint was color differences (ΔE) between GIM and surrounding mucosa in each modality. RESULTS: For surrounding mucosa, the mean a* value with Mint-LCI was significantly higher than the mean values with WLI and LCI (P < 0.01). The mean b* value of GIM with LCI was significantly lower than that of surrounding mucosa, and spraying l-menthol decreased the b* values of GIM with a change to a deeper lavender color (LCI: 10.0 ± 5.8, Mint-LCI: 3.7 ± 6.1, P < 0.01). However, there was no significant difference in mean ΔE values between LCI and Mint LCI (LCI: 21.1 ± 6.6, Mint-LCI: 22.7 ± 5.4, NS). After spraying l-menthol, the microstructure of GIM changed to translucent and microvessels were obscured. CONCLUSIONS: As shown by LCI, spraying l-menthol optically enhances the color of GIM in the antrum.
• Efficacy of a novel ultra-sharp dilation device for dilating bare metal stent mesh in patients with hilar malignant biliary obstruction.

  Shin Kato, Masaki Kuwatani, Kazumichi Kawakubo, Ryutaro Furukawa, Koji Hirata, Yunosuke Takishin, Hajime Hirata, Naoya Sakamoto

  Scandinavian journal of gastroenterology 56 (3) 374 - 377 2021/03 

  The placement of additional stents in patients with hilar malignant biliary obstruction can be challenging when a metal stent already exists because occasionally, the catheter and delivery system of the additional stent cannot pass through the mesh of the formerly placed stent. We studied ten consecutive patients with hilar malignant biliary obstruction who underwent mesh dilation using a novel ultra-sharp dilation device (ES dilator) to assess the efficacy and safety of the ES dilator for mesh dilation. Mesh dilation using the ES dilator was successful in eight patients (8/10; 80.0%), which was the same rate as that of patients with pre-dilation using a Soehendra biliary dilation catheter (4/5, 80.0%) and patients without pre-dilation (4/5, 80.0%). In the two patients with dilation failure, the angle of the hilar bile duct branch was too steep to permit the passage of a stiff dilation device. Nonetheless, stent placement was uncomplicated in all mesh-dilated patients (8/8, 100.0%), and no adverse events related to the ES dilator were observed. The efficacy of an ultra-sharp dilation device appears promising for metallic stent mesh dilation, especially in patients where conventional methods are unsuccessful. However, additional data are necessary to confirm our findings.
• Crohn's Disease Activity Evaluation by Transabdominal Ultrasonography: Correlation with Double-Balloon Endoscopy.

  Kana Yamanashi, Takehiko Katsurada, Mutsumi Nishida, Reizo Onishi, Satomi Omotehara, Shinsuke Otagiri, Kensuke Sakurai, Kazunori Nagashima, Kenji Kinoshita, Ryo Takagi, Naoya Sakamoto

  Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine 2021/02/17 

  OBJECTIVES: Transabdominal ultrasonography (US) has been reported as a useful tool for evaluating Crohn's disease (CD) activity. Endoscopic findings and Crohn's disease activity index (CDAI) are currently considered the gold standard for assessing CD activity. We assessed the correlation between US and double-balloon endoscopy (DBE), and CDAI for evaluating CD activity. METHODS: We analyzed patients with CD undergoing US and DBE within 10 days between the procedures. The intestine was divided into four segments and analyzed by the US scoring system (US-CD) and the simple endoscopic score for Crohn's disease (SES-CD). CDAI was compared with US-CD and SES-CD. Spearman's rank correlation coefficient was used for statistical analysis. RESULTS: Twenty-five patients with CD (11 women, 14 men; mean age 35.4 ± 14.9 years, range 16-65 years) were enrolled. Twenty-four patients received antitumor necrosis factor inhibitor therapy. CDAI was 128.1 (range 36-227). A significant moderate correlation was found between the US-CD and SES-CD in all segments (ρ = .64, P < .01). The US-CD showed a strong correlation with CDAI (ρ = .78, P < .01), whereas the SES-CD showed a moderate correlation (ρ = .55, P < .05). CONCLUSIONS: US-CD and SES-CD showed a moderate correlation for assessing CD activity. US-CD showed a stronger correlation with CDAI than SES-CD, suggesting that US could more accurately evaluate the disease activity.
• Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling.

  Taku Shigesawa, Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Megumi Kimura, Tomoe Shimazaki, Koji Yamamoto, Ren Yamada, Takashi Kitagataya, Akihisa Nakamura, Kazuharu Suzuki, Masatsugu Ohara, Naoki Kawagishi, Machiko Umemura, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Masaya Sugiyama, Masashi Mizokami, Hiroshi Takeda, Naoya Sakamoto

  Carcinogenesis 42 (1) 58 - 69 2021/02/11 [Refereed][Not invited]
   

  In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1-4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.
• Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection.

  Kazuharu Suzuki, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Akinobu Nakamura, Hideaki Miyoshi, Megumi Kimura, Osamu Maehara, Ren Yamada, Takashi Kitagataya, Koji Yamamoto, Taku Shigesawa, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  Journal of gastroenterology 56 (2) 168 - 180 2021/02 

  BACKGROUND: Entecavir and tenofovir-disoproxil-fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. METHODS: A retrospective study was performed on HBV patients administered entecavir or tenofovir-disoproxil-fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6-12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir-disoproxil-fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. RESULTS: Administration of tenofovir-disoproxil-fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir-disoproxil-fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir-disoproxil-fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir-disoproxil-fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir-disoproxil-fumarate on CD36. CONCLUSIONS: Tenofovir-disoproxil-fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA.
• Near-infrared photoimmunotherapy (NIR-PIT) on cholangiocarcinoma using a novel catheter device with light emitting diodes.

  Hajime Hirata, Masaki Kuwatani, Kohei Nakajima, Yuki Kodama, Yasuo Yoshikawa, Mikako Ogawa, Naoya Sakamoto

  Cancer science 112 (2) 828 - 838 2021/02 

  Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy for cancers that uses NIR light and antibody-photosensitizer (IR700) conjugates. However, it is difficult to deliver NIR light into the bile duct for cholangiocarcinoma (CCA) from the conventional extracorporeal apparatus. Thus, in this study, we developed a dedicated catheter with light emitting diodes (LEDs) that supersedes conventional external irradiation devices; we investigated the therapeutic effect of NIR-PIT for CCA using the novel catheter. The new catheter was designed to be placed in the bile duct and a temperature sensor was attached to the tip of the catheter to avoid thermal burn. An anti-epidermal growth factor receptor (EGFR) antibody, Panitumumab-IR700 conjugate or anti-human epidermal growth factor receptor type 2 (HER2) antibody, Trastuzumab-IR700 conjugate, was used with EGFR- or HER2-expressing cell lines, respectively. The in vitro efficacy of NIR-PIT was confirmed in cultured cells; the capability of the new catheter for NIR-PIT was then tested in a mouse tumor model. NIR-PIT via the developed catheter treated CCA xenografts in mice. NIR-PIT had an effect in Panitumumab-IR700 conjugate- and Trastuzumab-IR700 conjugate-treated CCA cells that depended on the receptor expression level. Tumor growth was significantly suppressed in mice treated with NIR-PIT using the novel catheter compared with controls (P < .01). NIR-PIT was an effective treatment for EGFR- and HER2-expressing CCA cells, and the novel catheter with mounted LEDs was useful for NIR-PIT of CCA.
• Effectiveness of administering zinc acetate hydrate to patients with inflammatory bowel disease and zinc deficiency: a retrospective observational two-center study.

  Kensuke Sakurai, Shigeru Furukawa, Takehiko Katsurada, Shinsuke Otagiri, Kana Yamanashi, Kazunori Nagashima, Reizo Onishi, Keiji Yagisawa, Haruto Nishimura, Takahiro Ito, Atsuo Maemoto, Naoya Sakamoto

  Intestinal research 2021/01/22 

  Background/Aims: Inflammatory bowel disease (IBD) patients frequently have zinc deficiency. IBD patients with zinc deficiency have higher risks of IBD-related hospitalization, complications, and requiring surgery. This study aimed to examine the effectiveness of zinc acetate hydrate (ZAH; Nobelzin) in IBD patients with zinc deficiency. Methods: IBD patients with zinc deficiency who received ZAH from March 2017 to April 2020 were registered in this two-center, retrospective, observational study. Changes in serum zinc levels and disease activity (Crohn's Disease Activity Index [CDAI]) before and after ZAH administration were analyzed. Results: Fifty-one patients with Crohn's disease (CD, n = 40) or ulcerative colitis (UC, n = 11) were registered. Median serum zinc level and median CDAI scores significantly improved (55.5-91.0 μg/dL, P< 0.001; 171.5-129, P< 0.001, respectively) in CD patients 4 weeks after starting ZAH administration. Similarly, median serum zinc levels and CDAI scores significantly improved (57.0-81.0 μg/dL, P< 0.001; 177-148, P= 0.012, respectively) 20 weeks after starting ZAH administration. Similar investigations were conducted in groups where no treatment change, other than ZAH administration, was implemented; significant improvements were observed in both serum zinc level and CDAI scores. Median serum zinc levels in UC patients 4 weeks after starting ZAH administration significantly improved from 63.0 to 94.0 μg/dL (P= 0.002), but no significant changes in disease activity were observed. One patient experienced side effects of abdominal discomfort and nausea. Conclusions: ZAH administration is effective in improving zinc deficiency and may contribute to improving disease activity in IBD.
• Effectiveness of red dichromatic imaging for dissection of the submucosal layer when hematoma is encountered.

  Shuichi Miyamoto, Tomohiko R Ohya, Kaori Nishi, Satoshi Abiko, Ryo Sugiura, Yoshiya Yamamoto, Naoya Sakamoto

  Endoscopy 53 (11) E413-E414  2021/01/14
• 【肝・胆道系症候群(第3版)-その他の肝・胆道系疾患を含めて-肝臓編(上)】血行異常 肝内動静脈短絡(A-V shunt)

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  日本臨床 (株)日本臨床社 別冊 (肝・胆道系症候群I) 303 - 306 0047-1852 2021/01
• Triple-loop clip for the traction-assisted colorectal endoscopic submucosal dissection: multidirectional triple-loop traction method.

  Shuichi Miyamoto, Tomohiko R Ohya, Masayoshi Ono, Naoya Sakamoto

  VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy 6 (1) 1 - 3 2021/01
• Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma.

  Taku Shigesawa, Goki Suda, Megumi Kimura, Osamu Maehara, Yoshimasa Tokuchi, Akinori Kubo, Ren Yamada, Ken Furuya, Masaru Baba, Takashi Kitagataya, Kazuharu Suzuki, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  PloS one 16 (3) e0247728  2021 

  A deteriorated liver functional reserve during systemic therapy for unresectable hepatocellular carcinoma (HCC) causes poor patient outcomes. We aimed to identify predictive factors associated with the deterioration of Child-Pugh score at 8 weeks after lenvatinib initiation. Patients with adequate clinical data and baseline preserved serum samples available were included. Baseline fibroblast growth factor (FGF)19 and 21, angiopoietin (ANG)2, and vascular endothelial growth factor (VEGF) levels were evaluated. Thirty-seven patients were included, and 6, 15, 14, and 2 experienced complete response, partial response, stable disease, and progressive disease, respectively. Twenty-four (65%) and 13 (35%) patients showed a maintained/improved and deteriorated Child-Pugh-score, respectively. While baseline clinical data, treatment response, and laboratory data were similar between these two patient groups, baseline ANG2 and VEGF levels were significantly higher (P = 0.0017) and lower (P = 0.0231), respectively, in patients with deteriorated Child-Pugh score than in those without. Based on receiver operating characteristic curve analysis, cut-off values for ANG2 and VEGF were found to be 3,108 pg/mL and 514.9 pg/mL, respectively. Among patients with low VEGF and high ANG2, 89% (8/9) exhibited a deteriorated Child-Pugh score, whereas none of the patients (0/9) with high VEGF and low ANG2 did. The deterioration of the Child-Pugh score in patients with unresectable HCC who are treated with lenvatinib may be predictable based on combined baseline serum ANG2 and VEGF levels.
• Red dichromatic imaging helps in detecting exposed blood vessels in gastric ulcer induced by endoscopic submucosal dissection.

  Shuichi Miyamoto, Ryo Sugiura, Satoshi Abiko, Kazuteru Hatanaka, Yoshiya Yamamoto, Hirohito Naruse, Naoya Sakamoto

  Endoscopy 53 (11) E403-E404  2020/12/17
• Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell.

  Shoichi Ukai, Ririno Honma, Naoya Sakamoto, Yusuke Yamamoto, Quoc Thang Pham, Kenji Harada, Tsuyoshi Takashima, Daiki Taniyama, Ryuichi Asai, Kaho Fukada, Kazuhito Naka, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui

  Oncogene 39 (50) 7265 - 7278 2020/12 

  5-FU is one of the key drugs in the treatment of gastric cancer (GC). Much evidence has shown that cancer stem cells (CSCs) play a key role in the acquisition of drug resistance. The organoid is a novel 3D cell culture system technology that sustains stem-cell-driven formation of near-physiological, self-renewing tissues using specific niche factors in a dish. In this study, we established GC organoids (GCOs) and gradually treated them with higher concentrations of 5-FU. We successfully harvested four 5-FU-resistant GCOs, which were supported by significant changes in the expression of molecules related to 5-FU metabolism. We then performed microarray analysis using three normal gastric organoids and three pairs of 5-FU-resistant and parental GCOs. Through the comparison of expression profiles and further validation, we chose KHDRBS3 as a target gene. We found KHDRBS3 to be an independent prognostic factor in GC patients, especially in GC patients treated with 5-FU chemotherapy. We also determined that KHDRBS3 might play an important role in the acquisition of stem cell-like features, such as multi-drug resistance and organoid formation, by regulating CD44 variant expression. We found KHDRBS3, which is thought to play an important role in the acquisition of characteristics of CSCs in GC, to be a promising candidate marker for predicting therapeutic effect and prognosis in GC patients.
• Durable response without recurrence to Tolvaptan improves long-term survival.

  Masato Nakai, Goki Suda, Akinori Kubo, Yoshimasa Tokuchi, Takashi Kitagataya, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Naoki Kawagishi, Masatsugu Ohara, Machiko Umemura, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Journal of gastroenterology 55 (12) 1150 - 1161 2020/12 

  BACKGROUND: Decompensated liver cirrhosis patients with refractory ascites or pleural effusion have a poor prognosis. Tolvaptan has been used for treating water retention associated with cirrhosis. However, despite the short-term response, water retention recurrence is still observed in some cases. This study aimed to clarify the water retention recurrence rate and the relationship between long-term response without recurrence and prognosis. METHODS: Altogether, 100 patients with decompensated cirrhosis treated with tolvaptan were retrospectively analyzed. Recurrence was evaluated according to the criteria of the EASL clinical practice guideline. The recurrence rate and prognosis of non-responders, patients with recurrence, and long-term responders were analyzed. The baseline factors related to short-term response, recurrence, and long-term response were also evaluated. RESULTS: Approximately 31.0% of the short-term responders had recurrence. Although there was no significant difference in the prognosis by short-term response (p = 0.07), the long-term responders had a significantly better prognosis than those with recurrence and non-responders (p < 0.01). Low CRP levels and high urinary Na/K ratios were significant factors related to short-term response, and the presence of acute kidney injury was also a factor related to non-response. The low CRP level (relapse: < 1.10 mg/dl, long-term response: < 0.94 mg/dl) was identified as a factor related to recurrence and long-term response. CONCLUSION: The long-term responders without recurrence had a significantly better prognosis. CRP was a useful predictor for long-term response, whereas renal function parameters were useful predictors for short-term response. Inflammation control may be important for long-term response and prognosis in cirrhosis patients with water retention.
• Digital PCR-based plasma cell-free DNA mutation analysis for early-stage pancreatic tumor diagnosis and surveillance.

  Tetsuhiro Okada, Yusuke Mizukami, Yusuke Ono, Hiroki Sato, Akihiro Hayashi, Hidemasa Kawabata, Kazuya Koizumi, Sakue Masuda, Shinichi Teshima, Kuniyuki Takahashi, Akio Katanuma, Yuko Omori, Hirotoshi Iwano, Masataka Yamada, Tomoki Yokochi, Shingo Asahara, Kazumichi Kawakubo, Masaki Kuwatani, Naoya Sakamoto, Katsuro Enomoto, Takuma Goto, Junpei Sasajima, Mikihiro Fujiya, Jun Ueda, Seiji Matsumoto, Kenzui Taniue, Ayumu Sugitani, Hidenori Karasaki, Toshikatsu Okumura

  Journal of gastroenterology 55 (12) 1183 - 1193 2020/12 

  BACKGROUND: Cell-free DNA (cfDNA) shed from tumors into the circulation offers a tool for cancer detection. Here, we evaluated the feasibility of cfDNA measurement and utility of digital PCR (dPCR)-based assays, which reduce subsampling error, for diagnosing pancreatic ductal adenocarcinoma (PDA) and surveillance of intraductal papillary mucinous neoplasm (IPMN). METHODS: We collected plasma from seven institutions for cfDNA measurements. Hot-spot mutations in KRAS and GNAS in the cfDNA from patients with PDA (n = 96), undergoing surveillance for IPMN (n = 112), and normal controls (n = 76) were evaluated using pre-amplification dPCR. RESULTS: Upon Qubit measurement and copy number assessment of hemoglobin-subunit (HBB) and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in plasma cfDNA, HBB offered the best resolution between patients with PDA relative to healthy subjects [area under the curve (AUC) 0.862], whereas MT-ND1 revealed significant differences between IPMN and controls (AUC 0.851). DPCR utilizing pre-amplification cfDNA afforded accurate tumor-derived mutant KRAS detection in plasma in resectable PDA (AUC 0.861-0.876) and improved post-resection recurrence prediction [hazard ratio (HR) 3.179, 95% confidence interval (CI) 1.025-9.859] over that for the marker CA19-9 (HR 1.464; 95% CI 0.674-3.181). Capturing KRAS and GNAS could also provide genetic evidence in patients with IPMN-associated PDA and undergoing pancreatic surveillance. CONCLUSIONS: Plasma cfDNA quantification by distinct measurements is useful to predict tumor burden. Through appropriate methods, dPCR-mediated mutation detection in patients with localized PDA and IPMN likely to progress to invasive carcinoma is feasible and complements conventional biomarkers.
• Immune checkpoint inhibitor-induced enteritis assessed using capsule endoscopy.

  Shinsuke Otagiri, Takehiko Katsurada, Kana Yamanashi, Kensuke Sakurai, Michiko T Sato, Jun Sakakibara-Konishi, Naoya Sakamoto

  JGH open : an open access journal of gastroenterology and hepatology 4 (6) 1231 - 1232 2020/12 

  We performed capsule endoscopy for a patient with immune checkpoint inhibitor-induced enteritis and found multiple erosions or small ulcers in the small intestine. No reports demonstrated the effectiveness of capsule endoscopy for immune checkpoint inhibitor-induced gastrointestinal adverse events, and our case suggests that capsule endoscopy may be useful to evaluate immune checkpoint inhibitor-induced enteritis.
• クローン病活動性評価の超音波検査とダブルバルーン内視鏡検査との相関の検討

  山梨 香菜, 桂田 武彦, 西田 睦, 大西 礼造, 表原 里実, 桜井 健介, 小田切 信介, 木下 賢治, 長島 一哲, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 47 (Suppl.) S317 - S317 1346-1176 2020/11
• 【肝細胞癌治療のパラダイムチェンジ-進化する薬物療法2020 Update Part II-(分子標的治療)】カボザンチニブ CELESTIAL試験の総括とサブ解析

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 81 (5) 986 - 992 0389-4991 2020/11
• Synchronous multiple needle tract seedings of the gastric wall after EUS-guided fine-needle biopsy for pancreatic cancer.

  Shuhei Hayasaka, Ryo Sugiura, Yoshiya Yamamoto, Hirohito Naruse, Naoya Sakamoto

  Gastrointestinal endoscopy 92 (5) 1126 - 1127 2020/11
• Risk factors for dysfunction of preoperative endoscopic biliary drainage for malignant hilar biliary obstruction.

  Ryo Sugiura, Masaki Kuwatani, Shin Kato, Kazumichi Kawakubo, Hirofumi Kamachi, Akinobu Taketomi, Takehiro Noji, Keisuke Okamura, Satoshi Hirano, Naoya Sakamoto

  Journal of hepato-biliary-pancreatic sciences 27 (11) 851 - 859 2020/11 [Refereed][Not invited]
   

  BACKGROUND: Few studies have focused on the risk factors for dysfunction of endoscopic biliary drainage (EBD) in preoperative patients with malignant hilar biliary obstruction (MHBO). METHODS: We searched the database between February 2011 and December 2018 and identified patients with MHBO who underwent radical operation. The rate of dysfunction of the initial EBD, risk factors for dysfunction of the initial EBD and survival after surgery were retrospectively evaluated. RESULTS: We analyzed a total of 131 patients [95 males (72.5%); mean age, 69.5 (±7.3) years; Bismuth-Corlette classification (BC) I/II/IIIa/IIIb/IV, 50/26/22/17/16; hilar cholangiocarcinoma/gall bladder cancer, 115/16]. Dysfunction of the initial EBD occurred in 28 patients (21.4%). The cumulative incidences of dysfunction of the initial EBD in all patients were 18.4%, 38.2% and 47.0% at 30, 60 and 90 days, respectively (Kaplan-Meier method). The rate of dysfunction of the initial EBD increased in patients with BC-IV (P = .03). Multivariate analysis showed that BC-IV and pre-EBD cholangitis were significantly associated with the occurrence of dysfunction of the initial EBD. Survival rates were not significantly different according to the initial biliary drainage methods and presence/absence of the initial EBD dysfunction. CONCLUSIONS: Dysfunction of the initial EBD frequently occurs in patients with the BC-IV and those with pre-EBD cholangitis.
• Relationships of early esophageal cancer with human papillomavirus and alcohol metabolism.

  Masaki Inoue, Yuichi Shimizu, Marin Ishikawa, Satoshi Abiko, Yoshihiko Shimoda, Ikko Tanaka, Sayoko Kinowaki, Masayoshi Ono, Keiko Yamamoto, Shoko Ono, Naoya Sakamoto

  World journal of gastroenterology 26 (39) 6047 - 6056 2020/10/21 

  BACKGROUND: It is well known that an alcohol consumption habit together with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2) is an important risk factor for the development of esophageal squamous cell carcinoma (ESCC). It remains controversial whether human papillomavirus (HPV) infection contributes to the occurrence/development of ESCC. There has been no study in which the relationship between ESCC and HPV in addition to alcohol dehydrogenase-1B (ADH1B) and ALDH2 genotypes was evaluated. AIM: To evaluate relationships between HPV infection and development of esophageal cancer, particularly early esophageal cancer, based on ADH1B/ALDH2 polymorphisms. METHODS: We conducted an exploratory retrospective study using new specimens, and we enrolled 145 patients who underwent endoscopic resection for superficial ESCC and had been observed for more than two years by both physical examination and endoscopic examination in Hokkaido University Hospital. Saliva was collected to analyze genetic polymorphisms of ADH1B/ALDH2. We performed in situ hybridization for resected specimens to detect HPV by using an HPV type 16/18 probe. RESULTS: HPV was detected in 15 (10.3%) of the 145 patients with ESCC. HPV-positive rates in inactive ALDH2*1/*2 and ALDH2*1/*1 + *2/*2 were 10.8% and 9.8%, respectively (P = 1.00). HPV-positive rates in slow-metabolizing ADH1B*1/*1 and ADH1B*1/*2 + *2/*2 were 12.0% and 10.0%, respectively (P = 0.72). HPV-positive rates in the heavy or moderate alcohol consumption group and the light or rare consumption group were 11.1% and 8.7%, respectively (P = 0.68). HPV-positive rates in the heavy smoking group and the light or no smoking group were 11.8% and 8.3%, respectively (P = 0.59). The 3-year incidence rates of secondary ESCC or head and neck cancer after initial treatment in the HPV-positive and HPV-negative groups were 14.4% and 21.4% (P = 0.22), respectively. CONCLUSION: In the present situation, HPV status is considered to be less important than other risk factors, such as alcohol consumption, smoking habit, ADH1B/ALDH2 polymorphisms, and HPV status would therefore have no effect on ESCC risk management.
• In vivo optical cellular diagnosis for uterine cervical or vaginal intraepithelial neoplasia using flexible gastrointestinal endocytoscopy -a prospective pilot study.

  Shoko Ono, Ayako Nozaki, Kana Matsuda, Emi Takakuwa, Naoya Sakamoto, Hidemichi Watari

  BMC cancer 20 (1) 955 - 955 2020/10/02 

  BACKGROUUND: For patients with any kind of atypical squamous intraepithelial lesion of the uterine cervix or vagina, colposcopy and punch biopsy are common procedures for histological determination following cytology. However, colposcopy-guided biopsy does not provide a high level of diagnostic accuracy. The aim of this study was to determine the usefulness of optical biopsy in vivo using endocytoscopy compared with conventional procedures using colposcopy. METHODS: Between May 2018 and March 2019, patients who were scheduled for cervical conization or mapping biopsies of the vagina were prospectively enrolled. Endocytoscopy was performed by senior endoscopists prior to scheduled procedures, and endocytoscopic images and biopsy samples were taken from the most prominent site and surrounding area of the cervical or vaginal lesions. The collection process of images was randomized and anonymous, and three doctors separately evaluated the images according to the ECA classification. ECA 4 and 5 are indicative of endoscopic malignancy. The primary endpoint was diagnostic accuracy (benign or malignant: cervical intraepithelial neoplasia (CIN) 3 or vaginal intraepithelial neoplasia (VAIN) 3 or worse) of cell images at the most prominent site in each patient. RESULTS: A total of 28 consecutive patients were enrolled. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of endocytoscopic images were 95.0% (84.8-98.6%), 87.5% (61.9-96.5%), 95.0% (84.8-98.6%), 87.5% (61.9-96.5%) and 92.9% (78.2-98.0%), respectively. Inter-observer agreement among three reviewers was 0.78 (0.08-9.88, P < 0.01). On the other hand, the accuracy of colposcopy-guided biopsy was 74.1% (64.0-84.0%). CONCLUSIONS: Optical cell diagnosis of cervical or vaginal intraepithelial neoplasia using endocytoscopy provides a high level of diagnostic accuracy. TRIAL REGISTRATION: The study was registered with the UMIN database (ID: 000031712 ). UMIN000031712 . Registered 16 March 2017.
• 主膵管多発狭窄を呈した膵管上皮内病変の1例

  佐々木 貴志, 桑谷 将城, 三橋 智子, 浅野 賢道, 中村 透, 平野 聡, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 68 - 68 2020/10
• 慢性関節リウマチに対する免疫抑制療法中に重篤な小腸出血を来した1例

  田中 一光, 小野 尚子, 西村 友佑, 久保 茉理奈, 霜田 佳彦, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 清水 勇一, 坂本 直哉, 市川 伸樹, 吉田 雅, 本間 重紀, 杉野 弘和, 岡田 宏美

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 60 - 60 2020/10
• 高度貧血の原因となった胃の過形成性ポリープに対し、プロトンポンプ阻害薬の内服中止が著効した1例

  西村 友佑, 久保 茉理奈, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 小野 尚子, 清水 勇一, 清水 亜衣, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 53 - 53 2020/10
• 高度貧血をきたした回腸Pyogenic granulomaに対しEMRを施行した1例

  張 辛寒, 小野 尚子, 西村 友佑, 久保 茉理奈, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 清水 勇一, 清水 亜衣, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 60 - 60 2020/10
• 炎症性腸疾患に対する腹部超音波検査の有用性

  桂田 武彦, 小田切 信介, 桜井 健介, 木下 賢治, 山梨 香菜, 大西 礼造, 長島 一哲, 西田 睦, 表原 里実, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 48 - 48 2020/10
• Oxaliplatinによる類洞閉塞症候群の診断における腹部超音波検査の有用性の検討

  斎藤 里佳, 西田 睦, 岩井 孝仁, 菊池 穏香, 吉野 裕紀, 横田 勲, 高木 諒, 川本 泰之, 山村 貴洋, 伊藤 憲, 中野 真太郎, 原田 一顕, 結城 敏志, 小松 嘉人, 坂本 直哉

  日本癌治療学会学術集会抄録集 58回 P - 178 2020/10
• 消化管間質腫瘍(GIST)におけるレゴラフェニブ治療と骨格筋量の変化に関する検討

  伊藤 憲, 原田 一顕, 川本 泰之, 中積 宏之, 中野 真太郎, 斎藤 里佳, 山村 貴洋, 結城 敏志, 小松 嘉人, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 62 - 62 2020/10
• 消化器癌の化学療法で味覚異常を発症した症例の多施設共同医師主導前向き観察研究

  伊藤 憲, 結城 敏志, 中積 宏之, 安藤 孝将, 太宰 昌佳, 畑中 一映, 宮城島 拓人, 久居 弘幸, 石黒 敦, 植田 亮, 佐々木 尚英, 進藤 吉明, 坂本 直哉, 坂田 優, 小松 嘉人

  日本癌治療学会学術集会抄録集 58回 P - 180 2020/10
• 当院における門脈血栓症に対するアンチトロンビンIII製剤の使用成績

  北潟谷 隆, 小川 浩司, 山田 錬, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 44 - 44 2020/10
• ソホスブビル/ベルパタスビル投与によりSVR12が得られたC型非代償性肝硬変の1例

  山田 錬, 小川 浩司, 北潟谷 隆, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 127回・121回 45 - 45 2020/10
• 超音波内視鏡下瘻孔形成術における先端鋭拡張専用カテーテルと通電拡張カテーテルの有用性の比較

  加藤 新, 桑谷 将城, 平田 甫, 瀧新 悠之介, 平田 幸司, 古川 龍太郎, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2172 - 2172 0387-1207 2020/10
• 【肝細胞癌治療のパラダイムチェンジ-進化する薬物療法2020 Update Part I-(免疫療法)】免疫チェックポイント阻害剤による単剤治療 進行肝細胞癌に対するニボルマブ第III相試験(CheckMate 459試験)のUpdate results

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝胆膵 (株)アークメディア 81 (4) 651 - 657 0389-4991 2020/10
• 肝性脳症〜わが国における現状と課題〜 肝性脳症の疫学

  中井 正人, 小川 浩司, 久保 彰則, 得地 祐匡, 北潟谷 隆, 山田 錬, 重沢 拓, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  日本門脈圧亢進症学会雑誌 (一社)日本門脈圧亢進症学会 26 (3) 75 - 75 1344-8447 2020/10
• 子宮頸部・腟上皮内腫瘍における生体内細胞観察の診断能に関する検討 超拡大内視鏡は有用か

  小野 尚子, 松田 可奈, 石川 麻倫, 大野 正芳, 木脇 佐代子, 霜田 佳彦, 田中 一行, 井上 雅貴, 山本 桂子, 清水 勇一, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2165 - 2165 0387-1207 2020/10
• 食道ESD中の鎮静薬と塩酸ペチジン併用の後ろ向き検討

  大野 正芳, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 石川 麻倫, 山本 桂子, 小野 尚子, 清水 勇一, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.2) 2199 - 2199 0387-1207 2020/10
• Impact of single-heterozygous UGT1A1 on the clinical outcomes of irinotecan monotherapy after fluoropyrimidine and platinum-based combination therapy for gastric cancer: a multicenter retrospective study.

  Shintaro Nakano, Satoshi Yuki, Yasuyuki Kawamoto, Hiroshi Nakatsumi, Takayuki Ando, Shinya Kajiura, Ayumu Yoshikawa, Kazuaki Harada, Kazuteru Hatanaka, Aya Tanimoto, Atsushi Ishiguro, Takuya Honda, Masayoshi Dazai, Takahide Sasaki, Naoya Sakamoto, Yoshito Komatsu

  International journal of clinical oncology 25 (10) 1800 - 1806 2020/10 

  BACKGROUND: It is unclear whether the UGT1A1 status, single heterozygous (SH) or wild type (WT), is associated with the efficacy and toxicity of irinotecan monotherapy in advanced gastric cancer (AGC). We investigated the association between clinical outcomes (efficacy and safety) and UGT1A1 status in patients who received irinotecan monotherapy. METHODS: We evaluated AGC patients who received irinotecan monotherapy between January 2011 and December 2017. Efficacy was assessed according to overall survival (OS) and progression-free survival (PFS). Toxicity was graded using the Common Toxicity Criteria for Adverse Events (version 4.0). RESULTS: A total of 100 patients were evaluated (62 and 38 patients with UGT1A1 WT and SH, respectively). In the WT and SH groups, the irinotecan dose was reduced in 19 (30.6%) and 18 (47.2%) patients (p = 0.135), respectively; treatment was delayed due to adverse events (AEs) in 19 (30.6%) and 13 (34.2%) patients (p = 0.826), respectively; the median PFS was 3.15 and 3.25 months (HR, 0.734; 95% CI 0.465-1.158; p = 0.184), respectively; and the median OS was 10.4 and 7.26 months (HR, 1.137; 95% CI 0.752-1.721; p = 0.543), respectively. Severe hematological AEs (Grade ≥ 3) were significantly more frequent in the SH group than in the WT group (63% vs. 36%; p = 0.008), while severe non-hematological AEs was not significantly different (16.0% vs. 6.5%; p = 0.173). CONCLUSION: There was no significant difference in the efficacy of irinotecan monotherapy between UGT1A1 WT and UGT1A1 SH, but UGT1A1 SH was associated with a high frequency of severe hematological toxicity.
• Time-dependent changes in the seroprevalence of COVID-19 in asymptomatic liver disease outpatients in an area in Japan undergoing a second wave of COVID-19.

  Goki Suda, Koji Ogawa, Megumi Kimura, Osamu Maehara, Takashi Kitagataya, Masatsugu Ohara, Yoshimasa Tokuchi, Akinori Kubo, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 50 (10) 1196 - 1200 2020/10 

  AIM: Coronavirus disease 2019 (COVID-19) is a serious public health concern, with unclarified prevalence in Japan. Concomitant liver disease could increase the severity of COVID-19 disease, and chronic liver disease patients sometimes require frequent admission and gastrointestinal endoscopy. Thus, clarifying the prevalence of asymptomatic COVID-19 in outpatients with liver disease is essential for preventing nosocomial infections. We aimed to clarify the time-dependent changes in COVID-19 seroprevalence in liver disease outpatients, who were asymptomatic for COVID-19, in an area of Japan experiencing a second wave of COVID-19. METHODS: We included the preserved sera of 100, 300, and 300 consecutive liver disease outpatients, who were asymptomatic for COVID-19, from May 2019, March 2020, and May 2020, respectively. The sera were analyzed immunochromatographically to detect immunoglobulin G against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (KURABO) and by Elecsys Anti-SARS-CoV-2-assay (Roche Diagnostics). RESULTS: Analysis of 100 cases from May 2019, before COVID-19 became pandemic, revealed that the specificity of immunochromatographic tests and Elecsys were 98% (95% confidence interval [CI], 93-99.8%) and 100% (95% CI, 97-100%), respectively. Analysis of 300 cases from March 2020 revealed a seroprevalence of 0.3% (1/300; 95% CI, 0-1.8%) for COVID-19 by Elecsys Anti-SARS-CoV-2 assay. Analysis of 300 cases from May 2020 revealed a seroprevalence of 0% (0/300; 95% CI, 0-1.0%). CONCLUSIONS: The Elecsys Anti-SARS-CoV-2 assay has high specificity. The cumulative seroprevalence of COVID-19 by the Elecsys Anti-SARS-CoV-2 assay in outpatients with liver disease in Sapporo, who were asymptomatic for COVID-19, was 0.17% (1/600; 95% CI, 0.0-0.9%) until May 2020.
• Baseline angiopoietin-2 and FGF19 levels predict treatment response in patients receiving multikinase inhibitors for hepatocellular carcinoma.

  Taku Shigesawa, Goki Suda, Megumi Kimura, Tomoe Shimazaki, Osamu Maehara, Ren Yamada, Takashi Kitagataya, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  JGH open : an open access journal of gastroenterology and hepatology 4 (5) 880 - 888 2397-9070 2020/10 [Refereed][Not invited]
   

  Background: Sorafenib and lenvatinib are first-line systemic therapies for unresectable hepatocellular carcinoma (HCC). However, the criteria for their selection remain unclear. Methods: We identified patients with unresectable HCC who were treated with sorafenib or lenvatinib between August 2009 and January 2019 at the Hokkaido University Hospital. Patients who continued treatment for >2 months, underwent evaluation by computed tomography every 2-3 months, and had complete clinical data were included. Responders were patients with objective response (OR) for lenvatinib and patients with stable disease (SD) exceeding 6 months (long-SD) or OR for sorafenib. The predictive factors for treatment response, including fibroblast growth factor (FGF)19 and 21, angiopoietin 2 (ANG2), hepatocyte growth factor, and vascular endothelial growth factor, were evaluated. Results: Overall, 27 and 29 patients treated with lenvatinib and sorafenib, respectively, were included. The responders for lenvatinib and sorafenib were 63% (17/27) and 38% (11/29), respectively. No significant predictive factors for treatment response were identified in patients treated with sorafenib. However, baseline serum FGF19 and ANG2 levels were significantly associated with treatment response to lenvatinib. All (9/9) patients with low baseline ANG2 and FGF19 levels who received lenvatinib achieved OR. Conversely, the OR was low (13%; 1/9) in patients with high baseline ANG2 and FGF19 levels. Responder rate was 40% (2/5) in patients with high baseline ANG2 and FGF19 levels who received sorafenib. Conclusion: This study is, to our knowledge, the first to demonstrate that baseline ANG2 and FGF19 levels may aid in selecting optimal systemic therapy for patients with unresectable HCC.
• Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.

  Takashi Kitagataya, Goki Suda, Kazunori Nagashima, Takehiko Katsurada, Koji Yamamoto, Megumi Kimura, Osamu Maehara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Yoshito Komatsu, Hiroo Hata, Satoshi Takeuchi, Takashige Abe, Jun Sakakibara-Konishi, Takanori Teshima, Akihiro Homma, Naoya Sakamoto

  Journal of gastroenterology and hepatology 35 (10) 1782 - 1788 2020/10 [Refereed][Not invited]
   

  BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.
• Association between the use of antibiotics and efficacy of gemcitabine plus nab-paclitaxel in advanced pancreatic cancer.

  Shintaro Nakano, Yoshito Komatsu, Yasuyuki Kawamoto, Rika Saito, Ken Ito, Hiroshi Nakatsumi, Satoshi Yuki, Naoya Sakamoto

  Medicine 99 (39) e22250  2020/09/25 

  It is unclear whether the use of antibiotics is related to the efficacy of gemcitabine plus nab-paclitaxel (GnP). Therefore, we investigated the association between the use of antibiotics and efficacy of GnP.We conducted a retrospective single center study from January 2014 to December 2018 in Hokkaido University Hospital.Ninety-nine patients were eligible for the study. Thirty-seven used antibiotics (U) and 62 did not use antibiotics (NU) during GnP therapy. In the U group, 15 patients used β-lactam antibiotics, 21 used new quinolones, and 1 used carbapenem. The median progression-free survival was 5.8 and 2.7 months (hazards ratio [HR] .602, 95% confidence interval [CI] .391-.928, P = .022) and the median overall survival was 11.0 and 8.4 months (HR .768, 95% CI .491-1.202, P = .248) in the U and not use antibiotics groups, respectively. Antibiotic use (HR .489, 95% CI .287-.832, P = .008) and locally advanced pancreatic cancer (HR 1.808, 95% CI 1.051-3.112, P = .032) were independent prognostic factors for progression-free survival.Antibiotic use was associated with a higher efficacy of GnP, and therefore, it may be employed as a novel treatment strategy.
• HCC既往の無いC型肝炎SVR後の初発肝発癌の囲い込み因子としての肝弾性度の有用性

  中井 正人, 山本 義也, 馬場 英, 古家 乾, 北潟谷 隆, 山田 錬, 重沢 拓, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.2) A682 - A682 0451-4203 2020/09
• 免疫チェックポイント阻害剤関連肝炎の頻度、予測因子、臨床経過の検討

  北潟谷 隆, 須田 剛生, 中井 正人, 荘 拓也, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.2) A705 - A705 0451-4203 2020/09
• Clip with thread attachment prior to incision - new strategy for traction-assisted esophageal endoscopic submucosal dissection.

  Shuichi Miyamoto, Tomohiko R Ohya, Masayuki Higashino, Kazuteru Hatanaka, Yoshiya Yamamoto, Hirohito Naruse, Naoya Sakamoto

  Endoscopy 52 (9) E328-E329  2020/09
• Treatment of hepatocellular carcinoma during the COVID-19 outbreak: The Working Group report of JAMTT-HCC.

  Masatoshi Kudo, Masayuki Kurosaki, Masafumi Ikeda, Hiroshi Aikata, Atsushi Hiraoka, Takuji Torimura, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 50 (9) 1004 - 1014 2020/09 

  This contingency guide was formulated on the premise that delivering standard treatment for hepatocellular carcinoma (HCC) has come under strain due to the coronavirus (COVID-19) pandemic. Measures required are likely to vary largely across regions and individual institutions, depending on the level of the strain imposed by the pandemic (e.g., number of inpatients infected with COVID-19 and the availability of resources, including personal protective equipment and inpatient beds). In addition, models suggest that the second and third waves of COVID-19 will occur before effective vaccines and medicines become widely available in Japan (expected time, 2-3 years). This guide should serve as a good reference for best practices in the management of HCC, which is in light of the possible risk of impending collapse of the healthcare system due to a surge in COVID-19 infections.
• Plasma Lipid Profiling of Three Types of Drug-Induced Liver Injury in Japanese Patients: A Preliminary Study.

  Kosuke Saito, Tatehiro Kagawa, Keiji Tsuji, Yuji Kumagai, Ken Sato, Shotaro Sakisaka, Naoya Sakamoto, Mitsuhiko Aiso, Shunji Hirose, Nami Mori, Rieko Tanaka, Toshio Uraoka, Kazuhide Takata, Koji Ogawa, Kazuhiko Mori, Motonobu Sato, Takayoshi Nishiya, Kazuhiko Takamatsu, Noriaki Arakawa, Takashi Izumi, Yasuo Ohno, Yoshiro Saito, Hajime Takikawa

  Metabolites 10 (9) 2020/08/31 

  Drug-induced liver injury (DILI) is a major adverse event caused by drug treatment, which can be categorized into three types: hepatocellular, mixed, and cholestatic. Although nearly every class of drugs can cause DILI, an overall understanding of lipid profiles in DILI patients is lacking. We used lipidomics to analyze the plasma lipid profiles of patients to understand their hepatic pathophysiology and identify DILI biomarkers. We identified 463 lipids and compared their levels between the acute and recovery phases of the three types of DILI patients. Mixed and cholestatic types demonstrated specific plasma lipid alterations between the phases, but the hepatocellular type did not. Moreover, as specific indicators of mixed-type DILI, levels of several ceramides increased in the acute phase, while those of arachidonic acid-containing ether-linked phosphoglycerolipids decreased. In contrast, as specific indicators of cholestatic-type DILI, levels of palmitic acid-containing saturated or monounsaturated phosphatidylcholines increased in the acute phase, while those of arachidonic acid- or docosahexaenoic acid-containing ether-linked phosphoglycerolipids and phosphatidylinositols decreased. We also identified lipids with a relatively high capacity to discriminate the acute phase from the recovery phase and healthy subjects. These findings may help with understanding the pathophysiology of different DILI types and identify candidate biomarkers.
• 難渋する胆道ドレナージの工夫 肝門部胆管金属ステント留置困難症例におけるES dilatorの有用性(Eligible cases of stent-in-stent placement for malignant hilar biliary obstructions in consideration of endoscopic reintervention)

  滝新 悠之介, 桑谷 将城, 坂本 直哉, 古川 龍太郎, 平田 甫, 平田 幸司, 加藤 新

  胆道 34 (3) 452 - 452 0914-0077 2020/08
• 乳頭膨張型胆管癌と術前診断された胆管上皮内癌の一例

  古川 龍太郎, 桑谷 将城, 三橋 智子, 平田 甫, 瀧新 悠之介, 平田 幸司, 加藤 新, 平野 聡, 坂本 直哉

  胆道 日本胆道学会 34 (3) 528 - 528 0914-0077 2020/08
• 肝門部金属ステント留置困難例でのESダイレーターを用いたトラブルシューティング

  加藤 新, 桑谷 将城, 坂本 直哉, 平田 甫, 瀧新 悠之介, 平田 幸司, 古川 龍太郎

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.1) 1234 - 1234 0387-1207 2020/08
• 膵周囲液体貯留に対する超音波内視鏡下ドレナージの有効性と安全性

  古川 龍太郎, 桑谷 将城, 坂本 直哉, 平田 甫, 瀧新 悠之介, 平田 幸司, 加藤 新

  Gastroenterological Endoscopy 62 (Suppl.1) 1312 - 1312 0387-1207 2020/08
• 高齢者食道ESDの治療成績と予後解析

  霜田 佳彦, 清水 勇一, 坂本 直哉, 石川 麻倫, 田中 一光, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 小野 尚子

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.1) 1216 - 1216 0387-1207 2020/08
• 生体ブタ全周性食道ESD施行後のバルーン拡張時の病理組織学的検討

  木脇 佐代子, 清水 勇一, 大西 俊介, 大野 正芳, 楊 子健, 霜田 佳彦, 井上 雅貴, 田中 一光, 石川 麻倫, 山本 桂子, 小野 尚子, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 62 (Suppl.1) 1320 - 1320 0387-1207 2020/08
• Acute progressing hepatic angiosarcoma: An autopsy case report.

  Masaki Inoue, Mio Matsumoto, Yusuke Sakuhara, Yasunari Takakuwa, Shinji Yoshii, Nobuaki Akakura, Naoya Sakamoto

  Radiology case reports 15 (8) 1403 - 1407 2020/08 

  A man in his 50s presented with pitting edema of both lower legs and abdominal distension as his chief complaint. His personal medical history and family history were unremarkable, except that he was a heavy drinker consuming 66 g of alcohol per day and a heavy smoker. Blood tests upon admission showed slight hepatic dysfunction, thrombocytopenia, jaundice, hypoalbuminemia, and decreased coagulability. Tumor marker tests showed elevated levels of CA19-9 and PIVKA-II. Contrast-enhanced computed tomography revealed enhancement of multiple masses predominantly in the right lobe of the liver in the early phase, followed by diffuse enhancement of the entire liver in the delayed phase. Hepatic arteriography demonstrated large hemangioma-like lesions corresponding to the masses revealed by computed tomography. That findings seemed to be cotton wool appearance. On magnetic resonance images, there were multiple mass-like lesions that showed homogeneous or heterogeneous low signal intensity on T1-weighted images, and clearly high signal intensity on T2-weighted images. The findings were atypical and no definite diagnosis could be made. Hepatic failure then rapidly worsened, and the patient died on hospital day 20. Autopsy led to the diagnosis of hepatic angiosarcoma.
• Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria.

  Takuya Sho, Goki Suda, Koji Ogawa, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Jun Ito, Yoshiya Yamamoto, Tomoe Kobayashi, Takashi Meguro, Akiyoshi Saga, Takuto Miyagishima, Katsumi Terasita, Tomofumi Takagi, Toshiya Kamiyama, Akinobu Taketomi, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 50 (8) 966 - 977 2020/08 [Refereed][Not invited]
   

  AIM: This study aimed to determine the efficacy and safety of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC) who did not meet REFLECT eligibility criteria (phase 3 clinical trial). METHODS: In this multicenter retrospective study, patients with unresectable HCC treated with lenvatinib between 2018 and 2019 and had adequate clinical data were included. Objective response rate, progression-free-survival (PFS) and safety were evaluated according to meeting or not meeting the REFLECT eligibility criteria and according to the criteria of the REFLECT trial. RESULTS: Of the 105 patients included, 61% (64 of 105) did not meet the REFLECT eligibility criteria. Safety and median PFS of lenvatinib were similar between the patients who did and those who did not meet the criteria. Among the patients who did not meet the criteria, 28, 27, 14, six, seven and five had a history of tyrosine kinase inhibitor (TKI) treatment, Child-Pugh score B, HCC in ≥50% of the liver, reduced platelet count, bile duct invasion and main portal vein invasion, respectively. The efficacy and safety of lenvatinib for patients with or without Child-Pugh-score B or HCC in ≥50% of the liver were similar. Although treatment outcome was not significantly different, patients with TKI treatment history tended to have longer median PFS, whereas those with main portal vein invasion tended to have shorter median PFS. CONCLUSION: Lenvatinib was effective for patients who did not meet the REFLECT inclusion criteria. However, the treatment outcome may vary according to several factors, such as a history of TKI treatment and tumor invasion.
• Computed tomography, not bioelectrical impedance analysis, is the proper method for evaluating changes in skeletal muscle mass in liver disease

  Masatsugu Ohara, Goki Suda, Megumi Kimura, Osamu Maehara, Tomoe Shimazaki, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  JCSM Rapid Communications 3 (2) 103 - 114 2617-1619 2020/07
• 進行肝細胞癌に対するREFLECT内/外におけるレンバチニブの治療効果と安全性の検討

  荘 拓也, 須田 剛生, 北潟谷 隆, 山田 錬, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A253 - A253 0446-6586 2020/07
• 部分的脾動脈塞栓術(PSE)により肝予備能は改善するか

  中井 正人, 小川 浩司, 北潟谷 隆, 山田 錬, 鈴木 和治, 中村 晃久, 梅村 真知子, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A367 - A367 0446-6586 2020/07
• 慢性膵炎による主膵管高度狭窄に対する経乳頭的通電拡張術の有効性

  加藤 新, 桑谷 将城, 平田 甫, 瀧新 悠之介, 平田 幸司, 古川 龍太郎, 坂本 直哉

  膵臓 (一社)日本膵臓学会 35 (3) A326 - A326 0913-0071 2020/07
• IgG4関連硬化性胆管炎の臨床的特徴とステロイド維持療法の妥当性

  瀧新 悠之介, 桑谷 将城, 古川 龍太郎, 平田 甫, 平田 幸司, 加藤 新, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A297 - A297 0446-6586 2020/07
• Helicobacter pylori除菌後SM浸潤癌の臨床病理学的特徴

  山本 桂子, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 石川 麻倫, 大野 正芳, 小野 尚子, 清水 勇一, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A306 - A306 0446-6586 2020/07
• 大腸EMRにおける抗凝固薬服用者の周術期管理と出血リスク

  田中 一光, 小野 尚子, 霜田 佳彦, 井上 雅貴, 木脇 佐代子, 石川 麻倫, 大野 正芳, 山本 桂子, 清水 勇一, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 117 (臨増総会) A361 - A361 0446-6586 2020/07
• Side-by-side placement of fully covered self-expandable metal stents for malignant distal biliary obstruction.

  Koji Hirata, Masaki Kuwatani, Hajime Hirata, Ryo Sugiura, Shin Kato, Naoya Sakamoto

  Clinical journal of gastroenterology 13 (3) 455 - 458 2020/06 

  A covered self-expandable metal stent is an efficient and established tool for solution of biliary obstruction. The use of multiple fully covered self-expandable metal stents (SEMSs) for distal malignant biliary obstruction has never been reported. The first case, a 33-year-old female with pancreatic head cancer had low bifurcation of the hepatic ducts and developed obstructive cholangitis by the first single SEMS. The second case, a-59-year-old female with pancreatic head cancer repeatedly underwent biliary decompression by a single SEMS (10-mm, 12-mm), because placed SEMSs were repeatedly dislocated. For solving these problems, we performed side-by-side placement of covered self-expandable metal stents. Finally, side-by-side placement of SEMSs across the papilla for distal malignant biliary obstruction was feasible and available for the two cases.
• High serum angiopoietin-2 level predicts non-regression of liver stiffness measurement-based liver fibrosis stage after direct-acting antiviral therapy for hepatitis C.

  Naoki Kawagishi, Goki Suda, Megumi Kimura, Osamu Maehara, Tomoe Shimazaki, Ren Yamada, Takashi Kitagataya, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Yusuke Kudo, Mutsumi Nishida, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 50 (6) 671 - 681 2020/06 [Refereed][Not invited]
   

  AIM: Factors associated with improvement of liver fibrosis after successful hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting antiviral agents (DAAs) have been not clarified well. Angiopoietin-2 (Ang2) is reported to be associated with vascular leak and inflammation observed in patients with advanced liver fibrosis. METHODS: In this retrospective study, patients treated with IFN-free DAAs who underwent transient elastography before and at 24-weeks post-treatment and achieved sustained viral response were enrolled. Baseline serum Ang2 was measured, and its relationship with other clinical factors was analyzed. Liver fibrosis stage was defined based on liver stiffness according to a previous report. Predictive factors for regression of liver fibrosis stage after DAA therapy were evaluated. RESULTS: Overall, 116 patients were analyzed. Baseline serum Ang2 levels were significantly associated with liver stiffness, spleen index, and liver stiffness-based liver fibrosis stage. Moreover, 75% of patients experienced regression of liver fibrosis stage after DAA therapy. Multivariate analysis revealed that advanced liver fibrosis stage and Ang2 levels were significantly associated with regression of liver fibrosis stage after DAA therapy. In patients with advanced liver fibrosis (F3/4), baseline Ang2 level alone could predict regression of liver fibrosis stage. A baseline Ang2 cut-off value (354 pg/ML) could predict regression of liver fibrosis stage after DAA therapy with high accuracy (sensitivity 0.882, specificity 0.733). CONCLUSIONS: Evaluation of serum Ang2 levels before DAA therapy is important. Our results provide a novel mechanistic insight into non-regression of liver stiffness after DAA therapy. Long-term and larger studies are required.
• Analysis of the optimal psoas muscle mass index cut-off values, as measured by computed tomography, for the diagnosis of loss of skeletal muscle mass in Japanese people.

  Masatsugu Ohara, Goki Suda, Megumi Kimura, Osamu Maehara, Tomoe Shimazaki, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Tomoe Kobayashi, Minoru Uebayashi, Ryo Takagi, Isao Yokota, Tsuyoshi Shimamura, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 50 (6) 715 - 725 2020/06 [Refereed][Not invited]
   

  This study aimed to determine the optimal psoas muscle mass index (PMI) cut-off values for diagnosis of skeletal muscle mass loss. METHODS: We evaluated PMI in two groups of normal controls: a medical check-up group and a liver donation candidate group. We analyzed two novel PMI cut-off values, one based on the mean - two standard deviations (2SD) and one based on the lower 5%. Skeletal muscle mass index (SMI) evaluations using computed tomography (sliceOmatic; TomoVision) and bioelectrical impedance analysis and PMI evaluation were undertaken simultaneously. We analyzed the correlation between our PMI cut-off values and the Japan Society of Hepatology-defined SMI cut-off values. The prevalence of skeletal muscle mass loss in patients with liver disease was assessed using the novel PMI cut-off values. RESULTS: In 504 normal controls aged ≤50 years, the PMI cut-off values based on mean -2SD and the lower 5% were set at 3.30 cm2 /m2 for men and 1.69 cm2 /m2 for women and 3.74 cm2 /m2 for men and 2.29 cm2 /m2 for women, respectively. The PMI cut-off values based on the lower 5% alone showed that skeletal muscle mass loss increased with age. Furthermore, they correlated well with Japan Society of Hepatology-defined SMI (sliceOmatic) cut-off values and showed a significantly higher prevalence of skeletal muscle mass loss in patients with liver cirrhosis than those without liver cirrhosis. CONCLUSIONS: We propose the following PMI cut-off values: 3.74 cm2 /m2 for male individuals and 2.29 cm2 /m2 for female individuals. These cut-off values can facilitate accurate diagnosis and management of sarcopenia in patients with chronic liver disease.
• JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study.

  Tetsuo Takehara, Kazuaki Chayama, Masayuki Kurosaki, Hiroshi Yatsuhashi, Yasuhito Tanaka, Naoki Hiramatsu, Naoya Sakamoto, Yasuhiro Asahina, Akito Nozaki, Toshikazu Nakano, Yosuke Hagiwara, Hiroko Shimizu, Hiroki Yoshida, Yuhan Huang, Michael Biermer, Leen Vijgen, Norio Hayashi

  Journal of gastroenterology 55 (6) 640 - 652 0944-1174 2020/06 [Refereed][Not invited]
   

  BACKGROUND: The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis. METHODS: In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs). RESULTS: Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up. CONCLUSIONS: In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.
• 【消化管腫瘍の内視鏡診断2020】胃腫瘍性病変の内視鏡診断 リンパ増殖性疾患の診断

  小野 尚子, 田中 一光, 木脇 佐代子, 井上 雅貴, 霜田 佳彦, 大野 正芳, 坂本 直哉, 石川 麻倫, 山本 桂子, 清水 勇一, 清水 亜衣, 松野 吉宏

  胃と腸 (株)医学書院 55 (5) 593 - 601 0536-2180 2020/05 

  ＜文献概要＞「考える内視鏡診断」のポイント 通常観察では・多彩な内視鏡像が同時に観察される.・非上皮性腫瘍としての性質(粘膜下腫瘍様)が観察され,蚕食像はなく,硬さが目立たない.拡大内視鏡観察では・腫瘍浸潤により腺管構造が破壊された無構造領域や異常血管が観察される.・間質の細胞浸潤により窩間が引き延ばされ,腺管の膨化所見がみられることがある.・前述の特徴を捉え,狙撃生検を行うことで,診断能は向上する.・治療後に腺管構造や上皮下毛細血管の回復が観察され,治療後評価にも有用である.
• Histological and magnified endoscopic evaluation of villous atrophy in gastrointestinal graft-versus-host disease.

  Kana Matsuda, Shoko Ono, Ikko Tanaka, Masaki Inoue, Sayoko Kinowaki, Marin Ishikawa, Momoko Tsuda, Keiko Yamamoto, Yuichi Shimizu, Shuichiro Takahashi, Eiko Hayase, Daigo Hashimoto, Takanori Teshima, Naoya Sakamoto

  Annals of hematology 99 (5) 1121 - 1128 2020/05 

  AIM:  To measure histological villous atrophy and to clarify the diagnostic accuracy of endoscopic villous atrophy in gastrointestinal graft-versus-host disease. METHODS:  Data for patients who underwent upper and/or lower endoscopic examinations after hematopoietic stem cell transplantation were retrospectively collected. In study 1, group A included 56 patients in whom GI-GVHD was histologically confirmed and group B included 60 patients in whom GI-GVHD was not histologically confirmed. Group C included 59 patients before HSCT. The lengths of villi and crypts in the duodenum and terminal ileum were histologically measured. In study 2, the diagnostic accuracies of villous atrophy of the duodenum and of the terminal ileum using magnifying endoscopy were evaluated. RESULTS:  In study 1, the lengths of villi and the villi/crypt (V/C) ratios of the duodenum and terminal ileum in group A were significantly smaller than those in the other groups (p < 0.05). V/C ratio was moderately correlated with clinical severity, histological grades, and endoscopic grades in the terminal ileum. In study 2, the diagnostic accuracies of magnified images for villous atrophy were 83.8% in the duodenum and 94.9% in the terminal ileum. CONCLUSION:  Magnifying endoscopy enables evaluation of villous atrophy and is useful for optical biopsy of GVHD.
• Feasibility of a distal pigtail shaped stent placement above the papilla for biliary obstruction.

  Koji Hirata, Masaki Kuwatani, Naoya Sakamoto

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 32 (4) e73-e74  2020/05
• ストレス応答と肝疾患進展 ストレス応答よりみえてくるB型およびC型肝炎ウイルスの戦略

  森川 賢一, 須田 剛生, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.1) A99 - A99 0451-4203 2020/04
• トルバプタン奏効後の再燃と炎症および尿L-FABP値の関連

  中井 正人, 北潟谷 隆, 山田 錬, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.1) A347 - A347 0451-4203 2020/04
• 大規模健常人データ(肝移植ドナー・検診受験者)を用いた低骨格筋量に対する最適psoas muscle mass index cut-off値検討と肝疾患患者における評価

  須田 剛生, 大原 正嗣, 小川 浩司, 荘 拓也, 中井 正人, 森川 賢一, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.1) A474 - A474 0451-4203 2020/04
• NAFLD患者におけるMRエラストグラフィ診断能の検討

  山田 錬, 小川 浩司, 北潟谷 隆, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.1) A495 - A495 0451-4203 2020/04
• 進行肝細胞癌に対するレンバチニブ治療成績からみた適格使用時期の検討 多施設共同研究

  荘 拓也, 須田 剛生, 北潟谷 隆, 山田 錬, 重沢 拓, 鈴木 和治, 梅村 真知子, 中井 正人, 森川 賢一, 小川 浩司, 川岸 直樹, 宮城島 拓人, 馬場 英, 古家 乾, 山本 義也, 小林 智絵, 目黒 高志, 高木 智史, 神山 俊哉, 武冨 紹信, 坂本 直哉

  肝臓 (一社)日本肝臓学会 61 (Suppl.1) A334 - A334 0451-4203 2020/04
• Long-term outcomes and risk factors of recurrent biliary obstruction after permanent endoscopic biliary stenting for choledocholithiasis in high-risk patients.

  Ryo Sugiura, Hirohito Naruse, Hiroaki Yamato, Taiki Kudo, Yoshiya Yamamoto, Kazuteru Hatanaka, Jun Ito, Kenji Kinoshita, Shuichi Miyamoto, Masayuki Higashino, Shuhei Hayasaka, Naoya Sakamoto

  Journal of digestive diseases 21 (4) 246 - 251 2020/04 

  OBJECTIVE: To elucidate the long-term outcomes of permanent endoscopic biliary stenting (EBS) and risk factors for recurrent biliary obstruction (RBO) in high-risk or elderly patients with common bile duct (CBD) stones. METHODS: The electronic database of Hakodate Municipal Hospital was searched to identify elderly or high-risk patients with CBD stones who had undergone permanent EBS using a plastic stent without stone removal and were followed up between April 2011 and May 2019, with no further intervention until symptoms occurred. RESULTS: We analyzed a total of 47 patients, of whom 19 (40.4%) were men, with a median age of 86 years (interquartile range 80-90 years). RBO and death without biliary disease occurred in 14 (29.8%) and 19 (40.4%) patients, respectively. The cumulative RBO rates at 20, 40, and 60 months were 22.1%, 31.8%, and 35.5%, respectively. The median time to RBO was 13.0 and 38.0 months in the group with CBD stone  ≥15 mm and 11-14 mm in diameter, respectively. The cumulative RBO incidence rate in the group with CBD stone ≤10 mm in diameter did not reach 50%. The cumulative RBO incidence rates were significantly different among the three groups based on the CBD stone diameter (competing risk analysis, P < 0.01). Multivariate analysis showed that an increase in CBD stone diameter predicted the increased risk of RBO (hazard ratio 1.26, P = 0.01). CONCLUSIONS: Permanent EBS is a feasible option for high-risk patients with small CBD stones.
• Inutility of endoscopic sphincterotomy to prevent pancreatitis after biliary metal stent placement in the patients without pancreatic duct obstruction.

  Shin Kato, Masaki Kuwatani, Tsuyoshi Hayashi, Kazunori Eto, Michihiro Ono, Nobuyuki Ehira, Hiroaki Yamato, Itsuki Sano, Yoko Taya, Manabu Onodera, Kimitoshi Kubo, Hideyuki Ihara, Hajime Yamazaki, Naoya Sakamoto

  Scandinavian journal of gastroenterology 55 (4) 503 - 508 2020/04 [Refereed][Not invited]
   

  Background: The incidence of post-ERCP pancreatitis (PEP) has been reported to be significantly higher in patients without main pancreatic duct (MPD) obstruction who undergo transpapillary biliary metal stent (MS) placement than in those with ordinary ERCP setting.Objective: To evaluate the benefit of endoscopic sphincterotomy (ES) prior to MS placement in preventing PEP in patients with distal malignant biliary obstruction (MBO) without MPD obstruction.Materials and methods: In total, 160 patients who underwent initial MS placement for MBO were enrolled. Eighty-two patients underwent ES immediately prior to MS placement, whereas 78 underwent MS placement without ES. An inverse probability of treatment weighting method was adopted to adjust the differences of the patients' characteristics. The primary outcome was the incidence of PEP. The secondary outcomes included the incidence of other adverse events (bleeding, cholangitis, perforation and stent dislocation) and time to recurrent biliary obstruction.Results: The incidence of PEP was 26.8% in the ES and 23.1% in the non-ES (unadjusted odds ratio [OR] [95%CI]: 1.22, [0.60-2.51], adjusted OR [95%CI]: 1.23, [0.53-2.81], p = .63). Logistic-regression analysis revealed no factors that could be attributed to the occurrence of PEP. The incidence of other adverse events was not different between the groups. The median time to recurrent biliary obstruction was 131 (2-465) days and 200 (4-864) days in the ES and non-ES, respectively (p = .215).Conclusions: ES prior to MS placement for patients with distal MBO without MPD obstruction does not reduce the incidence of PEP.
• Endoscopic ultrasound‐guided fine‐needle biopsy for definitive diagnosis of malignant peritoneal mesothelioma

  Masayuki Higashino, Ryo Sugiura, Naoya Sakamoto

  Digestive Endoscopy 32 (3) e40 - e42 0915-5635 2020/03 [Refereed]
  
• Hepatobiliary and Pancreatic: Hemosuccus pancreaticus due to an intraductal papillary mucinous neoplasm: A rare cause of obscure gastrointestinal bleeding

  R Sugiura, K Kinoshita, H Naruse, Y Yamamoto, K Hatanaka, J Ito, S Miyamoto, M Higashino, S Hayasaka, N Tsuchida, K Nakanishi, S Ueki, M Umehara, N Shimoyama, T Mitsuhashi, N Sakamoto

  Journal of Gastroenterology and Hepatology 35 (3) 363 - 363 0815-9319 2020/03 [Refereed]
  
• Clinical characteristics of elderly pulmonary tuberculosis in an acute-care general hospital in Tokyo, Japan: A 12-year retrospective study.

  Mayu Hikone, Yusuke Ainoda, Naoya Sakamoto, Kenji Ohnishi

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 26 (3) 245 - 250 2020/03 

  OBJECTIVE: A significant feature of tuberculosis (TB) in Japan is the fact that a high proportion of cases belong to the elderly population. Furthermore, previous reports have pointed out the delayed diagnosis of pulmonary TB in acute-care settings. We aimed to examine the clinical characteristics of pulmonary TB patients in an acute-care general hospital, particularly focusing on the elderly population. METHODS: We retrospectively reviewed the medical records of patients with pulmonary TB who presented at our institution between May 2005 and December 2016. We described the overall clinical characteristics of these patients and compared them according to age. RESULTS: Overall, 289 patients were eligible for the analysis, with a median age of 58 [42-73] years, and 29.4% being older than 70 years. Among the elderly patients, 42.4% were characterized by atypical presentation. CONCLUSION: Our findings suggest that the elderly population tends to present as atypical cases lacking respiratory complaints, thereby being at a risk of misdiagnosis.
• ペムブロリズマブが奏効した高頻度マイクロサテライト不安定性の肝内胆管癌の1例

  斎藤 里佳, 伊藤 憲, 中野 真太郎, 川本 泰之, 中積 宏之, 結城 敏志, 小松 嘉人, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 126回 41 - 41 2020/03
• 進行膵癌における化学療法施行例の予後因子解析

  中野 真太郎, 小松 嘉人, 斉藤 里佳, 伊藤 憲, 川本 泰之, 中積 宏之, 結城 敏志, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 126回 58 - 58 2020/03
• 消化器がん内視鏡診断・治療の最前線 胆嚢癌に対する術前胆道ドレナージ 肝門部領域胆管癌との比較検討

  平田 幸司, 桑谷 将城, 加藤 新, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 126回 35 - 35 2020/03
• 悪性胆道狭窄に対するトリプルルーメンカテーテルの有用性

  平田 甫, 桑谷 将城, 瀧新 悠之介, 古川 龍太郎, 平田 幸司, 加藤 新, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 126回 43 - 43 2020/03
• 【EUSの現状と将来】治療 胆管挿管困難例に対するRendezvous法

  桑谷 将城, 川久保 和道, 加藤 新, 平田 幸司, 平田 甫, 坂本 直哉

  肝胆膵 (株)アークメディア 80 (3) 471 - 479 0389-4991 2020/03
• 表在型非乳頭部十二指腸上皮性腫瘍の内視鏡所見についての検討

  木脇 佐代子, 小野 尚子, 霜田 佳彦, 井上 雅貴, 田中 一光, 石川 麻倫, 大野 正芳, 山本 桂子, 清水 勇一, 坂本 直哉, 三橋 智子, 松野 吉宏

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 126回 59 - 59 2020/03
• 表在性非乳頭部十二指腸腫瘍に対するエンドサイトスコピーシステムを用いた分類の検討

  宮本 秀一, 工藤 俊彦, 石川 麻倫, 小野 尚子, 清水 勇一, 土田 直央, 早坂 秀平, 東野 真幸, 杉浦 諒, 木下 賢治, 伊藤 淳, 畑中 一映, 山本 義也, 成瀬 宏仁, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 126回 73 - 73 2020/03
• 【慢性膵炎診療2020】基礎研究・病態 早期慢性膵炎は慢性膵炎確診・準確診例に移行するのか

  桑谷 将城, 加藤 新, 平田 幸司, 平田 甫, 坂本 直哉

  肝胆膵 (株)アークメディア 80 (2) 265 - 269 0389-4991 2020/02
• Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting

  Takuya Sho, Goki Suda, Koji Ogawa, Megumi Kimura, Tomoe Shimazaki, Osamu Maehara, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Tomoe Kobayashi, Takashi Meguro, Akiyoshi Saga, Takuto Miyagishima, Hideki Yokoo, Toshiya Kamiyama, Akinobu Taketomi, Naoya Sakamoto

  JGH OPEN 4 (1) 54 - 60 2397-9070 2020/02 [Refereed][Not invited]
   

  Background and AimLenvatinib has been recently approved as a first-line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child-Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real-world setting.MethodsAmong patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis.ResultsA total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups.ConclusionLenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria.
• Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting.

  Takuya Sho, Goki Suda, Koji Ogawa, Megumi Kimura, Tomoe Shimazaki, Osamu Maehara, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Mitsuteru Natsuizaka, Masato Nakai, Kenichi Morikawa, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Tomoe Kobayashi, Takashi Meguro, Akiyoshi Saga, Takuto Miyagishima, Hideki Yokoo, Toshiya Kamiyama, Akinobu Taketomi, Naoya Sakamoto

  JGH open : an open access journal of gastroenterology and hepatology 4 (1) 54 - 60 0168-8278 2020/02 [Refereed][Not invited]
   

  Background and Aim: Lenvatinib has been recently approved as a first-line systematic therapy for patients with advanced hepatocellular carcinoma (HCC) based on the results of the phase 3 clinical trial REFLECT. This trial excluded patients with a history of systemic chemotherapy, bile duct invasion, and Child-Pugh grade B. We aimed to investigate the efficacy and safety of lenvatinib for these patients and in the real-world setting. Methods: Among patients who were administered lenvatinib for advanced HCC between April and October 2018 in Hokkaido University Hospital and related hospitals, we evaluated those who were followed for more than 2 months and whose treatment response was evaluated via dynamic computed tomography at baseline and 2 months after treatment initiation. Meanwhile, patients were excluded if they had decompensated liver cirrhosis, were followed up less than 2 months, or were not evaluated at 2 months. Patients were also stratified according to compliance with the REFLECT inclusion criteria for further analysis. Results: A total of 41 patients were included; more than 50% did not meet the REFLECT inclusion criteria. In total, 5 (12.2%), 20 (48.8%), 12 (29.3%), and 4 (9.3%) showed complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 61.2%. The objective response rate and disease control rate were similar between patients who did and did not meet the REFLECT inclusion criteria. Moreover, the safety profile was also similar between the two patient groups. Conclusion: Lenvatinib showed high early response rate and tolerability in patients with advanced HCC. Favorable outcomes were similarly observed in patients who did not meet the REFLECT inclusion criteria.
• Up-to-date endoscopic diagnosis and treatment of gastric cancer

  Shoko Ono, Yuji Ono, Naoya Sakamoto

  Journal of Japanese Society of Gastroenterology 117 (2) 126 - 134 1349-7693 2020
• Esophagitis in Non-Small Cell Lung Carcinoma Treatment Caused by Pembrolizumab.

  Sonoe Yoshida, Shuichi Miyamoto, Hirohito Naruse, Jun Ito, Kenji Kinosita, Taiki Kudo, Kazuteru Hatanaka, Yoshiya Yamamoto, Naoya Sakamoto

  The American journal of gastroenterology 115 (1) 13 - 13 2020/01
• SPC18 Expression Is an Independent Prognostic Indicator of Patients with Esophageal Squamous Cell Carcinoma.

  Yuji Yamamoto, Naohide Oue, Ryuichi Asai, Narutaka Katsuya, Naohiro Uraoka, Naoya Sakamoto, Kazuhiro Sentani, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui

  Pathobiology : journal of immunopathology, molecular and cellular biology 87 (4) 254 - 261 2020 

  OBJECTIVES: Esophageal cancer is the sixth most common malignancy worldwide. Signal peptidase complex 18 (SPC18) protein, which is encoded by the SEC11A gene, is one of the subunits of the signal peptidase complex and plays an important role in the secretion of proteins including transforming growth factor α (TGF-α). In this study, we investigated the significance of SPC18 expression in human esophageal squamous cell carcinoma (ESCC). METHODS: SPC18 expression was examined by immunohistochemistry. RNA interference was used to inhibit SPC18 expression in ESCC cell lines. To examine cell viability, we performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The effects of SPC18 inhibition on epidermal growth factor receptor (EGFR) signaling were analyzed by Western blot. RESULTS: In total, 46 (50%) of 92 ESCC cases were positive for SPC18. SPC18 staining was observed more frequently in stage II/III/IV cases than in stage I cases (p = 0.028). We found that SPC18 expression was significantly associated with increased cancer-specific mortality (p = 0.006, log-rank test). SPC18 expression was frequently found in EGFR-positive cases compared with EGFR-negative cases. Cell proliferation and EGFR signaling were inhibited by SPC18 knockdown. CONCLUSION: Specific inhibitors of SPC18 may be promising anticancer drugs for patients with ESCC.
• Accuracies of Endoscopic Diagnosis of Helicobacter pylori-Gastritis: Multicenter Prospective Study Using White Light Imaging and Linked Color Imaging.

  Shoko Ono, Osamu Dohi, Nobuaki Yagi, Yoji Sanomura, Shinji Tanaka, Yuji Naito, Naoya Sakamoto, Mototsugu Kato

  Digestion 101 (5) 624 - 630 2020 

  INTRODUCTION: The diagnosis of Helicobacter pylori infection status with white light imaging (WLI) is difficult. We evaluated the accuracies of using WLI and linked color imaging (LCI) for diagnosing H. pylori-active gastritis in a multicenter prospective study setting. METHODS: Patients who underwent esophagogastroduodenoscopy were prospectively included. The image collection process was randomized and anonymous, and the image set included 4 images with WLI or 4 images with LCI in the corpus that 5 reviewers separately evaluated. Active gastritis was defined as positive when there was diffuse redness in WLI and crimson coloring in LCI. The H. pylori infection status was determined by the urea breath test and the serum antibody test. Cases in which both test results were negative but atrophy or intestinal metaplasia was histologically confirmed were defined as past infections. The primary endpoint was the diagnostic accuracies of WLI and LCI, and the secondary endpoint was inter-observer agreement. RESULTS: Data for 127 patients were analyzed. The endoscopic diagnostic accuracy for active gastritis was 79.5 (sensitivity of 84.4 and specificity of 74.6) with WLI and 86.6 (sensitivity of 84.4 and specificity of 88.9) with LCI (p = 0.029). LCI significantly improved the accuracy in patients with past infections over WLI (36.8 in WLI and 78.9 in LCI, p < 0.01). The κ values were 0.59 in WLI and 0.70 in LCI. CONCLUSIONS: LCI is useful for endoscopic diagnosis of H. pylori-active or inactive gastritis, and it is advantageous for patients with past infections of inactive gastritis.
• S-1またはカペシタビンを含む標準治療に不応・不耐の胃癌に対するbolus 5-FU/I-LV療法の多施設共同第II相試験 前治療別の解析

  村中 徹人, 小松 嘉人, 結城 敏志, 中野 真太郎, 澤田 憲太郎, 川本 泰之, 中積 宏之, 原田 一顕, 宮城島 拓人, 畑中 一映, 太宰 昌佳, 植田 亮, 笹木 祐介, 辻 靖, 西本 尚樹, 坂田 優, 坂本 直哉

  日本消化管学会雑誌 (一社)日本消化管学会 4 (Suppl.) 262 - 262 2433-3840 2020/01
• FGFR阻害剤およびMEK阻害剤は食道扁平上皮癌(ESCC)がん幹細胞を減少させる

  前原 経, 夏井坂 光輝, 須田 剛生, 大西 俊介, 坂本 直哉, 武田 宏司

  日本消化管学会雑誌 (一社)日本消化管学会 4 (Suppl.) 301 - 301 2433-3840 2020/01
• Detection of early adenocarcinoma of the esophagogastric junction by spraying an enzyme-activatable fluorescent probe targeting Dipeptidyl peptidase-IV

  Keikokw Yamamoto, Shunsuke Ohnishi, Takeshi Mizushima, Junichi Kodaira, Masayoshi Ono, Yutaka Hatanaka, Kanako C. Hatanaka, Yugo Kuriki, Mako Kamiya, Nobuyuki Ehira, Keisuke Shinada, Hiroaki Takahashi, Yuichi Shimizu, Yasuteru Urano, Naoya Sakamoto

  BMC CANCER 20 (1) 2020/01 

  Background It is still difficult to detect and diagnose early adenocarcinoma of the esophagogastric junction (EGJ) using conventional endoscopy or image-enhanced endoscopy. A glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG) fluorescent probe that can be enzymatically activated to become fluorescent after the cleavage of a dipeptidyl peptidase (DPP)-IV-specific sequence has been developed and is reported to be useful for the detection of squamous cell carcinoma of the head and neck, and esophagus; however, there is a lack of studies that focuses on detecting EGJ adenocarcinoma by fluorescence molecular imaging. Therefore, we investigated the visualization of early EGJ adenocarcinoma by applying EP-HMRG and using clinical samples resected by endoscopic submucosal dissection (ESD). Methods Fluorescence imaging with EP-HMRG was performed in 21 clinical samples resected by ESD, and the fluorescence intensity of the tumor and non-tumor regions of interest was prospectively measured. Immunohistochemistry was also performed to determine the expression of DPP-IV. Results Fluorescence imaging of the clinical samples showed that the tumor lesions were visualized within a few minutes after the application of EP-HMRG, with a sensitivity, specificity, and accuracy of 85.7, 85.7, and 85.7%, respectively. However, tumors with a background of intestinal metaplasia did not have a sufficient contrast-to-background ratio since complete intestinal metaplasia also expresses DPP-IV. Immunohistochemistry measurements revealed that all fluorescent tumor lesions expressed DPP-IV. Conclusions Fluorescence imaging with EP-HMRG could be useful for the detection of early EGJ adenocarcinoma lesions that do not have a background of intestinal metaplasia.
• Oleoylethanolamide Ameliorates Dextran Sulfate Sodium-Induced Colitis in Rats.

  Shinsuke Otagiri, Shunsuke Ohnishi, Masatsugu Ohara, Qingjie Fu, Koji Yamamoto, Keiko Yamamoto, Takehiko Katsurada, Naoya Sakamoto

  Frontiers in pharmacology 11 1277 - 1277 2020 

  Oleoylethanolamide (OEA) is an endogenous fatty acid ethanolamide known for its anti-inflammatory effects and its influence on gut microbiota composition; however, the effects of OEA in inflammatory bowel disease (IBD) remain unknown. During in vitro experiments, OEA downregulated the expression of tumor necrosis factor (TNF)-α and reduced phosphorylation of inhibitor of kappa (Iκ) Bα induced by lipopolysaccharide in human embryonic kidney cells. Moreover, OEA downregulated the expression of interleukin (IL)-8 and IL-1β and inhibited the phosphorylation of IκBα and p65 induced by TNF-α in human enterocytes (Caco-2). The effect of OEA in reducing the expression of IL-8 was blocked by the peroxisome proliferator-activated receptor (PPAR)-α antagonist. During in vivo experiments on rats, colitis was induced by the oral administration of 8% dextran sulfate sodium from day 0 through day 5, and OEA (20 mg/kg) was intraperitoneally injected once a day from day 0 for 6 days. OEA administration significantly ameliorated the reduction in body weight, the increase in disease activity index score, and the shortening of colon length. In rectums, OEA administration reduced the infiltration of macrophages and neutrophils and tended to reduce the histological score and the expression of inflammatory cytokines. Administration of OEA produced significant improvement in a colitis model, possibly by inhibiting the nuclear factor kappa B signaling pathway through PPAR-α receptors. OEA could be a potential new treatment for IBD.
• 【遺伝子・免疫異常に伴う消化管病変-最新のトピックスを中心に】免疫チェックポイント阻害薬関連消化管病変

  長島 一哲, 桂田 武彦, 大塚 拓也, 西田 睦, 表原 里実, 桜井 健介, 小田切 信介, 山梨 香菜, 小松 嘉人, 三橋 智子, 坂本 直哉

  胃と腸 (株)医学書院 54 (13) 1723 - 1732 0536-2180 2019/12 

  ＜文献概要＞免疫チェックポイント阻害薬は,既存の悪性腫瘍治療薬と異なる作用機序を持つ,新規抗悪性腫瘍薬である.しかし,免疫関連有害事象という既存治療薬では認めなかった有害事象を生じうる可能性がある.その一つに大腸炎があり,下痢,腹痛,血便などの症状を呈する.診断は除外診断が必要となるが,内視鏡検査が有用である.CTCAE Grade 2以上の重症度の際は,ステロイドを用いた治療が必要となる.ステロイド抵抗性の際はインフリキシマブを用いることが各種ガイドラインで推奨されている.免疫関連有害事象に対しては,がん治療主治医のみでなく,多診療科医師・コメディカルなど病院全体での対策・連携が重要である.
• Clinical impact of the perioperative management of oral anticoagulants in bleeding after colonic endoscopic mucosal resection

  Shoko Ono, Marin Ishikawa, Kana Matsuda, Momoko Tsuda, Keiko Yamamoto, Yuichi Shimizu, Naoya Sakamoto

  BMC Gastroenterology 19 (1) 2019/12 

  Heparin bridging therapy (HBT) is indeed related to a high frequency of bleeding after endoscopic mucosal resection (EMR). In this study, our aim was to investigate clinical impact of management of oral anticoagulants without HBT in bleeding after colonic EMR. From data for patients who underwent consecutive colonic EMR, the relationships of patient factors and procedural factors with the risk of bleeding were analysed. Our management of antithrombotic agents was based on the shortest cessation as follows: the administration of warfarin was generally continued within the therapeutic range, and direct oral anticoagulants (DOACs) were not administered on the day of the procedure. We calculated bleeding risks after EMR in patients who used antithrombotic agents and evaluated whether perioperative management of anticoagulants without HBT was beneficial for bleeding. A total of 1734 polyps in 825 EMRs were analysed. Bleeding occurred in 4.0% of the patients and 1.9% of the polyps. The odds ratios for bleeding using multivariate logistic regression analysis were 3.67 in patients who used anticoagulants and 4.95 in patients who used both anticoagulants and antiplatelet agents. In patients with one-day skip of DOACs, bleeding occurred in 6.5% of the polyps, and there were no significant differences in bleeding risk between HBT and continuous warfarin or one-day skip DOACs. The use of oral anticoagulants was related to bleeding after colonic EMR, and perioperative management of oral anticoagulants based on the shortest cessation without HBT would be clinically acceptable.
• Gastrointestinal: Endoscopic balloon dilations for an intestinal stricture in a patient with X‐linked inhibitor of apoptosis deficiency

  S Otagiri, R Sugiura, T Katsurada, K Yamanashi, K Nagashima, J Sugita, S Ohnishi, N Sakamoto

  Journal of Gastroenterology and Hepatology 2019/11/07 [Refereed][Not invited]
  
• クローン病の腸管病変における体外式超音波検査の有用性の検討

  山梨 香菜, 西田 睦, 表原 里実, 木下 賢治, 大西 礼造, 桂田 武彦, 坂本 直哉

  日本小腸学会学術集会プログラム・抄録集 日本小腸学会 57回 62 - 62 2434-2912 2019/11
• 胸部食道扁平上皮癌に対する術前補助化学療法・根治切除術および根治的化学放射線療法についての後方視的検討

  中積 宏之, 村中 徹人, 川本 泰之, 小松 嘉人, 結城 敏志, 中野 真太郎, 澤田 憲太郎, 坂本 直哉, 打浪 雄介, 田口 大志, 白土 博樹, 海老原 裕磨, 七戸 俊明, 平野 聡

  北海道医学雑誌 北海道医学会 94 (2) 120 - 121 0367-6102 2019/11
• 早期食道癌発癌因子としてのHuman Papilloma Virus感染およびアルコール代謝遺伝子多型に関する検討

  井上 雅貴, 清水 勇一, 田中 一光, 木脇 佐代子, 石川 麻倫, 松田 可奈, 津田 桃子, 山本 桂子, 小野 尚子, 三橋 智子, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 116 (臨増大会) A810 - A810 0446-6586 2019/11
• Entecavir treatment of hepatitis B virus-infected patients with severe renal impairment and those on hemodialysis.

  Kazuharu Suzuki, Goki Suda, Yoshiya Yamamoto, Ken Furuya, Masaru Baba, Megumi Kimura, Osamu Maehara, Tomoe Shimazaki, Koji Yamamoto, Taku Shigesawa, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 49 (11) 1294 - 1304 1386-6346 2019/11 [Refereed][Not invited]
   

  AIM: Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are first-line nucleos(t)ide analogues for hepatitis B virus (HBV)-infected patients. However, consecutive TDF treatment causes renal dysfunction, and the safety and efficacy of TAF have not been established in severe renal dysfunction patients, including hemodialysis patients. The efficacy and safety of ETV in these populations has not been clarified. The study aimed to clarify this. METHODS: In this retrospective multicenter study, between 2006 and 2018, a total of 567 HBV-infected patients treated with ETV monotherapy were screened. Patients were included if >20 years old, treated with ETV monotherapy for >1 year, and had proper clinical information. The efficacy of ETV and changes in renal function were evaluated according to renal function. RESULTS: A total of 273 patients were included: 9.2% (25/273), 1.8% (5/273), and 3.7% (10/273) had chronic kidney disease (CKD) stage G3, CKD stage G4/5, and were on hemodialysis, respectively. Overall, 84.2%, 94.0%, and 96.2% of patients experienced serum HBV-DNA disappearance at 1, 2, and 3 years, respectively, after treatment initiation. In patients with CKD stage G3-5, estimated glomerular filtration rate tended to restore with time, which was in contrast to patients without renal dysfunction. The rate of disappearance in serum HBV-DNA, alanine transaminase normalization, and virological breakthrough was similar between patients with or without renal dysfunction. ETV showed high efficacy for all 10 hemodialysis patients without virological breakthrough. CONCLUSIONS: Entecavir for HBV-infected patients with severe renal dysfunction, including hemodialysis patients, is highly effective and does not affect renal function.
• Effects of resistance-associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs.

  Goki Suda, Megumi Kimura, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Masato Nakai, Takuya Sho, Osamu Maehara, Tomoe Shimazaki, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 49 (11) 1275 - 1285 1386-6346 2019/11 [Refereed][Not invited]
   

  AIMS: Development of direct-acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant-associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non-structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. METHODS: We utilized HCV-2b/2a (JFH-1) chimeric virus (genotype 2a), which replicates more robustly than JFH-1. We constructed various genotype 2a JFH-1-based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti-HCV reagents. RESULTS: Genotype 2a-based HCV with NS5A-P32 deletion could not replicate even in long-term cultures. Genotype 2a-based HCV with NS5A-F28S/M31I showed significantly higher replication ability than the wild-type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000-10 000 fold-resistance compared with the wild-type strain). However, genotype 2a-based HCV with NA5A-F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon-α, and ribavirin. Genotype 2a-based HCV with NS5B-S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control. CONCLUSIONS: When undertaking retreatment for genotype 2a HCV-infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti-HCV drugs.
• 経口フッ化ピリミジン不応の胃がんに対するRPMI療法(HGCSG1502試験)OS・QOL解析結果

  太宰 昌佳, 村中 徹人, 川本 泰之, 中積 宏之, 原田 一顕, 宮城島 拓人, 畑中 一映, 植田 亮, 加藤 総介, 笹木 有佑, 結城 敏志, 坂本 直哉, 西本 尚樹, 坂田 優, 小松 嘉人

  日本癌治療学会学術集会抄録集 57回 P69 - 1 2019/10
• 転移を有する膵癌に対する化学療法薬剤使用歴と治療成績の関係の検討

  川本 泰之, 斎藤 里佳, 伊藤 憲, 中野 真太郎, 中積 宏之, 結城 敏志, 小松 嘉人, 坂本 直哉

  日本癌治療学会学術集会抄録集 57回 P86 - 7 2019/10
• 各都道府県における肝疾患対策取り組みの現状 北海道における肝炎対策の現状

  小川 浩司, 辻口 智美, 銭谷 菜子, 山下 真智子, 吉川 昇吾, 坂本 直哉

  肝臓クリニカルアップデート 医学図書出版(株) 5 (2) 221 - 225 2189-4469 2019/10
• 【肝胆膵の救急疾患とその最新の治療現場】肝胆膵における比較的新しい救急疾患概念 膵仮性嚢胞・WONへのアプローチ

  桑谷 将城, 川久保 和道, 加藤 新, 平田 幸司, 平田 甫, 坂本 直哉

  肝胆膵 (株)アークメディア 79 (4) 705 - 711 0389-4991 2019/10
• 悪性肝門部胆管閉塞症例の術前内視鏡的経鼻胆管ドレナージチューブ閉塞の危険因子解析

  杉浦 諒, 桑谷 将城, 平田 甫, 中島 正人, 平田 幸司, 加藤 新, 坂本 直哉

  胆道 日本胆道学会 33 (3) 493 - 493 0914-0077 2019/10
• 遠位良性胆道狭窄に対する経乳頭的金属ステント留置の効果

  加藤 新, 桑谷 将城, 平田 甫, 滝新 悠之介, 平田 幸司, 古川 龍太郎, 坂本 直哉

  胆道 日本胆道学会 33 (3) 603 - 603 0914-0077 2019/10
• さあ、どうする?治療内視鏡におけるトラブルシューティング(胆膵編) 胆管金属ステント留置後reintervention困難例におけるESダイレーターの有用性

  加藤 新, 桑谷 将城, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.2) 2054 - 2054 0387-1207 2019/10
• 当院における消化管内視鏡検査の鎮静剤使用の現状と課題

  大野 正芳, 霜田 佳彦, 田中 一光, 井上 雅貴, 木脇 佐代子, 石川 麻倫, 山本 桂子, 小野 尚子, 中川 学, 中川 宗一, 清水 勇一, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.2) 2260 - 2260 0387-1207 2019/10
• C型肝炎患者の血清Angiopoietin-2値はDAAs治療後の肝線維化非改善例を予測する

  川岸 直樹, 須田 剛生, 中井 正人, 荘 拓也, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 60 (Suppl.2) A653 - A653 0451-4203 2019/10 [Refereed][Not invited]
  
• カルニチンは肝硬変患者における筋肉量減少を抑制する

  大原 正嗣, 須田 剛生, 重沢 拓, 鈴木 和治, 中村 晃久, 川岸 直樹, 中井 正人, 荘 拓也, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 60 (Suppl.2) A677 - A677 0451-4203 2019/10 [Refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブ投与症例からみた適格使用時期の検討

  荘 拓也, 須田 剛生, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉

  肝臓 (一社)日本肝臓学会 60 (Suppl.2) A705 - A705 0451-4203 2019/10 [Refereed][Not invited]
  
• Assessing the risk of hepatocellular carcinoma by combining liver stiffness and the controlled attenuation parameter.

  Takaaki Izumi, Takuya Sho, Kenichi Morikawa, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Machiko Umemura, Tomoe Shimazaki, Megumi Kimura, Masato Nakai, Goki Suda, Mitsuteru Natsuizaka, Koji Ogawa, Yusuke Kudo, Mutsumi Nishida, Kota Ono, Masaru Baba, Ken Furuya, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 49 (10) 1207 - 1217 1386-6346 2019/10 [Refereed][Not invited]
   

  AIM: Ultrasound technology can now be used for liver stiffness measurement (LSM) and for evaluating the amount of hepatic fat quantitatively known as the controlled attenuation parameter (CAP). This study aimed to determine the applicable cut-off values of LSM and the CAP for primary hepatocellular carcinoma (HCC), and to investigate their clinical usefulness for assessing HCC risk in patients with chronic liver disease. METHODS: A total of 1054 patients (88 with primary HCC and 966 without HCC) whose LSM and the CAP were measured by transient elastography with clinically evident hepatitis C virus (419 patients), hepatitis B virus (377 patients), and non-alcoholic fatty liver disease (258 patients) were enrolled in this study. Subsequently, a total of 966 patients who did not have HCC initially were followed, and the usefulness of the cut-off values of LSM and CAP for HCC development were evaluated. RESULTS: In hepatitis C virus patients, the incidence of HCC development was significantly higher among those with a combination of LSM ≥8.0 kPa and CAP ≤221 dB/m than among those with other values (log-rank test 0.0239, hazard ratio 2.66, 95%CI 1.07-6.47, P = 0.0362). In non-alcoholic fatty liver disease patients, the incidence of HCC development was significantly higher among those with a combination of LSM ≥5.4 kPa and CAP ≤265 dB/m than among others (log-rank test 0.0040, hazard ratio 8.91, 95% CI 1.47-67.97, P = 0.0192). CONCLUSION: In the hepatitis C virus and non-alcoholic fatty liver disease groups, a combination of LSM and the CAP cut-off values would be useful for screening to identify the high-risk group for primary HCC development.
• Correlation between Liver Elasticity by Ultrasound Elastography and Liver Functional Reserve.

  Ryo Sugiura, Masaki Kuwatani, Mutsumi Nishida, Koji Hirata, Itsuki Sano, Shin Kato, Kazumichi Kawakubo, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Ultrasound in medicine & biology 45 (10) 2704 - 2712 0301-5629 2019/10 [Refereed][Not invited]
   

  No worldwide consensus on the assessment tool for liver functional reserve is currently available. The aim of this study was to evaluate the correlation between liver elasticity of both hepatic lobes and liver functional reserve tests. This prospective observational study comprised 40 patients scheduled for hepatectomy. Liver elasticity was assessed by Virtual Touch Quantification (VTQ). The mean VTQ value for the right and left lobes was defined as the mVTQ. Liver functional reserve was measured with technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin scintigraphy as LHL15 and HH15 and the indocyanine green (ICG) excretion test as ICG-R15 and ICG-K. All examinations were measured after biliary decompression confirmed serum a total bilirubin level ≤2 mg/dL. Mean VTQ values were moderately correlated with LHL15 (r = -0.42, p < 0.01), HH15 (r = 0.48, p < 0.01), ICG-R15 (r = 0.53, p < 0.01) and ICG-K (r = -0.61, p < 0.01) values. In conclusion, the liver elasticity determined by VTQ would be a useful predictor of liver functional reserve in patients scheduled for hepatectomy.
• 局所進行膵癌における化学療法および化学放射線療法の検討

  中野 真太郎, 小松 嘉人, 川本 泰之, 斎藤 里佳, 伊藤 憲, 中積 宏之, 結城 敏志, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 125回 55 - 55 2019/09
• 膵胆管合流異常症における画像所見の検討

  古川 龍太郎, 桑谷 将城, 平田 甫, 滝新 悠之介, 平田 幸司, 加藤 新, 岡村 圭佑, 平野 聡, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 125回 34 - 34 2019/09
• 胆管空腸吻合部狭窄に対するバルーン内視鏡治療の臨床成績

  平田 甫, 桑谷 将城, 瀧新 悠之介, 古川 龍太郎, 平田 幸司, 加藤 新, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 125回 35 - 35 2019/09
• 胆嚢原発神経内分泌腫瘍の4症例

  滝新 悠之介, 桑谷 将城, 古川 龍太郎, 平田 甫, 平田 幸司, 加藤 新, 坂本 直哉, 岡村 圭祐, 平野 聡, 三橋 智子

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 125回 37 - 37 2019/09
• Budd-Chiari症候群に対しPercutaneous transluminal angioplastyが奏功した一例

  吉田 苑永, 川岸 直樹, 小田 総一郎, 志藤 茜, 目野 晃光, 吉河 歩, 安孫子 怜史, 原田 一顕, 佐野 逸紀, 小田 寿, 須田 剛生, 小川 浩司, 吉野 裕紀, 阿保 大介, 宮城島 拓人, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 125回 31 - 31 2019/09
• 肝細胞癌細胞株においてメトホルミンはAMPK-CEBPβ経路を介してCD133の発現を制御する(Metformin regulates the expression of CD133 through the AMPK-CEBPβ pathway in hepatocellular carcinoma cell lines)

  前原 経, 大西 俊介, 夏井坂 光輝, 坂本 直哉

  日本癌学会総会記事 78回 P - 3258 0546-0476 2019/09
• Quantifying Protein-Specific N-Glycome Profiles by Focused Protein and Immunoprecipitation Glycomics.

  Takashi Kobayashi, Koji Ogawa, Jun-Ichi Furukawa, Hisatoshi Hanamatsu, Megumi Hato, Tomoyo Yoshinaga, Kenichi Morikawa, Goki Suda, Takuya Sho, Masato Nakai, Kenichi Higashino, Yoshito Numata, Yasuro Shinohara, Naoya Sakamoto

  Journal of proteome research 18 (8) 3133 - 3141 1535-3893 2019/08/02 [Refereed][Not invited]
   

  Serum N-glycans have been reported to be potential diagnostic and therapeutic biomarkers for many diseases and conditions, such as inflammation, fibrosis, and cancer progression. We previously described the focused protein glycomic analysis (FPG) from gel-separated serum proteins. With this methodology, we sought novel glycan biomarkers for nonalcoholic steatohepatitis (NASH) and successfully identified some N-glycans that were significantly elevated in NASH patients compared to nonalcoholic fatty liver patients. Among them, trisialylated monofucosylated triantennary glycan (A3F) of alpha-1 antitrypsin showed the most dynamic change. For rapid identification of N-glycans on the focused proteins, we constructed a simplified method called immunoprecipitation glycomics (IPG), where the target proteins were immunoprecipitated with affinity beads and subsequently subjected to glycomic analysis by MALDI-TOF MS. Focusing on alpha-1 antitrypsin and ceruloplasmin as the target proteins, we compared the values of N-glycans determined by FPG and IPG. The quantified values of each N-glycan by these two methods showed a statistically significant correlation, indicating that high throughput and quantitative N-glycomics of targeted proteins can be achieved by the simplified IPG method. Thus, an analytical strategy combining FPG and IPG can be adapted to general biomarker discovery and validation in appropriate disease areas.
• Cancer extracellular vesicles contribute to stromal heterogeneity by inducing chemokines in cancer-associated fibroblasts.

  Yutaka Naito, Yusuke Yamamoto, Naoya Sakamoto, Iwao Shimomura, Akiko Kogure, Minami Kumazaki, Akira Yokoi, Masakazu Yashiro, Tohru Kiyono, Kazuyoshi Yanagihara, Ryou-U Takahashi, Kosei Hirakawa, Wataru Yasui, Takahiro Ochiya

  Oncogene 38 (28) 5566 - 5579 0950-9232 2019/07 [Refereed][Not invited]
   

  Cancer-associated fibroblasts (CAFs), one of the major components of a tumour microenvironment, comprise heterogeneous populations involved in tumour progression. However, it remains obscure how CAF heterogeneity is governed by cancer cells. Here, we show that cancer extracellular vesicles (EVs) induce a series of chemokines in activated fibroblasts and contribute to the formation of the heterogeneity. In a xenograft model of diffuse-type gastric cancer, we showed two distinct fibroblast subpopulations with alpha-smooth muscle actin (α-SMA) expression or chemokine expression. MicroRNAs (miRNAs) profiling of the EVs and the transfection experiment suggested that several miRNAs played a role in the induction of chemokines such as CXCL1 and CXCL8 in fibroblasts, but not for the myofibroblastic differentiation. Clinically, aberrant activation of CXCL1 and CXCL8 in CAFs correlated with poorer survival in gastric cancer patients. Thus, this link between chemokine expression in CAFs and tumour progression may provide novel targets for anticancer therapy.
• Nutrition is often ignored in management of chronic liver diseases.

  Naoya Sakamoto, Goki Suda, Kennichi Morikawa, Koji Ogawa

  Journal of gastroenterology and hepatology 34 (7) 1127 - 1128 2019/07
• Effect of Pancreatic Mass Size on Clinical Outcomes of Endoscopic Ultrasound-Guided Fine-Needle Aspiration.

  Sugiura R, Kuwatani M, Hirata K, Sano I, Kato S, Kawakubo K, Sakamoto N

  Digestive diseases and sciences 64 (7) 2006 - 2013 0163-2116 2019/07 [Refereed][Not invited]
   

  BACKGROUND: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has high diagnostic accuracy for pancreatic diseases. However, the effect of mass size on diagnostic accuracy has yet to be determined, especially for small pancreatic lesions. We aimed to determine the effect of pancreatic mass size on the diagnostic yield of EUS-FNA. METHODS: We searched the database in Hokkaido University Hospital between May 2008 and December 2016 and identified solid pancreatic lesions examined by EUS-FNA. All lesions were stratified into five groups based on mass sizes: groups A (< 10 mm), B (10-20 mm), C (20-30 mm), D (30-40 mm) and E (≥ 40 mm). The sensitivity, specificity, diagnostic accuracy and adverse event rate were retrospectively evaluated. RESULTS: We analyzed a total of 788 solid pancreatic lesions in 761 patients. The patients included 440 males (57.8%) with a mean age of 65.7 years. The sensitivities in groups A (n = 36), B (n = 223), C (n = 304), D (n = 147) and E (n = 78) were 89.3%, 95.0%, 97.4%, 98.5% and 98.7%, respectively, and they significantly increased as the mass size increased (P < 0.01, chi-squared test for trend). The diagnostic accuracies were 91.7%, 96.4%, 97.7%, 98.6% and 98.7%, respectively, and they also significantly increased as the mass size increased (P = 0.03). Multivariate analysis showed that pancreatic mass size was associated with diagnostic accuracy. The adverse event rates were not significantly different among the five groups. CONCLUSIONS: The sensitivities and diagnostic accuracies of EUS-FNA for solid pancreatic lesions are higher for lesions ≥ 10 mm in size, and they are strongly correlated with mass size.
• Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection.

  Goki Suda, Chitomi Hasebe, Masami Abe, Masayuki Kurosaki, Jun Itakura, Namiki Izumi, Yoshihito Uchida, Satoshi Mochida, Hiroaki Haga, Yoshiyuki Ueno, Kazumichi Abe, Atsushi Takahashi, Hiromasa Ohira, Yoko Tsukuda, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Tomoe Kobayashi, Jun Inoue, Katsumi Terasita, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Journal of gastroenterology 54 (7) 641 - 649 0944-1174 2019/07 [Refereed][Not invited]
   

  BACKGROUND: Until recently, interferon-free anti-hepatitis C virus (HCV) therapy for genotype 2 (GT2) HCV-infected hemodialysis patients was an unfulfilled medical need. Recent clinical trials of glecaprevir and pibrentasvir (G/P) for hemodialysis patients showed high efficacy and safety; however, the number of GT2 HCV-infected patients, especially Asian patients, was limited and most of them were treated with a 12-week regimen. In this prospective multicenter study, we aimed to investigate the efficacy and safety of G/P in Japanese hemodialysis patients with GT2 HCV infection. METHODS: Twenty-seven Japanese hemodialysis patients with GT2 HCV infection who were started on with 8- or 12-week G/P regimen between November 2017 and June 2018 were included and followed up for around 12 weeks after treatment completion. RESULTS: Among the 27 included patients, 13 non-liver cirrhosis (LC) and direct-acting antivirals (DAAs)-naïve patients were treated with 8 weeks of G/P and 14 patients with LC (n = 13) or history of failure of DAAs (n = 1) were treated with a 12-week regimen. The overall sustained virological response at 12 weeks after treatment completion (SVR 12) was 96.3% (26/27). All patients with 8 weeks of treatment achieved SVR12. Two patients discontinued the therapy at 2 and 11 weeks after treatment initiation. The patient who discontinued at 2 weeks due to pruritus alone failed to respond to G/P. No patients experienced lethal adverse events during the therapy, and the most common adverse event was pruritus. CONCLUSIONS: An 8- or 12-week G/P regimen is highly effective and safe in GT2 HCV-infected hemodialysis patients.
• Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma.

  Makoto Chuma, Hidenori Toyoda, Juntaro Matsuzaki, Yoshimasa Saito, Takashi Kumada, Toshifumi Tada, Yuji Kaneoka, Atsuyuki Maeda, Hideki Yokoo, Koji Ogawa, Toshiya Kamiyama, Akinobu Taketomi, Yoshihiro Matsuno, Keiichi Yazawa, Kazuhisa Takeda, Chikara Kunisaki, Katsuaki Ogushi, Satoshi Moriya, Koji Hara, Akito Nozaki, Masaaki Kondo, Hiroyuki Fukuda, Kazushi Numata, Katsuaki Tanaka, Shin Maeda, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 49 (7) 810 - 822 1386-6346 2019/07 [Refereed][Not invited]
   

  AIMS: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. METHODS: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription-polymerase chain reaction (PCR). RESULTS: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor-node-metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528-5.071; P = 0.0008). CONCLUSION: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.
• Short- and long-term outcomes of a novel transpapillary dilation technique using a diathermic dilator for severe benign bile duct stricture.

  Kato S, Kuwatani M, Kawakubo K, Sugiura R, Hirata K, Nakajima M, Hirata H, Kawakami H, Sakamoto N

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 (4) 448 - 452 0915-5635 2019/07 [Refereed][Not invited]
   

  Endoscopic dilation for severe benign biliary stricture using mechanical dilation devices is occasionally ineffective. Hence, diathermic dilation has recently been gaining attention as a salvage procedure. We evaluated the short- and long-term outcomes of diathermic dilation for severe benign biliary stricture that could not be dilated using conventional mechanical dilation. Thirteen consecutive cases with severe benign biliary stricture that underwent diathermic dilation using 6-Fr electrocautery dilator were enrolled. Short- and long-term outcomes were analyzed. Diathermic dilation was successful in 13 cases (100%), whereas stent was successfully placed in 12 cases (92.3%). Adverse events occurred in two cases (15.4%): mild hemobilia and cholangitis. Recurrence of bile duct stricture was observed in five out of 12 cases (41. 7%) in the 1115-day median follow-up period. Finally, eight cases achieved stent-free state (61.5%) and have remained stent-free without any episode of cholangitis and abnormal liver function test. Diathermic dilation using 6-Fr electrocautery dilator is a promising salvage procedure for severe benign biliary stricture when the conventional dilation technique has been ineffective.
• Validity of endoscopic features for the diagnosis of Helicobacter pylori infection status based on the Kyoto classification of gastritis.

  Yoshii S, Mabe K, Watano K, Ohno M, Matsumoto M, Ono S, Kudo T, Nojima M, Kato M, Sakamoto N

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 32 (1) 74 - 83 0915-5635 2019/07 [Refereed][Not invited]
   

  OBJECTIVES: Evaluation of Helicobacter pylori infection status (non-infection, past infection, current infection) has become important. This study aimed to determine the usefulness of the Kyoto classification of gastritis for diagnosing H. pylori infection status by endoscopy. METHODS: In this prospective study, 498 subjects were recruited. Seven well-experienced endoscopists blinded to the history of eradication therapy performed the examinations. Endoscopic findings were assessed according to the Kyoto classification of gastritis: diffuse redness, regular arrangement of collecting venules (RAC), fundic gland polyp (FGP), atrophy, xanthoma, hyperplastic polyp, map-like redness, intestinal metaplasia, nodularity, mucosal swelling, white and flat elevated lesion, sticky mucus, depressive erosion, raised erosion, red streak, and enlarged folds. We established prediction models according to a machine learning procedure and compared them with general assessment by endoscopists using the Kyoto classification of gastritis. RESULTS: Significantly higher diagnostic odds were obtained for RAC (32.2), FGP (7.7), and red streak (4.7) in subjects with non-infection, map-like redness (12.9) in subjects with past infection, and diffuse redness (26.8), mucosal swelling (13.3), sticky mucus (10.2) and enlarged fold (8.6) in subjects with current infection. The overall diagnostic accuracy rate was 82.9% with the Kyoto classification of gastritis. The diagnostic accuracy of the prediction model was 88.6% for the model without H. pylori eradication history and 93.4% for the model with eradication history. CONCLUSIONS: The Kyoto classification of gastritis is useful for diagnosing H. pylori infection status based on endoscopic findings. Our prediction model is helpful for novice endoscopists. (UMIN000016674).
• Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines.

  Maehara O, Ohnishi S, Asano A, Suda G, Natsuizaka M, Nakagawa K, Kobayashi M, Sakamoto N, Takeda H

  Neoplasia (New York, N.Y.) 21 (6) 545 - 556 1522-8002 2019/06 [Refereed][Not invited]
  
• Verification of the effectiveness of fucosylated haptoglobin as a pancreatic cancer marker in clinical diagnosis.

  Kuwatani M, Kawakami H, Kubota Y, Kawakubo K, Ito YM, Togo S, Ikeda T, Kusama K, Kobayashi Y, Murata T, Sakamoto N

  Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 19 (4) 569 - 577 1424-3903 2019/06 [Refereed][Not invited]
   

  BACKGROUND: Fucosylated haptoglobin detected by Pholiota squarrosa lectin (PhoSL) that had specificity for fucose α1-6 was reported as an effective biomarker for several gastrointestinal diseases. The aim of this study was to verify Fucosylated haptoglobin detected by Pholiota squarrosa lectin (PhoSL-HP) as a pancreatic cancer (PC) marker using a new method of PhoSL-ELISA. METHODS: PhoSL-HP in sera from 98 PC patients and 158 non-PC samples including 32 intraductal papillary mucinous neoplasm (IPMN) patients, 21 chronic pancreatitis (CP) patients and 105 non-pancreatic disease controls (NPDC) were measured. We compared sensitivities, specificities and areas under the curves (AUC) of PhoSL-HP, CA19-9 and CEA as single markers. We also evaluated PhoSL-HP as combination marker by comparing AUC of CA19-9 combined with PhoSL-HP or CEA. RESULTS: The sensitivities of PhoSL-HP, CA19-9 and CEA for PC were 58%, 76% and 42%, respectively. Although the specificity of PhoSL-HP for NPDC was inferior to both of CA19-9 and CEA, that for pancreatic diseases was higher than both of CA19-9 and CEA. Combined CA19-9 with PhoSL-HP, the AUC was significantly higher at 0.880 than single use of CA19-9 at 0.825 in case of distinguishing PC from other pancreatic diseases. In contrast, the AUC of CA19-9 was not elevated significantly when combined with CEA. CONCLUSION: PhoSL-HP would be a useful marker for PC and have sufficient complementarity for CA19-9.
• miR-27b-mediated suppression of aquaporin-11 expression in hepatocytes reduces HCV genomic RNA levels but not viral titers.

  Fuminori Sakurai, Rina Hashimoto, Chieko Inoue, Keisaku Wakabayashi, Tomohito Tsukamoto, Tsutomu Imaizumi, Taracena Gandara Marcos Andres, Eiko Sakai, Kanae Itsuki, Naoya Sakamoto, Takaji Wakita, Hiroyuki Mizuguchi

  Virology journal 16 (1) 58 - 58 2019/05/02 [Refereed][Not invited]
   

  BACKGROUND: MicroRNAs (miRNAs) have gained much attention as cellular factors regulating hepatitis C virus (HCV) infection. miR-27b has been shown to regulate HCV infection in the hepatocytes via various mechanisms that have not been fully elucidated. In this study, therefore, we examined the mechanisms of miR-27b-mediated regulation of HCV infection. METHODS: In silico screening analysis, transfection with miR-27b mimic, and a cell-based reporter assay were performed to identify miR-27b target genes. Cell cultured-derived HCV (HCVcc) was added to Huh7.5.1 cells knocked down for aquaporin (AQP) 11 (AQP11) and overexpressing AQP11. HCV replication levels were evaluated by real-time RT-PCR analysis of HCVcc genome. RESULTS: Infection of Huh7.5.1 cells with HCVcc resulted in significant elevation in miR-27b expression levels. In silico analysis revealed that AQP11, which is an AQP family member and is mainly localized in the endoplasmic reticulum (ER), was a candidate for a target gene of miR-27b. Transfection of a miR-27b mimic significantly reduced AQP11 expression, but a cell-based reporter assay demonstrated that miR-27b did not suppress the expression of a reporter gene containing the 3'-untranslated region of the AQP11 gene, suggesting that miR-27b indirectly suppressed AQP11 expression. AQP11 expression levels were significantly reduced by infection with HCVcc in Huh7.5.1 cells. Knockdown and over-expression of AQP11 significantly reduced and increased HCVcc genome levels in the cells following infection, respectively, however, AQP11 knockdown did not show significant effects on the HCVcc titers in the culture supernatants. CONCLUSIONS: These results indicated that HCV infection induced a miR-27b-mediated reduction in AQP11 expression, leading to a modest reduction in HCV genome levels in the cells, not HCV titers in the culture supernatants.
• 主膵管閉塞を伴わない悪性胆管狭窄に対する金属ステント留置時の乳頭括約筋切開の必要性 多施設共同傾向スコア解析研究

  加藤 新, 桑谷 将城, 江藤 和範, 小野 道洋, 大和 弘明, 江平 宣起, 佐野 逸紀, 庵原 秀之, 久保 公利, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.1) 864 - 864 0387-1207 2019/05
• 内視鏡的乳頭括約筋切開術による出血に対する治療法

  平田 甫, 桑谷 将城, 坂本 直哉, 中島 正人, 平田 幸司, 杉浦 諒, 加藤 新

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.1) 922 - 922 0387-1207 2019/05
• カプセル内視鏡を施行した経口抗凝固薬服用者のOGIB ワルファリンとDOACの比較

  井上 雅貴, 小野 尚子, 田中 一光, 木脇 佐代子, 石川 麻倫, 松田 可奈, 津田 桃子, 高橋 正和, 山本 桂子, 中川 学, 中川 宗一, 清水 勇一, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.1) 885 - 885 0387-1207 2019/05
• 消化器内視鏡診療におけるトランスレーショナルリサーチ DPP-IV活性により蛍光を発するプローブによる食道胃接合部腺癌の検出

  山本 桂子, 大西 俊介, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 61 (Suppl.1) 822 - 822 0387-1207 2019/05
• Spraying l-menthol enhances gastric intestinal metaplasia in linked color imaging.

  Ono S, Ono Y, Sakamoto N

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 (3) e70 - e71 0915-5635 2019/05 [Refereed][Not invited]
  
• Transcribed ultraconserved region Uc.63+ promotes resistance to cisplatin through regulation of androgen receptor signaling in bladder cancer.

  Yohei Sekino, Naoya Sakamoto, Akira Ishikawa, Ririno Honma, Yoshinori Shigematsu, Tetsutaro Hayashi, Kazuhiro Sentani, Naohide Oue, Jun Teishima, Akio Matsubara, Wataru Yasui

  Oncology reports 41 (5) 3111 - 3118 1021-335X 2019/05 [Refereed][Not invited]
   

  Cisplatin (CDDP)‑based combination chemotherapy is the standard for muscle‑invasive bladder cancer (MIBC). However, nearly all patients undergoing CDDP chemotherapy become refractory due to the development of CDDP resistance. Therefore, clarification of the mechanisms of CDDP resistance is urgently needed. The transcribed ultraconserved regions (T‑UCRs) are a novel class of non‑coding RNAs that are highly conserved across species and are associated with carcinogenesis and cancer progression. In addition, emerging evidence has shown the involvement of androgen receptor (AR) signals in urothelial carcinoma (UC) progression. The aim of the present study was to investigate the expression of transcribed ultraconserved region Uc.63+, and to analyze the effects of Uc.63+ on AR expression and CDDP resistance in UC. Quantitative reverse transcription‑polymerase chain reaction (qRT‑PCR) revealed that the expression of Uc.63+ was higher in UC tissues than that in non‑neoplastic bladder tissues and 15 types of normal tissue. An MTT assay revealed that Uc.63+ was involved in cell proliferation. Western blotting demonstrated that the expression of AR was disrupted by the overexpression or knockdown of Uc.63+ in AR‑positive UMUC3 cells. Furthermore, knockdown of Uc.63+ increased sensitivity to CDDP in UMUC3 cells. Conversely, overexpression of Uc.63+ had no effect on CDDP sensitivity in AR‑negative RT112 cells. Additionally, we observed that the expression of Uc.63+ was increased in CDDP‑resistant UMUC3 cells (UMUC3‑CR) in comparison with that in parental UMUC3 cells. Knockdown of Uc.63+ re‑sensitized the UMUC3‑CR cells to CDDP. These results indicated that Uc.63+ may be a promising therapeutic target to overcome CDDP resistance in UC.
• Synchronous multiple pancreatic cancers developed long after severe postendoscopic retrograde cholangiopancreatography pancreatitis.

  Sugiura R, Kuwatani M, Hirata K, Kato S, Kawamoto Y, Kawakubo K, Mitsuhashi T, Asano T, Hirano S, Sakamoto N

  Endoscopic ultrasound 8 (3) 213 - 214 2303-9027 2019/05 [Refereed][Not invited]
  
• Budesonide foam for prevention of rectal stricture following endoscopic submucosal dissection.

  Miyamoto S, Naruse H, Sakamoto N

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 (5) 588 - 588 0915-5635 2019/05 [Refereed][Not invited]
  
• Long-term effect of nucleos (t)ide analogs on hepatitis B surface antigen in chronic hepatitis B patients

  Kenichi Morikawa, Machiko Umemura, Koji Ogawa, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Tomoe Shimazaki, Megumi Kimura, Takaaki Izumi, Masato Nakai, Takuya Sho, Goki Suda, Mitsuteru Natsuizaka, Kota Ono, Kazumoto Murata, Masaya Sugiyama, Mizokami Masashi, Naoya Sakamoto

  JOURNAL OF HEPATOLOGY 70 (1) E477 - E477 0168-8278 2019/04 [Refereed][Not invited]
  
• The Successful Retreatment with Glecaprevir and Pibrentasvir of Genotype 1 or 2 HCV-infected Hemodialysis Patients who Failed to Respond to NS5A and Protease Inhibitor Treatment.

  Goki Suda, Masato Nakai, Takuya Sho, Megumi Kimura, Tomoe Shimazaki, Osamu Maehara, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Masaru Baba, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Internal medicine (Tokyo, Japan) 58 (7) 943 - 947 0918-2918 2019/04/01 [Refereed][Not invited]
   

  Clinical trials and real-world data have proven that hepatitis C virus (HCV) in most infected patients can be eradicated by direct-acting antivirals (DAAs). However, the proper retreatment regimen for hemodialysis patients with HCV infection who have previously failed to respond to DAAs has not been clarified. We herein report, for the first time, the successful retreatment with glecaprevir and pibrentasvir, of three hemodialysis patients with genotype 1 or 2 HCV infection, who had previously failed to respond to combination therapy with an HCV-NA5A inhibitor (daclatasvir) and an HCV protease inhibitor (asunaprevir).
• Changes of Dyspeptic Symptom after Successful Eradication in Helicobacter pylori-Associated Dyspepsia.

  Tsuda M, Kato M, Ono S, Matsuda K, Miyamoto S, Abiko S, Ono M, Mizushima T, Yamamoto K, Nakagawa M, Mabe K, Nakagawa S, Kudo T, Nishikawa K, Shimizu Y, Asaka M, Sakamoto N

  Digestion 101 (2) 1 - 9 0012-2823 2019/04 [Refereed][Not invited]
   

  BACKGROUND: Helicobacter pylori (H. pylori) gastritis could cause dyspepsia, and eradication is recommended as the first-line treatment. Patients who continuously have their symptoms under control > 6 months after eradication are defined as having H. pylori-associated dyspepsia (HPD), whereas patients who do not benefit from successful eradication are defined as having functional dyspepsia. OBJECTIVES: We assessed changes in dyspeptic symptoms after successful eradication of H. pylori by using a questionnaire. METHODS: We studied H. pylori-infected dyspeptic participants with abdominal symptom scores > 4 points on the Global Overall Symptom (GOS) scoring items and received eradication therapy. We evaluated their symptoms using the GOS questionnaire before their eradications, at 1-month and at 1-year check-ups after eradication therapy. RESULTS: Thirty dyspeptic participants (mean age 59.6 ± 15.3 years) answered every questionnaire. Fourteen participants (46.7%) had HPD, whereas 16 participants (53.3%) were non-HPD patients. The questionnaire at 1 month showed sensitivity of 64.3% (9/14) and specificity of 56.3% (9/16) for HPD. Approximately 60% of H. pylori-infected dyspepsia participants were identified as having HPD or non-HPD within 1 month after their eradications. CONCLUSIONS: Approximately 60% of HPD participants improved at 1 month after eradication. The questionnaire at 1 month helped diagnose HPD in advance and guided next treatment choice.
• Detection of gastritis by a deep convolutional neural network from double-contrast upper gastrointestinal barium X-ray radiography

  Ren Togo, Nobutake Yamamichi, Katsuhiro Mabe, Yu Takahashi, Chihiro Takeuchi, Mototsugu Kato, Naoya Sakamoto, Kenta Ishihara, Takahiro Ogawa, Miki Haseyama

  Journal of Gastroenterology 54 (4) 321 - 329 0944-1174 2019/04 [Refereed][Not invited]
   

  © 2018, Japanese Society of Gastroenterology. Background: Deep learning has become a new trend of image recognition tasks in the field of medicine. We developed an automated gastritis detection system using double-contrast upper gastrointestinal barium X-ray radiography. Methods: A total of 6520 gastric X-ray images obtained from 815 subjects were analyzed. We designed a deep convolutional neural network (DCNN)-based gastritis detection scheme and evaluated the effectiveness of our method. The detection performance of our method was compared with that of ABC (D) stratification. Results: Sensitivity, specificity, and harmonic mean of sensitivity and specificity of our method were 0.962, 0.983, and 0.972, respectively, and those of ABC (D) stratification were 0.925, 0.998, and 0.960, respectively. Although there were 18 false negative cases in ABC (D) stratification, 14 of those 18 cases were correctly classified into the positive group by our method. Conclusions: Deep learning techniques may be effective for evaluation of gastritis/non-gastritis. Collaborative use of DCNN-based gastritis detection systems and ABC (D) stratification will provide more reliable gastric cancer risk information.
• Glecaprevir and Pibrentasvir for Japanese Patients with Human Immunodeficiency Virus and Genotype 3 Hepatitis C Virus Coinfection: A Report of Three Cases.

  Takuya Sho, Goki Suda, Megumi Kimura, Tomoe Shimazaki, Osamu Maehara, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Takaaki Izumi, Naoki Kawagishi, Masaru Baba, Masato Nakai, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Internal medicine (Tokyo, Japan) 58 (6) 797 - 802 0918-2918 2019/03/15 [Refereed][Not invited]
   

  The efficacy and safety of glecaprevir and pibrentasvir in Japanese patients with human immunodeficiency virus (HIV) and/or genotype 3 hepatitis C virus (HCV) infection is yet to be clarified. This is because no or only a few patients have been included in Japanese phase 3 trials. We herein report for the first time the successful treatment of glecaprevir and pibrentasvir in three Japanese patients with HIV and genotype 3 HCV coinfection as well as hemophilia. Glecaprevir and pibrentasvir treatment is safe and effective for Japanese patients with genotype 3 HCV and HIV coinfection.
• 胆道病変に対する超音波内視鏡下穿刺吸引法の臨床成績

  平田 甫, 桑谷 将城, 中島 正人, 平田 幸司, 杉浦 諒, 加藤 新, 坂本 直哉

  日本消化器病学会北海道支部例会プログラム・抄録集 日本消化器病学会-北海道支部 124回 66 - 66 2019/03
• Unusual reintervention through a fistula for ampullary penetration of a plastic stent in malignant distal biliary obstruction.

  Sugiura R, Kuwatani M, Sakamoto N

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 (2) e48 - e49 0915-5635 2019/03 [Refereed][Not invited]
  
• Long-term outcomes after therapeutic endoscopic retrograde cholangiopancreatography using balloon-assisted enteroscopy for anastomotic stenosis of choledochojejunostomy/pancreaticojejunostomy.

  Sano I, Katanuma A, Kuwatani M, Kawakami H, Kato H, Itoi T, Ono M, Irisawa A, Okabe Y, Iwashita T, Yasuda I, Ryozawa S, Kaino S, Sakamoto N

  Journal of gastroenterology and hepatology 34 (3) 612 - 619 0815-9319 2019/03 [Refereed][Not invited]
   

  BACKGROUND AND AIM: Data on long-term outcomes after therapeutic endoscopic retrograde cholangiopancreatography (ERCP) using balloon-assisted enteroscopy (BAE) for choledochojejunal anastomotic stenosis (CJS) or pancreaticojejunal anastomotic stenosis (PJS) remain limited. We retrospectively assessed the long-term results of patients who achieved clinical success using BAE for CJS and PJS. METHODS: Patients who achieved technical and clinical success for CJS or PJS by BAE-ERCP and were followed up for more than 6 months after the initial BAE-ERCP therapy were retrospectively identified at 11 Japanese institutions. The primary end-point was CJS or PJS recurrence rates. The secondary end-points were initial therapy details, initial therapy complications, and CJS or PJS recurrence treatment details. We also evaluated restenosis-associated factors. RESULTS: From September 2008 to December 2015, 67 patients (CJS, 61; PJS, six) were included. The overall CJS and PJS recurrence rates were 34.4% and 33.3%, respectively. The 1-year CJS recurrence rate was 18.5% (95% confidence interval, 10.7-31.0). Of all the patients, 88.1% underwent balloon dilation at the anastomotic stenosis site; stent placement was performed in 15 of 67 patients (22.4%). The complication rate was 8.2% in CJS and 0% in PJS. In patients who underwent balloon dilation, "remaining waist" was significantly associated with CJS recurrence after anastomotic balloon dilation (P = 0.001). CONCLUSIONS: The long-term outcomes of BAE-ERCP were comparable with those of percutaneous transhepatic treatment or surgical re-anastomosis.
• Better too big than too small?

  Kawakubo K, Kuwatani M, Kato S, Sakamoto N

  Gastrointestinal endoscopy 89 (3) 650 - 651 0016-5107 2019/03 [Refereed][Not invited]
  
• Prospective, multicenter, observational study of tissue acquisition through EUS-guided fine-needle biopsy using a 25G Franseen needle.

  Sugiura R, Kuwatani M, Yane K, Taya Y, Ihara H, Onodera M, Eto K, Sano I, Kudo T, Mitsuhashi T, Katanuma A, Sakamoto N, Hokkaido Interventional EUS, ERCP study, HONEST) group

  Endoscopic ultrasound 2303-9027 2019/03 [Refereed][Not invited]
  
• Comparative sequence analysis of patient-matched primary colorectal cancer, metastatic, and recurrent metastatic tumors after adjuvant FOLFOX chemotherapy.

  Harada K, Okamoto W, Mimaki S, Kawamoto Y, Bando H, Yamashita R, Yuki S, Yoshino T, Komatsu Y, Ohtsu A, Sakamoto N, Tsuchihara K

  BMC cancer 19 (1) 255 - 255 2019/03 [Refereed][Not invited]
   

  BACKGROUND: In the era of genome-guided personalized cancer treatment, we must understand chemotherapy-induced genomic changes in tumors. This study evaluated whether adjuvant FOLFOX chemotherapy modifies the mutational profile of recurrent colorectal cancer (CRC). METHODS: Whole exome sequencing was performed on samples from primary CRC tumors, untreated metastatic tumors, and recurrent tumors following adjuvant FOLFOX chemotherapy. The samples were resected from four patients. RESULTS: The number of mutations or the mutation spectrum in individual patients was nearly identical. Copy number variants persisted regardless of FOLFOX therapy administration. The genomic signature of oxaliplatin exposure (G > T/C > A, T > A/A > T) was not enriched after FOLFOX chemotherapy. Overlapping single nucleotide variants (SNVs) and indels remained in 26-65% of the patient-matched tumor samples. One patient harbored an AKT1 E17K mutation in the recurrent tumor, whereas PIK3CA E542K and E88Q mutations were detected in the primary and untreated metastatic tumor samples. Genes related to intracellular Ca2+ homeostasis were enriched among the genes uniquely mutated after FOLFOX chemotherapy. CONCLUSIONS: We found that the mutation rates, mutation spectrum, and copy number variants were nearly identical regardless of the administration of FOLFOX therapy in the four CRC cases. The mutational discordance between the patient-matched tumor samples is likely caused by tumor heterogeneity and chemotherapy-induced clonal selection. These findings might be useful as pilot data for larger studies to clarify the changes in the mutational landscape induced by adjuvant FOLFOX chemotherapy.
• A Novel Approach for the Genetic Analysis of Biliary Tract Cancer Specimens Obtained Through Endoscopic Ultrasound-Guided Fine Needle Aspiration Using Targeted Amplicon Sequencing.

  Hirata K, Kuwatani M, Suda G, Ishikawa M, Sugiura R, Kato S, Kawakubo K, Sakamoto N

  Clinical and translational gastroenterology 10 (3) e00022  2019/03 [Refereed][Not invited]
   

  OBJECTIVES: Biliary tract cancer (BTC) is an aggressive malignant tumor, and biomarker-based clinical trials for this cancer are currently ongoing. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a safe procedure and enables pathological diagnoses; however, it is uncertain whether a tiny tumor sample of BTC obtained through EUS-FNA can be analyzed for diverse genetic alterations in the development and tolerance of BTC. Thus, we aimed to verify the feasibility of genetic analyses with EUS-FNA samples of BTC. METHODS: Targeted amplicon sequencing using a cancer gene panel with 50 genes was performed with tissue samples of 21 BTC patients obtained through EUS-FNA with a novel rapid on-site process compared with paired peripheral blood samples. RESULTS: Pathogenic gene alterations were successfully identified in 20 out of 21 patients (95.2%) with EUS-FNA specimens of BTC, which included 19 adenocarcinomas and 2 adenosquamous carcinomas. Eighty single nucleotide variants and 8 indels in 39 genes were identified in total, and 28 pathogenic alterations in 14 genes were identified (average, 1.4 alterations per patient). The most common alterations were TP53, KRAS, and CDKN2A in gallbladder carcinoma; TP53, KRAS, PIK3CA, and BRAF in intrahepatic cholangiocarcinoma; and TP53 and SMAD4 in extrahepatic cholangiocarcinoma. Actionable gene alterations (BRAF, NRAS, PIK3CA, and IDH1) were identified in 7 out of 21 patients. CONCLUSIONS: A novel approach in genetic analysis using targeted amplicon sequencing with BTC specimens obtained through EUS-FNA was feasible and enabled us to identify genomic alterations.
• Evaluation of gastric acid suppression with vonoprazan using calcium carbonate breath test.

  Miyamoto S, Tsuda M, Kato M, Mabe K, Muto S, Ono S, Shimizu Y, Sakamoto N

  Journal of clinical biochemistry and nutrition 64 (2) 174 - 179 0912-0009 2019/03 [Refereed][Not invited]
   

  Vonoprazan, a potassium-competitive acid blocker, is a new class of acid-suppressing agent. The acid-inhibitory effect of vonoprazan has been well-documented. However, there is no report on the extent to which the amount of gastric acid secretion is suppressed, not pH measurement, by the use of vonoprazan. The aim of this study was to evaluate this suppression effect. This was a single-arm, interventional pilot study involving 7 healthy Japanese men. The subjects were administered 20 mg vonoprazan for 6 days. The amount of gastric acid secretion was determined using the calcium carbonate breath test. The acid outputs were defined as the maximum Δ13C‰ (Δ13C max) and area under the curve (AUC) during the 30 min sampling period. The Δ13C max and AUC values significantly decreased on the administration of 20 mg vonoprazan. The AUC dropped by approximately 78% on day 1 and by 84% on day 6 and subsequently returned to the control level after cessation of vonoprazan therapy (reduction by 68% on day 7 and by 42% on day 8). In conclusion, the amount of gastric acid secretion rapidly decreased by the administration of vonoprazan; this inhibitory effect was found to be potent and long-lasting. (UMIN ID: UMIN000025469).
• DPP-IV活性により蛍光を発するプローブによる頭頸部扁平上皮表在がんの検出

  山本 桂子, 大西 俊介, 水島 健, 清水 勇一, 坂本 直哉

  耳鼻咽喉科展望 耳鼻咽喉科展望会 62 (1) 42 - 43 0386-9687 2019/02
• Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer.

  Kobayashi G, Sentani K, Hattori T, Yamamoto Y, Imai T, Sakamoto N, Kuraoka K, Oue N, Sasaki N, Taniyama K, Yasui W

  Human pathology 84 8 - 17 0046-8177 2019/02 [Refereed][Not invited]
   

  Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Spheroid colony formation is a useful method to identify cancer stem cells (CSCs). The aim of this study was to identify a novel prognostic marker or therapeutic target for GC using a method to identify CSCs. We analyzed the microarray data in spheroid body-forming and parental cells and focused on the CLSPN gene because it is overexpressed in the spheroid body-forming cells in both the GC cell lines MKN-45 and MKN-74. Quantitative reverse-transcription polymerase chain reaction analysis revealed that CLSPN messenger RNA expression was up-regulated in GC cell lines MKN-45, MKN-74, and TMK-1. Immunohistochemistry of claspin showed that 94 (47%) of 203 GC cases were positive. Claspin-positive GC cases were associated with higher T and N grades, tumor stage, lymphatic invasion, and poor prognosis. In addition, claspin expression was coexpressed with CD44, human epidermal growth factor receptor type 2, and p53. CLSPN small interfering RNA treatment decreased GC cell proliferation and invasion. These results indicate that the expression of claspin might be a key regulator in the progression of GC and might play an important role in CSCs of GC.
• Evaluation of clinical utility of PIVKA-II using a chemiluminescent immunoassay

  Koji Ogawa, Kazuharu Suzuki, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Naoya Sakamoto

  Acta Hepatologica Japonica 60 (11) 397 - 404 1881-3593 2019 

  PIVKA-II is a tumor marker highly specific for hepatocellular carcinoma. We investigated the utility of Architect PIVKA-II, a chemiluminescent immunoassay, in 168 patients with liver disease (chronic hepatitis, n = 29 liver cirrhosis, n = 28 and hepatocellular carcinoma by stage: stage 1, n = 29 stage 2, n = 29 stage 3, n = 26 and stage 4, n = 27). Architect PIVKA-II was measured in preserved serum and compared with LumipulseⓇ PIVKA-II and alpha fetoprotein (AFP) values measured that had been measured during patient evaluation. Both methods indicated increasing PIVKA-II levels with each higher stage of hepatocellular carcinoma. The diagnostic accuracy when combined with AFP was equivalent. Architect PIVKA-II has a diagnostic accuracy comparable to conventional tests in cases of hepatocellular carcinoma and should be useful in clinical practice.
• Esptein-Barr virus陽性リンパ上皮腫様大腸癌の1例

  木脇 佐代子, 山本 桂子, 井上 雅貴, 田中 一光, 松田 可奈, 石川 麻倫, 津田 桃子, 小野 尚子, 清水 勇一, 岡田 宏美, 三橋 智子, 松野 吉宏, 坂本 直哉

  日本大腸肛門病学会雑誌 (一社)日本大腸肛門病学会 72 (1) 43 - 43 0047-1801 2019/01
• 消化管に多発潰瘍を認めた造血幹細胞移植後EBウイルス関連リンパ増殖性疾患の1例

  松田 可奈, 小野 尚子, 井上 雅貴, 田中 一光, 木脇 佐代子, 石川 麻倫, 津田 桃子, 山本 桂子, 清水 勇一, 坂本 直哉

  日本大腸肛門病学会雑誌 (一社)日本大腸肛門病学会 72 (1) 44 - 44 0047-1801 2019/01
• Analysis of 307 cases with drug-induced liver injury between 2010 and 2018 in Japan.

  Mitsuhiko Aiso, Hajime Takikawa, Keiji Tsuji, Tatehiro Kagawa, Masaaki Watanabe, Atsushi Tanaka, Ken Sato, Shotaro Sakisaka, Yoichi Hiasa, Yoshiyuki Takei, Hiromasa Ohira, Minoru Ayada, Etsuko Hashimoto, Shuichi Kaneko, Yoshiyuki Ueno, Kenji Ohmoto, Akinobu Takaki, Takuji Torimura, Yasushi Matsuzaki, Kazuto Tajiri, Masashi Yoneda, Takayoshi Ito, Naoya Kato, Kenichi Ikejima, Satoshi Mochida, Hiroshi Yasuda, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 49 (1) 105 - 110 1386-6346 2019/01 [Refereed][Not invited]
   

  AIM: In order to know the present status of drug-induced liver injury (DILI) in Japan, we present the data of prospectively collected DILI cases between 2010 and 2018 from 27 hospitals. METHODS: Drug-induced liver injury cases diagnosed by DILI experts from 27 hospitals all over Japan have been prospectively collected since 2010. Alanine aminotransferase level ≥150 U/L and/or alkaline phosphatase ≥2× upper limit of normal were inclusion criteria. RESULTS: In total, data of 307 cases (125 male and 182 female individuals) aged between 17 and 86 years old were collected. The types of liver injury were as follows: 64% hepatocellular type, 20% mixed type, and 16% cholestatic type. A drug-induced lymphocyte stimulation test was carried out in 59% of cases, and was positive in 48% and semipositive in 3% of cases. Eosinophilia ≥6% was observed in 27% of cases. Fifty-three percent of DILI cases occurred within 30 days and 79% of DILI cases occurred within 90 days after starting drug administration. By the diagnostic scale of the Digestive Disease Week (DDW)-Japan 2004 workshop, 93.8% of cases were diagnosed as "highly probable", and 5.9% as "possible". CONCLUSIONS: Japanese DILI patients are somewhat different from those of Europe and North America. The diagnostic scale of the DDW-Japan 2004 workshop has been used in Japan. However, there are many issues to improve the causality assessment of DILI that we must investigate in the future. It is critical to elucidate the mechanisms of drug metabolism and the pathophysiology of liver injury by various drugs to prevent DILI.
• Safety and efficacy of elbasvir and grazoprevir in Japanese hemodialysis patients with genotype 1b hepatitis C virus infection.

  Goki Suda, Masayuki Kurosaki, Jun Itakura, Namiki Izumi, Yoshihito Uchida, Satoshi Mochida, Chitomi Hasebe, Masami Abe, Hiroaki Haga, Yoshiyuki Ueno, Ikuto Masakane, Kazumichi Abe, Atsushi Takahashi, Hiromasa Ohira, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Tomoe Kobayashi, Atsuhiko Kawakami, Kenichi Kumagai, Katsumi Terasita, Masatsugu Ohara, Naoki Kawagishi, Machiko Umemura, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Journal of gastroenterology 54 (1) 78 - 86 0944-1174 2019/01 [Refereed][Not invited]
   

  BACKGROUND: The prevalence of hepatitis C virus (HCV) infection in hemodialysis patients is high and results in a poor prognosis. Thus, safer and more effective treatment regimens are required. In this prospective multicenter study, we investigated the efficacy and safety of the novel HCV-NS5A-inhibitor, elbasvir, and protease inhibitor, grazoprevir in Japanese hemodialysis patients with genotype 1b HCV infection. METHODS: This study is registered at the UMIN Clinical Trials Registry as UMIN00002578. A total of 23 Japanese dialysis patients with genotype 1b HCV infection who were treated with elbasvir and grazoprevir between January 2017 and March 2018 and followed for more than 12 weeks after treatment completion were included. We evaluated the sustained virologic response at 12 weeks after treatment completion (SVR12) and safety during treatment. RESULTS: Of the 23 patients, 7 had advanced liver fibrosis and 2 had a signature resistance-associated variant of NS5A (NS5A RAVs)-L31M/V or Y93H at baseline. All patients completed therapy, and 96.7% (22/23) of the patients achieved SVR12. All patients with advanced liver fibrosis and signature NS5A RAVs at baseline achieved SVR12 with a high safety profile. No patient experienced lethal or severe adverse events during therapy, and the most common adverse event was anemia. One patient, who was a non-responder to this therapy, had a history of failure with daclatasvir and asunaprevir therapies and had NS5A RAVs of A92K at baseline, but not signature NS5A RAVs. CONCLUSIONS: Grazoprevir and elbasvir combination is highly effective and safe for hemodialysis patients with genotype 1b HCV infection.
• Usefulness of transabdominal ultrasonography for assessing ulcerative colitis: a prospective, multicenter study.

  Kinoshita K, Katsurada T, Nishida M, Omotehara S, Onishi R, Mabe K, Onodera A, Sato M, Eto K, Suya M, Maemoto A, Hasegawa T, Yamamoto J, Mitsumori D, Yoshii S, Ono K, Sakamoto N

  Journal of gastroenterology 54 (6) 521 - 529 0944-1174 2018/12 [Refereed][Not invited]
   

  BACKGROUND: Transabdominal ultrasonography (US) has been reported to be a useful tool for evaluating ulcerative colitis (UC) although with less well-established data than for Crohn's disease. This prospective multicenter study aimed to establish the usefulness of US compared with colonoscopy (CS) for assessing disease extent and activity of UC. METHODS: Altogether, 173 patients with UC were prospectively enrolled, among whom 156 were eligible for this study. All patients underwent US and CS within 2 days at five facilities. We divided the colon into six segments and examined each segment and the rectum using US and CS. US severity was graded 1-4 regarding bowel wall thickness, stratification, and ulceration. CS severity was also graded 1-4 according to Matts' endoscopic classification. Concordance between US and CS grades for all colonic segments was analyzed using kappa statistics. US and CS findings were also compared with the clinical disease activity index (CAI) and histological grade using Spearman's correlation coefficient. RESULTS: There was moderate concordance between US and CS grades in all colonic segments (weighted κ = 0.55, p < 0.001). Concordance was rated moderate for each colonic segment but only slight for the rectum. The US grade was significantly correlated with the CAI score (r = 0.40, p < 0.001) and histological grade (r = 0.35, p < 0.001). CONCLUSIONS: This prospective multicenter study showed moderate concordance between US and CS for assessing the disease activity of UC. Hence, US may be used more generally for evaluating UC in daily clinical practice.
• EUS versus transpapillary drainage of malignant biliary obstruction: still a long way to go.

  Kawakubo K, Kuwatani M, Sakamoto N

  Gastrointestinal endoscopy 88 (5) 884  0016-5107 2018/11 [Refereed][Not invited]
  
• Sialic Acid Linkage Specific Derivatization of Glycosphingolipid Glycans by Ring-Opening Aminolysis of Lactones.

  Hanamatsu H, Nishikaze T, Miura N, Piao J, Okada K, Sekiya S, Iwamoto S, Sakamoto N, Tanaka K, Furukawa JI

  Analytical chemistry 90 (22) 13193 - 13199 0003-2700 2018/11 [Refereed][Not invited]
  
• The Risk of Hepatocellular Carcinoma Development after Sustained Virologic Response Are Similar between Japanese Patients with HCV Genotype 1 Infection Treated with Ledipasvir/Sofosbuvir and Protease Inhibitor with Peg-Interferon Plus Ribavirin.

  Masaaki Korenaga, Namiki Izumi, Nobuharu Tamaki, Osamu Yokosuka, Tetsuo Takehara, Naoya Sakamoto, Goki Suda, Shuhei Nishiguchi, Hirayuki Enomoto, Fusao Ikeda, Mikio Yanase, Hidenori Toyoda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Kazumi Yamasaki, Tatsuya Ide, Nobuo Toda, Tatsuo Kanda, Kazushige Nirei, Yoshiyuki Ueno, Hiroaki Haga, Yohichi Nishigaki, Masao Omata, Hitoshi Mochiduki, Tatsuya Kanto, Masashi Mizokami

  HEPATOLOGY 68 535A - 536A 0270-9139 2018/10 [Refereed]
  
• Innovative therapeutic endoscopy良性胆管・膵管狭窄に対する内視鏡治療 良性胆管・膵管狭窄に対する経乳頭的通電拡張術の効果

  加藤 新, 桑谷 将城, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 60 (Suppl.2) 2013 - 2013 0387-1207 2018/10
• 良性胆管・膵管狭窄に対する内視鏡治療 良性胆管・膵管狭窄に対する経乳頭的通電拡張術の効果

  加藤 新, 桑谷 将城, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 115 (臨増大会) A633 - A633 0446-6586 2018/10
• 内視鏡を用いた小腸絨毛萎縮診断の正診率についての検討

  松田 可奈, 小野 尚子, 石川 麻倫, 宮本 秀一, 安孫子 怜史, 津田 桃子, 山本 桂子, 工藤 俊彦, 清水 勇一, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 60 (Suppl.2) 2123 - 2123 0387-1207 2018/10
• 食道癌内視鏡的切除後の異時性多発癌に及ぼす節酒禁煙効果の検討

  安孫子 怜史, 清水 勇一, 石川 麻倫, 松田 可奈, 宮本 秀一, 津田 桃子, 山本 桂子, 小野 尚子, 工藤 俊彦, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 115 (臨増大会) A756 - A756 0446-6586 2018/10
• Higher Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein (M2BPGi) Not M2BP and Pre-Sarcopenia Are Prognostic and Recurrence Markers of Primary Hepatocellular Carcinoma Treated By RFA in HCV-Negative and HCV-Eradicated Patients.

  Masato Nakai, Goki Suda, Koji Ogawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Naoki Kawagishi, Machiko Umemura, Takuya Sho, Kenichi Morikawa, Naoya Sakamoto

  HEPATOLOGY 68 843A - 844A 0270-9139 2018/10 [Refereed][Not invited]
  
• Hepatitis B Virus x Protein Attenuate Interferon Signaling Throughup-Regulation of SOCS3 and Protein Phosphatase 2A Via up-Regulation of ER Stress

  Kenichi Morikawa, Ogawa Koji, Goki Suda, Naoya Sakamoto

  HEPATOLOGY 68 345A - 345A 0270-9139 2018/10 [Refereed][Not invited]
  
• Clinicopathological significance of RCAN2 production in gastric carcinoma.

  Hattori Y, Sentani K, Shinmei S, Oo HZ, Hattori T, Imai T, Sekino Y, Sakamoto N, Oue N, Niitsu H, Hinoi T, Ohdan H, Yasui W

  Histopathology 74 (3) 430 - 442 0309-0167 2018/10 [Refereed][Not invited]
   

  AIMS: Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Genes expressed only in cancer tissue may be useful biomarkers for cancer diagnosis and therapeutics. The aims of the present study were to analyse regulator of calcineurin 2 (RCAN2) in a large number of GCs, and to investigate how these expression patterns correlate with clinicopathological parameters and various markers. METHODS AND RESULTS: An immunohistochemical analysis of RCAN2 in 207 GC tissue samples showed that 110 (53%) GCs were positive for RCAN2. RCAN2-positive GCs were more advanced in terms of TNM classification and tumour stage than RCAN2-negative GCs. Furthermore, RCAN2 was an independent prognostic classifier for GC patients. The cell growth and invasiveness of RCAN2 small interfering RNA (siRNA)-transfected GC cell lines were less than those of the negative control siRNA-transfected cell lines, whereas those of RCAN2-transfected cells were significantly increased as compared with those of empty vector-transfected cells. RCAN2 siRNA inhibits the phosphorylation of AKT and p44/p42 (ERK1/2). RCAN2 was colocalised with EGFR, nuclear β-catenin, MMP7, laminin-γ2, VEGF-A, and VEGF-C. CONCLUSION: These results suggest that RCAN2 is involved in tumour progression and is an independent prognostic classifier in patients with GC.
• Direct recanalization of pancreaticogastrostomy obstruction with a forward-viewing echoendoscope.

  Kuwatani M, Kato S, Sakamoto N

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 (1) e18 - e19 0915-5635 2018/10 [Refereed][Not invited]
  
• No difference does not always mean equivalent.

  Kawakubo K, Kuwatani M, Sakamoto N

  Gastrointestinal endoscopy 88 (3) 573  0016-5107 2018/09 [Refereed][Not invited]
  
• Efficacy and safety of sofosbuvir-velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial.

  Takehara T, Sakamoto N, Nishiguchi S, Ikeda F, Tatsumi T, Ueno Y, Yatsuhashi H, Takikawa Y, Kanda T, Sakamoto M, Tamori A, Mita E, Chayama K, Zhang G, De-Oertel S, Dvory-Sobol H, Matsuda T, Stamm LM, Brainard DM, Tanaka Y, Kurosaki M

  Journal of gastroenterology 54 (1) 87 - 95 0944-1174 2018/09 [Refereed][Not invited]
   

  BACKGROUND: In Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child-Pugh-Turcotte (CPT) class B or C] in Japan. METHODS: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint. RESULTS: Of the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41-83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir-velpatasvir and seven (14%) who received sofosbuvir-velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression. CONCLUSION: Sofosbuvir-velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.
• Prenatally diagnosed large mediastinal lymphangioma: A case report.

  Tanaka H, Masumoto K, Aoyama T, Sanmoto Y, Ono K, Sakamoto N, Kawakami H

  Clinical case reports 6 (9) 1880 - 1884 2018/09 [Refereed][Not invited]
  
• Regulation of interferon signaling and HCV‑RNA replication by extracellular matrix.

  Kuwashiro T, Iwane S, Jinghe X, Matsuhashi S, Eguchi Y, Anzai K, Fujimoto K, Mizuta T, Sakamoto N, Ikeda M, Kato N, Ozaki I

  International journal of molecular medicine 42 (2) 957 - 965 1107-3756 2018/08 [Refereed][Not invited]
  
• L-Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis.

  Masatsugu Ohara, Koji Ogawa, Goki Suda, Megumi Kimura, Osamu Maehara, Tomoe Shimazaki, Kazuharu Suzuki, Akihisa Nakamura, Machiko Umemura, Takaaki Izumi, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Shunsuke Ohnishi, Naoya Sakamoto

  Hepatology communications 2 (8) 906 - 918 2018/08 [Refereed][Not invited]
   

  Liver cirrhosis (LC) is a major cause of secondary sarcopenia. Sarcopenia makes the prognosis worse; thus, novel therapeutic options for sarcopenia in patients with LC are urgently required as they are currently limited. In this retrospective study, 158 patients with LC were screened, and 35 of those patients who were treated with L-carnitine for more than 6 months and for whom skeletal muscle mass changes could be evaluated by computer tomography were enrolled. Of the 158 patients, 79 patients who did not receive L-carnitine supplementation served as controls. Cases and controls were propensity score matched for age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration, and changes in skeletal muscle mass and clinical data were compared. The 35 patients who received L-carnitine supplementation and 35 propensity score-matched patients who did not receive carnitine supplementation comprised the final enrollment. Compared with control patients, patients who received L-carnitine had significantly worse liver function, which is associated with rapid progress of skeletal muscle depletion. However, loss of skeletal muscle mass was significantly suppressed in patients receiving L-carnitine, and a significant effect was observed in patient subgroups stratified by age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration. The change ratios of most laboratory data, including vitamin D and insulin-like growth factor 1 levels, were similar in the two groups, but ammonia levels were significantly less in those receiving L-carnitine. However, even in patients receiving L-carnitine but not showing an ammonia decrease, loss of skeletal muscle was significantly suppressed. Conclusion: L-carnitine suppresses loss of skeletal muscle mass and may therefore be a novel therapeutic option for sarcopenia in patients with LC. (Hepatology Communications 2018; 00:000-000).
• Bacterial Meningitis Caused by β-lactamase Non-producing Ampicillin-resistant Haemophilus influenzae Type F in an Immunocompetent Woman.

  Sakamoto S, Sakamoto N

  Internal medicine (Tokyo, Japan) 58 (2) 307 - 310 0918-2918 2018/08 [Refereed][Not invited]
  
• Fluid shear stress suppresses ICAM-1-mediated transendothelial migration of leukocytes in coculture model

  Naoya Sakamoto, Yosuke Ueki, Masaki Oi, Takuya Kiuchi, Masaaki Sato

  Biochemical and Biophysical Research Communications 502 (3) 403 - 408 1090-2104 2018/07/20 [Refereed][Not invited]
   

  The adhesion and migration of leukocytes to arterial endothelial cells (ECs), one of the indicators of early atherogenesis, is believed to be correlated with the blood flow conditions and interactions between vascular cells including vascular smooth muscle cells (SMCs). In this study, we investigated the effect of fluid shear stress on the transendothelial migration of leukocytes in a coculture model (CM) composed of human umbilical ECs and SMCs, a layer of collagen type I, and a porous membrane. Following exposure to a fluid shear stress of 1.5 Pa for 24 h, human mononuclear leukocytes were seeded on the EC surface and cultured for 1 h. Leukocytes migrating across the EC layer were observed by confocal laser scanning microscopy. The number of migrating leukocytes in the statically cultured CM was significantly larger than that in the static EC monoculture model. The exposure to the shear stress significantly decreased the leukocyte migration induced by the coculture condition. In the static CM, fluorescence staining and Western blotting showed a higher expression of intercellular adhesion molecule-1 (ICAM-1) of ECs. These results indicate that SMC-derived bioactive soluble factors may stimulate the ICAM-1 expression of cocultured ECs, possibly leading to leukocyte migration into the subendothelial space.
• Hepatobiliary and Pancreatic: Pancreatic cancer with elevated serum IgG4 level due to multiple myeloma mimicking localized autoimmune pancreatitis

  S. Kato, M. Kuwatani, K. Kawakubo, R. Sugiura, K. Hirata, S. Tanikawa, T. Mitsuhashi, S. Shiratori, N. Sakamoto

  Journal of Gastroenterology and Hepatology (Australia) 33 (7) 1310  1440-1746 2018/07/01 [Refereed][Not invited]
  
• Randomized controlled trial: PPI-based triple therapy containing metronidazole versus clarithromycin as first-line treatment for Helicobacter pylori in adolescents and young adults in Japan

  Katushiro Mabe, Masumi Okuda, Shogo Kikuchi, Kenji Amagai, Rie Yoshimura, Mototsugu Kato, Naoya Sakamoto, Masahiro Asaka, Japan Gast Study Group

  Journal of Infection and Chemotherapy 24 (7) 538 - 543 1437-7780 2018/07/01 [Refereed][Not invited]
   

  Background/Aims: Treating Helicobacter pylori infection in young people is effective for preventing gastric cancer. This study compares the efficacy of triple therapies in adolescents and young adults in Japan. Methods: This multicenter, randomized trial was conducted between February 2012 and March 2015. Infected participants were stratified into adolescents (13–19 years) and young adults (20–39 years). They were randomly assigned to a clarithromycin based (PAC) or metronidazole based (PAM) triple therapy for 1 week. Results: Overall, 137 and 169 participants received the PAC and PAM treatments, respectively. In adolescents, the H. pylori eradication rates were 60.5% and 63.4% for PAC, and 98.3% and 100% for PAM in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively. In young adults, the eradication rates were 67.0% and 66.7% for PAC, and 95.5% and 96.3% for PAM in ITT and PP analyses, respectively. The eradication rate of PAM was significantly higher than that of PAC in both strata. No severe adverse events were observed. Conclusion: In Japan, PAM may be selected as a first-line treatment for young people with H. pylori if antibiotic susceptibility tests cannot be performed.
• Lavender Color in Linked Color Imaging Enables Noninvasive Detection of Gastric Intestinal Metaplasia.

  Ono S, Kato M, Tsuda M, Miyamoto S, Abiko S, Shimizu Y, Sakamoto N

  Digestion 98 (4) 222 - 230 0012-2823 2018/07 [Refereed][Not invited]
   

  BACKGROUND AND AIMS: Recently, there have been some reports that image-enhanced endoscopy may improve detection of gastric intestinal metaplasia (GIM). Our aim was to determine the usefulness of linked color imaging (LCI) for detection of GIM. METHODS: In prospectively recruited patients, the whole antrum was observed by white light imaging (WLI) followed by LCI. When a whitish flat elevation (WFE) in WLI and a lavender color sign (LCS) in LCI were detected, target biopsies were performed after LCI. Random biopsies were performed in patients who had neither WFE nor LCS. The primary endpoint was the diagnostic accuracy of GIM per patient in WLI and LCI and the secondary endpoints were that of GIM per biopsy and interobserver agreement. RESULTS: Data from 128 patients were analyzed and 58 patients (45.3%) had histological GIM in the antrum. The per-patient yields of WLI and LCI to detect GIM were 19.0% (11/58) and 91.4% (53/58) respectively. Diagnostic accuracies of target biopsies for GIM were 23.7% in WLI and 84.2% in LCI. Kappa values among 3 doctors were 0.60 for WFE and 0.78 for LCS respectively. CONCLUSION: LCI could be a new diagnostic tool for detecting GIM during routine endoscopy.
• PREVENTIVE EFFECT OF MESENCHYMAL STEM CELL-CULTURE SUPERNATANT ON LUMINAL STRICTURE AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION IN THE RECTUM OF PIGS

  Ohnishi Shunsuke, Tsuda Momoko, Mizushima Takeshi, Ishikawa Marin, Abiko Satoshi, Shimizu Yuichi, Sakamoto Naoya

  GASTROINTESTINAL ENDOSCOPY 87 (6) AB501  0016-5107 2018/06 [Refereed][Not invited]
  
• Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction.

  Takuya Sho, Goki Suda, Atsushi Nagasaka, Yoshiya Yamamoto, Ken Furuya, Kenichi Kumagai, Minoru Uebayashi, Katsumi Terashita, Tomoe Kobayashi, Izumi Tsunematsu, Manabu Onodera, Takashi Meguro, Megumi Kimura, Jun Ito, Machiko Umemura, Takaaki Izumi, Naoki Kawagishi, Masatsugu Ohara, Yuji Ono, Masato Nakai, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 48 (7) 529 - 538 1386-6346 2018/06 [Refereed][Not invited]
   

  AIM: The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. METHODS: The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. RESULTS: A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. CONCLUSIONS: Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction.
• Successful endoscopic sphincterotomy for choledocholithiasis in a patient with severe hemophilia A and inhibitors

  Ryo Sugiura, Masaki Kuwatani, Kazumichi Kawakubo, Itsuki Sano, Shin Kato, Tomoyuki Endo, Naoya Sakamoto

  Clinical Journal of Gastroenterology 11 (3) 188 - 192 1865-7265 2018/06/01 [Refereed][Not invited]
   

  Endoscopic sphincterotomy (ES) is a standard procedure for bile duct stone removal. However, the safety of ES in patients with hemophilia remains unknown. We treated a 46-year-old man who had choledocholithiasis and severe hemophilia A with high-responding inhibitors during immune tolerance induction therapy. Since coagulation factor VIII inhibitors neutralize and inactivate endogenous and exogenous factor VIII, bleeding risk is higher in hemophilia A patients with inhibitors than in those without inhibitors. With adequate pre- and post-procedure monitoring of the clotting factor and supplemented clotting factor, the patient could safely undergo ES without bleeding complications. ES can be also an effective and safe first-line therapy for choledocholithiasis in patients with hemophilia and inhibitors under the condition of appropriate management.
• Endoscopic papillary large balloon dilation and endoscopic papillary balloon dilation both without sphincterotomy for removal of large bile duct stones: A propensity-matched analysis.

  Hakuta R, Kawahata S, Kogure H, Nakai Y, Saito K, Saito T, Hamada T, Takahara N, Uchino R, Mizuno S, Tsujino T, Tada M, Sakamoto N, Isayama H, Koike K

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 31 (1) 59 - 68 0915-5635 2018/06 [Refereed][Not invited]
   

  BACKGROUND AND AIM: Endoscopic papillary large balloon dilation (EPLBD) without endoscopic sphincterotomy (EST) may facilitate extraction of large bile duct stones through achieving adequate dilation of the ampulla. However, contrary to favorable long-term outcomes after endoscopic papillary balloon dilation (EPBD), that of EPLBD without EST has been little investigated. Therefore, we conducted the current study to evaluate short- and long-term outcomes of EPLBD without EST and EPBD after removal of large bile duct stones (LBDS; ≥10 mm). METHODS: This retrospective study included patients without a previous history of EST, EPBD or EPLBD who underwent EPLBD without EST or EPBD for removal of LBDS. Each patient in the EPLBD without EST group was matched to a patient in the EPBD group using propensity scores. RESULTS: Forty-four patients in each group were matched for the analysis. Baseline characteristics were balanced after propensity matching. Rate of complete stone removal in a single session was higher (80% vs 16%, P < 0.001), number of ERCP sessions (1.3 ± 0.7 vs 2.4 ± 1.5, P < 0.001) and rate of lithotripsy use (30% vs 80%, P < 0.001) were smaller in the matched EPLBD without EST group. Contrary to null between-group differences in early adverse events (P = 0.99), a cumulative rate of late biliary complications was higher in the EPLBD without EST group (P = 0.02). CONCLUSION: EPLBD without EST showed higher efficacy for removal of LBDS but was associated with worse long-term outcomes when compared to EPBD.
• Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma.

  Hiromi Sawai, Nao Nishida, Seik-Soon Khor, Masao Honda, Masaya Sugiyama, Natsumi Baba, Kayoko Yamada, Norie Sawada, Shoichiro Tsugane, Kazuhiko Koike, Yuji Kondo, Hiroshi Yatsuhashi, Shinya Nagaoka, Akinobu Taketomi, Moto Fukai, Masayuki Kurosaki, Namiki Izumi, Jong-Hon Kang, Kazumoto Murata, Keisuke Hino, Sohji Nishina, Akihiro Matsumoto, Eiji Tanaka, Naoya Sakamoto, Koji Ogawa, Kazuhide Yamamoto, Akihiro Tamori, Osamu Yokosuka, Tatsuo Kanda, Isao Sakaida, Yoshito Itoh, Yuichiro Eguchi, Satoshi Oeda, Satoshi Mochida, Man-Fung Yuen, Wai-Kay Seto, Yong Poovorawan, Nawarat Posuwan, Masashi Mizokami, Katsushi Tokunaga

  Scientific reports 8 (1) 7958 - 7958 2018/05/21 [Refereed][Not invited]
   

  We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10-4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10-12; rs1110446: OR = 1.79, P = 1.66 × 10-13; and rs3094137: OR = 1.73, P = 7.09 × 10-9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10-4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.
• Treatment of hepatitis C in special populations.

  Goki Suda, Koji Ogawa, Kenichi Morikawa, Naoya Sakamoto

  Journal of gastroenterology 53 (5) 591 - 605 0944-1174 2018/05 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is high and is moreover associated with a poor prognosis. In liver transplantation patients with HCV infection, recurrent HCV infection is universal, and re-infected HCV causes rapid progression of liver fibrosis and graft loss. Additionally, in patients with HCV and human immunodeficiency virus (HIV) co-infection, liver fibrosis progresses rapidly. Thus, there is an acute need for prompt treatment of HCV infection in these special populations (i.e., hemodialysis, liver transplantation, HIV co-infection). However, until recently, the standard anti-HCV treatment involved the use of interferon-based therapy. In these special populations, interferon-based therapies could not achieve a high rate of sustained viral response and moreover were associated with a higher rate of adverse events. With the development of novel direct-acting antivirals (DAAs), the landscape of anti-HCV therapy for special populations has changed dramatically. Indeed, in special populations treated with interferon-free DAAs, the sustained viral response rate was above 90%, with a lower incidence and severity of adverse events.
• Cecum ulcer is a reliable endoscopic finding in cytomegalovirus colitis concomitant with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

  Kana Matsuda, Shoko Ono, Marin Ishikawa, Shuichi Miyamoto, Satoshi Abiko, Momoko Tsuda, Keiko Yamamoto, Takahiko Kudo, Yuichi Shimizu, Eiko Hayase, Daigo Hashimoto, Takanori Teshima, Yoshihiro Matsuno, Naoya Sakamoto

  Annals of Hematology 97 (5) 877 - 883 1432-0584 2018/05/01 [Refereed][Not invited]
   

  Although graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), cytomegalovirus (CMV) reactivation also occurs in patients after allo-HSCT and these conditions often clinically overlap. The aim of this study was to determine reliable endoscopic findings of CMV colitis in patients with gastrointestinal graft-versus-host-disease (GI-GVHD). Patients after allo-HSCT who were histologically confirmed to have GI-GVHD with or without CMV colitis and patients with an immunosuppressive condition were retrospectively analyzed. We divided the patients into three groups: GI-GVHD with CMV colitis (group A), GI-GVHD without CMV colitis (group B), and CMV colitis without undergoing allo-HSCT (group C). From medical records, the involved colorectal areas and endoscopic findings according to the groups were compared. A total of 70 patients were divided into three groups (group A: n = 19, group B: n = 28, group C: n = 23). Mucosal injuries in groups A and C frequently occurred in the cecum including ileocecal valves. On the other hand, there were no abnormal lesions on ileocecal valves in group B. Furthermore, ulcer lesions were more frequently observed in groups A and C than in group B (p < 0.001). The sensitivity and specificity of mucosal injuries in the cecum for prediction of CMV colitis were 89.5 and 76.5%, respectively, and mucosal injuries in the cecum were more reliable findings than CMV antigenemia. Ulcer lesions in the cecum are reliable endoscopic findings for CMV colitis in patients with GI-GVHD after allo-HSCT.
• A prospective multicenter study evaluating bleeding risk after endoscopic ultrasound-guided fine needle aspiration in patients prescribed antithrombotic agents

  Kazumichi Kawakubo, Kei Yane, Kazunori Eto, Hirotoshi Ishiwatari, Nobuyuki Ehira, Shin Haba, Ryusuke Matsumoto, Keisuke Shinada, Hiroaki Yamato, Taiki Kudo, Manabu Onodera, Toshinori Okuda, Yoko Taya-Abe, Shuhei Kawahata, Kimitoshi Kubo, Yoshimasa Kubota, Masaki Kuwatani, Hiroshi Kawakami, Akio Katanuma, Michihiro Ono, Tsuyoshi Hayashi, Minoru Uebayashi, Naoya Sakamoto

  Gut and Liver 12 (3) 353 - 359 2005-1212 2018/05/01 [Refereed][Not invited]
   

  Background/Aims: Although the risk of bleeding after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is low, the safety of EUS-FNA in patients prescribed antithrombotic agents is unclear. Therefore, this study evaluated the incidence of bleeding after EUS-FNA in those patients. Methods: Between September 2012 and September 2015, patients who were prescribed antithrombotic agents underwent EUS-FNA at 13 institutions in Japan were prospectively enrolled in the study. The antithrombotic agents were managed according to the guidelines of the Japanese Gastrointestinal Endoscopy Society. The rate of bleeding events, thromboembolic events and other complications within 2 weeks after EUS-FNA were analyzed. Results: Of the 2,629 patients who underwent EUS-FNA during the study period, 85 (62 males median age, 74 years) patients were included in this stduy. Two patients (2.4% 95% confidence interval [CI], 0.6% to 8.3%) experienced bleeding events. One patient required surgical intervention for hemothorax 5 hours after EUS-FNA, and the other experienced melena 8 days after EUS-FNA and required red blood cell transfusions. No thromboembolic events occurred (0% 95% CI, 0.0% to 4.4%). Three patients (3.5% 95% CI, 1.2% to 10.0%) experienced peri-puncture abscess formation. Conclusions: The rate of bleeding after EUS-FNA in patients prescribed antithrombotic agents might be considerable.
• Preoperative biliary drainage using a fully covered self-expandable metallic stent for pancreatic head cancer: A prospective feasibility study

  Osamu Togawa, Hiroyuki Isayama, Hiroshi Kawakami, Yousuke Nakai, Dai Mohri, Tsuyoshi Hamada, Hirofumi Kogure, Kazumichi Kawakubo, Naoya Sakamoto, Kazuhiko Koike, Hiroto Kita

  Saudi Journal of Gastroenterology 24 (3) 151 - 156 1998-4049 2018/05/01 [Refereed][Not invited]
   

  Background/Aims: The role of endoscopic preoperative biliary drainage (PBD) for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. This study was performed to evaluate the feasibility and safety of PBD using a fully covered self-expandable metallic stent (FCSEMS). Patients and Methods: This multicenter prospective study involved 26 patients treated for pancreatic head cancer with distal bile duct obstruction from April 2011 to March 2013. An FCSEMS was endoscopically placed in 24 patients. Among these, 7 patients were diagnosed with unresectable cancer, and 17 underwent surgery at a median of 18 days after FCSEMS placement. The main outcome measure was preoperative and postoperative adverse events. Results: Two adverse events (cholecystitis and insufficient resolution of jaundice) occurred between FCSEMS placement and surgery (12%). Postoperative adverse events occurred in eight patients (47%). The cumulative incidence of stent-related adverse events 4 and 8 weeks after FCSEMS placement among the 24 patients who underwent this procedure were 19%. Conclusions: PBD using an FCSEMS is feasible in patients with resectable pancreatic head cancer. Placement of an FCSEMS can be an alternative PBD technique when surgery without delay is impossible. A larger randomized controlled trial is warranted.
• Mixed ductal-neuroendocrine carcinoma with unique intraductal growth in the main pancreatic duct.

  Hirata K, Kuwatani M, Mitsuhashi T, Sugiura R, Kato S, Kawakubo K, Yamada T, Asano T, Hirano S, Sakamoto N

  Endoscopic ultrasound 8 (2) 129 - 130 2303-9027 2018/05 [Refereed][Not invited]
  
• Combined use of a two-channel endoscope and a flexible tip catheter for difficult biliary cannulation

  Masaki Kuwatani, Yoshimasa Kubota, Shuhei Kawahata, Kimitoshi Kubo, Kazumichi Kawakubo, Hiroshi Kawakami, Naoya Sakamoto

  International Journal of Gastrointestinal Intervention 7 (1) 34 - 35 2018/04/30 [Refereed][Not invited]
  
• 胆管ステントの現況と将来 悪性胆道狭窄に対するメタリックステント留置時の乳頭括約筋切開術付加は、ERCP後膵炎の発症を抑制するか

  加藤 新, 桑谷 将城, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 60 (Suppl.1) 612 - 612 0387-1207 2018/04
• 咽頭癌CRT後遺残再発に対するサルベージEMR/ESD

  安孫子 怜史, 清水 勇一, 石川 麻倫, 松田 可奈, 宮本 秀一, 津田 桃子, 高橋 正和, 山本 桂子, 森 康明, 中川 学, 小野 尚子, 中川 宗一, 工藤 俊彦, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 60 (Suppl.1) 684 - 684 0387-1207 2018/04
• Helicobacter pylori除菌後発見胃癌からみた効率的な内視鏡スクリーニング

  津田 桃子, 小野 尚子, 石川 麻倫, 松田 可奈, 宮本 秀一, 安孫子 怜史, 山下 充孝, 高橋 正和, 山本 桂子, 中川 学, 森 康明, 中川 宗一, 工藤 俊彦, 清水 勇一, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 60 (Suppl.1) 696 - 696 0387-1207 2018/04
• DPP-IV活性により蛍光を発するプローブによる食道胃接合部腺癌の検出

  山本 桂子, 大西 俊介, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 60 (Suppl.1) 715 - 715 0387-1207 2018/04
• Preventive effect of mesenchymal stem cell culture supernatant on luminal stricture after endoscopic submucosal dissection in the rectum of pigs.

  Tsuda M, Ohnishi S, Mizushima T, Hosono H, Yamahara K, Ishikawa M, Abiko S, Katsurada T, Shimizu Y, Sakamoto N

  Endoscopy 50 (10) 1001 - 1016 0013-726X 2018/04 [Refereed][Not invited]
   

  Background Mesenchymal stem cells (MSCs) are valuable in regenerative medicine, and MSC culture supernatant (MSC-CS) reportedly inhibits inflammation and fibrosis. We investigated whether colorectal luminal stricture develops after circumferential endoscopic submucosal dissection (ESD) in the colorectum, and whether the development of luminal stricture could be prevented by using MSC-CS enema.Methods In the first experiment, we performed circumferential ESD in the rectums or distal colons of pigs (n=4 in each group). We sacrificed the pigs on Day22 and measured the degree of luminal stricture. In the second experiment, we performed circumferential ESD in the rectums of pigs and administered an MSC-CS gel or a control gel enema after ESD for 4days. We sacrificed the pigs on Day8 (n=3 in each group) or 22 (n=3 in each group) to measure the degree of luminal stricture, and performed histological analysis.Results Severe luminal stricture was observed in the rectum but not in the distal colon. Moreover, fiber accumulation in the submucosa and hypertrophy of the muscularis propria were observed in the rectum but not in the distal colon. The degree of luminal stricture in the rectum was significantly lower in the MSC-CS group than in the control group.Furthermore, MSC-CS attenuated myofibroblast activation and hypertrophy of the muscularis propria on Day22, and reduced inflammatory cell infiltration on Day8.Conclusions Luminal stricture after ESD developed only in the rectum because of the difference in myofibroblast activation and fiber accumulation. In addition, MSC-CS enema prevented luminal stricture after ESD, possibly by inhibiting the inflammatory reaction and fibrosis.
• Safety of Cold Polypectomy for Colorectal Polyps in Patients on Antithrombotic Medication

  Mio Matsumoto, Shinji Yoshii, Taku Shigesawa, Masayoshi Dazai, Manabu Onodera, Mototsugu Kato, Naoya Sakamoto

  Digestion 97 (1) 76 - 81 1421-9867 2018/03/01 [Refereed][Not invited]
   

  Background: The cold polypectomy (CP) technique has been increasingly used in recent years. However, there have been few studies about post-polypectomy bleeding (PPB) in patients who underwent CP and who were on antithrombotic drugs. The objective of this study was to determine the safety of CP in patients on antithrombotic medication. Methods: The subjects were patients who underwent CP in our hospital between April 2014 and March 2016. PPB rates were examined in relation to the use of antithrombotic medication. Results: CP was performed to remove 2,466 polyps in 1,003 patients. There were 549 polyps (22.3%) in186 patients in the antithrombotic group and 1,917 polyps (77.7%) in 817 patients in the non-Antithrombotic group. PPB occurred in 0.55% (3/549) of patients in the antithrombotic group and in 0.10% (2/1,917) of patients in the non-Antithrombotic group, showing no significant difference (p = 0.07). Patients in the antithrombotic group in whom PPB occurred included 1 aspirin user with 1 polyp and 1 aspirin plus clopidogrel user with 2 polyps. No PPB occurred in patients on other antithrombotic agents or receiving heparin bridging. There was no significant difference between PPB rates in patients with small polyps (6-9 mm) in the antithrombotic and non-Antithrombotic groups, but there was a significant difference between PPB rates in the 2 groups for patients with diminutive group (1-5 mm). Conclusion: CP is a safe procedure even in patients on antithrombotic medication.
• Rapid detection of superficial head and neck squamous cell carcinoma by topically spraying fluorescent probe targeting dipeptidyl peptidase-IV.

  Mizushima T, Ohnishi S, Shimizu Y, Hatanaka Y, Hatanaka KC, Kuriki Y, Kamiya M, Homma A, Yamamoto K, Ono S, Urano Y, Sakamoto N

  Head & neck 40 (7) 1466 - 1475 1043-3074 2018/03 [Refereed][Not invited]
  
• Direct puncture of the ampulla as a modified Endoscopic ultrasound-guided rendezvous technique

  Kazumichi Kawakubo, Masaki Kuwatani, Shin Kato, Ryo Sugiura, Itsuki Sano, Naoya Sakamoto

  Endoscopic Ultrasound 7 (2) 133 - 134 2226-7190 2018/03/01 [Refereed][Not invited]
  
• Preliminary study of automatic gastric cancer risk classification from photofluorography

  Ren Togo, Kenta Ishihara, Katsuhiro Mabe, Harufumi Oizumi, Takahiro Ogawa, Mototsugu Kato, Naoya Sakamoto, Shigemi Nakajima, Masahiro Asaka, Miki Haseyama

  World Journal of Gastrointestinal Oncology 10 (2) 62 - 70 1948-5204 2018/02/15 [Refereed][Not invited]
   

  AIM To perform automatic gastric cancer risk classification using photofluorography for realizing effective mass screening as a preliminary study. METHODS We used data for 2100 subjects including X-ray images, pepsinogen ? and ? levels, PG?/PG? ratio, Helicobacter pylori (H. pylori ) antibody, H. pylori eradication history and interview sheets. We performed two-stage classification with our system. In the first stage, H. pylori infection status classification was performed, and H. pylori -infected subjects were automatically detected. In the second stage, we performed atrophic level classification to validate the effectiveness of our system. RESULTS Sensitivity, specificity and Youden index (YI) of H. pylori infection status classification were 0.884, 0.895 and 0.779, respectively, in the first stage. In the second stage, sensitivity, specificity and YI of atrophic level classification for H. pylori -infected subjects were 0.777, 0.824 and 0.601, respectively. CONCLUSION Although further improvements of the system are needed, experimental results indicated the effectiveness of machine learning techniques for estimation of gastric cancer risk.
• Conditioned Medium Obtained from Amnion-Derived Mesenchymal Stem Cell Culture Prevents Activation of Keloid Fibroblasts.

  Sato C, Yamamoto Y, Funayama E, Furukawa H, Oyama A, Murao N, Hosono H, Kawakubo K, Sakamoto N, Ohnishi S

  Plastic and reconstructive surgery 141 (2) 390 - 398 0032-1052 2018/02 [Refereed][Not invited]
   

  Background: Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium obtained from mesenchymal stem cells reportedly inhibits inflammation. Keloids are characterized by abnormal fibrosis, caused by fibroblasts in response to inflammation. In this study, the authors evaluated whether conditioned medium obtained from amnion-derived mesenchymal stem cells suppressed activation of keloid fibroblasts.Methods: Keloid (n = 7), mature (n = 5), and normal (n = 5) fibroblasts were harvested from patients. Fibroblasts were stimulated with transforming growth factor (TGF)-beta, and the effects of conditioned medium obtained from amni-on-derived mesenchymal stem cells on cell proliferation, activation, and expression of extracellular matrix-related genes were analyzed. The effect of concentrating the conditioned medium by ultrafiltration on fibroblast activation was also analyzed.Results: Conditioned medium obtained from amnion-derived mesenchymal stem cells significantly up-regulated proliferation of mature fibroblasts but tended to suppress that of keloid fibroblasts. Conditioned medium obtained from amnion-derived mesenchymal stem cells significantly suppressed the TGF-ss-induced up-regulation of a-smooth muscle actin in keloid and normal fibroblasts and collagen I in keloid fibroblasts, but not in mature fibroblasts. The conditioned medium obtained from amnion-derived mesenchymal stem cells concentrated by ultrafiltration and the filtrate significantly suppressed TGF-ss-induced a-smooth muscle actin expression.Conclusion: Conditioned medium obtained from amnion-derived mesenchymal stem cells prevents proliferation and activation of keloid fibroblasts and is a promising keloid treatment for administration as a topical agent.
• Risk assessment of metachronous squamous cell carcinoma after endoscopic resection for esophageal carcinoma based on the genetic polymorphisms of alcoholdehydrogense-1B aldehyde dehydrogenase-2: temperance reduces the risk.

  Abiko S, Shimizu Y, Miyamoto S, Ishikawa M, Matsuda K, Tsuda M, Mizushima T, Yamamoto K, Ono S, Kudo T, Ono K, Sakamoto N

  Journal of gastroenterology 53 (10) 1120 - 1130 0944-1174 2018/02 [Refereed][Not invited]
  
• Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study.

  Goki Suda, Jun Ito, Atsushi Nagasaka, Yoshiya Yamamoto, Ken Furuya, Munenori Okamoto, Katsumi Terashita, Tomoe Kobayashi, Izumi Tsunematsu, Junichi Yoshida, Takashi Meguro, Masatsugu Ohara, Naoki Kawagishi, Megumi Kimura, Machiko Umemura, Takaaki Izumi, Yoko Tsukuda, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 48 (3) E146-E154 - E154 1386-6346 2018/02 [Refereed][Not invited]
   

  BACKGROUND: The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS: This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS: Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS: This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.
• Increased serum C-reactive protein and decreased urinary aquaporin 2 levels are predictive of the efficacy of tolvaptan in patients with liver cirrhosis.

  Masato Nakai, Koji Ogawa, Rei Takeda, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Machiko Umemura, Jun Ito, Takuya Sho, Goki Suda, Kenichi Morikawa, Naoya Sakamoto

  Hepatology research : the official journal of the Japan Society of Hepatology 48 (3) E311-E319 - E319 1386-6346 2018/02 [Refereed][Not invited]
   

  AIM: Water retention, hepatic ascites, and peripheral edema are significant problems in patients with liver cirrhosis (LC). Although furosemide and spironolactone are commonly used as treatment, they are often insufficient to treat hyponatremia and renal insufficiency in patients with LC. Tolvaptan (TVP) could provide an effective treatment alternative. However, predictive factors of a therapeutic response to TVP are unclear. Our aim was to examine clinical predictors of the response to TVP in patients with LC and water retention. METHODS: Fifty-two patients were treated with TVP, with therapeutic effects judged by a decrease in body weight (≥2 kg) and increase in urinary volume (≥500 mL) within 7 days. Blood biochemical tests were carried out at baseline and post-treatment, including serum soluble CD14 (sCD14) and urinary aquaporin 2 (AQP2) levels. Clinical and laboratory predictive factors of a TVP response were evaluated by univariate and multivariate analyses. RESULTS: The overall response to TVP was 55.8%. On univariate analyses, serum C-reactive protein (CRP) level, the neutrophil-to-lymphocyte ratio, urinary blood urea nitrogen, and urinary AQP2 were predictors of the TVP response, with only serum CRP retained on multivariate analysis. A higher serum sCD14 level was strongly associated with a non-response to TVP. A decrease in urinary AQP2 to undetectable level was associated with a response. CONCLUSION: Tolvaptan provides a rapid and strong effect to improve water retention in patients with LC. Baseline serum sCD14 and CRP levels are useful predictors of a response to TVP, with a decrease in urinary AQP2 during treatment indicating an early response.
• Gastric mucosal cracked and cobblestone-like changes resulting from proton pump inhibitor use

  Shuichi Miyamoto, Mototsugu Kato, Momoko Tsuda, Kana Matsuda, Tetsuhito Muranaka, Satoshi Abiko, Masayoshi Ono, Takeshi Mizushima, Saori Omori, Keiko Yamamoto, Katsuhiro Mabe, Shoko Ono, Takahiko Kudo, Yuichi Shimizu, Naoya Sakamoto

  Gastroenterological Endoscopy 60 (1) 68 - 77 0387-1207 2018/01/01 [Refereed][Not invited]
   

  Background and Aim : Use of proton pump inhibitors (PPI) is histologically associated with oxyntic gland dilatations. Two interesting mucosal changes are often detected endoscopically in patients who use PPI : gastric cracked mucosa (GCM) and gastric cobblestone-like mucosa (GCSM). The aim of the present study was to clarify the relationship between PPI use and these mucosal changes. Methods : This was a single-center observational study. All successive subjects who underwent a routine esophagogastroduodenoscopy (EGD) between August and November 2014 in Hokkaido University Hospital were enrolled. Endoscopists carried out the assessment blinded to the use of PPI and checked for GCSM and GCM using original diagnostic criteria for GCM and GCSM. Subjects were divided into two groups : those who used PPI (PPI group) and those who did not (control group). Endoscopic findings and backgrounds were compared between the two groups. Results : A total of 538 patients were analyzed (control group : 374 patients, men/women : 204/170, median age : 65.2 years PPI group : 164 patients, men/women : 89/75, median age : 67.1 years). GCM was detected in 54 (10.0%) subjects, and GCSM was detected in 18 (3.3%) subjects. There was a significant difference in the prevalence rate of GCM between the control group (14/374, 3.7 %) and the PPI group (40/164, 24.4%) (P< 0.01). GCSM was significantly more prevalent in the PPI group (15/164, 9.1%) than in the control group (3/374, 0.8%) (P< 0.01). Conclusion : Novel GCM and GCSM endoscopic findings in the corpus area seem to be strongly associated with PPI use.
• Detection of Superficial Head and Neck Squamous Cell Carcinoma by Topically Spraying Fluorescent Probe Targeting DPP-IV

  Ohnishi Shunsuke, Mizushima Takeshi, Shimizu Yuichi, Hatanaka Yutaka, Hatanaka Kanako, Yamamoto Keiko, Homma Akihiro, Kuriki Yugo, Kamiya Mako, Urano Yasuteru, Sakamoto Naoya

  CANCER SCIENCE 109 730  1349-7006 2018/01 [Refereed][Not invited]
  
• Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis.

  Naoki Kawagishi, Goki Suda, Akinobu Nakamura, Megumi Kimura, Osamu Maehara, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Takaaki Izumi, Machiko Umemura, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Yusuke Kudo, Mutsumi Nishida, Hideaki Miyoshi, Naoya Sakamoto

  PloS one 13 (12) e0209615  2018 [Refereed][Not invited]
   

  AIM: We comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk. METHODS: Patients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed. RESULTS: A total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels. CONCLUSIONS: Generally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring.
• Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats.

  Ohara M, Ohnishi S, Hosono H, Yamamoto K, Yuyama K, Nakamura H, Fu Q, Maehara O, Suda G, Sakamoto N

  Stem cells international 2018 3212643 - 3212643 1687-966X 2018 [Refereed][Not invited]
   

  Background: There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. Methods: NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15 μg/kg) and at week 3 in rats with liver fibrosis (20 μg/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated in vitro. Results: AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (Tnf-) α, interleukin- (Il-) 1β and Il-6, and transforming growth factor- (Tgf-) β. Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. In vitro, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway. Conclusions: AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.
• A Case of Olmesartan-associated Sprue-like Enteropathy

  Kazunori Nagashima, Takehiko Katsurada, Naoya Sakamoto

  Clinical Gastroenterology and Hepatology 16 (10) A45 - A46 1542-7714 2018 [Refereed][Not invited]
  
• Multicenter observational study on functional bowel disorders diagnosed using Rome III diagnostic criteria in Japan.

  Ono M, Kato M, Miyamoto S, Tsuda M, Mizushima T, Ono S, Nakagawa M, Mabe K, Nakagawa S, Muto S, Shimizu Y, Kudo M, Katsuki S, Meguro T, Sakamoto N

  Journal of gastroenterology 53 (8) 916 - 923 0944-1174 2018/01 [Refereed][Not invited]
  
• Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan.

  Goki Suda, Norihiro Furusyo, Hidenori Toyoda, Yoshiiku Kawakami, Hiroki Ikeda, Michihiro Suzuki, Keiko Arataki, Nami Mori, Keiji Tsuji, Yoshio Katamura, Koichi Takaguchi, Toru Ishikawa, Kunihiko Tsuji, Noritomo Shimada, Atsushi Hiraoka, Sho Yamsaki, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Mineo Kudo, Atsushi Nagasaka, Ken Furuya, Yoshiya Yamamoto, Kanji Kato, Yoshiyuki Ueno, Etsuko Iio, Yasuhito Tanaka, Masayuki Kurosaki, Takashi Kumada, Kazuaki Chayama, Naoya Sakamoto

  Journal of gastroenterology 53 (1) 119 - 128 0944-1174 2018/01 [Refereed][Not invited]
   

  BACKGROUND: Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV). METHODS: Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events. RESULTS: Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12. CONCLUSIONS: This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).
• Mesenchymal stem cell therapy for acute and chronic pancreatitis

  Kazumichi Kawakubo, Shunsuke Ohnishi, Masaki Kuwatani, Naoya Sakamoto

  Journal of Gastroenterology 53 (1) 1 - 5 1435-5922 2018/01/01 [Refereed][Not invited]
   

  Mesenchymal stem cells (MSCs) have attracted attention as a cell source for regenerative medicine. In particular, MSCs have an anti-inflammatory effect by secreting several kinds of bioactive molecules. MSC therapy is now being applied to various gastrointestinal diseases, such as graft-versus-host disease, inflammatory bowel disease, and liver cirrhosis. Therefore, MSC therapy has the potential to be a novel treatment for acute and chronic pancreatitis by suppressing inflammation. Several studies have investigated the effect of MSC therapy on acute and chronic pancreatitis, but the underlying mechanisms remain unknown. In this review, we summarize the present status of MSC therapy for acute and chronic pancreatitis.
• Safety and efficacy of elbasvir/grazoprevir for the treatment of chronic hepatitis C: current evidence.

  Kenichi Morikawa, Akihisa Nakamura, Tomoe Shimazaki, Naoya Sakamoto

  Drug design, development and therapy 12 2749 - 2756 2018 [Refereed][Not invited]
   

  Treatments for hepatitis C virus (HCV) have advanced greatly, becoming more efficacious with fewer adverse events, due to the availability of direct-acting antiviral agents, which target specific steps in the HCV life cycle. Recently, a combination regimen consisting of the HCV nonstructural protein 5A inhibitor elbasvir (EBR) and the HCV NS3/4A protease inhibitor grazoprevir (GZR) was approved for the treatment of patients with chronic HCV and genotypes (Gts) 1 and 4 in various countries. In Phase III trials, the combination of EBR/GZR (fixed-dose combination table or single agent) for 12 or 16 weeks of treatment with or without ribavirin resulted in a high sustained virological response at 12 weeks in treatment-naïve and treatment-experienced patients with HCV Gt 1a, 1b, 4, or 6, including special populations, such as individuals with advanced chronic kidney disease, HCV-HIV coinfection, and compensated cirrhosis. In this review, we focus on the mode of action, pharmacokinetics, clinical applications, efficacy, and safety profile of EBR/GZR, including special populations who have been considered refractory from the extensive evidence of clinical trials.
• Conditioned Medium from Human Amnion-Derived Mesenchymal Stem Cells Regulates Activation of Primary Hepatic Stellate Cells.

  Fu Q, Ohnishi S, Sakamoto N

  Stem cells international 2018 4898152 - 4898152 1687-966X 2018 [Refereed][Not invited]
   

  Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells, are present in almost all organs and tissues, including the amnion. Human amnion-derived mesenchymal stem cell (hAMSC) transplantation has been reported to ameliorate liver fibrosis in animal models. However, the mechanism for the prevention of liver fibrosis is poorly understood. In this study, we investigated the effects, and underlying mechanisms, of a conditioned medium obtained from hAMSC cultures (hAMSC-CM) on a primary culture of rat hepatic stellate cells (HSCs). We observed that in routine culture, hAMSC-CM in HSCs significantly inhibited the expression of alpha-smooth muscle actin (α-SMA), an activation marker of HSCs, and the production of collagen type 1 (COL1), a dominant component of the extracellular matrix (ECM) in the culture medium. In addition, hAMSC-CM upregulated the expression of ECM degradation-related genes, such as metalloproteinase- (Mmp-) 2, Mmp-9, Mmp-13, and tissue inhibitor of metalloproteinase- (Timp-) 1; however, it did not affect the expression of collagen type 1α1 (Col1a1). These regulatory effects on HSCs were concentration-dependent. A cell proliferation assay indicated that hAMSC-CM significantly suppressed HSC proliferation and downregulated the expression of cyclin B (Ccnb), a proliferation-related gene. Transforming growth factor-beta (TGF-β) treatment further activated HSCs and hAMSC-CM significantly inhibited the upregulation of α-Sma and Col1a1 induced by TGF-β. These findings demonstrated that hAMSC-CM can modulate HSC function via secretory factors and provide a plausible explanation for the protective role of hAMSCs in liver fibrosis.
• Macrophage-Derived Extracellular Vesicles Induce Long-Lasting Immunity Against Hepatitis C Virus Which Is Blunted by Polyunsaturated Fatty Acids.

  Chengcong Cai, Benjamin Koch, Kenichi Morikawa, Goki Suda, Naoya Sakamoto, Sabrina Rueschenbaum, Sami Akhras, Julia Dietz, Eberhard Hildt, Stefan Zeuzem, Christoph Welsch, Christian M Lange

  Frontiers in immunology 9 723 - 723 2018 [Refereed][Not invited]
   

  Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. In this study, we aimed to further characterize the role of macrophage-derived EVs in immune responses against hepatitis C virus (HCV) and the potential of polyunsaturated fatty acids (PUFAs) to modulate this modality of innate immunity. To this end, EVs were isolated from interferon-stimulated macrophage cultures or from serum of patients with acute or chronic hepatitis C. EVs were characterized by electron microscopy, flow cytometry, RNA-sequencing, and Western blot analysis. The effect of EVs on replication of HCV was assessed in coculture models. Functional analyses were performed to assess the impact of PUFAs on EV-mediated antiviral immunity. We found that macrophages secreted various cytokines shortly after stimulation with type I and II IFN, which orchestrated a fast but short-lasting antiviral state. This rapid innate immune answer was followed by the production of macrophage-derived EVs, which induced a late, but long-lasting inhibitory effect on HCV replication. Of note, exposure of macrophages to PUFAs, which are important regulators of immune responses, dampened EV-mediated antiviral immune responses. Finally, EVs from patients with hepatitis C exhibited long-lasting antiviral activities during IFN therapy as well. The antiviral effect of EVs from Caucasian and Japanese patients differed, which may be explained by different nutritional uptake of PUFAs. In conclusion, our data indicate that macrophage-derived EVs mediate long-lasting inhibitory effects on HCV replication, which may bridge the time until efficient adaptive immune responses are established, and which can be blunted by PUFAs.
• Prognostic and Predictive Value of HER2 Amplification in Patients With Metastatic Colorectal Cancer

  Kentaro Sawada, Yoshiaki Nakamura, Takeharu Yamanaka, Yasutoshi Kuboki, Daisuke Yamaguchi, Satoshi Yuki, Takayuki Yoshino, Yoshito Komatsu, Naoya Sakamoto, Wataru Okamoto, Satoshi Fujii

  Clinical Colorectal Cancer 17 (3) 198 - 205 1938-0674 2018 [Refereed][Not invited]
   

  We evaluated the prognostic impact of human epidermal growth factor receptor 2 (HER2) amplification in metastatic colorectal cancer as well as the efficacy of anti–epidermal growth factor receptor (EGFR) therapy. HER2 amplification was as potentially prognostic for overall survival as RAS or BRAFV600E mutation as well as a potential negative predictive factor of anti-EGFR therapy in metastatic colorectal cancer. Purpose: To evaluate a prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer (mCRC). Patients and Methods: Patients with mCRC who underwent surgical resection of the primary tumor and who received best supportive care with or without palliative chemotherapy between 2005 and 2015 were included. HER2 immunohistochemistry was performed using formalin-fixed, paraffin-embedded primary tumor specimens. HER2 amplification was confirmed by fluorescence in-situ hybridization. The RAS and BRAFV600E mutations were centrally assessed using a PCR-based method. Patients were divided into 4 subgroups: R (RAS mutant), B (BRAFV600E mutant), H (wild-type RAS/BRAF with HER2 amplification), and W (wild-type RAS/BRAF without HER2 amplification). Overall survival (OS) and progression-free survival of anti–epidermal growth factor receptor (EGFR) therapy were assessed. Results: Among 370 eligible patients, data of 359 were successfully analyzed. Fifteen tumors harbored HER2 amplifications, including 4 tumors with concomitant RAS mutation (group R). The number of patients in groups R, B, H, and W was 204, 13, 11, and 131, respectively. The median OS was 27.4 months, and the median follow-up time was 63.2 months. The median OS for groups R, B, H, and W was 24.0, 14.2, 19.9, and 39.1 months, respectively. The number of patients who received anti-EGFR therapy in groups R, B, H, and W was 17, 4, 5, and 49, respectively. Progression-free survival of anti-EGFR therapy was significantly shorter in groups R, B, and H than in group W. Conclusion: HER2 amplification was predictive of anti-EGFR therapy response and appeared to be prognostic in mCRC patients.
• Evaluation of amnion-derived mesenchymal stem cells for treatment-resistant moderate Crohn's disease: study protocol for a phase I/II, dual-centre, open-label, uncontrolled, dose-response trial.

  Shinsuke Otagiri, Shunsuke Ohnishi, Arisa Miura, Hiroshi Hayashi, Izumi Kumagai, Yoichi M Ito, Takehiko Katsurada, Shiro Nakamura, Rika Okamoto, Kenichi Yamahara, Kyu Yong Cho, Toshiyuki Isoe, Norihiro Sato, Naoya Sakamoto

  BMJ open gastroenterology 5 (1) e000206  2018 [Refereed][Not invited]
   

  Introduction: The medical treatment options for patients with Crohn's disease (CD) are limited and patients resistant to those therapies are left requiring surgical operations that usually only achieve some symptomatic relief. Mesenchymal stem cells (MSC) have been shown to be effective for the treatment of CD, and we have demonstrated in animal experiments that human amnion-derived MSCs (AMSC) are a potential new therapeutic strategy. Therefore, we designed this study to investigate the safety and efficacy of AMSCs in patients with treatment-resistant CD. Methods and analysis: This is the protocol for an ongoing phase I/II, dual-centre, open-label, uncontrolled, dose-response study. The estimated enrolment is 6-12 patients with treatment-resistant, moderate CD. A dose of 1.0×106 cells/kg will be administered intravenously in the low-dose group at days 0 and 7. After confirming the safety of low-dose administration, a dose of 4.0×106 cells/kg will be administered intravenously in the high-dose group on days 0 and 7. The primary endpoint will measure the occurrence of adverse events related to acute infusion toxicity, and secondary endpoints will include long-term adverse events and efficacy of AMSC administration. Ethics and dissemination: The Institutional Review Board of Hokkaido University Hospital approved this study protocol (approval number H29-6). A report releasing study results will be submitted to an appropriate journal. Discussion: This study is the first to investigate the safety and efficacy of AMSC use for CD treatment. Our results will advance studies on more efficient and convenient methods to overcome the limits of available CD treatments. Trial registration number: UMIN000029841.
• Palmitoylethanolamide Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Rats.

  Ohara M, Ohnishi S, Hosono H, Yamamoto K, Fu Q, Maehara O, Suda G, Sakamoto N

  Frontiers in pharmacology 9 709 - 709 2018 [Refereed][Not invited]
   

  Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of α-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-β1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-β1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-β1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-β1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.
• Effects of human amnion-derived mesenchymal stem cells and conditioned medium in rats with sclerosing cholangitis.

  Sugiura R, Ohnishi S, Ohara M, Ishikawa M, Miyamoto S, Onishi R, Yamamoto K, Kawakubo K, Kuwatani M, Sakamoto N

  American journal of translational research 10 (7) 2102 - 2114 1943-8141 2018 [Refereed][Not invited]
   

  Mesenchymal stem cells (MSCs) represent a valuable cell source in regenerative medicine, and large numbers of MSCs can be isolated from the amnion noninvasively. Sclerosing cholangitis is a chronic cholestatic disease and characterized by progressive biliary destruction leading to cirrhosis. Many factors are involved in the development of sclerosing cholangitis; however, effective medical therapy is not established. We investigated the effects of human amnion-derived MSCs (hAMSCs) and conditioned medium (CM) obtained from hAMSC cultures in rats with sclerosing cholangitis. Sclerosing cholangitis was induced via the intragastric administration of 100 mg/kg alpha-naphthylisothiocyanate (ANIT) twice weekly for 4 weeks. One million hAMSCs or 200 mu L of CM were intravenously administered on days 15 and 22. Rats were sacrificed on day 29 and evaluated via histological, immunohistochemical, and mRNA expression analyses. hAMSC transplantation and CM administration significantly improved the histological score. In addition, these two interventions significantly improved biliary hyperplasia, peribiliary fibrosis, and inflammation in Glisson's sheath. Accordingly, CK19, MMP-9, and TNF-alpha, and MCP-1 expression in the liver was also decreased by hAMSC and CM administration. In conclusion, hAMSC and CM administration ameliorated biliary hyperplasia, peribiliary fibrosis, and inflammation in a rat model of sclerosing cholangitis. hAMSCs and CM may represent new modalities for treating sclerosing cholangitis.
• Parietal Cell Protrusions and Dilated Oxyntic Glands from Use of Vonoprazan

  Shuichi Miyamoto, Yoshihiro Matsuno, Mototsugu Kato, Takahiko Kudo, Shouko Ono, Yuichi Shimizu, Naoya Sakamoto

  AMERICAN JOURNAL OF GASTROENTEROLOGY 112 (12) 1899 - 1901 0002-9270 2017/12 [Refereed][Not invited]
  
• Study protocol of HGCSG1404 SNOW study: a phase I/II trial of combined chemotherapy of S-1, nab-paclitaxel and oxaliplatin administered biweekly to patients with advanced gastric cancer

  Yasuyuki Kawamoto, Yoshito Komatsu, Satoshi Yuki, Kentaro Sawada, Tetsuhito Muranaka, Kazuaki Harada, Hiroshi Nakatsumi, Hiraku Fukushima, Atsushi Ishiguro, Masayoshi Dazai, Kazuteru Hatanaka, Michio Nakamura, Ichiro Iwanaga, Minoru Uebayashi, Susumu Sogabe, Yoshimitsu Kobayashi, Takuto Miyagishima, Kota Ono, Naoya Sakamoto, Yuh Sakata

  BMC CANCER 17 (1) 837  1471-2407 2017/12 [Refereed][Not invited]
   

  Background: In Japan, S-1 plus cisplatin (SP) regimen has become a standard therapy for patients with advanced gastric cancer. Moreover, the S-1 plus oxaliplatin regimen is now a standard treatment. Nab-paclitaxel was developed for chemotherapy of gastric cancer in Japanese clinical practice. Nab-paclitaxel, created with albumin-bound paclitaxel particles, has high transferability to tumour tissues and does not cause hypersensitivity reactions because of a different chemical composition compared with docetaxel and paclitaxel. A combination of S-1, nab-paclitaxel and oxaliplatin (which we named ` SNOW regimen') can be a promising triplet therapy for advanced gastric cancer. Although we have to pay attention to chemotherapy-induced neuropathy, we aim to investigate the recommended dose of this regimen in a phase I study. Furthermore, we will investigate its efficacy and toxicity in a phase II study. Methods: The phase I study is a dose-escalation study using a standard 3 plus 3 design, followed by expansion cohorts. The SNOW regimen involves 28-day cycles with escalated doses of nab-paclitaxel (100-175 mg/m2 on days 1 and 15) and fixed doses of oxaliplatin (65 mg/m(2) on days 1 and 15) and S-1 (80 mg/m(2)/day on day 1 to 14). The primary endpoints are assessment of dose limiting toxicities and determination of maximum tolerated dose to investigate the recommended dose in the subsequent phase II study. In the phase II study, the primary endpoint is objective response rate. Secondary endpoints are assessment of safety, progression-free survival, disease control rate, overall survival and time to treatment failure. Adverse events were monitored and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Discussion: Triplet therapies for advanced gastric cancer patients have been evaluated in clinical trials. The SNOW regimen can be a promising new triplet therapy.
• Gastrointestinal: Transurethral endoscopic retrograde pancreatography

  K. Kawakubo, M. Kuwatani, T. Shimamura, K. Yamashita, R. Goto, M. Watanabe, Y. Koshizuka, N. Kawamura, D. Iwami, K. Hotta, I. Sano, R. Sugiura, S. Kato, N. Shinohara, A. Taketomi, N. Sakamoto

  Journal of Gastroenterology and Hepatology (Australia) 32 (11) 1791  1440-1746 2017/11/01 [Refereed][Not invited]
  
• Transcribed ultraconserved region Uc.63+promotes resistance to docetaxel through regulation of androgen receptor signaling in prostate cancer

  Yohei Sekino, Naoya Sakamoto, Keisuke Goto, Ririno Honma, Yoshinori Shigematsu, Kazuhiro Sentani, Naohide Oue, Jun Teishima, Akio Matsubara, Wataru Yasui

  ONCOTARGET 8 (55) 94259 - 94270 1949-2553 2017/11 [Refereed][Not invited]
   

  Docetaxel is the standard chemotherapy for metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients ultimately become refractory due to the development of docetaxel resistance. The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are absolutely conserved across species and are involved in carcinogenesis including prostate cancer (PC). In this study, we investigated the transcriptional levels of 26 representative T-UCRs and determined the regions that were differentially expressed in PC. Quantitative real-time polymerase chain reaction analysis revealed that the expression of T-UCR Uc.63+ was increased in PC tissues. MTT assay and wound healing assay revealed that Uc.63+ was involved in cell growth and cell migration. miR-130b was predicted to have binding sites within the Uc.63+ sequence. The expression of miR-130b was significantly disturbed by the overexpression or knockdown of Uc.63+. We also showed that Uc.63+ regulated the expression of MMP2 via miR-130b regulation. Furthermore, overexpression of Uc.63+ increased the expression of AR and its downstream molecule PSA and promoted resistance to docetaxel through AR regulation. In patients treated with docetaxel, the expression of serum Uc.63+ in the docetaxel-resistant patients was higher than that in the docetaxel-sensitive patients (P = 0.011). Moreover, Kaplan-Meier analysis showed that the high expression of serum Uc.63+ correlated with a worse prognosis (P = 0.020). These results substantially support the important role that Uc.63+ plays in PC progression by interacting with miR-130b and indicate that Uc.63+ could potentially be a promising serum marker for deciding the best treatment for patients with CRPC.
• Long-term follow-up study of gastric adenoma; tumor-associated macrophages are associated to carcinoma development in gastric adenoma

  Daiki Taniyama, Kiyomi Taniyama, Kazuya Kuraoka, Junichi Zaitsu, Akihisa Saito, Hirofumi Nakatsuka, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Wataru Yasui

  GASTRIC CANCER 20 (6) 929 - 939 1436-3291 2017/11 [Refereed][Not invited]
   

  Background Some gastric adenomas may progress to adenocarcinoma in a short time, but others remain as adenoma for a long time. Methods Among 1138 cases diagnosed as adenoma by biopsy at Kure Medical Association Hospital between 1990 and 2010, 51 adenomas were enrolled. Of these, 28 adenomas (group A) were followed for 60 months or longer with no progression to adenocarcinoma within 60 months, and the other 23 adenomas (group B) were upgraded to carcinoma by consecutive biopsies performed within 1 year after the first biopsy. These adenomas were compared clinicopathologically and immunohistochemically. Results Macroscopically, the mean size of group B adenomas was significantly larger than that of group A adenomas (18.6 vs. 9.9 mm) at the first biopsy. The frequency of a depressed area in the adenoma was significantly higher in group B than group A. Microscopically none of group A but 7 (30.4%) of 23 group B adenomas showed severe atypia. Each of a highly proliferative gland measured by Ki-67 labeling, cellular atypical grade, gastric phenotype defined by MUC5AC and MUC6 and CD204-positive tumor-associated macrophage (TAM) was a significant risk factor for adenocarcinoma development in gastric adenoma by univariate analysis. Only moderate or severe atypia of adenoma cells and the TAM number in the stroma of adenomas were independent risk factors by multivariate analysis. Conclusions As independent risk factors, cellular atypia may reconfirm the importance of morphological analysis, and the TAM number may indicate the significance of TAM function in gastric adenoma.
• Expression and function of Uc.160+, a transcribed ultraconserved region, in gastric cancer

  Ririno Honma, Keisuke Goto, Naoya Sakamoto, Yohei Sekino, Kazuhiro Sentani, Naohide Oue, Wataru Yasui

  GASTRIC CANCER 20 (6) 960 - 969 1436-3291 2017/11 [Refereed][Not invited]
   

  Background Transcribed ultraconserved regions (T-UCRs) are a novel class of noncoding RNAs that are highly conserved among the orthologous regions in most vertebrates. It has been reported that T-UCRs have distinct signatures in human cancers. We previously discovered the downregulation of T-UCR expression in gastric cancer (GC), indicating that T-UCRs could play an important role in GC biology. Uc.160+, a T-UCR reported to be downregulated in human cancer, has not been examined in GC. Methods We analyzed the expression pattern of Uc.160+ in nonneoplastic and tumor tissues of the stomach by using uantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH), specifically focusing on the mechanism of transcriptional regulation and target genes that are regulated by T-UCRs. We also attempted to determine the effect of Uc.160+ expression on biological features of GC cell lines by Western blotting. Results On the basis of the qRT-PCR and ISH results, Uc.160+ expression in adenoma and GC tissues was clearly downregulated compared with that in nonneoplastic mucosa tissues of the stomach. Cancer-specific DNA methylation in the promoter region of Uc.160 was observed by bisulfite genomic DNA sequencing analysis. The effect of DNA methylation on Uc.160+ expression was further confirmed by reporter gene assay. We also revealed that Uc.160+ inhibited the phosphorylation of Akt by regulating phosphatase and tensin homolog (PTEN) expression. Conclusions These results indicate that Uc.160+ could possibly have a tumor suppressive role in GC.
• Endocytoscopy of Superficial Nonampullary Duodenal Epithelial Tumor: Two Cases of Tubular Adenocarcinoma and Adenoma

  Shuichi Miyamoto, Takahiko Kudo, Satoshi Abiko, Shouko Ono, Yuichi Shimizu, Yoshihiro Matsuno, Naoya Sakamoto

  AMERICAN JOURNAL OF GASTROENTEROLOGY 112 (11) 1638 - 1638 0002-9270 2017/11 [Refereed][Not invited]
  
• Hepatitis B virus reactivation during hepatitis C direct-acting antiviral therapy in patients with previous HBV infection

  Naoki Kawagishi, Goki Suda, Masahiro Onozawa, Megumi Kimura, Osamu Maehara, Jun Ito, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  JOURNAL OF HEPATOLOGY 67 (5) 1106 - 1108 0168-8278 2017/11 [Refereed][Not invited]
  
• Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma

  Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Kelly A. Whelan, Hiroshi Nakagawa, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto

  CARCINOGENESIS 38 (11) 1073 - 1083 0143-3334 2017/11 [Refereed][Not invited]
   

  In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchym al-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.
• Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment

  Goki Suda, Atsushi Nagasaka, Yoshiya Yamamoto, Ken Furuya, Kenichi Kumagai, Mineo Kudo, Katsumi Terashita, Tomoe Kobayashi, Izumi Tsunematsu, Junichi Yoshida, Takashi Meguro, Megumi Kimura, Jun Ito, Machiko Umemura, Takaaki Izumi, Seiji Tsunematsu, Fumiyuki Sato, Yoko Tsukuda, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  HEPATOLOGY RESEARCH 47 (11) 1127 - 1136 1386-6346 2017/10 [Refereed][Not invited]
   

  Aim: Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment.Methods: The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12weeks after the end of treatment and safety was evaluated according to renal function.Results: Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44mL/min/1.73m(2)) and stage G4/5 (eGFR, 15-29/<15mL/min/1.73m(2)), respectively. Baseline presence of the NS5A resistance-associated variant, previous simeprevir treatment, and HCV RNA titers, which were predictors of a sustained viral response, were similar between patients with eGFR <45mL/min/1.73m(2) and eGFR >45mL/min/1.73m(2). Notably, the 12-week sustained viral response rate was comparable in patients with eGFR <45mL/min/1.73m(2) (100%, 24/24) and those with eGFR >45mL/min/1.73m(2) (88.9%, 265/298; P=0.07). Treatment discontinuation rates and adverse events, including alanine aminotransferase elevation, anemia, and renal disorders, were similar between the two groups.Conclusion: Daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe.
• Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy

  Goki Suda, Koji Ogawa, Yoshiya Yamamoto, Masaki Katagiri, Ken Furuya, Kenichi Kumagai, Jun Konno, Megumi Kimura, Naoki Kawagishi, Masatsugu Ohara, Machiko Umemura, Jun Ito, Takaaki Izumi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Akihito Tsubota, Noritomo Shimada, Etsuko Iio, Yasuhito Tanaka, Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY 52 (10) 1122 - 1129 0944-1174 2017/10 [Refereed][Not invited]
   

  Background The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy.Methods This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12 weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated.Results Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7%(13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92 K at baseline.Conclusions This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.
• Effect on Helicobacter pylori eradication therapy against gastric cancer in Japan

  Momoko Tsuda, Masahiro Asaka, Mototsugu Kato, Rumiko Matsushima, Kenji Fujimori, Kozo Akino, Shogo Kikuchi, Yingsong Lin, Naoya Sakamoto

  HELICOBACTER 22 (5) 1083-4389 2017/10 [Refereed][Not invited]
   

  Background: In Japan, there have been approximately 50 000 deaths from gastric cancer annually for over 40 years with little variation. It has been reported that most gastric cancers in Japan are caused by Helicobacter pylori infection. H. pylori eradication therapy was approved for patients with chronic gastritis by the Japanese national health insurance scheme in February 2013 for patients with an endoscopic diagnosis of chronic gastritis is positive for H. pylori. We examined the effect on gastric cancer death rate 4 years after expansion of health insurance coverage. Aim: We conducted an epidemiological study and analyzed trends in prescription for H. pylori eradication therapy. We used the electronic medical claims database from Hokkaido, Japan to evaluate the impact of expansion of national health insurance coverage for H. pylori eradication therapy on deaths from gastric cancer. Methods: Data on deaths from gastric cancer were obtained from the Japanese Ministry of Health, Labour and Welfare and the Cancer Statistics in Japan (2015). Analysis of electronic claims records was performed using the National Database, mainly focusing on Hokkaido. Prescriptions for H. pylori eradication therapy and the number of patients treated for gastric cancer were also extracted from the Hokkaido database. Results: Approximately 1.5 million prescriptions for H. pylori eradication therapy were written annually. Gastric cancer deaths fell each year: 48 427 in 2013, 47 903 in 2014, 46 659 in 2015, and 45 509 in 2016, showing a significant decrease after expansion of insurance coverage for H. pylori eradication therapy (P<.0001). Conclusions: Prescriptions for H. pylori eradication therapy increased markedly after approval of the gastritis indication by the national health insurance scheme and was associated with a significant decrease in gastric cancer deaths.
• Hepatitis C virus-induced innate immune responses in human iPS cell-derived hepatocyte-like cells

  Fuminori Sakurai, Takemaru Kunito, Kazuo Takayama, Rina Hashimoto, Masashi Tachibana, Naoya Sakamoto, Takaji Wakita, Hiroyuki Mizuguchi

  VIRUS RESEARCH 242 7 - 15 0168-1702 2017/10 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) infection is a major cause of liver-related morbidity and mortality. In order to develop effective remedies for hepatitis C, it is important to understand the HCV infection profile and host-HCV interaction. HCV-induced innate immune responses play a crucial role in spontaneous HCV clearance; however, HCV-induced innate immune responses have not been fully evaluated in hepatocytes, partly because there are few in vitro models of HCV-induced innate immunity. Recently, human induced pluripotent stem (iPS) cells have received much attention as an in vitro model of infection with various pathogens, including HCV. We previously established highly functional hepatocyte-like cells differentiated from human iPS cells (iPS-HLCs). Here, we examined the potential of iPS-HLCs as an in vitro HCV infection model, especially for evaluation of the relationship between HCV infection levels and HCV-induced innate immunity. Significant expressions of type I and III interferons (IFNs) and IFN-stimulated genes (ISGs) were induced following transfection with HCV genomic replicon RNA in iPS-HLCs. Following inoculation with the HCV JFH-1 strain in iPS-HLCs, peaks of HCV genome replication and HCV protein expression were observed on day 2, and then both the HCV genome and protein levels gradually declined, while the mRNA levels of type III IFNs and ISGs peaked at day 2 following inoculation. These results suggest that the HCV genome efficiently replicates in iPS-HLCs, resulting in HCV genome-induced up-regulation of IFNs and ISGs, and thereafter, HCV genome-induced up-regulation of IFNs and ISGs mediates a reduction in the HCV genome and protein levels in iPS-HLCs.
• Dipeptidylpeptidase-IVの酵素活性により蛍光を発するプローブによる頭頸部表在癌の検出

  大西 俊介, 水島 健, 清水 勇一, 畑中 豊, 畑中 佳奈子, 山本 桂子, 本間 明宏, 栗木 優五, 神谷 真子, 浦野 泰照, 坂本 直哉

  日本癌学会総会記事 日本癌学会 76回 P - 2320 0546-0476 2017/09 [Not refereed][Not invited]
  
• PSM解析による切除不能転移性大腸癌における原発巣切除の意義の検討

  市川 伸樹, 本間 重紀, 吉田 雅, 大野 陽介, 川村 秀樹, 川本 泰之, 中積 宏之, 結城 敏志, 小松 嘉人, 石川 倫啓, 江本 慎, 小笠原 和宏, 曽我部 進, 中西 一彰, 数井 啓蔵, 古家 乾, 上泉 洋, 加藤 寛士, 坂本 直哉, 武冨 紹信

  日本大腸肛門病学会雑誌 (一社)日本大腸肛門病学会 70 (抄録号) A137 - A137 0047-1801 2017/09
• 粘膜下局注併用APCと標準的APCの生体ブタ組織に対する焼灼効果の検討

  安孫子 怜史, 清水 勇一, 大西 俊介, 水島 健, 加藤 麻倫, 松田 可奈, 宮本 秀一, 津田 桃子, 山本 桂子, 小野 尚子, 工藤 俊彦, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 59 (Suppl.2) 2223 - 2223 0387-1207 2017/09
• Overexpression of PCDHB9 promotes peritoneal metastasis and correlates with poor prognosis in patients with gastric cancer

  Shoichiro Mukai, Naohide Oue, Takashi Oshima, Takeharu Imai, Yohei Sekino, Ririno Honma, Naoya Sakamoto, Kazuhiro Sentani, Hiroki Kuniyasu, Hiroyuki Egi, Kazuaki Tanabe, Kazuhiro Yoshida, Hideki Ohdan, Wataru Yasui

  JOURNAL OF PATHOLOGY 243 (1) 100 - 110 0022-3417 2017/09 [Refereed][Not invited]
   

  Gastric cancer (GC) is one of the most common human cancers. Genes expressed only in cancer tissue, especially on the cell membrane, may be useful biomarkers for cancer diagnosis and therapeutics. In the present study, we focused on the PCDHB9 gene, which encodes the transmembrane protein protocadherin B9. Immunohistochemical analysis revealed that 62 (36%) of 173 GC cases were positive for protocadherin B9. Protocadherin B9 staining was mainly observed on the GC cell membrane. Expression of protocadherin B9 was frequently found in intestinal-type GC and correlated with poor prognosis in patients with intestinal-type GC. Although PCDHB9 knockdown or forced expression of PCDHB9 did not change cell growth or invasion activity in a GC cell line, cell adhesion to fibronectin was significantly reduced by PCDHB9 knockdown and significantly enhanced by overexpression of PCDHB9. Expression levels of ITGA3, ITGA4, ITGA5, and ITGB1 were significantly reduced by knockdown of PCDHB9 and significantly enhanced by overexpression of PCDHB9. Furthermore, both the number and the size of spheres in culture were significantly decreased by PCDHB9 knockdown and significantly increased by overexpression of PCDHB9. In a peritoneal dissemination mouse model, the weight of the total disseminated nodules of MKN-74 cells was significantly increased by forced expression of PCDHB9. These results indicate that protocadherin B9 plays an important role in the progression rather than the pathogenesis of intestinal-type GC. Specific inhibitors of protocadherin B9 may constitute promising anti-cancer drugs with fewer side-effects. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
• Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs

  Takeshi Mizushima, Shunsuke Ohnishi, Hidetaka Hosono, Kenichi Yamahara, Momoko Tsuda, Yuichi Shimizu, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 86 (3) 542 - U356 0016-5107 2017/09 [Refereed][Not invited]
   

  Background and Aims: Endoscopic submucosal dissection (ESD) for esophageal cancer often causes postoperative stricture when more than three fourths of the circumference of the esophagus is dissected. Mesenchymal stem cells are a valuable cell source in regenerative medicine, and conditioned medium (CM) obtained from mesenchymal stem cells reportedly inhibits inflammation. In this study we evaluated whether CM could prevent esophageal stricture after ESD. Methods: We resected a semi-circumference of pig esophagus by ESD. We prepared CM gel by mixing with 5% carboxymethyl cellulose and endoscopically applied it onto the wound bed immediately after ESD and on days 8 and 15 (weekly CM group) or administered it orally from days 1 to 4 (daily CM group). We also injected triamcinolone acetonide into the remaining submucosa immediately after ESD (steroid group). We killed the pigs on day 8 or day 22 to measure the stricture rate and to perform histologic analysis. Results: Stricture rate in weekly and daily CM groups and steroid groups were significantly lower than in the control group on day 22. Moreover, CM significantly attenuated the number of activated myofibroblasts and fiber thickness on day 22. CM also significantly decreased the infiltration of neutrophils and macrophages compared with the control group on day 8. Conclusions: CM gel prevents esophageal stricture formation by suppressing myofibroblast activation and fibrosis after the infiltration of neutrophils and macrophages. Oral administration of CM gel is a promising treatment for the prevention of post-ESD stricture.
• A Phase I Study of Combination Therapy with Sorafenib and 5-Fluorouracil in Patients with Advanced Hepatocellular Carcinoma.

  Takuya Sho, Mitsuru Nakanishi, Kenichi Morikawa, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Machiko Umemura, Jun Ito, Masato Nakai, Goki Suda, Koji Ogawa, Makoto Chuma, Takashi Meguro, Michio Nakamura, Atsushi Nagasaka, Hiromasa Horimoto, Yoshiya Yamamoto, Naoya Sakamoto

  Drugs in R&D 17 (3) 381 - 388 1174-5886 2017/09 [Refereed][Not invited]
   

  BACKGROUND AND AIMS: Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial. METHODS: This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle. RESULTS: Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%. CONCLUSIONS: Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.
• 転移性および原発性病変による肝門部悪性胆管狭窄に対する内視鏡的胆管ドレナージ術の臨床成績

  杉浦 諒, 桑谷 将城, 佐野 逸紀, 加藤 新, 川久保 和道, 坂本 直哉

  胆道 (一社)日本胆道学会 31 (3) 566 - 566 0914-0077 2017/08
• Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit

  Yasunobu Arima, Takuto Ohki, Naoki Nishikawa, Kotaro Higuchi, Mitsutoshi Ota, Yuki Tanaka, Junko Nio-Kobayashi, Mohamed Elfeky, Ryota Sakai, Yuki Mori, Tadafumi Kawamoto, Andrea Stofkova, Yukihiro Sakashita, Yuji Morimoto, Masaki Kuwatani, Toshihihiko Iwanaga, Yoshichika Yoshioka, Naoya Sakamoto, Akihiko Yoshimura, Mitsuyoshi Takiguchi, Saburo Sakoda, Marco Prinz, Daisuke Kamimura, Masaaki Murakami

  ELIFE 6 2050-084X 2017/08 [Refereed][Not invited]
   

  Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-ofhypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.
• Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer (vol 46, pg 335, 2017)

  H. Hayashi, T. Kohno, H. Ueno, N. Sakamoto

  PANCREAS 46 (7) E64 - E64 0885-3177 2017/08 [Refereed][Not invited]
  
• The first case report of infective endocarditis caused by Gemella taiwanensis

  Mayu Hikone, Naoya Sakamoto, Masayuki Ota, Takuya Washino, Ken-ichiro Kobayashi, Sentaro Iwabuchi, Haruko Kazama, Akiko Kounosu, Kumiko Negishi, Yusuke Ainoda, Shigekazu Iguchi, Atsushi Yoshida, Ken Kikuchi, Kenji Ohnishi

  JOURNAL OF INFECTION AND CHEMOTHERAPY 23 (8) 567 - 571 1341-321X 2017/08 [Refereed][Not invited]
   

  Gemella is a facultative anaerobic Gram-positive coccus and a rare cause of infective endocarditis (IE). Gram staining may eventually misidentify the organism, which tends to easily decolorize and manifest as either Gram-negative or Gram-variable. Commercial biochemical tests are often used to identify Gemella, but the methods they employ sometimes lack accuracy. A 52-year-old woman was diagnosed with Gemella taiwanensis IE after initial identification of the pathogen as Gemella haemolysans using biochemical tests combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). She was treated successfully with penicillin, gentamicin, and mitral valve replacement. To our knowledge, this is the first case of IE confirmed by 16S rRNA gene and groEL sequencing to have been caused by G. taiwanensis. The accurate diagnosis of rare or difficult-to-identify pathogens is a major challenge for clinical microbiological laboratories. The concurrent use of molecular methods could lead to the recognition of new or different pathogens. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
• Effect of endoscopic transpapillary biliary drainage with/without endoscopic sphincterotomy on postendoscopic retrograde cholangiopancreatography pancreatitis in patients with biliary stricture (E-BEST): a protocol for a multicentre randomised controlled trial

  Shin Kato, Masaki Kuwatani, Ryo Sugiura, Itsuki Sano, Kazumichi Kawakubo, Kota Ono, Naoya Sakamoto

  BMJ OPEN 7 (8) e017160  2044-6055 2017/08 [Refereed][Not invited]
   

  Introduction The effect of endoscopic sphincterotomy prior to endoscopic biliary stenting to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis remains to be fully elucidated. The aim of this study is to prospectively evaluate the non-inferiority of non-endoscopic sphincterotomy prior to stenting for naive major duodenal papilla compared with endoscopic sphincterotomy prior to stenting in patients with biliary stricture. Methods and analysis We designed a multicentre randomised controlled trial, for which we will recruit 370 patients with biliary stricture requiring endoscopic biliary stenting from 26 high-volume institutions in Japan. Patients will be randomly allocated to the endoscopic sphincterotomy group or the non-endoscopic sphincterotomy group. The main outcome measure is the incidence of pancreatitis within 2 days of initial transpapillary biliary drainage. Data will be analysed on completion of the study. We will calculate the 95% confidence intervals (CIs) of the incidence of pancreatitis in each group and analyse weather the difference in both groups with 95% CIs is within the non-inferiority margin (6%) using the Wald method. Ethics and dissemination This study has been approved by the institutional review board of Hokkaido University Hospital (IRB:016-0181). Results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal.
• Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

  Yoshinori Shigematsu, Naohide Oue, Yuri Nishioka, Naoya Sakamoto, Kazuhiro Sentani, Yohei Sekino, Shoichiro Mukai, Jun Teishima, Akio Matsubara, Wataru Yasui

  ONCOLOGY LETTERS 14 (1) 999 - 1004 1792-1074 2017/07 [Refereed][Not invited]
   

  Bladder cancer, the majority of which is urothelial carcinoma (UC), is a common malignancy worldwide. Genes encoding transmembrane/secretory proteins expressed specifically in certain cancers may be ideal biomarkers for cancer diagnosis and may represent therapeutic targets. In the present study, the expression and function of the bone marrow stromal cell antigen 2 (BST2) gene was analyzed in UC. Reverse transcription-quantitative polymerase chain reaction demonstrated that expression of BST2 in normal tissue samples was the highest in liver tissue. However, expression of BST2 in UC tissue samples was higher than in normal liver. Immunohistochemical analysis revealed weak or no staining of BST-2 in non-neoplastic mucosa, whereas UC tissue exhibited stronger and more extensive staining compared with non-neoplastic mucosa. BST-2 staining was observed mainly on UC cell membranes. In total, 28 (41%) of 69 UC cases were positive for BST-2. UC cases positive for BST-2 were more frequently T2/3/4 cases [so-called muscle-invasive bladder cancer (MIBC)] than Ta/is/1 cases (P=0.0001). However, Kaplan-Meier analysis demonstrated no association between BST-2 expression and survival. BST2 small interfering RNA (siRNA)-transfected T24 cells exhibited significantly reduced cell growth relative to negative control siRNA-transfected T24 cells. The levels of phosphorylated Akt and extracellular signal-regulated kinase were lower in BST2 siRNA-transfected T24 cells than in control cells. These results suggest the involvement of BST-2 in the pathogenesis of UC. Since BST-2 is expressed on the cell membrane, BST-2 may be a good therapeutic target for MIBC.
• Retinoid derivative Tp80 exhibits anti-hepatitis C virus activity through restoration of GI-GPx expression

  Bao Ngoc Nguyen, Yukiko Okuno, Masahiko Ajiro, Kei Iida, Masatsugu Denawa, Makoto Yamamoto, Naoya Sakamoto, Hiroyuki Kagechika, Masatoshi Hagiwara

  JOURNAL OF MEDICAL VIROLOGY 89 (7) 1224 - 1234 0146-6615 2017/07 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) is a positive-sense single-stranded RNA virus with an estimated infection in similar to 180 million people worldwide, and its chronic infection leads to development of cirrhosis and hepatocellular carcinoma. Although recent development of direct acting antiviral (DAA) compounds improved anti-HCV regimens, alternative therapeutic compounds are still demanded due to an expected emergence of escape mutants for those DAAs. In order to identify novel anti-HCV agents, we conducted chemical library screening for 2086 compounds using HCV Rep-Feo reporter replicon in Huh7 hepatoma cells. Our screening identified retinoid derivative Tp80, which inhibits replication of HCV Rep-Feo (genotype 1b) and JFH1 HCV (genotype 2a) with 0.62 mu M and 1.0 mu M, respectively, of 50% effective concentration (EC50), at which cytotoxicity is not evident for host hepatocytes. Subsequent transcriptome profiling revealed Tp80 exhibits anti-HCV activity through restoration of gastrointestinal glutathione peroxidase (GI-GPx), suppression of which is responsible for HCV-induced oxidative stress to facilitate HCV replication. Furthermore, comparison of Tp80 with other retinoid derivatives revealed Tp80 shows best potency in both GI-GPx restoration and anti-HCV activity among compounds we examined. In conclusion, our current study provides Tp80 as a promising candidate of anti-HCV compound, suppressing host cellular oxidative stress through a restoration of GI-GPx.
• Fluid shear stress combined with shear stress spatial gradients regulates vascular endothelial morphology

  Daisuke Yoshino, Naoya Sakamoto, Masaaki Sato

  INTEGRATIVE BIOLOGY 9 (7) 584 - 594 1757-9694 2017/07 [Refereed][Not invited]
   

  High shear stress (SS) causes local changes around arterial bifurcations, which are common sites for cerebral aneurysms. High SS and SS spatial gradient (SSG) are thought to play important roles in the pathology of cerebral aneurysms. However, whether SS and SSG independently affect the function and morphology of vascular endothelial cells (ECs) exposed to fluid flow remains unclear. This study evaluated the morphology of ECs exposed to various SS and SSG combinations. Confluent ECs were exposed to a SS of 2-60 Pa and a uniform SSG of 0, 5, 10, or 15 Pa mm (1) for 24 h. Although ECs exposed to lower levels of SS/SSG were not oriented or elongated in the direction of flow, they began to exhibit orientation, elongation, and development of actin stress fibers under the conditions of SS with a SSG when the SS exceeded a threshold value depending on the magnitude of SSG. Using a simplified computational model, we found that the presence of a SSG affects the strain field in ECs, resulting in a morphological response. SS combined with a SSG can alter the localization of SS mechano-sensing proteins along the strain field as a result of shear flow. Our results suggest that the magnitude of the relationship between SS and SSG plays an important role in regulating morphological changes in ECs in response to fluid flow by regulating EC polarity.
• The Expression of BTS-2 Enhances Cell Growth and Invasiveness in Renal Cell Carcinoma

  Quoc Thang Pham, Naohide Oue, Yuji Yamamoto, Yoshinori Shigematsu, Yohei Sekino, Naoya Sakamoto, Kazuhiro Sentani, Naohiro Uraoka, Mamata Tiwari, Wataru Yasui

  ANTICANCER RESEARCH 37 (6) 2853 - 2860 0250-7005 2017/06 [Refereed][Not invited]
   

  Background: Renal cell carcinoma (RCC) is one of the most common types of cancer in developed countries. Bone marrow stromal cell antigen 2 (BST2) gene, which encodes BST2 transmembrane glycoprotein, is overexpressed in several cancer types. In the present study, we analyzed the expression and function of BST2 in RCC. Materials and Methods: BST2 expression was analyzed by immunohistochemistry in 123 RCC cases. RNA interference was used to inhibit BST2 expression in a RCC cell line. Results: Immunohistochemical analysis showed that 32% of the 123 RCC cases were positive for BST2. BST2 expression was positively associated with tumour stage. Furthermore, BST2 expression was an independent predictor of survival in patients with RCC. BST2 siRNA-transfected Caki-1 cells displayed significantly reduced cell growth and invasive activity relative to negative control siRNA-transfected cells. Conclusion: These results suggest that BST2 plays an important role in the progression of RCC. Because BST2 is expressed on the cell membrane, BST2 is a good therapeutic target for RCC.
• Vonoprazan improves the efficacy of Helicobacter pylori eradication therapy with a regimen consisting of clarithromycin and metronidazole in patients allergic to penicillin

  Shoko Ono, Mototsugu Kato, Soichi Nakagawa, Katsuhiro Mabe, Naoya Sakamoto

  HELICOBACTER 22 (3) 1083-4389 2017/06 [Refereed][Not invited]
   

  BackgroundAlthough all Helicobacter pylori (H.pylori)-positive patients should receive eradication therapy, the therapy is a challenge for patients allergic to penicillin. There have been a few reports on the efficacy of eradication therapy for such patients. ObjectiveTo analyze the efficacy of vonoprazan or proton pump inhibitor (PPI)-based 7-day triple therapy in patients allergic to penicillin. Materials and MethodsA total of 88 consecutive patients allergic to penicillin who received H.pylori eradication therapy were retrospectively analyzed. Thirty-one patients had a history of failed eradication therapy. Four 7-day regimens were prescribed during the study period: clarithromycin-metronidazole-PPI (13 patients), clarithromycin-metronidazole-vonoprazan (14 patients), metronidazole-sitafloxacin-PPI (44 patients) and metronidazole-sitafloxacin-vonoprazan (17 patients). A C-13-urea breath test was used for confirmation of eradication, and efficacy of eradication was evaluated by intention-to-treat analysis and per-protocol analysis. ResultsIntention-to-treat and per-protocol eradication rates were 46.2%/54.6% for patients who received clarithromycin-metronidazole-PPI, 92.9/92.9% for patients who received clarithromycin-metronidazole-vonoprazan, 100/100% for patients who received metronidazole-sitafloxacin-PPI and 88.2/93.8% for patients who received metronidazole-sitafloxacin-vonoprazan. For first eradication, vonoprazan significantly raised the intention-to-treat efficacy of the triple therapy including clarithromycin-metronidazole (vonoprazan: 92.9%, PPI: 46.2%, P=.0128). A 7-day regimen consisting of metronidazole and sitafloxacin was effective for patients allergic to penicillin with or without past failure of eradication. ConclusionFor first eradication in patients allergic to penicillin, a 7-day triple therapy consisting of clarithromycin, metronidazole and vonoprazan could be a candidate eradication regimen.
• Endoscopic ultrasonography features of gastric mucosal cobblestone-like changes from a proton-pump inhibitor

  Shuichi Miyamoto, Takahiko Kudo, Mototsugu Kato, Kana Matsuda, Satoshi Abiko, Momoko Tsuda, Takeshi Mizushima, Keiko Yamamoto, Shoko Ono, Yuichi Shimizu, Naoya Sakamoto

  Clinical Journal of Gastroenterology 10 (3) 220 - 223 1865-7265 2017/06/01 [Refereed][Not invited]
   

  A 68-year-old man with no symptoms presented to Hokkaido University Hospital for esophagogastroduodenoscopy screening. He had a history of Helicobacter pylori eradication. Initial esophagogastroduodenoscopy showed no gastric cobblestone-like mucosa or gastric cracked mucosa. After 1 year, he received esomeprazole (20 mg) once daily for heartburn at another hospital. Esophagogastroduodenoscopy was performed after 2 years of esomeprazole administration. Endoscopic findings showed that after H. pylori eradication, according to the Kyoto classification, gastric cobblestone-like mucosa presented in the gastric body area. Dilation of the oval crypt opening and intervening part in the gastric cobblestone-like mucosa was detected by endoscopy with narrow band imaging. Endoscopic ultrasonography revealed a thick gastric second layer and sporadic small a-echoic lesions in the low-echoic thickened second layer in the gastric cobblestone-like mucosa. The gastric cobblestone-like mucosa biopsy specimen showed parietal cell protrusions and oxyntic gland dilatations. Recently, we reported that gastric mucosal changes such as gastric cracked mucosa and gastric cobblestone-like mucosa were caused by proton-pump inhibitors however, the gastric cobblestone-like mucosa was not examined by endoscopic ultrasonography. In this case, endoscopic ultrasonography findings suggested that oxyntic gland dilatations caused the elevated gastric mucosa, such as gastric cobblestone-like mucosa, from the use of proton-pump inhibitors.
• Interferon-free therapy with sofosbuvir plus ribavirin for successful treatment of genotype 2 hepatitis C virus with lichen planus: a case report.

  Ayumu Yoshikawa, Katsumi Terashita, Kenichi Morikawa, Soichiro Matsuda, Takahiro Yamamura, Koichiro Sarashina, Shintaro Nakano, Yoshimitsu Kobayashi, Susumu Sogabe, Kazuhiro Takahashi, Shin Haba, Hisashi Oda, Tatsuro Takahashi, Takuto Miyagishima, Naoya Sakamoto

  Clinical journal of gastroenterology 10 (3) 270 - 273 1865-7257 2017/06 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) infection remains the main cause of liver disease and can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HCV may also develop extrahepatic manifestations in the skin, eyes, joints, kidneys, nervous system, and immune system. In fact, several studies reported that up to 70% of HCV patients experienced extrahepatic manifestations. Lichen planus (LP), which is an immune system disorder that is triggered by viral infections, allergens, and stress, can affect the skin, mouth, nails, and scalp. The association of LP with HCV has been reported, but the effect of HCV treatment on LP remission is controversial. We encountered a 53-year-old man with HCV genotype 2a and LP that were successfully treated with sofosbuvir and ribavirin for 12 weeks. After treatment, he achieved sustained virological response against HCV and remission of erosive LP lesions on the lip. In the era of interferon (IFN)-based treatment for HCV, exacerbation of autoimmune diseases is a common adverse event. Therefore, use of an IFN-free regimen of direct-acting antivirals for HCV might prevent the extrahepatic manifestation of an immune disorder.
• Comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine with nab-paclitaxel in unresectable pancreatic cancer

  Tetsuhito Muranaka, Masaki Kuwatani, Yoshito Komatsu, Kentaro Sawada, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Satoshi Yuki, Yoshimasa Kubota, Kimitoshi Kubo, Shuhei Kawahata, Kazumichi Kawakubo, Hiroshi Kawakami, Naoya Sakamoto

  Journal of Gastrointestinal Oncology 8 (3) 566 - 571 2219-679X 2017/06/01 [Refereed][Not invited]
   

  Background: Irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) and the combination regimen of gemcitabine and nanoparticle albumin-bound paclitaxel (GnP) (nab-PTX) improve the prognosis of patients with metastatic pancreatic cancer. However, no study has compared the efficacy of the two regimens. We compared retrospectively the efficacy and safety of the two regimens in patients with unresectable pancreatic cancer. Methods: Thirty-eight patients with unresectable locally advanced or metastatic pancreatic cancer received FOLFIRINOX or GnP as first-line chemotherapy between December 2013 and September 2015. In the FOLFIRINOX group, patients received 85 mg/m2 oxaliplatin followed by 180 mg/m2 irinotecan and 200 mg/m2 L-leucovorin, and by 400 mg/m2 fluorouracil as a bolus and 2,400 mg/m2 fluorouracil as a 46-h continuous infusion every 14 days. In the GnP group, patients received 125 mg/m2 nab-PTX followed by 1 g/m2, and gemcitabine on days 1, 8 and 15, repeated every 28 days. Results: Response rate was 6.3% in the FOLFIRINOX group and 40.9% in the GnP group (P=0.025). Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 3.0-4.5] in the FOLFIRINOX group and 6.5 months (95% CI, 6.2-6.9 months) in the GnP group (P=0.031). Drug toxicity in the GnP group was less than in the FOLFIRINOX group. Conclusions: Efficacy and safety of GnP compare favorably to those of FOLFIRINOX in patients with pancreatic cancer. Additional prospective trials are warranted
• ウイルソン病における各診断ガイドラインの有用性の検討

  中井 正人, 森川 賢一, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 伊藤 淳, 常松 聖司, 佐藤 史幸, 荘 拓也, 須田 剛生, 小川 浩司, 坂本 直哉

  日本消化器病学会雑誌 (一財)日本消化器病学会 114 (5) 839 - 845 0446-6586 2017/05 [Refereed][Not invited]
   

  ウイルソン病は原因不明の肝機能障害、肝硬変における鑑別診断の1つである。多くは幼少期に診断されるが、成人後に肝硬変として発見される症例も経験する。血清セルロプラスミン、尿中銅などの測定にて診断可能な症例もあるが、診断に苦慮し、ATP7B遺伝子変異検査や肝組織中銅含有量測定が必要な場合もある。米国肝臓病学会、ヨーロッパ肝臓学会から診断ガイドラインが提唱されており、本邦でも2015年にウイルソン病診断ガイドラインが発表され、診断困難例においても、各ガイドラインに従った診断が可能となった。当科でのウイルソン病症例を各ガイドラインの診断基準、フローチャートを用いて検討し、その有用性を報告する。(著者抄録)
• Rapid Detection of Superficial Head and Neck Squamous Cell Carcinoma by Topically Spraying Fluorescent Probe Targeting Dipeptidylpeptidase-Iv

  Shunsuke Ohnishi, Takeshi Mizushima, Yuichi Shimizu, Yutaka Hatanaka, Kanako Hatanaka, Keiko Yamamoto, Akihiro Homma, Yugo Kuriki, Mako Kamiya, Yasuteru Urano, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 85 (5) AB530 - AB530 0016-5107 2017/05 [Refereed][Not invited]
  
• Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

  Kentaro Matsuura, Hiromi Sawai, Kazuho Ikeo, Shintaro Ogawa, Etsuko Iio, Masanori Isogawa, Noritomo Shimada, Atsumasa Komori, Hidenori Toyoda, Takashi Kumada, Tadashi Namisaki, Hitoshi Yoshiji, Naoya Sakamoto, Mina Nakagawa, Yasuhiro Asahina, Masayuki Kurosaki, Namiki Izumi, Nobuyuki Enomoto, Atsunori Kusakabe, Eiji Kajiwara, Yoshito Itoh, Tatsuya Ide, Akihiro Tamori, Misako Matsubara, Norifumi Kawada, Ken Shirabe, Eiichi Tomita, Masao Honda, Shuichi Kaneko, Sohji Nishina, Atsushi Suetsugu, Yoichi Hiasa, Hisayoshi Watanabe, Takuya Genda, Isao Sakaida, Shuhei Nishiguchi, Koichi Takaguchi, Eiji Tanaka, Junichi Sugihara, Mitsuo Shimada, Yasuteru Kondo, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Katsushi Tokunaga, Yasuhito Tanaka

  Gastroenterology 152 (6) 1383 - 1394 1528-0012 2017/05 [Refereed][Not invited]
   

  BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10-8). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.
• Gastric mucosal cracked and cobblestone-like changes resulting from proton pump inhibitor use

  Shuichi Miyamoto, Mototsugu Kato, Momoko Tsuda, Kana Matsuda, Tetsuhito Muranaka, Satoshi Abiko, Masayoshi Ono, Takeshi Mizushima, Saori Omori, Keiko Yamamoto, Katsuhiro Mabe, Shoko Ono, Takahiko Kudo, Yuichi Shimizu, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 29 (3) 307 - 313 0915-5635 2017/05 [Refereed][Not invited]
   

  Background and Aim: Use of proton pump inhibitors (PPI) is histologically associated with oxyntic gland dilatations. Two interesting mucosal changes are often detected endoscopically in patients who use PPI: gastric cracked mucosa (GCM) and gastric cobblestone-like mucosa (GCSM). The aim of the present study was to clarify the relationship between PPI use and these mucosal changes. Methods: This was a single-center observational study. All successive subjects who underwent a routine esophagogastroduodenoscopy (EGD) between August and November 2014 in Hokkaido University Hospital were enrolled. Endoscopists carried out the assessment blinded to the use of PPI and checked for GCSM and GCM using original diagnostic criteria for GCM and GCSM. Subjects were divided into two groups: those who used PPI (PPI group) and those who did not (control group). Endoscopic findings and backgrounds were compared between the two groups. Results: A total of 538 patients were analyzed (control group: 374 patients, men/women: 204/170, median age: 65.2 years; PPI group: 164 patients, men/women: 89/75, median age: 67.1 years). GCM was detected in 54 (10.0%) subjects, and GCSM was detected in 18 (3.3%) subjects. There was a significant difference in the prevalence rate of GCM between the control group (14/374, 3.7%) and the PPI group (40/164, 24.4%) (P < 0.01). GCSM was significantly more prevalent in the PPI group (15/164, 9.1%) than in the control group (3/374, 0.8%) (P < 0.01). Conclusion: Novel GCM and GCSM endoscopic findings in the corpus area seem to be strongly associated with PPI use.
• Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection

  Kentaro Matsuura, Hiromi Sawai, Kazuho Ikeo, Shintaro Ogawa, Etsuko Iio, Masanori Isogawa, Noritomo Shimada, Atsumasa Komori, Hidenori Toyoda, Takashi Kumada, Tadashi Namisaki, Hitoshi Yoshiji, Naoya Sakamoto, Mina Nakagawa, Yasuhiro Asahina, Masayuki Kurosaki, Namiki Izumi, Nobuyuki Enomoto, Atsunori Kusakabe, Eiji Kajiwara, Yoshito Itoh, Tatsuya Ide, Akihiro Tamori, Misako Matsubara, Norifumi Kawada, Ken Shirabe, Eiichi Tomita, Masao Honda, Shuichi Kaneko, Sohji Nishina, Atsushi Suetsugu, Yoichi Hiasa, Hisayoshi Watanabe, Takuya Genda, Isao Sakaida, Shuhei Nishiguchi, Koichi Takaguchi, Eiji Tanaka, Junichi Sugihara, Mitsuo Shimada, Yasuteru Kondo, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Katsushi Tokunaga, Yasuhito Tanaka

  GASTROENTEROLOGY 152 (6) 1383 - 1394 0016-5085 2017/05 [Refereed][Not invited]
   

  BACKGROUND & AIMS: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. METHODS: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). RESULTS: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 x 10(-8)). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of alpha-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. CONCLUSIONS: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.
• Combination of neutrophil-to-lymphocyte ratio and early des--carboxyprothrombin change ratio as a useful predictor of treatment response for hepatic arterial infusion chemotherapy against advanced hepatocellular carcinoma

  Seiji Tsunematsu, Goki Suda, Kazushi Yamasaki, Megumi Kimura, Izumi Takaaki, Machiko Umemura, Jun Ito, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Toshiya Kamiyama, Akinobu Taketomi, Naoya Sakamoto

  HEPATOLOGY RESEARCH 47 (6) 533 - 541 1386-6346 2017/05 [Refereed][Not invited]
   

  AimHepatic arterial infusion chemotherapy (HAIC) is a potent therapeutic option for advanced hepatocellular carcinoma (HCC). However, there are few known predictive factors of treatment response to HAIC. We clarified the most accurate predictive factors early on in treatment.MethodsStudy subjects were 70 patients with advanced HCC who had been treated with HAIC. We assessed the relationships between patient characteristics, change ratios of early tumor markers, tumor response, progression-free survival (PFS), and overall survival.ResultsAfter two courses of HAIC, 1 (1.4%), 16 (22.9%), 30 (42.8%), and 23 (32.9%) of the 70 patients showed complete response, partial response, stable disease, and progressive disease, respectively. Overall survival was related to Child-Turcotte-Pugh score, extrahepatic metastasis, and the des--carboxyprothrombin (DCP) response. Univariate and multivariate analyses identified the neutrophil-to-lymphocyte ratio (NLR) and DCP response as significant determinants of treatment response and PFS. Progression-free survival with a low NLR (<2.87) was significantly longer than with a high NLR (median, 8.4months vs. 2.8months, respectively). Progression-free survival was 7.2months for patients with a responsive DCP (<0.7) and 2.3months for an unresponsive DCP (0.7). Additionally, even with baseline high NLR, patients with responsive DCP achieved better PFS.ConclusionBaseline NLR and early DCP response were significant predictors of treatment response and PFS after HAIC for patients with advanced HCC. The combination of baseline NLR and early DCP response could be accurate and useful predictive factors of response to HAIC and could help optimize treatments for patients with advanced HCC.
• Anti-Adipogenic and Antiviral Effects of L-Carnitine on Hepatitis C Virus Infection

  Yoko Tsukuda, Goki Suda, Seiji Tsunematsu, Jun Ito, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Takuya Sho, Osamu Maehara, Tomoe Shimazaki, Megumi Kimura, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Makoto Chuma, Naoya Sakamoto

  JOURNAL OF MEDICAL VIROLOGY 89 (5) 857 - 866 0146-6615 2017/05 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti-HCV activity of L-carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH-1 or HCV replicontransfected Huh7.5.1 cells were treated with or without L-carnitine to examine its anti-HCV effects. The effects of L-carnitine on HCV entry, HCV-induced adipogenesis and lipid droplet formation, and HCV-induced oxidative stress were examined. Treatment of JFH1-infected cells with L-carnitine inhibited HCV propagation in a concentration-dependent manner. In contrast, L-carnitine had no antiHCV activity in the HCV replicon system, which is lacking viral assembly. In addition, Lcarnitine did not affect HCV entry. However, Lcarnitine treatment decreased intracellular lipid droplets, which are crucial for HCV assembly in JFH-1-infected cells. The expression level of CPT-1 was decreased in JFH-1-infected cells, and L-carnitine treatment restored this expression. HCV-infected cells exhibited increased production of reactive oxygen species and glutathione oxidation. L-carnitine decreased oxidative stress induced by JFH-1-infection, as shown by glutathione/glutathione disulfide assays and MitoSOX staining. L-carnitine exhibited anti-HCV activity, possibly by inhibiting HCV assembly and through its anti-adipogenic activity in HCV-infected cells. Moreover, L-carnitine has antioxidant properties in HCVinfected hepatocytes. Overall, these results indicated that L-carnitine may be an effective adjunctive agent in antiviral therapies to treat chronic hepatitis C. (C) 2016 Wiley Periodicals, Inc.
• 高度悪性胆道狭窄に対する経乳頭的通電拡張術の有効性と諸問題

  加藤 新, 桑谷 将城, 杉浦 諒, 佐野 逸紀, 川久保 和道, 坂本 直哉

  Gastroenterological Endoscopy (一社)日本消化器内視鏡学会 59 (Suppl.1) 993 - 993 0387-1207 2017/04
• Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer

  Hideyuki Hayashi, Takashi Kohno, Hideki Ueno, Nobuyoshi Hiraoka, Shunsuke Kondo, Motonobu Saito, Yoko Shimada, Hitoshi Ichikawa, Mamoru Kato, Tatsuhiro Shibata, Chigusa Morizane, Yasunari Sakamoto, Kazuaki Shimada, Yoshito Komatsu, Naoya Sakamoto, Takuji Okusaka

  PANCREAS 46 (3) 335 - 340 0885-3177 2017/03 [Refereed][Not invited]
   

  Objectives: KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer- related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer. Methods: Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a nextgeneration sequencer, and the associations with clinicopathological factors were analyzed. Results: Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040). Conclusions: The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.
• Too short to choose biliary drainage?

  Kazumichi Kawakubo, Masaki Kuwatani, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 85 (3) 690 - 690 0016-5107 2017/03 [Refereed][Not invited]
  
• Decreased RNA-binding motif 5 expression is associated with tumor progression in gastric cancer

  Takahiko Kobayashi, Junich Ishida, Yuichi Shimizu, Hiroshi Kawakami, Goki Suda, Tetsuhito Muranaka, Yoshito Komatsu, Masahiro Asaka, Naoya Sakamoto

  TUMOR BIOLOGY 39 (3) 1010428317694547  1010-4283 2017/03 [Refereed][Not invited]
   

  RNA-binding motif 5 is a putative tumor suppressor gene that modulates cell cycle arrest and apoptosis. We recently demonstrated that RNA-binding motif 5 inhibits cell growth through the p53 pathway. This study evaluated the clinical significance of RNA-binding motif 5 expression in gastric cancer and the effects of altered RNA-binding motif 5 expression on cancer biology in gastric cancer cells. RNA-binding motif 5 protein expression was evaluated by immunohistochemistry using the surgical specimens of 106 patients with gastric cancer. We analyzed the relationships of RNA-binding motif 5 expression with clinicopathological parameters and patient prognosis. We further explored the effects of RNA-binding motif 5 downregulation with short hairpin RNA on cell growth and p53 signaling in MKN45 gastric cancer cells. Immunohistochemistry revealed that RNA-binding motif 5 expression was decreased in 29 of 106 (27.4%) gastric cancer specimens. Decreased RNA-binding motif 5 expression was correlated with histological differentiation, depth of tumor infiltration, nodal metastasis, tumor-node-metastasis stage, and prognosis. RNA-binding motif 5 silencing enhanced gastric cancer cell proliferation and decreased p53 transcriptional activity in reporter gene assays. Conversely, restoration of RNA-binding motif 5 expression suppressed cell growth and recovered p53 transactivation in RNA-binding motif 5-silenced cells. Furthermore, RNA-binding motif 5 silencing reduced the messenger RNA and protein expression of the p53 target gene p21. Our results suggest that RNA-binding motif 5 downregulation is involved in gastric cancer progression and that RNA-binding motif 5 behaves as a tumor suppressor gene in gastric cancer.
• Characteristic expression of fukutin in gastric cancer among atomic bomb survivors

  Trang T. B. Pham, Naohide Oue, Manabu Yamamoto, Megumu Fujihara, Teruyoshi Ishida, Shoichiro Mukai, Naoya Sakamoto, Kazuhiro Sentani, Wataru Yasui

  ONCOLOGY LETTERS 13 (2) 937 - 941 1792-1074 2017/02 [Refereed][Not invited]
   

  Approximately 70 years have passed since the atomic bombs were dropped on Nagasaki and Hiroshima. To elucidate potential biomarkers and possible mechanisms of radiation-induced cancer, the expression of FKTN, which encodes fukutin protein and causes Fukuyama-type congenital muscular dystrophy, was analyzed in gastric cancer (GC) tissue samples from atomic bomb survivors. Expression of cluster of differentiation (CD) 10 was also evaluated, as it has previously been observed that positive fukutin expression was frequently noted in CD10-positive GC cases. In the first cohort from Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital (Hiroshima, Japan; n=92),102 (53%) of the GC cases were positive for fukutin. Expression of fukutin was not associated with exposure status, but was associated with CD10 expression (P=0.0001). The second cohort was from Hiroshima University Hospital (Hiroshima, Japan; n=86), and these patients were also in the Life Span Study cohort, in which atomic bomb radiation doses were precisely estimated using the DS02 system. Expression of fukutin was detected in 58 (67%) of GC cases. GC cases positive for fukutin were observed more frequently in the low dose-exposed group than in the high dose-exposed group (P=0.0001). Further studies with a larger cohort, including precise radiation dose estimation, may aid in clarifying whether fukutin could serve as a potential biomarker to define radiation-induced GC in atomic-bomb survivors.
• Rescue technique using a diathermic dilator for an unremovable stent in malignant perihilar biliary obstruction

  Ryo Sugiura, Hiroshi Kawakami, Nobuyuki Ehira, Ichiro Iwanaga, Minoru Uebayashi, Masaki Kuwatani, Naoya Sakamoto

  ENDOSCOPY 49 (S 01) E42 - E45 0013-726X 2017/02 [Refereed][Not invited]
  
• Hepatitis B virus Xprotein impairs alpha-interferon signaling via up-regulation of suppressor of cytokine signaling 3 and protzin phosphatase 2A

  Seiji Tsunematsu, Goki Suda, Kazushi Yamasaki, Megumi Kimura, Takaaki Izumi, Machiko Umemura, Jun Ito, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Yasuhito Tanaka, Koichi Watashi, Takaji Wakita, Naoya Sakamoto

  JOURNAL OF MEDICAL VIROLOGY 89 (2) 267 - 275 0146-6615 2017/02 [Refereed][Not invited]
   

  Hepatitis B Virus (HBV) causes liver cirrhosis and hepatocellular carcinoma. Standard therapy includes treatment with interferon (IFN); however, its efficacy is limited. HBV has been reported to impair IFN signaling; however, the mechanism is unclear. Here, the relationship between HBV X protein (HBx) and IFN signaling was investigated by establishing HepG2 cells, stably expressing HBx (HepG2/HBx) via retrovirus-mediated gene transfer. Subsequently, IFN negative-regulator expression and its mechanism were studied. HepG2/HBx cells showed reduced expression of IFN-stimulated genes and expressed higher levels of suppressor of cytokine signaling 3 (SOCS3) and protein phosphatase 2A (PP2A) suppressor compared with control cells. Knockdown of SOCS3 and PP2A restored IFN sensitivity. Moreover, HepG2/HBx cells showed higher phosphorylation levels of signal transducers and activators of transcription 3 and endoplasmic reticulum stress, which are inducers of SOCS3 and PP2A, respectively. Additionally, HBx-knockdown restored IFN sensitivity in HepG2.2.15.7 cells. It was also confirmed that SOCS3 and PP2A expression levels were up-regulated in the liver of patients with HBV infection. The results of this study demonstrated that HBx impairs IFN signaling via increased expression of SOCS3 and PP2A, a novel mechanistic insight, providing a potential therapeutic target to enhance the efficiency of IFN therapy. J. Med. Virol. 89:267-275, 2017. (c) 2016 Wiley Periodicals, Inc.
• Hepatobiliary and Pancreatic: A rare case of a well-differentiated neuroendocrine tumor in the bile duct with spontaneous regression diagnosed by EUS-FNA

  I. Sano, M. Kuwatani, R. Sugiura, S. Kato, K. Kawakubo, T. Ueno, Y. Nakanishi, T. Mitsuhashi, H. Hirata, S. Haba, S. Hirano, N. Sakamoto

  Journal of Gastroenterology and Hepatology (Australia) 32 (1) 11  1440-1746 2017/01/01 [Refereed][Not invited]
  
• The paradoxical effects of different Hepatitis C viral loads on host DNA damage and repair abilities

  Shu-Chi Wang, Kuan-Ru Lai, Chia-Yang Li, Chi-Shiun Chiang, Guann-Yi Yu, Naoya Sakamoto, Wen-Yu Tu, Meng-Hsuan Hsieh, Jee-Fu Huang, Wan-Long Chuang, Chia-Yen Dai, Ming-Lung Yu

  PLoS ONE 12 (1) 1932-6203 2017/01/01 [Refereed][Not invited]
   

  Hepatitis C virus (HCV)-induced hepatic stress is associated with increased oxidative DNA damage and has been implicated in hepatic inflammation. However, HCV infection and replication are uneven and vary among individual hepatocytes. To investigate the effect of the viral load on host DNA damage, we used an Enhanced Yellow Fluorescent Protein gene (EYFP)-tagged HCV virus to distinguish between HCV intracellular high viral load (HVL) cells and low viral load (LVL) cells. The cell sorting efficiency was confirmed by the high expression of the HCV polyprotein. We found DNA damage γ-H2AX foci in the HVL population. Comet assays demonstrated that HVL was related to the extent of the DNA strand breaks. Surprisingly, the DNA qPCR arrays and western blotting showed that the damage-related genes GPX2, MRE11, phospho-ATM, and OGG1 were significantly up-regulated in LVL cells but inversely down-regulated or consistently expressed in HVL cells. The colony survival assay to examine the repair abilities of these cells in response to irradiation showed that the LVL cells were more resistant to irradiation and had an increased ability to repair radiation-induced damage. This study found that intracellular viral loads drove cellular DNA damage levels but suppressed damage-related gene expression. However, the increase in damage-related gene expression in the LVL cells may be affected by ROS from the HVL cells. These findings provide new insights into the distinct DNA damage and repair responses resulting from different viral loads in HCV-infected cells.
• Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression

  Takuya Hattori, Kazuhiro Sentani, Oue Naohide, Naoya Sakamoto, Wataru Yasui

  CANCER SCIENCE 108 (1) 143 - 150 1347-9032 2017/01 [Refereed][Not invited]
   

  Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. In order to identify novel prognostic markers or therapeutic targets for CRC, we searched for candidate genes in our comprehensive gene expression libraries, and focused on SEC11A, which encodes the SPC18 protein. SPC18 plays a key role in the endoplasmic reticulum-Golgi secretory pathway and presumably regulates the secretion of various secretory proteins. An immunohistochemical analysis of SPC18 in 137 CRC tissue samples demonstrated that 79 (58%) CRC cases were positive for SPC18. SPC18-positive CRC cases were more advanced in terms of N classification (P=0.0315) and tumor stage (P=0.0240) than SPC18-negative CRC cases. Furthermore, the expression of SPC18 was an independent prognostic classifier for CRC patients. The cell growth and invasiveness of SPC18 siRNA-transfected CRC cell lines was less than that of the negative control siRNA-transfected cell lines. The levels of phosphorylated epidermal growth factor receptor, Erk and Akt were lower in SPC18 siRNA-transfected CRC cells than in control cells. The expression of SPC18 was colocalized with -catenin nuclear localization and MMP7 at the invasive front. An immunohistochemical analysis of human colorectal polyp specimens revealed a sequential increase in the expression of SPC18 through the conventional adenoma-carcinoma pathway, while SPC18 was not expressed or was expressed to a lesser extent in serrated pathway-related tumors. These results suggest that SPC18 is involved in tumor progression, and is an independent prognostic classifier in patients with CRC.
• KIF11 Is Required for Spheroid Formation by Oesophageal and Colorectal Cancer Cells

  Takeharu Imai, Naohide Oue, Kazuhiro Sentani, Naoya Sakamoto, Naohiro Uraoka, Hiroyuki Egi, Takao Hinoi, Hideki Ohdan, Kazuhiro Yoshida, Wataru Yasui

  ANTICANCER RESEARCH 37 (1) 47 - 55 0250-7005 2017/01 [Refereed][Not invited]
   

  Background: Oesophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) are common types of human cancer. Spheroid colony formation is used to characterize cancer stem cell (CSCs). In the present study, we analyzed the significance of kinesin family 11 (KIF11 in human ESCC and CRC. Materials and Methods: Expression of KIF11 in 105 ESCC and 100 CRC cases was determined using immunohistochemistry. RNA interference was used to inhibit KIF11 expression in ESCC and CRC cell lines. Results: In total, 61 out of 105 (58%) ESCC and 62 out of 100 (62%) CRC cases were positive for KIF11. Expression of KIF11 was not associated with any clinicopathological characteristics. Both the number and size of spheres produced by from TE-5 ESCC cells and DLD-1 CRC cells were significantly reduced upon KIF11 siRNA transfection compared to negative control siRNA transfection. Conclusion: These results indicate that KIF11 plays an important role in CSCs of ESCC and CRC.
• Diagnosis and treatment of gastric malignant lymphoma

  Shoko Ono, Yuji Ono, Naoya Sakamoto

  Journal of Japanese Society of Gastroenterology 114 (11) 1948 - 1956 1349-7693 2017 [Refereed][Not invited]
  
• Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors

  Koji Hontani, Takahiro Tsuchikawa, Takaki Hiwasa, Toru Nakamura, Takashi Ueno, Toshihiro Kushibiki, Mizuna Takahashi, Kazuho Inoko, Hironobu Takano, Satoshi Takeuchi, Hirotoshi Dosaka-Akita, Masaki Kuwatani, Naoya Sakamoto, Yutaka Hatanaka, Tomoko Mitsuhashi, Hideaki Shimada, Toshiaki Shichinohe, Satoshi Hirano

  Oncotarget 8 (63) 106206 - 106221 1949-2553 2017 [Refereed][Not invited]
   

  Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1-2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactosidebinding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs.
• Therapeutic effects of human amnion-derived mesenchymal stem cell transplantation and conditioned medium enema in rats with trinitrobenzene sulfonic acid-induced colitis

  Shuichi Miyamoto, Shunsuke Ohnishi, Reizo Onishi, Ikuki Tsuchiya, Hidetaka Hosono, Takehiko Katsurada, Kenichi Yamahara, Hiroshi Takeda, Naoya Sakamoto

  AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH 9 (3) 940 - 952 1943-8141 2017 [Refereed][Not invited]
   

  Cell therapy with mesenchymal stem cells (MSCs) is expected to provide a new strategy for the treatment of inflammatory bowel disease (IBD). Large amounts of MSCs can be obtained from human amnion. Therefore, we investigated the effect of transplantation of human amnion-derived MSCs (hAMSCs) or enema of conditioned medium (CM) from hAMSCs into rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. In the first experiment, 10-week-old male Sprague-Dawley rats were intravenously injected with hAMSCs (1 x 10(6) cells) 3 h after rectal administration of TNBS (45 mg/kg). In the second experiment, rats with TNBS-induced colitis received CM by enema into the colon for 3 days. Colitis was investigated by endoscopy, histology, immunohistochemistry, and by measuring mRNA expression of inflammatory mediators. Administration of hAMSCs or CM enema significantly improved the endoscopic score. In addition, these two interventions resulted in significantly decreased infiltration of neutrophils and monocytes/macrophages and decreased expression levels of TNF-alpha, CXCL1, and CCL2. In conclusion, transplantation of hAMSCs and CM enema provided significant improvement in rats with TNBS-induced colitis. CM from hAMSCs and hAMSCs may be new strategies for the treatment of IBD.
• Investigation of the utility of various diagnostic guidelines for Wilson's disease.

  Nakai M, Morikawa K, Ohara M, Kawagishi N, Izumi T, Umemura M, Ito J, Tsunematsu S, Sato F, Sho T, Suda G, Ogawa K, Sakamoto N

  Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 114 (5) 839 - 845 0446-6586 2017 [Refereed][Not invited]
  
• Gastric Hyperplastic Polyps Associated with Proton Pump Inhibitor Use in a Case without a History of Helicobacter pylori Infection

  Shuichi Miyamoto, Mototsugu Kato, Kana Matsuda, Satoshi Abiko, Momoko Tsuda, Takeshi Mizushima, Keiko Yamamoto, Shoko Ono, Takahiko Kudo, Yuichi Shimizu, Kanako C. Hatanaka, Izumi Tsunematsu, Naoya Sakamoto

  INTERNAL MEDICINE 56 (14) 1825 - 1829 0918-2918 2017 [Refereed][Not invited]
   

  A 56-year-old man with gastroesophageal reflux disease (GERD) was referred to our hospital. Esophagogastroduodenoscopy (EGD) revealed no evidence of any polypoid lesions in the stomach, and the patient had no history of Helicobacter pylori infection. He received omeprazole (20 mg) once daily for the GERD. EGD was performed at 1 year after the start of omeprazole administration, and this time, gastric hyperplastic polyps (GHPs) were detected. The GHPs increased in size as the omeprazole treatment continued, but they markedly decreased in size following omeprazole discontinuation. Thus, the administration of proton pump inhibitors may be a risk factor for the development of GHP independent of H. pylori infection.
• A prospective, multicenter survey on the validity of shorter periendoscopic cessation of antithrombotic agents in Japan.

  Katsuhiro Mabe, Mototsugu Kato, Koji Oba, Soichi Nakagawa, Hideyuki Seki, Shinichi Katsuki, Kentaro Yamashita, Shoko Ono, Yuichi Shimizu, Naoya Sakamoto

  Journal of gastroenterology 52 (1) 50 - 60 0944-1174 2017/01 [Refereed][Not invited]
   

  BACKGROUND: The management of antithrombotic agents for endoscopic procedures has recently focused on preventing periprocedural thrombosis in Western countries. However, this focus on shorter cessation of antithrombotic agents needs to be examined for its implications for post-procedural bleeding, with potential risk factors for such bleeding clarified in real-world clinical settings in Japan. METHODS: A Sapporo consensus group convened and developed a consensus document on the criteria for cessation of antithrombotic agents. In the multicenter, prospective, observational study that followed to validate the criteria in a real-world clinical setting, of all patients ≥20 years of age receiving antithrombotic agents and undergoing endoscopic procedures, all consenting patients were enrolled. All participating facilities were followed up on their adherence to the criteria and clinical outcomes, such as the occurrence of post-procedural bleeding and thrombosis. RESULTS: A total of 5250 patients, who accounted for 6944 endoscopic procedures, were enrolled from 19 study sites. The consensus criteria, which proved to be nearly consistent with the JSGE criteria revised in 2012, had been adhered to in a total of 6531 procedures performed in 4921 patients. Bleeding and thrombosis were reported in 53 (0.76 %) and two (0.03 %) patients, respectively, among those receiving antithrombotic agents. Post-procedural bleeding was significantly associated with high-bleeding-risk procedures, a high thromboembolic risk with heparin bridging, and the presence of renal failure/dialysis. CONCLUSIONS: With the new criteria in place for cessation of antithrombotic agents focused on prevention of periprocedural thrombosis, endoscopic procedures may be safely performed without substantially increasing bleeding in clinical practice in Japan.
• Novel Treatment of Hepatitis C Virus Infection for Patients with Renal Impairment.

  Goki Suda, Koji Ogawa, Megumi Kimura, Masato Nakai, Takuya Sho, Kenichi Morikawa, Naoya Sakamoto

  Journal of clinical and translational hepatology 4 (4) 320 - 327 2225-0719 2016/12/28 [Refereed][Not invited]
   

  Prevalence of hepatitis C virus (HCV) infection is high in patients with end-stage renal dysfunction, including patients undergoing hemodialysis (HD). The HCV infection itself can cause glomerulonephritis and puts individuals at increased risk of developing end-stage renal disease; fortunately, successful HCV eradication sometimes restore HCV-related renal dysfunction. Moreover, the prognosis of dialysis patients infected with HCV is significantly worse and the renal allograft survival in HCV-infected patients is also worse than in dialysis patients without HCV infection. If life prognosis is favorable, therefore, anti-HCV therapy is strongly recommended for HCV-infected patients with severe renal dysfunction. The standard therapy for HCV-infected patients with severe renal dysfunction has historically been interferon-based therapy. However, this therapy remains ineffective in achieving high, sustained viral response rates and the rate of adverse events and treatment discontinuation due to treatment-induced adverse events continues to be high in patients with severe renal dysfunction. Safe and effective anti-HCV therapies are urgently needed, and crucial, for patients with severe renal dysfunction. Recently, direct-acting antivirals (DAAs) that specifically target viral proteins have been developed, and these targets include the NS3, NS5A, and NS5B of HCV. Clinical trials have revealed high efficacy and safety of the DAA-based therapies, but patients with severe renal dysfunction were not included in the majority of these trials. However, several recent reports have shown high efficacy and safety for some regimens of DAA combination therapy for HCV-infected patients with severe renal dysfunction. In this review, we discuss novel treatments for HCV-infected patients with severe renal dysfunction and the pharmacokinetics of these drugs.
• 【肝硬変を理解する-分子機構から実臨床に至るまで-】 治療 抗ウイルス治療(C型肝硬変)

  中井 正人, 須田 剛生, 坂本 直哉

  肝・胆・膵 (株)アークメディア 73 (6) 1093 - 1099 0389-4991 2016/12 [Not refereed][Not invited]
  
• Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection

  Jun Ito, Goki Suda, Yoshiya Yamamoto, Atsushi Nagasaka, Ken Furuya, Kenichi Kumagai, Hideaki Kikuchi, Takuto Miyagishima, Tomoe Kobayashi, Megumi Kimura, Kazushi Yamasaki, Machiko Umemura, Takaaki Izumi, Seiji Tsunematsu, Fumiyuki Sato, Yoko Tsukuda, Katsumi Terashita, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  HEPATOLOGY RESEARCH 46 (13) 1294 - 1303 1386-6346 2016/12 [Refereed][Not invited]
   

  Aim: Sofosbuvir (SOF), a nucleotide analog pro-drug, targets hepatitis C virus (HCV) NS5B polymerase and shows potential for treating HCV infection, given its high efficacy and good barrier to resistance. However, in addition to the rare resistant-associated variant (RAV) of non-structural protein NS5B S282T, several new potential RAVs of SOF have been reported, especially related to HCV genotype 1b. However, the prevalence and characteristics of these RAVs have not been clarified.Methods: We analyzed the prevalence of variants in the NS3/NS5A/NS5B regions in 96 patients treated with simeprevir (SMV) combination therapy, and the prevalence of RAVs in patients showing treatment failure was determined by direct- or deep-sequencing methods. Associations between these potential RAVs and clinical factors were also analyzed.Results: Prevalence of NS5B RAV C316N was high (46.9%, 45/96), whereas that of NS5B L159F was relatively low (1.04%, 1/96); however, deep sequencing showed that 30.0% of patients with C316N also had NS5B RAV L159F. Additionally, there was no significant relationship between the existence of potential NS5B and NS5A or NS3 RAVs. However, the presence of NS5B C316N was significantly associated with an HCV core amino acid 91 substitution. No significant difference was detected between each RAV and sustained virological response in simeprevir combination therapy.Conclusion: We provide clear evidence of the high prevalence of two potential naturally occurring NS5B RAVs (C316N and L159F) in Japan. It may be important to pay particular attention to these new potential RAVs, especially when using SOF-based therapy in patients with RAVs due to previous direct-acting antiviral therapy failure.
• Hypergastrinemia and a duodenal ulcer caused by gastric duplication.

  Tanaka H, Masumoto K, Sasaki T, Sakamoto N, Gotoh C, Urita Y, Shinkai T, Takayasu H, Nakano N, Noguchi M, Kudo T

  Surgical case reports Springer Open 2 (1) 75 - 75 2198-7793 2016/12 [Refereed][Not invited]
   

  BackgroundHypergastrinemia and the resultant peptic ulcer related to an enteric duplication has been quite rarely reported in the literature.Case presentationWe herein report the case of a 4-year-old girl who presented with hypergastrinemia and a duodenal ulcer at 2 years of age. She had been followed up with a proton pump inhibitor, which resulted in resolution of the ulcer; however, unexplained hypergastrinemia had continued. A cystic lesion at the antrum was discovered at 4 years of age, which we suspected to be a gastric duplication. After we resected the lesion, the hypergastrinemia resolved without recurrence of the duodenal ulcer. The histology was compatible with a gastric duplication, and the lumen was lined with antral mucosa that strongly stained positive for gastrin. We presumed that the antral mucosa inside the duplication in our case had no hydrogen ion feedback inhibition of gastrin release from gastrin cells and increased release of gastrin from the mucosa inside the duplication led to the duodenal ulcer. Only two cases have been reported in the literature that had hypergastrinemia related to enteric duplication.ConclusionGastric duplication should be included in the differential diagnosis of sustained hypergastrinemia in children.
• No Benefit of Oral Diclofenac on Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

  Hirotoshi Ishiwatari, Takahiro Urata, Ichiro Yasuda, Shimpei Matsusaki, Hiroyuki Hisai, Hiroshi Kawakami, Michihiro Ono, Takuji Iwashita, Shinpei Doi, Kazumichi Kawakubo, Tsuyoshi Hayashi, Tomoko Sonoda, Naoya Sakamoto, Junji Kato

  DIGESTIVE DISEASES AND SCIENCES 61 (11) 3292 - 3301 0163-2116 2016/11 [Refereed][Not invited]
   

  Pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) is a serious complication. Rectal diclofenac (100 mg) has been shown to reduce the incidence of pancreatitis; however, this dosage form is unavailable in several countries. We aimed to investigate the preventive effect of oral diclofenac on pancreatitis after ERCP in a multicenter, randomized, prospective, placebo-controlled, double-blind trial. Patients undergoing a first ERCP in seven high-volume centers between July 2012 and August 2014 were considered eligible. Participants were administered oral diclofenac (50 mg) or placebo before and after ERCP. The primary endpoint was the incidence of pancreatitis. A subgroup analysis was performed for patients at high or low risk of pancreatitis. Secondary endpoints were pancreatic enzyme levels (amylase and lipase). We initially enrolled 430 patients (216 in the diclofenac and 214 in the placebo group), and 23 were excluded after randomization. The overall incidence of pancreatitis was 9.8 % (20/205) and 9.4 % (19/202) in the diclofenac and placebo groups, respectively (p = 0.90). The incidence of pancreatitis was 20.3 % (13/64) and 21.3 % (13/61) in patients at high risk of pancreatitis (p = 0.78) and 5.0 % (7/141) and 4.3 % (6/141) in patients at low risk of pancreatitis in the diclofenac and placebo groups (p = 0.94), respectively. There were no significant differences in serum amylase and lipase levels between the two groups before and 24 h after ERCP. Oral administration of diclofenac before and after ERCP showed no benefit in the prevention of pancreatitis. UMIN000008109.
• Efficacy and tolerability of IFN-free direct acting antivirals therapy (daclatasvir and asunaprevir) in chronic hemodialysis patients with chronic hepatitis C

  Goki Suda, Koji Ogawa, Kenichi Morikawa, Masato Nakai, Naoya Sakamoto

  HEPATOLOGY 64 975A - 975A 0270-9139 2016/10 [Refereed][Not invited]
  
• Resistance Analyses of Japanese Hepatitis C-Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies

  M. Mizokami, H. Dvory-Sobol, N. Izumi, S. Nishiguchi, B. Doehle, E. S. Svarovskaia, S. De-Oertel, S. Knox, D. M. Brainard, M. D. Miller, H. Mo, N. Sakamoto, T. Takehara, M. Omata

  JOURNAL OF VIRAL HEPATITIS 23 (10) 780 - 788 1352-0504 2016/10 [Refereed][Not invited]
   

  High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had 1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.
• Significance of fully automated tests for the diagnosis of antiphospholipid syndrome

  Kenji Oku, Olga Amengual, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Naoya Sakamoto, Masahiro Ieko, Gary L. Norman, Tatsuya Atsumi

  THROMBOSIS RESEARCH 146 1 - 6 0049-3848 2016/10 [Refereed][Not invited]
   

  Antiphospholipid antibodies (aPLs) can vary both immunologically and funcLionally, thus i is important to effectively and correctly identify their presence when diagnosing antiphospholipid syndrome. Furthermore, since many immunologicallfunclional tests are necessary Lo measure aPLs, complete examinations are often no performed in many cases due o significath burden on the testing departments. To address this issue, we measured aPLs defined accordingio the classification criteria (anlicardiolipin araibody: aCL) IgG/IgM and anti-132 glycoprotein I antibody (a beta(2)GPI) (IgG/IgM) as well as non-criteria antibodies (aCL IgA, a beta(2)GPI IgA and a beta(2)GPI domain I), in a cohort 01 211 patients (61 APS, 140 disease controls and 10 healthy individuals). APLs were measured using a fully automated chemiluminescent immunoassay instrument (BIO-FLASH (R)/ACL AcuStara (R)) and with conventional ELISA tests. We demonstrated that both sensitivity and accuracy of diagnosis of aCL IgG and beta(2)GPI IgG were high, in agreement with the past reports. When multiple aPLs were examined, the accuracy of diagnosis increased. The proportion of APS patients that were positive for 2 Of more types of aPLs (47/61, 77%) was higher than that of patients with systemic lupus erythematosus (SLE)( 3/37, 9%), those with non-SLE connective tissues diseases (1/53,2%), those with other diseases or healthy volunteers. Based on these findings, it was concluded that the fully automated chemiluminescent immunoassay instrument, which allows the simultaneous evaluation of many types of aPLs, offers clear advantages for a more complete, more rapid and less labor-intensive alternative to running multiple ELISA and could help in better diagnosis for suspected APS patients. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (thip://creativecommons.orglicenscs,thy-nc-nd/4.0,/).
• Efficacy and Safety of Bolus 5-Fluorouracil and L-Leucovorin as Salvage Chemotherapy for Oral Fluoropyrimidine-Resistant Unresectable or Recurrent Gastric Cancer: A Single Center Experience

  Tetsuhito Muranaka, Satoshi Yuki, Yoshito Komatsu, Kentaro Sawada, Kazuaki Harada, Yasuyuki Kawamoto, Hiroshi Nakatsumi, Naoya Sakamoto

  JOURNAL OF GASTRIC CANCER 16 (3) 177 - 181 2093-582X 2016/09 [Refereed][Not invited]
   

  Purpose: The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods: We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin (250 mg/m(2)/2 h) and bolus 5-FU (600 mg/m(2)) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results: A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3 similar to 2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7 similar to 7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions: Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study.
• Hepatitis B: progress in understanding chronicity, the innate immune response, and cccDNA protection.

  Kenichi Morikawa, Tomoe Shimazaki, Rei Takeda, Takaaki Izumi, Machiko Umumura, Naoya Sakamoto

  Annals of translational medicine 4 (18) 337 - 337 2305-5839 2016/09 [Refereed][Not invited]
   

  Hepatitis B virus (HBV) infection is a serious health threat around the world. Despite the availability of an effective hepatitis B vaccine, the number of HBV carriers is estimated to be as high as 240 million worldwide. Global mortality due to HBV-related liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) may be as high as 1 million deaths per year. HBV is transmitted via blood and body fluids, and is much more infectious than both human immunodeficiency virus (HIV) and hepatitis C virus. While HBV infection exhibits a variety of clinical presentations, even asymptomatic carriers can develop HCC without liver fibrosis. Current therapeutic options against HBV include pegylated interferon (Peg-IFN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs), with clinical studies showing a significant association between loss of HBV DNA and a decrease in cancer risk. However, the ultimate goal of HBV therapy is a complete cure of HBV-including the elimination of covalently closed circular DNA (cccDNA)-in order to further decrease the risk of developing HCC. The development of hepatitis B is associated with the host immune response to virus-infected hepatocytes, as HBV is understood to lack direct cytotoxicity. While HBV-specific CD8+ T cells are thus involved in hepatitis development, they also play an important role in eliminating HBV infection. Indeed, the innate immune response during the initial phase of HBV infection is essential to the induction of acquired immunity. However, the innate immune response to HBV infection, including the roles of specific immunocompetent cells and associated molecules, is not well understood. In this review, we focus on the current understanding of the mechanisms underlying hepatitis development by HBV infection. We also address the mechanisms by which HBV protects cccDNA.
• Overexpression of KIF11 in Gastric Cancer with Intestinal Mucin Phenotype

  Takeharu Imai, Naohide Oue, Masahiro Nishioka, Shoichiro Mukai, Takashi Oshima, Naoya Sakamoto, Kazuhiro Sentani, Keisuke Matsusaki, Kazuhiro Yoshida, Wataru Yasui

  PATHOBIOLOGY 84 (1) 16 - 24 1015-2008 2016/09 [Refereed][Not invited]
   

  Objective: Gastric cancer (GC) is one of the most common human cancers. A useful method of gastric cancer stem cell (CSC) characterization is spheroid colony formation. Previously, we reported that KIF11 expression is >2-fold in spheroid-body-forming GC cells compared with parental cells. Here, we analyzed the expression and distribution of KIF11 in human GC by immunohistochemistry. Methods: Expression of KIF11 in 165 GC cases was determined using immunohistochemistry. For mucin phenotypic expression analysis of GC, immunostaining of MUC5AC, MUC6, MUC2 and CD10 was evaluated. RNA interference was used to inhibit KIF11 expression in GC cell lines. Results: In total, 119 of 165 GC cases (72%) were positive for KIF11. Expression of KIF11 was not associated with any clinicopathologic characteristics; however, it was observed frequently in GC exhibiting an intestinal phenotype. Both the number and size of spheres formed by MKN-74 cells were significantly reduced following transfection of KIF11 -targeting siRNA compared with negative-control siRNA. Furthermore, levels of phosphorylated Erk1/2 were lower in KIF11 siRNA-transfected cells than with negative-control siRNA-transfected cells. Conclusion: These results indicate that KIF11 is involved in intestinal mucin phenotype GC. (C) 2016 S. Karger AG, Basel
• Erratum to: Liver elasticity measurement before and after biliary drainage in patients with obstructive jaundice: a prospective cohort study.

  Kubo K, Kawakami H, Kuwatani M, Nishida M, Kawakubo K, Kawahata S, Taya Y, Kubota Y, Amano T, Shirato H, Sakamoto N

  BMC gastroenterology 16 (1) 116  2016/09 [Refereed][Not invited]
  
• Viral life cycle of hepatitis B virus: Host factors and druggable targets

  Kenichi Morikawa, Goki Suda, Naoya Sakamoto

  HEPATOLOGY RESEARCH 46 (9) 871 - 877 1386-6346 2016/08 [Refereed][Not invited]
   

  Hepatitis B virus (HBV) infection is a globally distributed health problem. The number of carriers of HBV is estimated to exceed 240million people worldwide. Compared with uninfected individuals, HBV carriers have an increased risk of developing hepatocellular carcinoma. The prevention of HBV infection is therefore strongly recommended, and a HBV vaccine is available. For carriers, treatment with nucleoside/nucleotide reverse transcriptase inhibitors is available, but infection frequently requires chronic treatment via a lifetime of medication. Thus, curing HBV infection remains a major challenge. However, despite the development of an infectious HBV cell culture system and recent intense research, many aspects of the HBV life cycle remain poorly characterized. In this review, we focus on the current understanding of the HBV life cycle and involved host factors, as well as potential targets for therapeutic intervention against HBV. We also consider possible immunotherapeutic strategies for eliminating HBV, including the removal of cccDNA from infected hepatocytes.
• Analysis of Helicobacter pylori genotypes in clinical gastric wash samples

  Shuichi Miyamoto, Yoshiyuki Watanabe, Ritsuko Oikawa, Shoko Ono, Katsuhiro Mabe, Takahiko Kudo, Hiroyuki Yamamoto, Fumio Itoh, Mototsugu Kato, Naoya Sakamoto

  TUMOR BIOLOGY 37 (8) 10123 - 10132 1010-4283 2016/08 [Refereed][Not invited]
   

  Helicobacter pylori is a key factor in the development of gastric cancer; indeed, clearance of H. pylori helps prevent gastric cancer. However, the relationship between gastric cancer and the abundance and diversity of H. pylori genotypes in the stomach remains unknown. Here, we present, for the first time, a quantitative analysis of H. pylori genotypes in gastric washes. A method was first developed to assess diversity and abundance by pyrosequencing and analysis of single nucleotide polymorphisms in 23S ribosomal RNA (rRNA), a gene associated with clarithromycin resistance. This method was then validated using arbitrarily mixed plasmids carrying 23S rRNA with single nucleotide polymorphisms. Multiple strains were detected in many of 34 clinical samples, with frequency 24.3 +/- 24.2 and 26.3 +/- 33.8 % for the A2143G and A2144G strains, respectively. Importantly, results obtained from gastric washes were similar to those obtained from biopsy samples. The method provides opportunities to investigate drug resistance in H. pylori and assess potential biomarkers of gastric cancer risk, and should thus be validated in large-scale clinical trials.
• ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma

  Katsumi Terashita, Makoto Chuma, Yutaka Hatanaka, Kanako Hatanaka, Tomoko Mitsuhashi, Hideki Yokoo, Takumi Ohmura, Hiroyuki Ishizu, Shunji Muraoka, Atsushi Nagasaka, Takahiro Tsuji, Yoshiya Yamamoto, Nobuaki Kurauchi, Norihiko Shimoyama, Hidenori Toyoda, Takashi Kumada, Yuji Kaneoka, Atsuyuki Maeda, Koji Ogawa, Mitsuteru Natsuizaka, Hirofumi Kamachi, Tatsuhiko Kakisaka, Toshiya Kamiyama, Akinobu Taketomi, Yoshihiro Matsuno, Naoya Sakamoto

  JOURNAL OF CLINICAL PATHOLOGY 69 (7) 593 - 599 0021-9746 2016/07 [Refereed][Not invited]
   

  Background/Aim Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial-mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins. Methods We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated. Results ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan-Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival. Conclusions ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC.
• Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C

  Goki Suda, Mineo Kudo, Atsushi Nagasaka, Ken Furuya, Yoshiya Yamamoto, Tomoe Kobayashi, Keisuke Shinada, Miki Tateyama, Jun Konno, Yoko Tsukuda, Kazushi Yamasaki, Megumi Kimura, Machiko Umemura, Takaaki Izumi, Seiji Tsunematsu, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY 51 (7) 733 - 740 0944-1174 2016/07 [Refereed][Not invited]
   

  HCV infection in chronic hemodialysis patients is high, has a poor prognosis and high risk of renal graft failure, and requires nosocomial infection control measures. However, options of anti-HCV therapy in such patients are limited and unsatisfactory. In this study, we report effectiveness and safety of HCV-NS5A-inhibitor daclatasvir (DCV) and protease-inhibitor asunaprevir (ASV) combination therapy for hemodialysis patients with HCV infection.This study was registered at the UMIN Clinical Trials Registry as UMIN000016355. Thirty-four dialysis patients were treated with DCV/ASV combination therapy between January 2015 and November 2015. Of those, 21 patients who were followed more than 12 weeks after treatment ended were included. We evaluated the 12-week sustained virologic response (SVR12) and adverse events during treatment.Of the 21 patients, four had compensated liver cirrhosis and three had resistance-associated variant of NS5A (NS5A RAVs)-Y93H at baseline. Overall, total of 95.5 % (20/21) of the patients achieved SVR12. Of note, all patients with cirrhosis or NS5A RAVs achieved SVR12. One relapser patient at 4 weeks post-treatment had NS3 D168E RAVs at baseline. A total of 20 patients (95.5 %) completed the 24-week therapy. One patient discontinued treatment at week 12 due to ALT elevations and achieved SVR12.DAV and ASV combination therapy for chronic hemodialysis patients with HCV infection was highly effective and well tolerated, even in elderly patients and patients with liver cirrhosis and NS5A-RAVs.
• Multicenter randomized controlled study to assess the effect of prophylactic clipping on post-polypectomy delayed bleeding.

  Mio Matsumoto, Mototsugu Kato, Koji Oba, Satoshi Abiko, Momoko Tsuda, Shuichi Miyamoto, Takeshi Mizushima, Masayoshi Ono, Saori Omori, Masakazu Takahashi, Shoko Ono, Katsuhiro Mabe, Manabu Nakagawa, Soichi Nakagawa, Takahiko Kudo, Yuichi Shimizu, Naoya Sakamoto

  Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 28 (5) 570 - 6 0915-5635 2016/07 [Refereed][Not invited]
   

  BACKGROUND AND AIM: Prophylactic clipping has been widely used to prevent post-procedural bleeding in colon polypctomy. However, its efficiency has not been confirmed and there is no consensus on the usefulness of prophylactic clipping. The aim of the present study was to evaluate the preventive effect of prophylactic clipping on post-polypectomy bleeding. METHODS: A multicenter randomized controlled study was conducted from January 2012 to July 2013 in Japan. Patients who had polyps <2 cm in diameter were divided into a clipping group and a non-clipping group by cluster randomization. After endoscopic polypectomy, patients allocated to the clipping group underwent prophylactic clipping, whereas the procedure was completed without clipping in patients allocated to the non-clipping group. Occurrence of post-polypectomy bleeding was compared between the two groups. RESULTS: Seven hospitals participated in this study. A total of 3365 polyps in 1499 patients were evaluated. The clipping group consisted of 1636 polyps in 752 patients, and the non-clipping group consisted of 1729 polyps in 747 patients. Post-polypectomy bleeding occurred in 1.10% (18/1636) of the cases in the clipping group, and in 0.87% (15/1729) of those in the non-clipping group. The difference was -0.22% (95% confidence interval [CI]: -0.96, 0.53). Upper limit of the 95% CI was lower than the non-inferiority margin (1.5%), and we could thus prove non-inferiority of non-clipping against clipping. CONCLUSION: Prophylactic clipping is not necessary to prevent post-polypectomy bleeding for polyps <2 cm in diameter.
• Reply to Rimbaş et al

  Hiroshi Kawakami, Kazumichi Kawakubo, Yoshimasa Kubota, Masaki Kuwatani, Naoya Sakamoto

  Endoscopy 48 (7) 687  1438-8812 2016/07/01 [Refereed][Not invited]
  
• Reply to Saritas and Ustundag

  Hiroshi Kawakami, Kazumichi Kawakubo, Yoshimasa Kubota, Masaki Kuwatani, Naoya Sakamoto

  Endoscopy 48 (7) 689  1438-8812 2016/07/01 [Refereed][Not invited]
  
• Fluorescent imaging of superficial head and neck squamous cell carcinoma using a Upsilon-glutamyltranspeptidase-activated targeting agent: a pilot study

  Takeshi Mizushima, Shunsuke Ohnishi, Yuichi Shimizu, Yutaka Hatanaka, Kanako C. Hatanaka, Hidetaka Hosono, Yoshimasa Kubota, Mitsuteru Natsuizaka, Mako Kamiya, Shouko Ono, Akihiro Homma, Mototsugu Kato, Naoya Sakamoto, Yasuteru Urano

  BMC CANCER 16 411  1471-2407 2016/07 [Refereed][Not invited]
   

  Background: Detecting superficial head and neck squamous cell carcinoma (HNSCC) by endoscopy is challenging because of limited morphological hallmarks, and iodine cannot be applied to head and neck lesions due to severe mucosal irritation. Upsilon-glutamyltranspeptidase (GGT), a cell surface enzyme, is overexpressed in several cancers, and it has been reported that Upsilon-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent targeting agent which can be enzymatically activated and becomes fluorescent after cleavage of a GGT-specific sequence, can be activated within a few minutes after application to animal models. We investigated whether early HNSCC can be detected by applying gGlu-HMRG to clinical samples. Methods: gGlu-HMRG was applied to four HNSCC cell lines, and fluorescence was observed by fluorescence microscopy and flow cytometry. Immunohistological examination was performed in three recent cases of endoscopic submucosal dissection (ESD) to investigate GGT expression. Fluorescence imaging with gGlu-HMRG in eight clinical samples resected by ESD or surgery was performed, and fluorescence intensity of tumor and normal mucosa regions of interest (ROI) was prospectively measured. Results: All four gGlu-HMRG-applied cell lines emitted green fluorescence. Immunohistological examination demonstrated that GGT was highly expressed in HNSCC of the recent three ESD cases but barely in the normal mucosa. Fluorescence imaging showed that iodine-voiding lesions became fluorescent within a few minutes after application of gGlu-HMRG in all eight resected tumors. Tumor ROI fluorescence intensity was significantly higher than in the normal mucosa five minutes after gGlu-HMRG application. Conclusions: Fluorescence imaging with gGlu-HMRG would be useful for early detection of HNSCC.
• Liver elasticity measurement before and after biliary drainage in patients with obstructive jaundice: a prospective cohort studya prospective cohort study

  Kimitoshi Kubo, Hiroshi Kawakami, Masaki Kuwatani, Mutsumi Nishida, Kazumichi Kawakubo, Shuhei Kawahata, Yoko Taya, Yoshimasa Kubota, Toraji Amano, Hiroki Shirato, Naoya Sakamoto

  BMC GASTROENTEROLOGY 16 (1) 65  1471-230X 2016/07 [Refereed][Not invited]
   

  Background: Obstructive jaundice has been reported to influence liver elasticity, independent of liver fibrosis. The aim of our prospective study was to evaluate the changes in liver elasticity, before and after biliary drainage, in patients with obstructive jaundice, and to evaluate the correlation between elasticity measures and serum markers of liver fibrosis. Methods: This is a prospective cohort study of 20 patients with obstructive jaundice. Liver elasticity was assessed by Transient Elastography (TE) and Virtual Touch (TM) Quantification (VTQ). Serum total bilirubin (T-Bil) level was measured before biliary drainage (Day 0), with measures repeated at 2 days (Day 2) and 7 days (Day 7) after biliary drainage. Serum levels of the following markers of liver fibrosis were also obtained on Day 0 and Day 7: hyaluronic acid (HA), procollagen-III-peptide (P-III-P). Results: T-Bil, TE, and VTQ for the left (VTQ-L) and right (VTQ-R) lobes of the liver were all elevated before biliary drainage, with respective levels, measured at Day 0, of 11.9 +/- 1.5 mg/dl, 12.1 +/- 0.9 kPa, 2.23 +/- 0.10 m/s, and 1.85 +/- 0. 10 m/s. All values decreased on Day 7 after drainage: T-Bil, 4.7 +/- 1.0 mg/dl (P < 0.001); TE, 7.6 +/- 0.6 kPa (P < 0.001); VTQ-L, 1.53 +/- 0.08 m/s (P < 0.001); and VTQ-R, 1.30 +/- 0.05 m/s (P < 0.001). Similar changes were observed in serum markers of liver fibrosis. Liver elasticity measures correlated with serum levels of T-Bil, P-III-P, and HA (r = 0.35-0.67, P < 0.001). Conclusions: This study confirmed decreases in liver elasticity, measured by TE and VTQ, after biliary drainage. Measures of liver elasticity correlated to levels of T-Bil and serum markers of liver fibrosis.
• Feasibility of Using an Enzymatically Activatable Fluorescence Probe for the Rapid Evaluation of Pancreatic Tissue Obtained Using Endoscopic Ultrasound-Guided Fine Needle Aspiration: a Pilot Study

  Kazumichi Kawakubo, Shunsuke Ohnishi, Yutaka Hatanaka, Kanako C. Hatanaka, Hidetaka Hosono, Yoshimasa Kubota, Mako Kamiya, Masaki Kuwatani, Hiroshi Kawakami, Yasuteru Urano, Naoya Sakamoto

  MOLECULAR IMAGING AND BIOLOGY 18 (3) 463 - 471 1536-1632 2016/06 [Refereed][Not invited]
   

  Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most reliable method for the histological diagnosis of pancreatic tumors. Rapid on-site fluorescence-guided histological diagnosis was evaluated by topically applying an enzymatically activatable probe onto the EUS-FNA samples; the probe fluoresces in the presence of gamma-glutamyltranspeptidase (GGT). We evaluated GGT expression in pancreatic cancer cell lines in vitro. EUS-FNA was performed in 10 pancreatic tumors. After topical application of the probe, signal intensity was measured using a fluorescence imaging system for 13 min. GGT was expressed in Panc-1, AsPC-1, and AR42J, but not in KP4 cells. In samples from six cases, several regions of the specimens fluoresced and contained adequate tissue for pathological diagnosis. The remaining four non-fluorescent samples contained very small amounts of carcinoma, normal epithelial cells, or no epithelial cells. The signal intensity at 5 min was 25.5 +/- 7.7 and 7.7 +/- 0.5 in fluorescent and non-fluorescent regions, respectively (p < 0.05). Application of enzymatically activatable probe onto EUS-FNA samples would be feasible for the rapid evaluation of tissues suitable for histological diagnosis.
• 【肝不全-その常識は正しいか?-】 慢性肝不全 その常識は正しいか? ウイルス性慢性肝不全に対する抗ウイルス治療は有用である

  中井 正人, 須田 剛生, 坂本 直哉

  救急・集中治療 (株)総合医学社 28 (5-6) 377 - 381 1346-0935 2016/05 [Not refereed][Not invited]
   

  ＜Point＞B型慢性肝不全患者に核酸アナログを投与することで肝がん抑制、肝予備能改善、予後改善を得ることができる。インターフェロンを用いないDAAs(Direct Acting Antivirals)の登場により、海外のC型慢性肝不全患者に対する良好な抗ウイルス治療の成績が報告されつつある。C型慢性肝不全(非代償性肝硬変)患者に対する抗ウイルス治療の効果・安全性は、十分には確立していない。(著者抄録)
• Prevention of Subsequent Stricture Formation After Esophageal Endoscopic Submucosal Dissection Using Conditioned Medium Obtained From Amnion-Derived Mesenchymal Stem Cell Culture

  Takeshi Mizushima, Shunsuke Ohnishi, Hidetaka Hosono, Momoko Tsuda, Masayoshi Ono, Reizo Onishi, Mototsugu Kato, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 83 (5) AB583 - AB583 0016-5107 2016/05 [Refereed][Not invited]
  
• Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis

  Kazumichi Kawakubo, Shunsuke Ohnishi, Hirotoshi Fujita, Masaki Kuwatani, Reizo Onishi, Atsushi Masamune, Hiroshi Takeda, Naoya Sakamoto

  PANCREAS 45 (5) 707 - 713 0885-3177 2016/05 [Refereed][Not invited]
   

  Objectives: Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine and can be isolated from fetal membranes (FMs), particularly amniotic membranes. We investigated the effect of rat FM-derived MSCs (rFM-MSCs) and human amnion-derived MSCs (hAMSCs) on the inflammatory reaction in vitro and therapeutic effects in rats with acute and chronic pancreatitis. Methods: Effect of rFM-MSCs or hAMSC-conditioned medium was investigated in vitro. Acute pancreatitis was induced by intraductal injection of 4% taurocholate, and rFM-MSCs were transplanted intravenously. Chronic pancreatitis was induced by intravenous injection of 5 mg/kg dibutyltin dichloride, and hAMSCs were transplanted intravenously. Results: The inflammatory reaction of macrophages induced by lipopolysaccharide and trypsin was significantly suppressed by rFM-MSC coculture. Pancreatic acinar cell injury induced by cerulein was significantly ameliorated by hAMSC-conditioned medium. Pancreatic stellate cell activation induced by tumor necrosis factor-a was significantly decreased by hAMSC-conditioned medium. Transplantation of rFM-MSCs significantly reduced the histological score and infiltration of CD68-positive macrophages in the rat pancreas. The hAMSC transplantation significantly decreased the expression of MCP-1 and attenuated the downregulation of amylase expression in the pancreas. Conclusions: Transplantation of FM-MSCs and AMSCs suppressed the inflammatory reaction of acute and chronic pancreatitis in rats.
• Lower incidence of complications in endoscopic nasobiliary drainage for hilar cholangiocarcinoma.

  Kawakubo K, Kawakami H, Kuwatani M, Haba S, Kudo T, Taya YA, Kawahata S, Kubota Y, Kubo K, Eto K, Ehira N, Yamato H, Onodera M, Sakamoto N

  World journal of gastrointestinal endoscopy 8 (9) 385 - 390 2016/05 [Refereed][Not invited]
  
• 切除可能大腸癌の術前精査における、体外式超音波検査による局在診断の有用性

  津田 桃子, 西田 睦, 水島 健, 佐藤 恵美, 工藤 悠輔, 表原 里実, 本間 重紀, 川村 秀樹, 加藤 元嗣, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 43 (Suppl.) S523 - S523 1346-1176 2016/04
• 肝臓における超音波組織弾性測定の機種間差の検討

  若林 倭, 工藤 悠輔, 西田 睦, 堀江 達則, 岩井 孝仁, 表原 里美, 佐藤 恵美, 高杉 莉佳, 小川 浩司, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 43 (Suppl.) S618 - S618 1346-1176 2016/04
• Transpapillary selective bile duct cannulation technique: Review of Japanese randomized controlled trials since 2010 and an overview of clinical results in precut sphincterotomy since 2004

  Hiroshi Kawakami, Yoshimasa Kubota, Shuhei Kawahata, Kimitoshi Kubo, Kazumichi Kawakubo, Masaki Kuwatani, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 28 77 - 95 0915-5635 2016/04 [Refereed][Not invited]
   

  In 1970, a Japanese group reported the first use of endoscopic retrograde cholangiopancreatography (ERCP), which is now carried out worldwide. Selective bile duct cannulation is a mandatory technique for diagnostic and therapeutic ERCP. Development of the endoscope and other devices has contributed to the extended use of ERCP, which has become a basic procedure to diagnose and treat pancreaticobiliary diseases. Various techniques related to selective bile duct cannulation have been widely applied. Although the classical contrast medium injection cannulation technique remains valuable, use of wire-guided cannulation has expanded since the early 2000s, and the technique is now widely carried out in the USA and Europe. Endoscopists must pay particular attention to a patient's condition and make an attendant choice about the most effective technique for selective bile duct cannulation. Some techniques have the potential to shorten procedure time and reduce the incidence of adverse events, particularly post-ERCP pancreatitis. However, a great deal of experience is required and endoscopists must be skilled in a variety of techniques. Although the development of the transpapillary biliary cannulation approach is remarkable, it is important to note that, to date, there have been no reports of transpapillary cannulation preventing post-ERCP pancreatitis. In the present article, selective bile duct cannulation techniques in the context of recent Japanese randomized controlled trials and cases of precut sphincterotomy are reviewed and discussed.
• Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis

  Nao Nishida, Jun Ohashi, Seik-Soon Khor, Masaya Sugiyama, Takayo Tsuchiura, Hiromi Sawai, Keisuke Hino, Masao Honda, Shuichi Kaneko, Hiroshi Yatsuhashi, Osamu Yokosuka, Kazuhiko Koike, Masayuki Kurosaki, Namiki Izumi, Masaaki Korenaga, Jong-Hon Kang, Eiji Tanaka, Akinobu Taketomi, Yuichiro Eguchi, Naoya Sakamoto, Kazuhide Yamamoto, Akihiro Tamori, Isao Sakaida, Shuhei Hige, Yoshito Itoh, Satoshi Mochida, Eiji Mita, Yasuhiro Takikawa, Tatsuya Ide, Yoichi Hiasa, Hiroto Kojima, Ken Yamamoto, Minoru Nakamura, Hiroh Saji, Takehiko Sasazuki, Tatsuya Kanto, Katsushi Tokunaga, Masashi Mizokami

  SCIENTIFIC REPORTS 6 24767  2045-2322 2016/04 [Refereed][Not invited]
   

  Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 x 10(-18)) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.
• Delayed bleeding and hemorrhage of mucosal defects after gastric endoscopic submucosal dissection on second-look endoscopy

  Shoko Ono, Masayoshi Ono, Manabu Nakagawa, Yuichi Shimizu, Mototsugu Kato, Naoya Sakamoto

  GASTRIC CANCER 19 (2) 561 - 567 1436-3291 2016/04 [Refereed][Not invited]
   

  Although second-look endoscopy is performed within several days after gastric endoscopic submucosal dissection (ESD), there has been no evidence supporting the usefulness of the intervention. We investigated the relationship between delayed bleeding and hemorrhage of mucosal defects after ESD on second-look endoscopy and analyzed risk factors of active bleeding on second-look endoscopy. A total of 441 consecutive ESD cases with gastric cancer or adenoma were retrospectively analyzed. Second-look endoscopy was performed in the morning after the day of ESD. Bleeding of mucosal defects on second-look endoscopy was classified according to the Forrest classification, and active bleeding was defined as Forrest Ia or Ib. Delayed bleeding was defined as hematemesis or melena after second-look endoscopy. A total of 406 second-look endoscopies were performed, and delayed bleeding occurred in 11 patients. The incidence rate of delayed bleeding after second-look endoscopy in patients with Forrest Ia or Ib was significantly higher than that in patients with Forrest IIa, IIb or III (7.69 vs. 2.02 %, p < 0.05). Complication of a histological ulcer, large size of the resected specimen and long ESD procedure time were shown to be risk factors for hemorrhage of mucosal defects after ESD on second-look endoscopy by univariate analysis. Multivariate analysis indicated that only large size of the resected specimen was a risk factor. In a specimen size of > 35 mm, the odds ratio of active bleeding on second-look endoscopy was 1.9. Active bleeding of mucosal defects on second-look endoscopy is a risk factor for delayed bleeding.
• Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer

  Htoo Zarni Oo, Kazuhiro Sentani, Shoichiro Mukai, Takuya Hattori, Shunsuke Shinmei, Keisuke Goto, Naoya Sakamoto, Yutaka Naito, Katsuhiro Anami, Pharm Thi Binh Trang, Kazuyoshi Yanagihara, Naohide Oue, Wataru Yasui

  GASTRIC CANCER 19 (2) 443 - 452 1436-3291 2016/04 [Refereed][Not invited]
   

  Gastric cancer (GC) is the fifth commonest malignancy worldwide and still one of the leading causes of cancer-related death. The aim of this study was to identify a novel prognostic marker or therapeutic target for GC. We analyzed candidate genes from our previous Escherichia coli ampicillin secretion trap (CAST) libraries in detail, and focused on the FKTN gene because it was overexpressed in both GC cell line CAST libraries, MKN-1 and MKN-45. Quantitative reverse transcriptase PCR analysis of FKTN revealed that FKTN messenger RNA was overexpressed in nine of 28 (32.1 %) GC tissue samples compared with nonneoplastic gastric mucosa. Immunostaining of fukutin showed that 297 of 695 cases (42.7 %) were positive for fukutin. Fukutin-positive GC cases were significantly associated with differentiated histological features, and advanced T grade and N grade. In addition, fukutin expression was observed more frequently in the intestinal phenotype (51 %) of GC than in other phenotypes (37 %) when defined by the expression patterns of mucin 5AC, mucin 6, mucin 2, and CD10. FKTN small interfering RNA treatment decreased GC cell proliferation. These results indicate that the expression of fukutin may be a key regulator for progression of GC with the intestinal mucin phenotype.
• Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Gastrointestinal and Pancreatic Tumors: Is Negative Pressure Helpful or Does It Suck?

  Hiroshi Kawakami, Yoshimasa Kubota, Naoya Sakamoto

  DIGESTIVE DISEASES AND SCIENCES 61 (3) 660 - 662 0163-2116 2016/03 [Refereed][Not invited]
  
• Double Penetrated Duodenal Wall during Endoscopic Ultrasound-Guided Choledochoduodenostomy

  Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto

  GUT AND LIVER 10 (2) 318 - 319 1976-2283 2016/03 [Refereed][Not invited]
  
• [Programs for Continuing Medical Education: A session; 1. New therapeutic strategies for hepatitis C by direct-acting antivirals (DAA)].

  Sakamoto N

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 105 (3) 424 - 428 0021-5384 2016/03 [Refereed][Not invited]
  
• Relative contribution of physiological hydrostatic pressure and fluid shear stress to endothelial monolayer integrity

  Toshiro Ohashi, Yoshiaki Sugaya, Naoya Sakamoto, Masaaki Sato

  Biomedical Engineering Letters 6 (1) 31 - 38 2093-985X 2016/02/01 [Refereed][Not invited]
   

  Purpose: Vascular endothelial cells (ECs) are continuously subjected to mechanical forces such as fluid shear stress, stretching and hydrostatic pressure. The effect of hydrostatic pressure on EC responses has not been fully understood compared to that of the other two stimuli. The purpose of this study is to assess mechanical responses of ECs to these mechanical stimuli. Methods: Bovine aortic ECs were exposed to hydrostatic pressure of 50, 100, and 150 mmHg and fluid shear stress of 3 Pa in simultaneous or successive fashion. Immunofluorescence staining of actin filaments and VEcadherin was then performed to observe cell morphology and cell-cell junctions, respectively Results: The results showed that ECs subjected to 50, 100, and 150 mmHg for 24 h elongated without predominant orientation and exhibited multilayered structure, whereas simultaneous application of 50 and 100 mmHg and 3 Pa for 24 h induced marked elongation and orientation of ECs parallel to the direction of flow maintaining monolayer integrity. This monolayer integrity was lost in ECs subjected to 150 mmHg together with 3 Pa. A successive application of 100 mmHg for 24 h followed by 100 mmHg and 3 Pa for 24 h, indicated that the loss of monolayer integrity due to hydrostatic pressure could not be retrieved by the following simultaneous application. Conclusions: It can be concluded that physiological shear stress of 3 Pa is dominant to physiological hydrostatic pressure up to 100 mmHg, importantly suggesting the relative contribution of physiological hydrostatic pressure and fluid shear stress to endothelial monolayer integrity.
• Endoscopic ultrasound-guided choledochoduodenostomy vs. transpapillary stenting for distal biliary obstruction

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Yoshimasa Kubota, Shuhei Kawahata, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 48 (2) 164 - 169 0013-726X 2016/02 [Refereed][Not invited]
   

  Background and study aims: Endoscopic ultrasound-guided choledochoduodenostomy (EUSCDS) has gained popularity as an alternative to percutaneous biliary drainage for patients in whom endoscopic retrograde cholangiopancreatography has failed. There are no previous studies comparing EUS-CDS with endoscopic transpapillary stenting (ETS) as first-line treatment for distal malignant obstruction. The aim of this study was to compare the clinical efficacy and safety of EUS-CDS and ETS as first-line treatment in patients with distal malignant biliary obstruction. Patients and methods: A total of 82 patients with distal malignant biliary obstruction underwent initial biliary drainage using self-expandable metal stents at a tertiary care university hospital. ETS was performed between June 2009 and May 2012, and EUS-CDS was performed between May 2012 and March 2014. Clinical success rates, adverse event rates, and reintervention rates were retrospectively evaluated for EUS-CDS and ETS. Results: A total of 26 patients underwent EUSCDS and 56 underwent ETS. Clinical success rates were equivalent between the groups (EUS-CDS 96.2 %, ETS 98.2 %; P=0.54). The mean procedure time was significantly shorter with EUS-CDS than with ETS (19.7 vs. 30.2 minutes; P<0.01). The rate of overall adverse events was not significantly different between the groups (EUS-CDS 26.9 %, ETS 35.7 %; P=0.46). Post-procedural pancreatitis was only observed in the ETS group (0% vs. 16.1 %; P=0.03). The reintervention rate at 1 year was 16.6% and 13.6% for EUS-CDS and ETS, respectively (P=0.50). Conclusions: EUS-CDS performed by expert endoscopists was associated with a short procedure time and no risk of pancreatitis, and would therefore be feasible as a first-line treatment for patients with distal malignant biliary obstruction.
• A case with a fibrous polyp of the gallbladder with a formal change that was observed for seven years

  Kubo Kimitoshi, Kawakami Hiroshi, Kubota Yoshimasa, Kawahata Shuhei, Kawakubo Kazumichi, Kuwatani Masaki, Ueno Takashi, Mitsuhashi Tomoko, Sakamoto Naoya

  Tando 日本胆道学会 30 (4) 723 - 730 0914-0077 2016 

  A 60-year-old male with a tumor of the gallbladder that was detected by screening ultrasonography (US) was referred to our hospital for workup. US revealed a pedunculated polyp at the fundus of gallbladder and diffuse thickened wall of the gallbladder. We followed it on the diagnosis of cholesterol polyp and cholesterosis. During the follow-up period, the polyp tended to enlarge and change morphologically. Since adenoma or gallbladder carcinoma in situ could be considered as a diagnosis of the polyp based on various images, a laparoscopic cholecystectomy was carried out. Resected specimen revealed a light yellowish pedunculated polyp at the fundus of gallbladder and cholesterosis. Histologically, it was covered with a simple epithelium with low-grade atypia and was composed of mucinous edematous stroma with few infiltration of foamy cells in lamina propria, and finally diagnosed as a fibrous polyp. This is a rare case with a fibrous polyp of the gallbladder and has been suspected to change from a cholesterol polyp.
• 切除可能大腸癌の術前精査における、体外式超音波検査による局在診断の有用性

  津田 桃子, 西田 睦, 水島 健, 佐藤 恵美, 工藤 悠輔, 表原 里実, 下國 達志, 本間 重紀, 加藤 元嗣, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 43 (1) 129 - 130 1346-1176 2016/01
• Standard antiviral therapies against HCV infection

  Naoya Sakamoto

  Journal of Japanese Society of Gastroenterology 113 (1) 20 - 24 1349-7693 2016/01/01 [Refereed][Not invited]
  
• Peroral transhepatic cholangioscopy-guided electrohydraulic lithotripsy via an endoscopic ultrasonography-guided hepaticogastrostomy route for bile duct stones in a patient with Roux-en-Y anatomy

  Hiroshi Kawakami, Yoshimasa Kubota, Shuhei Kawahata, Kimitoshi Kubo, Shinji Okabayashi, Ryoji Tatsumi, Naoya Sakamoto

  ENDOSCOPY 48 E146 - E147 0013-726X 2016 [Refereed][Not invited]
  
• Peroral video cholangioscopic findings in a biliary intraductal mucinous cystic neoplasm

  Hiroshi Kawakami, Yoshimasa Kubota, Kimitoshi Kubo, Daisuke Sato, Tomoko Mitsuhashi, Satoshi Hirano, Naoya Sakamoto

  ENDOSCOPY 48 E152 - E153 0013-726X 2016 [Refereed][Not invited]
  
• Two Cases of Chronic Gastritis with non-Helicobacter pylori Helicobacter Infection

  Satoka Shiratori, Katsuhiro Mabe, Shinji Yoshii, Yasunari Takakuwa, Masaaki Sato, Masahiko Nakamura, Takahiko Kudo, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  INTERNAL MEDICINE 55 (14) 1865 - 1869 0918-2918 2016 [Refereed][Not invited]
   

  Two men, 48 and 54 years of age, were referred for medical checkups without any particular symptoms. Upper gastrointestinal endoscopy showed a normal gastric body, but white marbled appearance in the lesser curvature of the gastric angle and antrum. Biopsy specimens revealed relatively long and tightly coiled organisms. The two patients were diagnosed as having non-Helicobacter pylori helicobacter (NHPH) infection according to the findings of pathological and quantitative reverse transcription-polymerase chain reaction (qRTPCR) analyses. After triple therapy (amoxicillin, clarithromycin, and rabeprazole), endoscopy showed an improvement of the white marbled lesions and biopsy specimens showed no NHPH. The white marbled appearance limited to the gastric angle and antrum may be a potential characteristic finding of NHPH-infected gastritis.
• Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals

  N. Nishida, J. Ohashi, M. Sugiyama, T. Tsuchiura, K. Yamamoto, K. Hino, M. Honda, S. Kaneko, H. Yatsuhashi, K. Koike, O. Yokosuka, E. Tanaka, A. Taketomi, M. Kurosaki, N. Izumi, N. Sakamoto, Y. Eguchi, T. Sasazuki, K. Tokunaga, M. Mizokami

  TISSUE ANTIGENS 86 (6) 406 - 412 0001-2815 2015/12 [Refereed][Not invited]
   

  Significant associations of HLA-DP alleles with chronic hepatitis B (CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1*05: 01 and *09:01, and three protective alleles, DPB1*02:01, *04:01, and *04: 02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02: 01, *04: 01, and *04: 02) and the susceptible allele DPB1*05: 01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules.
• Streptococcal toxic shock syndrome secondary to group A Streptococcus vaginitis

  Mayu Hikone, Ken-ichiro Kobayashi, Takuya Washino, Masayuki Ota, Naoya Sakamoto, Sentaro Iwabuchi, Kenji Ohnishi

  Journal of Infection and Chemotherapy 21 (12) 873 - 876 1437-7780 2015/12/01 [Refereed][Not invited]
   

  Streptococcal toxic shock syndrome (TSS) is a systemic illness usually caused in the setting of infection by group A Streptococcus (GAS). The primary infections are often invasive infections of the respiratory tract or necrotizing infections of the skin and soft tissue, but some infections occur without relevant focus. GAS vaginitis is a rare condition among adult women and is accordingly thought to be uncommon as a cause of streptococcal TSS. Here we report the cases of two postmenopausal women with streptococcal TSS secondary to GAS vaginitis, one aged 55 and one aged 60. Both came to our emergency department with complaints or symptoms of abdominal pain, fever, hypotension, and multi-organ failure. In both cases, the relevant factor associated with streptococcal infection was a recent episode of GAS vaginitis. Both underwent fluid management and 14 days of antibiotic treatment and fully recovered without complications. Vaginitis was likely to be the primary infectious trigger of TSS in these two cases. Intrauterine device insertion, endometrial biopsy, and post-partum state have all been previously reported in TSS patients, and the female genital tract has been described as a portal of entry. GAS vaginitis warrants appropriate treatment as it may progress to severe systemic infection as described.
• Single-stage endoscopic treatment for mild to moderate acute cholangitis associated with choledocholithiasis: a multicenter, non-randomized, open-label and exploratory clinical trial

  Kazunori Eto, Hiroshi Kawakami, Shin Haba, Hiroaki Yamato, Toshinori Okuda, Kei Yane, Tsuyoshi Hayashi, Nobuyuki Ehira, Manabu Onodera, Ryusuke Matsumoto, Yu Matsubara, Tomofumi Takagi, Naoya Sakamoto

  JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 22 (12) 825 - 830 1868-6974 2015/12 [Refereed][Not invited]
   

  Background Two-stage treatment involving stone removal after drainage is recommended for mild to moderate acute cholangitis associated with choledocholithiasis. However, single-stage treatment has some advantages. We aimed to assess the efficacy and safety of single-stage endoscopic treatment for mild to moderate acute cholangitis associated with choledocholithiasis. Methods A multicenter, non-randomized, open-label, exploratory clinical trial was performed in 12 institutions. A total of 50 patients with a naive papilla and a body temperature 37 degrees C who were diagnosed with mild to moderate cholangitis associated with choledocholithiasis were enrolled between August 2012 and February 2014. Results Of the 50 patients, 15 had mild cholangitis and 35 had moderate cholangitis. The median number of common bile duct stones was 2 (range, 1-8), and the median diameter of the common bile duct stones was 7.5mm (range, 1-18). The cure rate of acute cholangitis within 4days after single-stage treatment was 90% (45/50) based on a body temperature <37 degrees C for 24h. The incidence of complications was 10% (5/50). Conclusion Single-stage endoscopic treatment may be effective and safe for mild to moderate acute cholangitis associated with choledocholithiasis (clinical trial registration number: UMIN000008494).
• Corrigendum: Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression.

  Tasaka-Fujita M, Sugiyama N, Kang W, Masaki T, Murayama A, Yamada N, Sugiyama R, Tsukuda S, Watashi K, Asahina Y, Sakamoto N, Wakita T, Shin EC, Kato T

  Scientific reports 5 17208  2015/12 [Refereed][Not invited]
  
• [Inhibitory effect of HCV-NS4B on IFN-λ induction].

  Nitta S, Sakamoto N, Asahina Y

  Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 9 124 - 127 0047-1852 2015/12 [Refereed][Not invited]
  
• [Predictive factors of response to Direct Acting Antivirals therapy Drug resistance hepatitis C virus].

  Suda G, Yamasaki K, Sakamoto N

  Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 9 189 - 192 0047-1852 2015/12 [Refereed][Not invited]
  
• Anterior mediastinal abscess diagnosed in a young sumo wrestler after closed blunt chest trauma

  Tatsuro Sassa, Ken-Ichiro Kobayashi, Masayuki Ota, Takuya Washino, Mayu Hikone, Naoya Sakamoto, Sentaro Iwabuchi, Mizuto Otsuji, Kenji Ohnishi

  Chinese Journal of Traumatology - English Edition 18 (6) 360 - 362 1008-1275 2015/12/01 [Refereed][Not invited]
   

  Most mediastinal abscesses result from infections after thoracotomy, esophageal perforation or penetrating chest trauma. This disease is rarely caused by closed blunt chest trauma. All previously reported such cases after closed blunt chest trauma presented with hematoma and sternal osteomyelitis resulting from sternal fracture. Here we report a 15-year-old sumo wrestler who presented with an anterior mediastinal abscess without any mediastinal fracture. The mediastinal abscess resulted from the hematogenous spread of Staphylococcus aureus to a hematoma that might have been caused by a closed blunt chest trauma incurred during sumo wrestling exercises.
• Effects of human amnion-derived mesenchymal stromal cell transplantation in rats with radiation proctitis

  Masayoshi Ono, Shunsuke Ohnishi, Minori Honda, Marin Ishikawa, Hidetaka Hosono, Reizo Onishi, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto

  CYTOTHERAPY 17 (11) 1545 - 1559 1465-3249 2015/11 [Refereed][Not invited]
   

  Background aims. Mesenchymal stromal cells (MSCs) have been reported to be a promising cell source in cell therapy, and large amounts of MSCs can easily be isolated from human amnion. Therapeutic irradiation for intra-pelvic cancer often causes radiation proctitis; however, there is currently no effective treatment. We therefore investigated the effect of transplantation of human amnion derived MSCs (AMSCs) in rats with radiation proctitis. Methods. Amnion was obtained at cesarean delivery, and AMSCs were isolated and expanded. Sprague-Dawley rats were gamma-irradiated (5 Gy/d) at the rectum for 5 days. On day 5, AMSCs (1 x 10(6) cells) were intravenously transplanted. Rats were killed on day 8. Histological analyses were performed, and messenger RNA expression of inflammatory mediators was measured. In vitro, after gamma-irradiation of rat intestinal epithelial cells (IEC-6), the cells were cultured with AMSC-conditioned medium (CM). The effect of AMSC-CM was evaluated by measurement of caspase-3/7 activity, p53 transcription activity and quantitative reverse-transcription polymerase chain reaction for p53-target genes. Results. Histological examination demonstrated that epithelial injury and infiltration of inflammatory cells in the rectum were significantly suppressed by transplantation of AMSCs. In vitro, the cell injury in IEC-6 cells induced by gamma-irradiation was inhibited by AMSC-CM, which also inhibited the upregulation of p53 transcription activity, caspase-3/7 activity and p21 expression. Conclusions. Transplantation of AMSCs improved radiation proctitis, possibly through inhibition of cell injury and inflammatory reactions. AMSC transplantation should be considered as a new treatment for radiation proctitis.
• Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing

  Kousho Wakae, Satoru Aoyama, Zhe Wang, Kouichi Kitamura, Guangyan Liu, Ahasan Md. Monjurul, Miki Koura, Mieko Imayasu, Naoya Sakamoto, Mitsuhiro Nakamura, Satoru Kyo, Satoru Kondo, Hiroshi Fujiwara, Tomokazu Yoshizaki, Iwao Kukimoto, Katsushi Yamaguchi, Shuji Shigenobu, Tomoaki Nishiyama, Masamichi Muramatsu

  VIROLOGY 485 460 - 466 0042-6822 2015/11 [Refereed][Not invited]
   

  Human papillomavirus type 16(HPV16) is a major cause of cervical cancer. We previously demonstrated that C-to-T and G-to-A hypermutations accumulated in the HPV16 genome by APOBEC3 expression in vitro. To investigate in vivo characteristics of hypermutation, differential DNA denaturation-PCR (3D-PCR) was performed using three clinical specimens obtained from HPV16-positive cervical dysplasia, and detected hypermutation from two out of three specimens. One sample accumulating hypermutations in both E2 and the long control region (LCR) was further subjected to Next-Generation Sequencing, revealing that hypermutations spread across the LCR and all early genes. Notably, hypermutation was more frequently observed in the LCR, which contains a viral replication origin and the early promoter. APOBEC3 expressed abundantly in an HPV16-positive cervix, suggesting that single-stranded DNA exposed during viral replication and transcription may be efficient targets for deamination. The results further strengthen a role of APOBEC3 in introducing HPV16 hypermutation in vivo. (C) 2015 Elsevier Inc. All rights reserved.
• Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium.

  Feng Y, Sakamoto N, Wu R, Liu JY, Wiese A, Green ME, Green M, Akyol A, Roy BC, Zhai Y, Cho KR, Fearon ER

  PLoS genetics 11 (11) e1005638  1553-7390 2015/11 [Refereed][Not invited]
  
• Involvement of FKBP6 in hepatitis C virus replication

  Hirotake Kasai, Kunihiro Kawakami, Hiromasa Yokoe, Kentaro Yoshimura, Masanori Matsuda, Jun Yasumoto, Shinya Maekawa, Atsuya Yamashita, Tomohisa Tanaka, Masanori Ikeda, Nobuyuki Kato, Toru Okamoto, Yoshiharu Matsuura, Naoya Sakamoto, Nobuyuki Enomoto, Sen Takeda, Hideki Fujii, Masayoshi Tsubuki, Masami Kusunoki, Kohji Moriishi

  SCIENTIFIC REPORTS 5 16699  2045-2322 2015/11 [Refereed][Not invited]
   

  The chaperone system is known to be exploited by viruses for their replication. In the present study, we identified the cochaperone FKBP6 as a host factor required for hepatitis C virus (HCV) replication. FKBP6 is a peptidyl prolyl cis-trans isomerase with three domains of the tetratricopeptide repeat (TPR), but lacks FK-506 binding ability. FKBP6 interacted with HCV nonstructural protein 5A (NS5A) and also formed a complex with FKBP6 itself or FKBP8, which is known to be critical for HCV replication. The Val(121) of NS5A and TPR domains of FKBP6 were responsible for the interaction between NS5A and FKBP6. FKBP6 was colocalized with NS5A, FKBP8, and double-stranded RNA in HCV-infected cells. HCV replication was completely suppressed in FKBP6-knockout hepatoma cell lines, while the expression of FKBP6 restored HCV replication in FKBP6-knockout cells. A treatment with the FKBP8 inhibitor N-(N', N'-dimethylcarboxamidomethyl) cycloheximide impaired the formation of a homo-or hetero-complex consisting of FKBP6 and/or FKBP8, and suppressed HCV replication. HCV infection promoted the expression of FKBP6, but not that of FKBP8, in cultured cells and human liver tissue. These results indicate that FKBP6 is an HCV-induced host factor that supports viral replication in cooperation with NS5A.
• Effect of a stylet on a histological specimen in EUS-guided fine-needle tissue acquisition by using 22-gauge needles: a multicenter, prospective, randomized, controlled trial.

  Yoko Abe, Hiroshi Kawakami, Koji Oba, Tsuyoshi Hayashi, Ichiro Yasuda, Tsuyoshi Mukai, Hiroyuki Isayama, Hirotoshi Ishiwatari, Shinpei Doi, Masanori Nakashima, Natsuyo Yamamoto, Masaki Kuwatani, Tomoko Mitsuhashi, Tadashi Hasegawa, Yoshinobu Hirose, Tetsuya Yamada, Mariko Tanaka, Naoya Sakamoto

  Gastrointestinal endoscopy 82 (5) 837 - 844 0016-5107 2015/11 [Refereed][Not invited]
   

  BACKGROUND: EUS-guided FNA (EUS-FNA) has become the most efficacious way to obtain specimens from a solid lesion adjacent to the GI tract. Previous reports regarding the use of a stylet during EUS-FNA were all based on cytological diagnosis and have showed no significant superiority in terms of diagnostic yield. OBJECTIVE: To clarify the noninferiority of EUS-FNA without a stylet (S-) compared with EUS-FNA with a stylet (S+) on histological assessment. DESIGN: A prospective, single-blind, randomized, controlled crossover study. SETTING: Five tertiary referral centers in Japan. PATIENTS: Patients referred for EUS-FNA of a solid lesion. INTERVENTION: EUS-FNA S+ and S- in a total of 4 alternate passes with randomization to S+ first or S- first. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the acquisition rate of an appropriate and sufficient specimen for histological assessment. The secondary endpoints were cellularity, contamination, bloodiness, diagnostic ability, and diagnostic accuracy. RESULTS: We enrolled 107 patients (110 lesions) and analyzed 220 specimens each in the S+ and S- groups. The acquisition rate of appropriate and sufficient specimens in the S+ group was 121 of 220 (55.0%) and 122 of 220 (55.5%) in the S- group. The difference in the acquisition rate of the specimen (S- minus S+) based on the generalized estimating equation was 0.42% (95% confidence interval, -6.72% to 7.56%), which was less than 10% of the prespecified noninferiority margin of this study. With regard to cellularity, contamination, bloodiness score, diagnostic ability, and diagnostic accuracy, there were no significant differences between both groups. There were no dropouts in the study. LIMITATIONS: A variety of target lesions, multiple pathologists, lack of an assessment of intraobserver and interobserver variability, and a single-blind study for the pathologists. CONCLUSION: EUS-FNA S- is noninferior to EUS-FNA S+ on histological assessment. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008695.).
• Dynamic Analysis Of Cellular Factors Modulated By Hepatitis B Virus Protein Expression And Replication

  Kenichi Morikawa, Tomoe Shimazaki, Takaaki Izumi, Machiko Umemura, Masato Nakai, Goki Suda, Darius Moradpour, Naoya Sakamoto

  HEPATOLOGY 62 1024A - 1024A 0270-9139 2015/10 [Refereed][Not invited]
  
• The decreased urinary aquaporin2 excretion is a predictive factor for the efficacy of Tolvaptan in patients with hepatic cirrhosis

  Masato Nakai, Jun Itoh, Fumiyuki Sato, Seiji Tsunematsu, Takuya Sho, Goki Suda, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  HEPATOLOGY 62 358A - 358A 0270-9139 2015/10 [Refereed][Not invited]
  
• Truncated Hepatitis B virus X protein up-regulates CD44+cancer stem like cells through LTBP1

  Goki Suda, Seiji Tsunematsu, Masato Nakai, Jun Itoh, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto

  HEPATOLOGY 62 1157A - 1157A 0270-9139 2015/10 [Refereed][Not invited]
  
• Interferon (IFN) and Cellular Immune Response Evoked in RNA-Pattern Sensing During Infection with Hepatitis C Virus (HCV)

  Masato Nakai, Hiroyuki Oshiumi, Kenji Funami, Masaaki Okamoto, Misako Matsumoto, Tsukasa Seya, Naoya Sakamoto

  SENSORS 15 (10) 27160 - 27173 1424-8220 2015/10 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) infects hepatocytes but not dendritic cells (DCs), but DCs effectively mature in response to HCV-infected hepatocytes. Using gene-disrupted mice and hydrodynamic injection strategy, we found the MAVS pathway to be crucial for induction of type III interferons (IFNs) in response to HCV in mouse. Human hepatocytes barely express TLR3 under non-infectious states, but frequently express it in HCV infection. Type I and III IFNs are induced upon stimulation with polyI:C, an analog of double-stranded (ds)RNA. Activation of TLR3 and the TICAM-1 pathway, followed by DC-mediated activation of cellular immunity, is augmented during exposure to viral RNA. Although type III IFNs are released from replication-competent human hepatocytes, DC-mediated CTL proliferation and NK cell activation hardly occur in response to the released type III IFNs. Yet, type I IFNs and HCV-infected hepatocytes can induce maturation of DCs in either human or mouse origin. In addition, mouse CD8+ DCs mature in response to HCV-infected hepatocytes unless the TLR3/TICAM-1 pathway is blocked. We found the exosomes containing HCV RNA in the supernatant of the HCV-infected hepatocytes act as a source of TLR3-mediated DC maturation. Here we summarize our view on the mechanism by which DCs mature to induce NK and CTL in a status of HCV infection.
• New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions

  Makoto Chuma, Katsumi Terashita, Naoya Sakamoto

  HEPATOLOGY RESEARCH 45 (10) E1 - E11 1386-6346 2015/10 [Refereed][Not invited]
   

  Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic therapy that has demonstrated an overall survival benefit in patients with advanced HCC, and new agents for treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation and survival provide many opportunities for the development of molecularly targeted therapies. Molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for treatment of advanced HCC. Agents targeting vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-mesenchymal-epithelial transition factor-1 and mammalian target of rapamycin signaling have been actively explored. This article focuses on the evaluation of molecular agents targeting pathogenic HCC and provides a review of recently completed phase III drug studies (e.g. involving sorafenib, sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab or orantinib) and ongoing drug studies (e.g. involving lenvatinib, regorafenib, tivantinib or cabozantinib) of molecularly targeted agents in advanced HCC, including a brief description of the biologic rationale behind these agents.
• A pivotal role of Kruppel-like factor 5 in regulation of cancer stem-like cells in hepatocellular carcinoma

  Osamu Maehara, Fumiyuki Sato, Mitsuteru Natsuizaka, Ayaka Asano, Yoshimasa Kubota, Jun Itoh, Seiji Tsunematsu, Katsumi Terashita, Yoko Tsukuda, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Koji Ogawa, Makoto Chuma, Koji Nakagawa, Shunsuke Ohnishi, Yoshito Komatsu, Kelly A. Whelan, Hiroshi Nakagawa, Hiroshi Takeda, Naoya Sakamoto

  CANCER BIOLOGY & THERAPY 16 (10) 1453 - 1461 1538-4047 2015/10 [Refereed][Not invited]
   

  In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Kruppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44(High)/CD133(High) and CD44(Low)/CD133(Low) cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44(High)/CD44(High) cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44(High)/CD133(High) subpopulation and, consistent with the up-regulation of CD44(High)/CD133(High) cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44(High)/CD133(High) subpopulation. When KLF5 was acetylated by TGF-1, the KLF5-mediated CD44(High)/CD133(High) subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44(High)/CD133(High) subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.
• 閉塞性黄疸患者における胆道ドレナージ術前後の肝硬度の変化

  久保 公利, 河上 洋, 桑谷 将城, 川久保 和道, 阿部 容子, 川畑 修平, 坂本 直哉, 作原 佑介, 白土 博樹, 工藤 悠輔, 西田 睦

  日本消化器病学会雑誌 (一財)日本消化器病学会 112 (臨増大会) A855 - A855 0446-6586 2015/09
• Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression

  Megumi Tasaka-Fujita, Nao Sugiyama, Wonseok Kang, Takahiro Masaski, Asako Murayama, Norie Yamada, Ryuichi Sugiyama, Senko Tsukuda, Koichi Watashi, Yasuhiro Asahina, Naoya Sakamoto, Takaji Wakita, Eui-Cheol Shin, Takanobu Kato

  SCIENTIFIC REPORTS 5 13994  2045-2322 2015/09 [Refereed][Not invited]
   

  Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells, and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV.
• Recent advances in endoscopic ultrasonography-guided biliary interventions

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Shin Haba, Shuhei Kawahata, Yoko Abe, Yoshimasa Kubota, Kimitoshi Kubo, Hiroyuki Isayama, Naoya Sakamoto

  WORLD JOURNAL OF GASTROENTEROLOGY 21 (32) 9494 - 9502 1007-9327 2015/08 [Refereed][Not invited]
   

  Interventional endoscopic ultrasonography (EUS) based on EUS-guided fine-needle aspiration has rapidly spread as a minimally invasive procedure. Especially in patients with failed endoscopic retrograde cholangiopancreatography, EUS-guided biliary intervention is reported to be useful as salvage therapy. EUS-guided biliary interventions are carried out using three techniques: EUS-guided bilioenteric anastomosis, EUS-guided rendezvous procedure, and EUS-guided antegrade treatment. Although interventional EUS is not yet a standardized procedure, there have been recent advances in this field that address various biliary diseases. Here, we summarize the indications, techniques, clinical results of previous studies, and future perspectives.
• Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions

  Goki Suda, Yoshiya Yamamoto, Astushi Nagasaka, Ken Furuya, Mineo Kudo, Yoshimichi Chuganji, Yoko Tsukuda, Seiji Tsunematsu, Fumiyuki Sato, Katsumi Terasita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuteru Natsuizaka, Kouji Ogawa, Shunsuke Ohnishi, Makoto Chuma, Yasuyuki Fujita, Riichiro Abe, Miki Taniguchi, Mina Nakagawa, Yasuhiro Asahina, Naoya Sakamoto

  HEPATOLOGY RESEARCH 45 (8) 837 - 845 1386-6346 2015/08 [Refereed][Not invited]
   

  Aim: Telaprevir-based therapy for chronic hepatitis C patients is effective; however, the high prevalence of dermatological reactions is an outstanding issue. The mechanism and characteristics of such adverse reactions are unclear; moreover, predictive factors remain unknown. Granulysin was recently reported to be upregulated in the blisters of patients with Stevens-Johnson syndrome (SJS). Therefore, we investigated the risk factors for severe telaprevir-induced dermatological reactions as well as the association between serum granulysin levels and the severity of such reactions. Methods: A total of 89 patients who received telaprevir-based therapy and had complete clinical information were analyzed. We analyzed the associations between dermatological reactions and clinical factors. Next, we investigated the time-dependent changes in serum granulysin levels in five and 14 patients with grade 3 and non-grade 3 dermatological reactions, respectively. Results: Of the 89 patients, 57 patients had dermatological reactions, including nine patients with grade 3. Univariate analysis revealed that grade 3 dermatological reactions were significantly associated with male sex. Moreover, serum granulysin levels were significantly associated with the severity of dermatological reactions. Three patients with grade 3 dermatological reaction had severe systemic manifestations including SJS, drug-induced hypersensitivity syndrome, and systemic lymphoid swelling and high-grade fever; all were hospitalized. Importantly, among the three patients, two patients' serum granulysin levels exceeded 8ng/mL at onset and symptoms deteriorated within 6 days. Conclusion: Male patients are at high risk for severe telaprevir-induced dermatological reactions. Moreover, serum granulysin levels are significantly associated with the severity of dermatological reactions and may be a predictive factor in patients treated with telaprevir-based therapy.
• Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma

  Seiji Tsunematsu, Makoto Chuma, Toshiya Kamiyama, Noriyuki Miyamoto, Satoshi Yabusaki, Kanako Hatanaka, Tomoko Mitsuhashi, Hirofumi Kamachi, Hideki Yokoo, Tatsuhiko Kakisaka, Yousuke Tsuruga, Tatsuya Orimo, Kenji Wakayama, Jun Ito, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Yoko Tsukuda, Takuya Sho, Goki Suda, Kenichi Morikawa, Mitsuteru Natsuizaka, Mitsuru Nakanishi, Koji Ogawa, Akinobu Taketomi, Yoshihiro Matsuno, Naoya Sakamoto

  ABDOMINAL IMAGING 40 (6) 1492 - 1499 0942-8925 2015/08 [Refereed][Not invited]
   

  Differentiating intrahepatic cholangiocarcinoma (ICC) from poorly differentiated hepatocellular carcinoma (p-HCC) is often difficult, but it is important for providing appropriate treatments. The purpose of this study was to examine the features differentiating ICC from p-HCC on contrast-enhanced dynamic-computed tomography (CT).This study examined 42 patients with pathologically confirmed ICC (n = 19) or p-HCC (n = 23) for which contrast-enhanced dynamic CT data were available. CT images were analyzed for enhancement patterns during the arterial phase, washout pattern, delayed enhancement, satellite nodules, capsular retraction, lesion shape, and presence of an intratumoral hepatic artery, intratumoral hepatic vein, intratumoral portal vein, and bile duct dilation around the tumor, portal vein tumor thrombus, lobar atrophy, or lymphadenopathy.Univariate analysis revealed the presence of rim enhancement (p = 0.037), lobulated shape (p = 0.004), intratumoral artery (p < 0.001), and bile duct dilation (p = 0.006) as parameters significantly favoring ICC, while a washout pattern significantly favored p-HCC (p < 0.001). Multivariate analysis revealed intratumoral artery as a significant, independent variable predictive of ICC (p = 0.037), and 15 ICCs (78.9%) showed this feature. Washout pattern was a significant, independent variable favoring p-HCC (p = 0.049), with 15 p-HCCs (65.2%) showing this feature.The presence of an intratumoral artery in the arterial phase on contrast-enhanced dynamic CT was a predictable finding for ICC, and the presence of a washout pattern was a predictable finding for p-HCC, differentiating between ICC and p-HCC.
• [H. pylori-negative gastric cancer].

  Kato M, Ono S, Shimizu Y, Sakamoto N, Mabe K

  Nihon rinsho. Japanese journal of clinical medicine 73 (7) 1215 - 1220 0047-1852 2015/07 [Refereed][Not invited]
  
• Multicenter study on hemorrhagic risk of heparin bridging therapy for periendoscopic thromboprophylaxis

  Mio Matsumoto, Katsuhiro Mabe, Momoko Tsuda, Masayoshi Ono, Saori Omori, Masakazu Takahashi, Takeshi Yoshida, Shoko Ono, Manabu Nakagawa, Soichi Nakagawa, Yuichi Shimizu, Takahiko Kudo, Naoya Sakamoto, Mototsugu Kato

  BMC GASTROENTEROLOGY 15 89  1471-230X 2015/07 [Refereed][Not invited]
   

  Background: For endoscopic interventions, heparin bridging therapy is recommended in patients who are at high risk from interruption of antithrombotic therapy. Although heparin bridging has been reported to be effective in preventing thrombosis, several reports have raised concerns about increased risk of bleeding. The aim of this study was to clarify complications of hepari bridging therapy in therapeutic endoscopy. Methods: A nationwide multicenter survey using questionnaire was performed about patients undergoing therapeutic endoscopy with heparin bridging. Patients who underwent therapeutic endoscopy without heparin bridging therapy were considered as controls. Compliance scores of heparin bridging therapy guideline were employed, and association was analyzed between the score and occurrence of post-procedural bleeding. Results: The incidence of post-procedural bleeding was significantly higher (13.5 %, 33/245) in the heparin group compared with the control group (2.7 %, 299/11102)(p < 0.001). Thrombosis occurred in 1 patient each in the two groups. In the heparin group, post-procedural bleeding was more likely to be delayed bleeding. Dose adjustment of heparin was a significant factor contributing to bleeding. The compliance score of heparin bridging therapy guideline was significantly higher in those who suffered bleeding. Conclusions: Heparin bridging therapy significantly increased the risk of post-procedural bleeding compared with the control. The bleeding risk was associated with greater adherence with guidelines for heparin bridging therapy.
• Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse to interferon-based therapy in chronic hepatitis C

  Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Naoya Sakamoto, Sayuri Nitta, Akiko Kusano-Kitazume, Takako Watanabe, Fukiko Kawai-Kitahata, Satoshi Otani, Miki Taniguchi, Fumio Goto, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe

  Journal of Gastroenterology and Hepatology (Australia) 30 (6) 1075 - 1084 1440-1746 2015/06/01 [Refereed][Not invited]
   

  Background and Aim: Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFNλ3) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNλs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B. Methods: We evaluated the basal mRNA levels and ex-vivo induction of IFNλ expression including IFNλ4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFNα/RBV. Furthermore, we investigated the effect of IFNλ4 on induction of IL28B in vitro. Results: When PBMCs were stimulated with IFNα and polyinosinic-polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC P=0.049). IL28B induction was lower in nonresponders than in relapsers (P=0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFNλ4mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFNλ4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFNα therapy (P=0.003). Overexpression of IFNλ4 suppressed IL28B induction and promoter activation. Conclusions: Impaired induction of IL28B, related to IFNλ4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFNα-based therapy for hepatitis C viral infection.
• [Progress in Examination and Treatment of Hepatitis C Virus].

  Suda G, Sakamoto N

  Rinsho byori. The Japanese journal of clinical pathology 日本臨床検査医学会事務所 ; 1953- 63 (6) 762 - 767 0047-1860 2015/06 [Refereed][Not invited]
  
• Impaired induction of interleukin 28B and expression of interferon lambda 4 associated with nonresponse to interferon-based therapy in chronic hepatitis C

  Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Naoya Sakamoto, Sayuri Nitta, Akiko Kusano-Kitazume, Takako Watanabe, Fukiko Kawai-Kitahata, Satoshi Otani, Miki Taniguchi, Fumio Goto, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 30 (6) 1075 - 1084 0815-9319 2015/06 [Refereed][Not invited]
   

  Background and AimInterferon (IFN) plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFN3) are strongly associated with treatment response to IFN therapy in chronic hepatitis C (CHC) patients. Recently, IFN4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B. MethodsWe evaluated the basal mRNA levels and ex-vivo induction of IFN expression including IFN4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFN/RBV. Furthermore, we investigated the effect of IFN4 on induction of IL28B in vitro. ResultsWhen PBMCs were stimulated with IFN and polyinosinic-polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC; P=0.049). IL28B induction was lower in nonresponders than in relapsers (P=0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFN4mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFN4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFN therapy (P=0.003). Overexpression of IFN4 suppressed IL28B induction and promoter activation. ConclusionsImpaired induction of IL28B, related to IFN4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFN-based therapy for hepatitis C viral infection.
• Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial

  Masashi Mizokami, Osamu Yokosuka, Tetsuo Takehara, Naoya Sakamoto, Masaaki Korenaga, Hitoshi Mochizuki, Kunio Nakane, Hirayuki Enomoto, Fusao Ikeda, Mikio Yanase, Hidenori Toyoda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Tatsuya Ide, Nobuo Toda, Kazushige Nirei, Yoshiyuki Ueno, Yoichi Nishigaki, Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote, Hongmei Mo, Kim Garrison, Phillip S. Pang, Steven J. Knox, William T. Symonds, John G. McHutchison, Namiki Izumi, Masao Omata

  LANCET INFECTIOUS DISEASES 15 (6) 645 - 653 1473-3099 2015/06 [Refereed][Not invited]
   

  Background Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. Methods In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1: 1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients <= 60 kg received 600 mg daily, patients >60 kg to <= 80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log(10) IU/mL, creatinine clearance of at least 1.0 mL/s, and a platelet count of at least 50 x 10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov,number NCT01975675. Findings Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98-100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95-100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1.2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29.2%] of 171), headache (12 [7.0%] of 171), and malaise (nine [5.3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23.5%] of 170), anaemia (23 [13.5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8.8%] of 170). Interpretation Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug-drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients.
• EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition

  Fumiyuki Sato, Yoshimasa Kubota, Mitsuteru Natsuizaka, Osamu Maehara, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Goki Suda, Shunsuke Ohnishi, Yuichi Shimizu, Yoshito Komatsu, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Kelly A. Whelan, Hiroshi Nakagawa, Naoya Sakamoto

  CANCER BIOLOGY & THERAPY 16 (6) 933 - 940 1538-4047 2015/06 [Refereed][Not invited]
   

  There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44. A novel therapy targeting these cancer stem-like cells (CSCs) is needed to improve prognosis of ESCC. CSCs of ESCC have a mesenchymal phenotype and epithelial-mesenchymal transition (EMT) is critical to enrich and maintain CSCs. EGFR, frequently overexpressed in ESCC, has pivotal roles in EMT induced by TGF- in invasive fronts. Thus, EMT in invasive fronts of ESCC might be important for CSCs and EGFR could be a target of a novel therapy eliminating CSCs. However, effects of EGFR inhibitors on CSCs in ESCC have not been fully examined. EGFR inhibitors, erlotinib and cetuximab, significantly suppressed enrichment of CSCs via TGF-1-mediated EMT. Importantly, EGFR inhibitors sharply suppressed ZEB1 that is essential for EMT in ESCC. Further, EGFR inhibitors activated Notch1 and Notch3, leading to squamous cell differentiation. EGFR inhibition may suppress expression of ZEB1 and induce differentiation, thereby blocking EMT-mediated enrichment of CSCs. In organotypic 3D culture, a form of human tissue engineering, tumor cells in invasive nests showed high expression of CD44. Erlotinib significantly blocked invasion into the matrix and CD44 high expressing CSCs were markedly suppressed by erlotinib in organotypic 3D culture. In conclusion, EMT is a critical process for generation of CSCs and the invasive front of ESCC, where EMT occurs, might form a CSC niche in ESCC. EGFR inhibitors could suppress EMT in invasive fronts and be one therapeutic option targeting against generation of CSCs in ESCC.
• Pazopanib-induced severe acute pancreatitis

  Kazumichi Kawakubo, Hiroo Hata, Hiroshi Kawakami, Masaki Kuwatani, Shuhei Kawahata, Kimitoshi Kubo, Keisuke Imafuku, Shinya Kitamura, Naoya Sakamoto

  Case Reports in Oncology 8 (2) 356 - 358 1662-6575 2015/05/06 [Refereed][Not invited]
   

  Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and c-Kit approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Nonselective kinase inhibitors, such as sunitinib and sorafenib, are known to be associated with acute pancreatitis. There are few case reports of severe acute pancreatitis induced by pazopanib treatment. We present a case of severe acute pancreatitis caused by pazopanib treatment for cutaneous angiosarcoma. The patient was an 82-year-old female diagnosed with cutaneous angiosarcoma. She had been refractory to docetaxel treatment and began pazopanib therapy. Three months after pazopanib treatment, CT imaging of the abdomen showed the swelling of the pancreas and surrounding soft tissue inflammation without abdominal pain. After she continued pazopanib treatment for 2 months, she presented with nausea and appetite loss. Abdominal CT showed the worsening of the surrounding soft tissue inflammation of the pancreas. Serum amylase and lipase levels were 296 and 177 IU/l, respectively. She was diagnosed with acute pancreatitis induced by pazopanib treatment and was managed conservatively with discontinuation of pazopanib, but the symptoms did not improve. Subsequently, an abdominal CT scan demonstrated the appearance of a pancreatic pseudocyst. She underwent endoscopic ultrasound-guided pseudocyst drainage using a flared-end fully covered self-expandable metallic stent. Then, the symptoms resolved without recurrence. Due to the remarkable progress of molecular targeted therapy, the oncologist should know that acute pancreatitis was recognized as a potential adverse event of pazopanib treatment and could proceed to severe acute pancreatitis.
• A Novel Technique for the Detection of Endoscopic Ultrasound-Guided Fine Needle Pancreatic Tissue Acquisition by an Enzymatically Rapid-Activatable Fluorescent Probe

  Kazumichi Kawakubo, Shunsuke Ohnishi, Yasuteru Urano, Yutaka Hatanaka, Kanako C. Hatanaka, Hiroshi Kawakami, Masaki Kuwatani, Shuhei Kawahata, Yoko Abe, Yoshimasa Kubota, Kimitoshi Kubo, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 81 (5) AB536 - AB537 0016-5107 2015/05 [Refereed][Not invited]
  
• Early use of double-guidewire technique to facilitate selective bile duct cannulation: the multicenter randomized controlled EDUCATION trial

  Naoki Sasahira, Hiroshi Kawakami, Hiroyuki Isayama, Rie Uchino, Yousuke Nakai, Yukiko Ito, Saburo Matsubara, Hirotoshi Ishiwatari, Minoru Uebayashi, Hiroshi Yagioka, Osamu Togawa, Nobuo Toda, Naoya Sakamoto, Junji Kato, Kazuhiko Koike

  ENDOSCOPY 47 (5) 421 - 429 0013-726X 2015/05 [Refereed][Not invited]
   

  Background and study aims: There are no guidelines for the timing of conversion from a single-guidewire to a double-guidewire technique to facilitate selective bile duct cannulation and reduce post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), when using wire-guided cannulation. We investigated whether early conversion to the double-guidewire method, at first unintentional insertion of a guidewire into the pancreatic duct, facilitated selective bile duct cannulation and reduced PEP compared with repeated single-guidewire attempts. Patients and methods: A multicenter prospective randomized controlled trial included 274 patients with a naive papilla, undergoing endoscopic retrograde cholangiography (ERC) using wire-guided cannulation in whom there was unintentional insertion of the guidewire into the pancreatic duct. With the guidewire still in the duct, patients were randomly assigned to undergo the double-guidewire technique or repeated single-wire cannulation. Main outcomes were success rates for selective bile duct cannulation and PEP frequency. Results: Success rates for selective bile duct cannulation within 10 attempts and 10 minutes were 75% and 70%, respectively, for the early double-guidewire (EDG) and repeated single-guidewire (RSG) cannulation groups (relative rate 1.07, 95% confidence interval [95 %CI] 0.93-1.24, P=0.42). Corresponding final selective bile duct cannulation rates were 98% and 97% (relative rate 1.01, 95% CI 0.97-1.05, P=1.00). PEP rates were 20% and 17%, respectively, for the EDG and RSG cannulation groups (relative risk 1.17, 95% CI 0.71-1.94, P=0.53). Double-guidewire cannulation was more effective in patients with malignant biliary stricture (relative rate 1.36, 95% CI 1.05-1.77, P=0.02). Conclusions: During therapeutic ERC using wire-guided cannulation, converting to a double-guidewire technique neither facilitated selective bile duct cannulation nor decreased PEP incidence compared with repeated use of a single-wire technique.
• Rho guanine nucleotide exchange factors involved in cyclic-stretch-induced reorientation of vascular endothelial cells

  Hiyori Abiko, Sachiko Fujiwara, Kazumasa Ohashi, Ryuichi Hiatari, Toshiya Mashiko, Naoya Sakamoto, Masaaki Sato, Kensaku Mizuno

  JOURNAL OF CELL SCIENCE 128 (9) 1683 - 1695 0021-9533 2015/05 [Refereed][Not invited]
   

  Cyclic stretch is an artificial model of mechanical force loading, which induces the reorientation of vascular endothelial cells and their stress fibers in a direction perpendicular to the stretch axis. Rho family GTPases are crucial for cyclic-stretch-induced endothelial cell reorientation; however, the mechanism underlying stretch-induced activation of Rho family GTPases is unknown. A screen of short hairpin RNAs targeting 63 Rho guanine nucleotide exchange factors (Rho-GEFs) revealed that at least 11 Rho-GEFs - Abr, alsin, ARHGEF10, Bcr, GEF-H1 (also known as ARHGEF2), LARG (also known as ARHGEF12), p190RhoGEF (also known as ARHGEF28), PLEKHG1, P-REX2, Solo (also known as ARHGEF40) and alpha-PIX (also known as ARHGEF6) - which specifically or broadly target RhoA, Rac1 and/or Cdc42, are involved in cyclic-stretch-induced perpendicular reorientation of endothelial cells. Overexpression of Solo induced RhoA activation and F-actin accumulation at cell-cell and cell-substrate adhesion sites. Knockdown of Solo suppressed cyclic-stretch- or tensile-force-induced RhoA activation. Moreover, knockdown of Solo significantly reduced cyclic-stretch-induced perpendicular reorientation of endothelial cells when cells were cultured at high density, but not when they were cultured at low density or pretreated with EGTA or VE-cadherin-targeting small interfering RNAs. These results suggest that Solo is involved in cell-cell-adhesion-mediated mechanical signal transduction during cyclic-stretch-induced endothelial cell reorientation.
• Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Liver Fibrosis in Rats.

  Kubo K, Ohnishi S, Hosono H, Fukai M, Kameya A, Higashi R, Yamada T, Onishi R, Yamahara K, Takeda H, Sakamoto N

  Transplantation direct 1 (4) e16  2015/05 [Refereed][Not invited]
   

  UNLABELLED: Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of transplantation of human amnion-derived MSCs (hAMSCs) in rats with liver fibrosis. METHODS: Liver fibrosis was induced by an intraperitoneal injection of 2 mL/kg of 50% carbon tetrachloride twice a week for 6 weeks. At 3 weeks, hAMSCs (1 × 10(6) cells) were transplanted intravenously. Rats were sacrificed at 7 weeks, and histological analyses and quantitative reverse-transcription polymerase chain reaction were performed. In vitro experiments were conducted to investigate the effect of hAMSCs on the activation of Kupffer cells. RESULTS: Transplantation of hAMSCs significantly reduced the fibrotic area, deposition of type-I collagen, the number of α-smooth muscle actin-positive hepatic stellate cells, and CD68-positive Kupffer cells in the livers. messenger RNA expression of α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 was significantly decreased and the expression of matrix metalloproteinase-9 and hepatocyte growth factor was significantly increased in the liver of hAMSC-treated rats. Transplantation of hAMSCs at 3 weeks plus 5 weeks did not have an additive effect. In vitro experiments demonstrated that Kupffer cell activation induced by lipopolysaccharide was significantly decreased by culturing with conditioned medium obtained from hAMSCs. CONCLUSIONS: Transplantation of hAMSCs provided significant improvement in a rat model of liver fibrosis, possibly through the inhibition of Kupffer cell and hepatic stellate cell activation. hAMSCs may be a potential new treatment for liver fibrosis.
• スクリーニング経腹的超音波検査による膀胱癌正診率

  津田 桃子, 西田 睦, 佐藤 恵美, 工藤 悠輔, 安部 崇重, 土屋 邦彦, 守屋 仁彦, 篠原 信雄, 加藤 元嗣, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 42 (Suppl.) S413 - S413 1346-1176 2015/04
• KLF5 Promotes Tumorigenicity of Hepatocellular Carcinoma by Upregulation of Cancer Stem-Like Cells

  Fumiyuki Sato, Mitsuteru Natsuizaka, Osamu Maehara, Ayaka Asano, Yoshimasa Kubota, Jun Itoh, Seiji Tsunematsu, Yoko Tsukuda, Katsumi Terashita, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  GASTROENTEROLOGY 148 (4) S43 - S43 0016-5085 2015/04 [Refereed][Not invited]
  
• Technical tips and troubleshooting of endoscopic biliary drainage for unresectable malignant hilar biliary obstruction

  Hiroshi Kawakami, Takao Itoi, Masaki Kuwatani, Kazumichi Kawakubo, Yoshimasa Kubota, Naoya Sakamoto

  Journal of Hepato-Biliary-Pancreatic Sciences 22 (4) E12 - E21 1868-6974 2015/04 [Refereed][Not invited]
   

  Unresectable malignant hilar biliary obstruction (MHBO) occurs in various diseases, such as cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, pancreatic cancer, and lymph node metastasis of the hilum of the liver. The majority of patients with advanced MHBO are not candidates for surgical resection because of the tumor location in the hepatic hilum and adjacent areas, advanced tumor stage, or comorbidities. Therefore, these patients often have a poor prognosis in terms of survival and quality of life. Most of these patients will require nonsurgical, palliative biliary drainage. To date, various biliary drainage techniques for unresectable MHBO (UMHBO) have been reported. Of these techniques, endoscopic biliary drainage is currently considered to be the most safe and minimally invasive procedure. However, endoscopic biliary drainage for UMHBO is still not standardized regarding the optimal stent, drainage area, stenting method, and reintervention technique. Recently, towards standardization of this technique for UMHBO, clinical research and trials including randomized controlled trials have been performed. In this article, we reviewed the most important issues regarding endoscopic biliary drainage for UMHBO, focusing on prospective studies. We also described in detail the techniques and future perspectives of endoscopic biliary drainage in patients with UMHBO.
• Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C.

  Etsuko Iio, Kentaro Matsuura, Nao Nishida, Shinya Maekawa, Nobuyuki Enomoto, Mina Nakagawa, Naoya Sakamoto, Hiroshi Yatsuhashi, Masayuki Kurosaki, Namiki Izumi, Yoichi Hiasa, Naohiko Masaki, Tatsuya Ide, Keisuke Hino, Akihiro Tamori, Masao Honda, Shuichi Kaneko, Satoshi Mochida, Hideyuki Nomura, Shuhei Nishiguchi, Chiaki Okuse, Yoshito Itoh, Hitoshi Yoshiji, Isao Sakaida, Kazuhide Yamamoto, Hisayoshi Watanabe, Shuhei Hige, Akihiro Matsumoto, Eiji Tanaka, Katsushi Tokunaga, Yasuhito Tanaka

  Human genetics 134 (3) 279 - 89 1432-1203 2015/03 [Not refereed][Invited]
   

  Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.
• Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C

  Etsuko Iio, Kentaro Matsuura, Nao Nishida, Shinya Maekawa, Nobuyuki Enomoto, Mina Nakagawa, Naoya Sakamoto, Hiroshi Yatsuhashi, Masayuki Kurosaki, Namiki Izumi, Yoichi Hiasa, Naohiko Masaki, Tatsuya Ide, Keisuke Hino, Akihiro Tamori, Masao Honda, Shuichi Kaneko, Satoshi Mochida, Hideyuki Nomura, Shuhei Nishiguchi, Chiaki Okuse, Yoshito Itoh, Hitoshi Yoshiji, Isao Sakaida, Kazuhide Yamamoto, Hisayoshi Watanabe, Shuhei Hige, Akihiro Matsumoto, Eiji Tanaka, Katsushi Tokunaga, Yasuhito Tanaka

  HUMAN GENETICS 134 (3) 279 - 289 0340-6717 2015/03 [Refereed][Not invited]
   

  Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 x 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.
• The JAK2 inhibitor AZD1480 inhibits hepatitis A virus replication in Huh7 cells

  Xia Jiang, Tatsuo Kanda, Shingo Nakamoto, Kengo Saito, Masato Nakamura, Shuang Wu, Yuki Haga, Reina Sasaki, Naoya Sakamoto, Hiroshi Shirasawa, Hiroaki Okamoto, Osamu Yokosuka

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 458 (4) 908 - 912 0006-291X 2015/03 [Refereed][Not invited]
   

  The JAK2 inhibitor AZD1480 has been reported to inhibit La protein expression. We previously demonstrated that the inhibition of La expression could inhibit hepatitis A virus (HAV) internal ribosomal entry-site (IRES)-mediated translation and HAV replication in vitro. In this study, we analyzed the effects of AZD1480 on HAV IRES-mediated translation and replication. HAV IRES-mediated translation in COS7-HAV-IRES cells was inhibited by 0.1-1 mu M AZD1480, a dosage that did not affect cell viability. Results showed a significant reduction in intracellular HAV HA11-1299 genotype IIIA RNA levels in Huh7 cells treated with AZD1480. Furthermore, AZD1480 inhibited the expression of phosphorylated-(Tyr-705)-signal transducer and activator of transcription 3 (STAT3) and La in Huh7 cells. Therefore, we propose that AZD1480 can inhibit HAV IRES activity and HAV replication through the inhibition of the La protein. (C) 2015 Elsevier Inc. All rights reserved.
• A Unique Use of a Double-Pigtail Plastic Stent: Correction of Kinking of the Common Bile Duct Due to a Metal Stent

  Masaki Kuwatani, Hiroshi Kawakami, Yoka Abe, Shuhei Kawahata, Kazumichi Kawakubo, Kimitoshi Kubo, Naoya Sakamoto

  GUT AND LIVER 9 (2) 251 - 252 1976-2283 2015/03 [Refereed][Not invited]
   

  A 72-year-old man with jaundice by ampullary adenocarcinonria was treated at our hospital. For biliary decompression, a transpapillary, fully covered, self-expandable metal stent (FCSEMS) was deployed. Four days later, the patient developed acute. cholangitis. Endoscopic carbon dioxide cholangiography revealed kinking of the common bile duct above the proximal end of the FCSEMS. A 7-F double-pigtail plastic stent was therefore placed through the FCSEMS to correct the kink, straightening the common bile duct (CBD) and improving cholangitis. This is the first report of a unique use of a double-pigtail plastic stent to correct CBD kinking. The placement of a double-pigtail plastic stent can correct CBD kinking, without requiring replacement or addition of a FCSEMS, and can lead to cost savings.
• [Multidisciplinary treatment of gallbladder cancer--biliary and duodenal stenting].

  Kawakami H, Kuwatani M, Sakamoto N

  Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 3 595 - 600 0047-1852 2015/03 [Refereed][Not invited]
  
• Single-step simultaneous side-by-side placement of a self-expandable metallic stent with a 6-Fr delivery system for unresectable malignant hilar biliary obstruction: a feasibility study

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Taiki Kudo, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Yoshimasa Kubota, Naoya Sakamoto

  JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 22 (2) 151 - 155 1868-6974 2015/02 [Refereed][Not invited]
   

  BackgroundBilateral self-expandable metallic stent (SEMS) placement for the management of unresectable malignant hilar biliary obstruction (UMHBO) is technically challenging to perform using the existing metallic stents with thick delivery systems. The recently developed 6-Fr delivery systems could facilitate a single-step simultaneous side-by-side placement through the accessory channel of the duodenoscope. The aim of this study was to evaluate the feasibility of this procedure. MethodsBetween May and September 2013, 13 consecutive patients with UMHBO underwent a single-step simultaneous side-by-side placement of SEMS with the 6-Fr delivery system. The technical success rate, stent patency, and rate of complications were evaluated from the prospectively collected database. ResultsTechnical success was achieved in 11 (84.6%, 95% confidence interval [CI]: 57.8-95.8) patients. The median procedure time was 25min. Early and late complications were observed in 23% (one segmental cholangitis and two liver abscesses) and 15% (one segmental cholangitis and one cholecystitis) patients, respectively. Median dysfunction free patency was 263 days (95% CI: 37-263). Five patients (38%) experienced stent occlusion that was successfully managed by endoscopic stent placement. ConclusionsA single-step simultaneous side-by-side placement of SEMS with a 6-Fr delivery system was feasible for the management of UMHBO.
• [New era of the treatment against hepatitis C virus].

  Natsuizaka M, Sakamoto N

  Nihon rinsho. Japanese journal of clinical medicine 日本臨床社 73 (2) 317 - 321 0047-1852 2015/02 [Refereed][Not invited]
  
• Association of Peripheral Total and Differential Leukocyte Counts with Obesity-Related Complications in Young Adults

  Aya Yoshimura, Shunsuke Ohnishi, Chieko Orito, Yukako Kawahara, Hiroyo Takasaki, Hiroshi Takeda, Naoya Sakamoto, Satoshi Hashino

  OBESITY FACTS 8 (1) 1 - 16 1662-4025 2015/02 [Refereed][Not invited]
   

  Objective: Obesity has been demonstrated to be associated with elevated leukocytes in adults and children. This study assessed the associations between peripheral total and differential leukocyte counts and obesity-related complications in young adults. Methods: 12 obese (median age 21.5 (range 19-28) years, median BMI 35.7 (range 32.0-44.9) kg/m 2) and 11 normal (median age 23 (range 18-27) years, median BMI 19.5 (range 18.1-21.7) kg/m 2) adults were enrolled. Complete blood count and serum levels of liver enzymes, fasting blood glucose, insulin and lipids were measured, and the homeostasis model assessment of insulin resistance was calculated. Fat mass was calculated using a bioimpedance analysis device, and ultrasonography was performed to measure fat thickness and to detect fatty change of the liver. Results: Total leukocyte and monocyte counts were significantly increased in obese young adults. Total leukocyte count was associated with liver enzyme levels, insulin resistance as well as visceral and subcutaneous fat thickness. Neutrophil count was associated with insulin resistance. Lymphocyte count was associated with serum liver enzymes, insulin resistance, and dyslipidemia. Monocyte count was associated with serum liver enzyme, insulin resistance, visceral and subcutaneous fat thickness, body fat mass, and percentage body fat. Conclusion: The results of this study suggest that chronic low-grade systemic inflammation is associated with obesity-related complications such as nonalcoholic fatty liver disease, insulin resistance, and dyslipidemia in young adults. (C) 2015 S. Karger GmbH, Freiburg
• CTNNB1 mutational analysis of solid-pseudopapillary neoplasms of the pancreas using endoscopic ultrasound-guided fine-needle aspiration and next-generation deep sequencing

  Yoshimasa Kubota, Hiroshi Kawakami, Mitsuteru Natsuizaka, Kazumichi Kawakubo, Katsuji Marukawa, Taiki Kudo, Yoko Abe, Kimitoshi Kubo, Masaki Kuwatani, Yutaka Hatanaka, Tomoko Mitsuhashi, Yoshihiro Matsuno, Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY 50 (2) 203 - 210 0944-1174 2015/02 [Refereed][Not invited]
   

  Solid-pseudopapillary neoplasm (SPN), a rare neoplasm of the pancreas, frequently harbors mutations in exon 3 of the cadherin-associated protein beta 1 (CTNNB1) gene. Here, we analyzed SPN tissue for CTNNB1 mutations by deep sequencing using next-generation sequencing (NGS). Tissue samples from 7 SPNs and 31 other pancreatic lesions (16 pancreatic ductal adenocarcinomas (PDAC), 11 pancreatic neuroendocrine tumors (PNET), 1 acinar cell carcinoma, 1 autoimmune pancreatitis lesion, and 2 focal pancreatitis lesions) were analyzed by NGS for mutations in exon 3 of CTNNB1. A single-base-pair missense mutations in exon 3 of CTNNB1 was observed in all 7 SPNs and in 1 of 11 PNET samples. However, mutations were not observed in the tissue samples of any of the 16 PDAC or other four pancreatic disease cases. The variant frequency of CTNNB1 ranged from 5.4 to 48.8 %. Mutational analysis of CTNNB1 by NGS is feasible and was achieved using SPN samples obtained by endoscopic ultrasound-guided fine needle aspiration.
• 閉塞性黄疸患者における胆道ドレナージ後の肝硬度の変化

  久保 公利, 河上 洋, 桑谷 将城, 川久保 和道, 阿部 容子, 川畑 修平, 坂本 直哉, 作原 佑介, 白土 博樹, 西田 睦

  超音波医学 (公社)日本超音波医学会 42 (1) 89 - 89 1346-1176 2015/01
• スクリーニング経腹的超音波検査による膀胱癌正診率

  津田 桃子, 松島 瑠美子, 西田 睦, 佐藤 恵美, 工藤 悠輔, 堀江 達則, 守屋 仁彦, 間部 克裕, 加藤 元嗣, 坂本 直哉

  超音波医学 (公社)日本超音波医学会 42 (1) 89 - 89 1346-1176 2015/01
• 定期超音波検査にて偶然発見されたメトトレキサート関連リンパ増殖性疾患の一症例

  松島 瑠美子, 梅村 真知子, 藤田 與茂, 高野 眞寿, 片桐 雅樹, 工藤 峰生, 津田 桃子, 加藤 元嗣, 坂本 直哉, 西田 睦

  超音波医学 (公社)日本超音波医学会 42 (1) 90 - 90 1346-1176 2015/01
• Pancreatic cancer with infectious pancreatic pseudocyst communicating to the portal vein

  KUBO Kimitoshi, KAWAKAMI Hiroshi, KUWATANI Masaki, MITSUHASHI Tomoko, KAWAKUBO Kazumichi, KAWAHATA Shuhei, KUBOTA Yoshimasa, SAKAMOTO Naoya

  Suizo Japan Pancreas Society 30 (5) 679 - 688 0913-0071 2015 

  A 69-year-old female with fever, a pancreatic mass and portal vein thrombosis was referred to our hospital. Blood culture test was positive for Escherichia coli. Abdominal contrast-enhanced CT revealed a heterogeneously enhanced oval mass in the head of the pancreas with a size of 16×14mm, and a non-enhanced nodule in the portal vein, which was adjacent to a cystic lesion in the body of the pancreas. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the mass in the head of the pancreas indicated adenocarcinoma. On the diagnosis of pancreatic cancer with infectious pseudocyst and portal vein thrombosis, she underwent subtotal stomach-preserving pancreaticoduodenectomy and partial round resection of the portal vein. Histopathological findings of the resected specimen revealed pancreatic head cancer followed by pancreatitis which caused the pancreatic pseudocyst. Infection of the pancreatic pseudocyst would lead to the communication between the cyst and the portal vein. This is the first case with pancreatic cancer with infectious pancreatic pseudocyst communicating to the portal vein.
• TGF-beta in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma

  Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa

  CANCER RESEARCH 75 (1) 0008-5472 2015/01 [Refereed][Not invited]
  
• Direct peroral ultraslim endoscopy-guided biliary drainage in a patient with cystic duct carcinoma and an occluded self-expandable metallic stent

  Hiroshi Kawakami, Masaki Kuwatani, Yoko Abe, Yoshimasa Kubota, Kazumichi Kawakubo, Kimitoshi Kubo, Shuhei Kawahata, Naoya Sakamoto

  ENDOSCOPY 47 E43 - E44 0013-726X 2015 [Refereed][Not invited]
  
• Significance of miR-148a in Colorectal Neoplasia: Downregulation of miR-148a Contributes to the Carcinogenesis and Cell Invasion of Colorectal Cancer

  Yumi Hibino, Naoya Sakamoto, Yutaka Naito, Keisuke Goto, Htoo Zarni Oo, Kazuhiro Sentani, Takao Hinoi, Hideki Ohdan, Naohide Oue, Wataru Yasui

  PATHOBIOLOGY 82 (5) 233 - 241 1015-2008 2015 [Refereed][Not invited]
   

  Objective: Colorectal cancer (CRC) develops through the deregulation of gene expression and the accumulation of epigenetic abnormalities, leading to tumor cell acquisition of malignant features. MicroRNAs (miRNAs) play a critical role in cancer development, where they can act as oncogenes or oncosuppressors. Methods: miR-148a expression was measured by qRT-PCR in patients with colorectal adenoma (n = 21) and CRC (stage I-IV, n = 159) using formalin-fixed paraffin-embedded tissue samples. In situ hybridization (ISH) using an miR-148a-specific probe was also performed. To further confirm the direct effect of miR-148a on matrix metalloproteinase (MMP)7 expression in CRC, MTT and cell invasion assays using HT29 and WiDr cells were performed. Results: miR-148a expression was found to be clearly downregulated in high-grade adenoma compared to low-grade adenoma on both qRT-PCR and ISH analysis. Downregulation of miR-148a expression was significantly correlated with advanced clinicopathological features and was an independent prognostic classifier in patients with stage III CRC. In CRC cells and tissues, miR-148a expression was inversely correlated with the expression of MMP7. Conclusion: We showed the collaborative participation of miR-148a and MMP7 in CRC cell invasion. These results also demonstrate that the downregulation of miR-148a expression promotes CRC progression, especially carcinogenesis and cancer cell invasion. (C) 2015 S. Karger AG, Basel
• Risk factors for technical failure of endoscopic double self-expandable metallic stent placement by partial stent-in-stent method

  Kazumichi Kawakubo, Hiroshi Kawakami, Yoshihide Toyokawa, Koichi Otani, Masaki Kuwatani, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Yoshimasa Kubota, Naoya Sakamoto

  JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 22 (1) 79 - 85 1868-6974 2015/01 [Refereed][Not invited]
   

  BackgroundEndoscopic double self-expandable metallic stent (SEMS) placement by the partial stent-in-stent (PSIS) method has been reported to be useful for the management of unresectable hilar malignant biliary obstruction. However, it is technically challenging, and the optimal SEMS for the procedure remains unknown. The aim of this study was to identify the risk factors for technical failure of endoscopic double SEMS placement for unresectable malignant hilar biliary obstruction (MHBO). MethodsBetween December 2009 and May 2013, 50 consecutive patients with MHBO underwent endoscopic double SEMS placement by the PSIS method. We retrospectively evaluated the rate of successful double SEMS placement and identified the risk factors for technical failure. ResultsThe technical success rate for double SEMS placement was 82.0% (95% confidence interval [CI]: 69.2-90.2). On univariate analysis, the rate of technical failure was high in patients with metastatic disease and unilateral placement. Multivariate analysis revealed that metastatic disease was a significant risk factor for technical failure (odds ratio: 9.63, 95% CI: 1.11-105.5). The subgroup analysis after double guidewire insertion showed that the rate of technical success was higher in the laser-cut type SEMS with a large mesh and thick delivery system than in the braided type SEMS with a small mesh and thick delivery system. ConclusionsMetastatic disease was a significant risk factor for technical failure of double SEMS placement for unresectable MHBO. The laser-cut type SEMS with a large mesh and thin delivery system might be preferable for the PSIS procedure.
• Serum HER2 levels and HER2 status in tumor cells in advanced gastric cancer patients

  Takahide Sasaki, Nozomu Fuse, Takeshi Kuwata, Shogo Nomura, Kazuhiro Kaneko, Toshihiko Doi, Takayuki Yoshino, Hiromichi Asano, Atsushi Ochiai, Yoshito Komatsu, Naoya Sakamoto, Atsushi Ohtsu

  JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 (1) 43 - 48 0368-2811 2015/01 [Refereed][Not invited]
   

  Objective: Increased serum human epidermal growth factor receptor 2 levels have been found in metastatic breast cancer patients and are correlated with human epidermal growth factor receptor 2 overexpression in tumor cells. However, the prevalence of serum human epidermal growth factor receptor 2 in gastric cancer patients has not been elucidated. Methods: We retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues and serum samples from 96 advanced gastric cancer patients. Human epidermal growth factor receptor 2 expression and gene amplification in tumor cells were determined by immunohistochemistry and fluorescence in situ hybridization. Serum human epidermal growth factor receptor 2 levels were measured using a chemiluminescent immunoassay. Human epidermal growth factor receptor 2 positivity in tumor cells was defined as immunohistochemistry 2+ with fluorescence in situ hybridization positive or immunohistochemistry 3+ with any fluorescence in situ hybridization results. Results: All tissue samples and serum samples were successfully measured. Nineteen patients (20%) were human epidermal growth factor receptor 2-positive in tumor cells. The median serum human epidermal growth factor receptor 2 level was 9.3 ng/ml (range, 5.0-332.4 ng/ml), and serum human epidermal growth factor receptor 2 levels were significantly separated according to human epidermal growth factor receptor 2 status in tumor cells (P < 0.0001, Wilcoxon's rank sum test); median serum human epidermal growth factor receptor 2 levels in human epidermal growth factor receptor 2-negative patients and -positive patients were 8.9 (range, 5.0-20.5) and 24.0 (range, 9.7-332.4), respectively. There were 15 serum human epidermal growth factor receptor 2-positive patients (16%) using a cutoff value of 15 ng/ml. The sensitivity and the specificity of serum human epidermal growth factor receptor 2 with respect to human epidermal growth factor receptor 2 positivity in tumor cells were 53 and 94%, respectively. Conclusions: Serum human epidermal growth factor receptor 2 measurements cannot be substituted for tissue human epidermal growth factor receptor 2 diagnosis in advanced gastric cancer patients. However, serum human epidermal growth factor receptor 2 levels are associated with human epidermal growth factor receptor 2 overexpression in tumor cells. Further investigations of clinical significance of serum human epidermal growth factor receptor 2 as a predictive marker and a therapy-monitoring marker are warranted.
• Endoscopic nasogallbladder tube or stent placement in acute cholecystitis: a preliminary prospective randomized trial in Japan (with videos)

  Takao Itoi, Hiroshi Kawakami, Akio Katanuma, Atsushi Irisawa, Atsushi Sofuni, Fumihide Itokawa, Takayoshi Tsuchiya, Reina Tanaka, Junko Umeda, Shomei Ryozawa, Shinpei Doi, Naoya Sakamoto, Ichiro Yasuda

  GASTROINTESTINAL ENDOSCOPY 81 (1) 111 - 118 0016-5107 2015/01 [Refereed][Not invited]
   

  Background: There are currently no prospective, controlled trials of endoscopic transpapillary gallbladder drainage in patients with acute cholecystitis. Objective: We evaluated the technical success rate and efficacy of endoscopic transpapillary gallbladder drainage by using either endoscopic nasogallbladder drainage (ENGBD) or endoscopic gallbladder stenting (EGBS) for patients with acute cholecystitis. Design: Randomized, controlled study. Setting: Tertiary-care referral centers. Patients: Seventy-three consecutive patients with acute cholecystitis were randomized. Interventions: ENGBD by using a 5F or 7F tube (n = 37) or EGBS (n = 36) by using a 7F stent. Main Outcome and Measurements: Technical success, clinical success, adverse events, and procedure-related pain score. Results: The overall technical success rates in the ENGBD and EGBS groups were 91.9% and 86.1%, respectively (P O.05). The mean procedure times of ENGBD and EGBS were 20.3 +/- 12.1 and 22.2 +/- 14.5 minutes, respectively (P O.05). The overall clinical success rates by per protocol analysis were 94.1% and 90.3% in the ENGBD and EGBS groups, respectively, whereas the rates by intention-to-treat analysis were 86.5% and 77.8%, respectively (P O.05). Moderate adverse events were observed in the ENGBD (n = 2) and EGBS (n = 1) groups. The mean visual analog score of postprocedure pain in the ENGBD group was significantly higher than that in the EGBS group (1.3 +/- 1.1 vs 0.4 +/- 0.8, respectively; P < .001). Limitations: Small sample size and the participation of multiple endoscopists who may have different levels of experience in endoscopic transpapillary gallbladder drainage. Conclusions: Both ENGBD and EGBS appear to be suitable for the treatment of acute cholecystitis in patients who are poor candidates for emergency cholecystectomy.
• Chromoendoscopy With Iodine Staining, as Well as Narrow-Band Imaging, Is Still Useful and Reliable for Screening of Early Esophageal Squamous Cell Carcinoma

  Yuichi Shimizu, Masakazu Takahashi, Takeshi Mizushima, Shouko Ono, Katsuhiro Mabe, Shunsuke Ohnishi, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  AMERICAN JOURNAL OF GASTROENTEROLOGY 110 (1) 193 - 194 0002-9270 2015/01 [Refereed][Not invited]
  
• Direct peroral ultraslim endoscopy-guided biliary drainage in a patient with cystic duct carcinoma and an occluded self-expandable metallic stent

  Hiroshi Kawakami, Masaki Kuwatani, Yoko Abe, Yoshimasa Kubota, Kazumichi Kawakubo, Kimitoshi Kubo, Shuhei Kawahata, Naoya Sakamoto

  ENDOSCOPY 47 E43 - E44 0013-726X 2015 [Refereed][Not invited]
  
• Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP.

  Yoshimitsu Kobayashi, Yoshito Komatsu, Satoshi Yuki, Hiraku Fukushima, Takahide Sasaki, Ichiro Iwanaga, Minoru Uebayashi, Hiroyuki Okuda, Takaya Kusumi, Takuto Miyagishima, Susumu Sogabe, Miki Tateyama, Kazuteru Hatanaka, Yasushi Tsuji, Michio Nakamura, Jun Konno, Fumiyasu Yamamoto, Manabu Onodera, Kazuhiro Iwai, Yuh Sakata, Riichiro Abe, Koji Oba, Naoya Sakamoto

  Future oncology (London, England) 11 (4) 617 - 27 1479-6694 2015 [Refereed][Not invited]
   

  AIM: We planned a randomized, open-label trial to evaluate differences between pre-emptive and reactive skin treatment for panitumumab (Pmab)-associated skin toxicities in Japanese patients with metastatic colorectal cancer. PATIENTS & METHODS: Patients receiving third-line Pmab-containing regimens were randomized to pre-emptive or reactive treatment. The primary end point was the cumulative incidence of ≥grade 2 skin toxicities during 6 weeks. Retrospectively, a dermatologist reviewed skin toxicities, in a blinded manner. RESULTS: A total of 95 patients were enrolled (pre-emptive: 47, reactive: 48). The primary end point was achieved (21.3 and 62.5% [risk ratio: 0.34; p < 0.001], for pre-emptive and reactive treatment, respectively). A similar trend was observed in central review. CONCLUSION: Pre-emptive skin treatment could reduce the severity of Pmab-associated skin toxicities in Japanese metastatic colorectal cancer patients.
• Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Dextran Sulfate Sodium-Induced Severe Colitis in Rats

  Reizo Onishi, Shunsuke Ohnishi, Ryosuke Higashi, Michiko Watari, Kenichi Yamahara, Naoto Okubo, Koji Nakagawa, Takehiko Katsurada, Goki Suda, Mitsuteru Natsuizaka, Hiroshi Takeda, Naoya Sakamoto

  CELL TRANSPLANTATION 24 (12) 2601 - 2614 0963-6897 2015 [Refereed][Not invited]
   

  Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of human amnion-derived MSCs (AMSCs) in rats with severe colitis. Colitis was induced by the administration of 8% dextran sulfate sodium (DSS) from day 0 to day 5, and AMSCs (1 x 10(6) cells) were transplanted intravenously on day 1. Rats were sacrificed on day 5, and the colon length and histological colitis score were evaluated. The extent of inflammation was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The effect of AMSCs on the inflammatory signals was investigated in vitro. AMSC transplantation significantly ameliorated the disease activity index score, weight loss, colon shortening, and the histological colitis score. mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and migration inhibitory factor (MIF) were significantly decreased in the rectums of AMSC-treated rats. In addition, the infiltration of monocytes/macrophages was significantly decreased in AMSC-treated rats. In vitro experiments demonstrated that activation of proinflammatory signals induced by TNF-alpha or lipopolysaccharide (LPS) in immortalized murine macrophage cells (RAW264.7) was significantly attenuated by coculturing with AMSCs or by culturing with a conditioned medium obtained from AMSCs. Although the phosphorylation of I kappa B induced by TNF-alpha or LPS was not inhibited by the conditioned medium, nuclear translocation of NF-kappa B was significantly inhibited by the conditioned medium. Taken together, AMSC transplantation provided significant improvement in rats with severe colitis, possibly through the inhibition of monocyte/macrophage activity and through inhibition of NF-kappa B activation. AMSCs could be considered as a new cell source for the treatment of severe colitis.
• Huge hemothorax caused by endoscopic ultrasound-guided fine-needle aspiration of a submucosal tumor of the gastric fornix

  Hiroshi Kawakami, Masaki Kuwatani, Kimitoshi Kubo, Yoshimasa Kubota, Kazumichi Kawakubo, Yoko Abe, Shuhei Kawahata, Naotake Homma, Yasuhiro Hida, Naoya Sakamoto

  ENDOSCOPY 47 E69 - E70 0013-726X 2015 [Refereed][Not invited]
  
• A guidewire-assisted biopsy technique to assist advancement through a biliary stricture to perform selective mapping biopsy

  Hiroshi Kawakami, Masaki Kuwatani, Yoko Abe, Shuhei Kawahata, Kazumichi Kawakubo, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 47 E217 - E218 0013-726X 2015 [Refereed][Not invited]
  
• Endoscopic ultrasound-guided pelvic abscess drainage using a dedicated, wide, flared-end, fully covered self-expandable metal stent

  Hiroshi Kawakami, Masaki Kuwatani, Shuhei Kawahata, Yoshimasa Kubota, Kimitoshi Kubo, Kazumichi Kawakubo, Naoya Sakamoto

  ENDOSCOPY 47 E265 - E266 0013-726X 2015 [Refereed][Not invited]
  
• Endoscopic ultrasound-guided antegrade bile duct stone treatment followed by direct peroral transhepatic cholangioscopy in a patient with Roux-en-Y reconstruction

  Hiroshi Kawakami, Masaki Kuwatani, Yoshimasa Kubota, Shuhei Kawahata, Kimitoshi Kubo, Kazumichi Kawakubo, Naoya Sakamoto

  ENDOSCOPY 47 E340 - E341 0013-726X 2015 [Refereed][Not invited]
  
• Acute pancreatitis-like bile leakage around the portal vein system after endoscopic ultrasound-guided choledochoduodenostomy

  Hiroshi Kawakami, Masaki Kuwatani, Kazumichi Kawakubo, Yoshimasa Kubota, Shuhei Kawahata, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 47 E346 - E347 0013-726X 2015 [Refereed][Not invited]
  
• Technical difficulty according to location, and risk factors for perforation, in endoscopic submucosal dissection of colorectal tumors

  Takeshi Mizushima, Mototsugu Kato, Ichiro Iwanaga, Fumiyuki Sato, Kimitoshi Kubo, Nobuyuki Ehira, Minoru Uebayashi, Shouko Ono, Manabu Nakagawa, Katsuhiro Mabe, Yuichi Shimizu, Naoya Sakamoto

  SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES 29 (1) 133 - 139 0930-2794 2015/01 [Refereed][Not invited]
   

  Colorectal endoscopic submucosal dissection (ESD) is a widely accepted treatment for colorectal tumors, but is technically more difficult and has a higher risk of complications such as perforation than gastric ESD. Few studies have investigated the factors associated with technical difficulty and perforation in colorectal ESD. This study aimed to evaluate the technical difficulty according to location, and the risk factors for perforation, in colorectal ESD. This retrospective study included 134 consecutive colorectal tumors treated by ESD in 122 patients at the Division of Endoscopy of Hokkaido University Hospital and the Department of Gastroenterology of Kitami Red Cross Hospital from November 2011 to February 2013. To evaluate the technical difficulty of performing ESD for colorectal tumors at specific locations, the en bloc R0 resection rate, specimen diameter, procedure speed, and procedure time were compared among tumor locations using the chi (2) test or analysis of variance. Risk factors for perforation were identified by multiple logistic regression analysis. The en bloc R0 resection rate was 86.6 % (116/134), the mean tumor diameter was 27.1 mm, and the mean procedure time was 63.5 min. The mean speed of procedures was significantly slower in the sigmoid colon (24.7 min/cm(2)) than in other areas. Perforation occurred in nine cases (6.7 %). Submucosal fibrosis was the only factor independently associated with perforation (odds ratio 5.684, 95 % confidence interval 1.307-24.727). ESD was slower for sigmoid colon tumors than for tumors in other areas, suggesting that ESD was technically more difficult in the sigmoid colon than in other colorectal areas. Submucosal fibrosis was independently associated with perforation during colorectal ESD.
• Dengue-Associated Hemophagocytic Syndrome in a Japanese Traveler: A Case Report

  Ken-ichiro Kobayashi, Mayu Hikone, Naoya Sakamoto, Sentaro Iwabuchi, Masahiro Kashiura, Tomohiko Takasaki, Hiroshi Fujita, Kenji Ohnishi

  JOURNAL OF TRAVEL MEDICINE 22 (1) 64 - 66 1195-1982 2015/01 [Refereed][Not invited]
   

  Hemophagocytic syndrome (HPS) can develop as a complication of dengue in rare cases, but its relationship with dengue is not well known. We report a case of dengue-associated HPS with liver involvement and coagulopathy. The patient, a Japanese female traveler who had recently returned from Thailand, had severe complications of dengue infection, but she recovered fully with symptomatic treatment.
• High and low negative pressure suction techniques in EUS- guided fine- needle tissue acquisition by using 25-gauge needles: a multicenter, prospective, randomized, controlled trial

  Taiki Kudo, Hiroshi Kawakami, Tsuyoshi Hayashi, Ichiro Yasuda, Tsuyoshi Mukai, Hiroyuki Inoue, Akio Katanuma, Kazumichi Kawakubo, Hirotoshi Ishiwatari, Shinpei Doi, Reiko Yamada, Hiroyuki Maguchi, Hiroyuki Isayama, Tomoko Mitsuhashi, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 80 (6) 1030 - + 0016-5107 2014/12 [Refereed][Not invited]
   

  Background: EUS-guided FNA (EUS-FNA) has a high diagnostic accuracy for pancreatic diseases. However, although most reports have typically focused on cytology, histological tissue quality has rarely been investigated. The effectiveness of EUS-FNA combined with high negative pressure (HNP) suction was recently indicated for tissue acquisition, but has not thus far been tested in a prospective, randomized clinical trial. Objective: To evaluate the adequacy of EUS-FNA with HNP for the histological diagnosis of pancreatic lesions by using 25-gauge needles. Design: Prospective, single-blind, randomized, controlled crossover trial. Setting: Seven tertiary referral centers. Patients: Patients referred for EUS-FNA of pancreatic solid lesions. From July 2011 to April 2012, 90 patients underwent EUS-FNA of pancreatic solid masses by using normal negative pressure (NNP) and HNP with 2 respective passes. The order of the passes was randomized, and the sample adequacy, quality, and histology were evaluated by a single expert pathologist. Intervention: EUS-FNA by using NNP and HNP. Main Outcome Measurements: The adequacy of tissue acquisition and the accuracy of histological diagnoses made by using the EUS-FNA technique with HNP. Results: We found that 72.2% (65/90) and 90% (81/90) of the specimens obtained using NNP and HNP, respectively, were adequate for histological diagnosis (P = .0003, McNemar test). For 73.3% (66/90) and 82.2% (74/90) of the specimens obtained by using NNP and HNP, respectively, an accurate diagnosis was achieved (P = .06, McNemar test). Pancreatitis developed in 1 patient after this procedure, which subsided with conservative therapy. Limitations: This was a single-blinded, crossover study. Conclusion: Biopsy procedures that combine the EUS-FNA with HNP techniques are superior to EUS-FNA with NNP procedures for tissue acquisition.
• Stress distribution of the spinal cord and clinical relevance in cervical spondylotic myelopathy

  Kohei Takahashi, Hiroshi Ozawa, Naoya Sakamoto, Yuka Minegishi, Masaaki Sato, Eiji Itoi

  Neuroprotection and Regeneration of the Spinal Cord 9784431545026 311 - 321 2014/11/01 [Refereed][Not invited]
   

  Intramedullary stress Intramedullary stress was analyzed in patients with cervical spondylotic myelopathy cervical spondylotic myelopathy (CSM) using a finite element method (FEM). A total of 99 disc levels of 30 patients with CSM were analyzed and divided into two groups: 33 disc levels with high signal intensity (HSI) on T2WI MRI (HSI group) and 66 disc levels without HSI (non-HSI group). Ninety disc levels of 30 patients without myelopathy were set up as a control group. The stress in the HSI group was significantly highest among three groups. The cutoff value to present HSI was 2.30 kPa from a receiver operator characteristics (ROC) analysis. A multiple logistic regression analysis was performed to compare the utility of the three parameters as prognosticators for the onset of myelopathy: intramedullary stress, the cross-sectional area of the spinal cord, and the anteroposterior compression ratio (APCR). Intramedullary stress had the highest odds ratio. The intramedullary stress significantly reduced after surgery. From the analysis of the correlation between the local kyphosis angle and the reduction of the stress after surgery in HSI group, the higher the kyphosis was, the less the reduction of the stress after surgery. In conclusion, intramedullary stress reflected clinical manifestations in patients with CSM.
• [Discussion Meeting on Infectious diseases in the global era--from travel medicine to countermeasures against emerging infectious diseases].

  Kawana A, Genka I, Sakamoto N, Kato Y, Nakashima K

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 (11) 2770 - 2782 0021-5384 2014/11 [Refereed][Not invited]
  
• Hypoxia-mediated CD24 expression is correlated with gastric cancer aggressiveness by promoting cell migration and invasion

  Nobuaki Fujikuni, Hideki Yamamoto, Kazuaki Tanabe, Yutaka Naito, Naoya Sakamoto, Yuka Tanaka, Kazuyoshi Yanagihara, Naohide Oue, Wataru Yasui, Hideki Ohdan

  CANCER SCIENCE 105 (11) 1411 - 1420 1347-9032 2014/11 [Refereed][Not invited]
   

  CD24 is a heavily glycosylated cell surface protein that is expressed in putative stem cells and is overexpressed in various human malignancies, yet the significant roles of CD24 in gastric cancer development are still elusive. We investigated the involvement of CD24 in gastric cancer aggressiveness, which is attributed to its heterogeneity. Cultured gastric cancer cells showed diverse expression patterns in CD24, whereas other defined cell surface markers, such as CD44 and CD133, were homogenous. Purely sorted CD24-negative gastric cancer cells showed strong alteration into the CD24-positive cell type in an autochthonous manner, and reached to steady expression levels. Our clinicopathological study revealed that CD24 positivity was an independent prognostic factor in both intestinal and diffuse types of gastric cancer. CD24 expression was correlated with the advanced stages, invasiveness, and lymph node metastasis of gastric cancer. Silencing of CD24 in cultured cells significantly decreased cell migration and invasion. Hypoxic treatment upregulated CD24 expression, and simultaneously induced cell motility and invasion of gastric cancer cells. Hypoxic treatment-induced CD24 expression was significantly attenuated by knockdown of hypoxia-inducible transcription factors. These data suggest that CD24-negative cells are capable of gaining cell motility and invasiveness through the induction of CD24, which is mediated by hypoxia. CD24 would be an attractive marker to define not only the heterogeneity but also the aggressiveness of gastric cancer cells. The mechanisms by which hypoxia induces CD24 expression would also be a potential therapeutic target for gastric cancer.
• Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open-label, phase 3 trial

  Masao Omata, Shuhei Nishiguchi, Yoshiyuki Ueno, Hitoshi Mochizuki, Namiki Izumi, Fusao Ikeda, Hidenori Toyoda, Osamu Yokosuka, Kazushige Nirei, Takuya Genda, Takeji Umemura, Tetsuo Takehara, Naoya Sakamoto, Yoichi Nishigaki, Kunio Nakane, Nobuo Toda, Tatsuya Ide, Mikio Yanase, Keisuke Hino, Bing Gao, Kimberly L. Garrison, Hadas Dvory-Sobol, Akinobu Ishizaki, Masa Omote, Diana Brainard, Steven Knox, William T. Symonds, John G. McHutchison, Hiroshi Yatsuhashi, Masashi Mizokami

  JOURNAL OF VIRAL HEPATITIS 21 (11) 762 - 768 1352-0504 2014/11 [Refereed][Not invited]
   

  Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-naive and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-naive patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-naive and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.
• TRANSPLANTATION OF HUMAN AMNIOTIC MEMBRANE-DERIVED MESENCHYMAL STEM CELLS IMPROVES RADIATION ENTERITIS

  Minori Honda, Shunsuke Ohnishi, Masayoshi Ono, Kenichi Yamahara, Jun Yoshimatsu, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto

  PLACENTA 35 (10) A7 - A7 0143-4004 2014/10 [Refereed][Not invited]
  
• THE ANTI-INFLAMMATORY EFFECT OF HUMAN AMNION-DERIVED MESENCHYMAL STEM CELLS

  Reizo Onishi, Shunsuke Ohnishi, Ryosuke Higashi, Kenichi Yamahara, Jun Yoshimatsu, Takehiko Katsurada, Naoto Okubo, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto

  PLACENTA 35 (10) A23 - A23 0143-4004 2014/10 [Refereed][Not invited]
  
• Clinical presentation and diagnosis of toxoplasmic encephalitis in Japan

  Naoya Sakamoto, Takuya Maeda, Kei Mikita, Yasuyuki Kato, Naoki Yanagisawa, Akihiko Suganuma, Akifumi Imamura, Fukumi Nakamura-Uchiyama, Yasushi Miyahira, Akihiko Kawana, Kenji Ohnishi, Atsushi Ajisawa

  PARASITOLOGY INTERNATIONAL 63 (5) 701 - 704 1383-5769 2014/10 [Refereed][Not invited]
   

  Distinguishing life-threatening toxoplasmic encephalitis (TE) from brain lymphoma in patients with acquired immunodeficiency syndrome (AIDS) may be difficult. Empiric anti-toxoplasmosis treatment is often initiated because of the reluctance in performing brain biopsies, which may delay the diagnosis and treatment of brain lymphoma in Japan. In this study, we retrospectively examined the clinical characteristics of 13 AIDS patients with TE in Japan, including magnetic resonance imaging and thallium 201 (201TI) single photon emission computed tomography (SPECT) findings, cerebral spinal fluid analysis, serology, and polymerase chain reaction (PCR) results. All patients improved on anti-toxoplasmosis treatment. Of the 11 patients who underwent serological testing, 6 (55%) had a positive serological result. Of the 7 patients who underwent PCR testing, 3 (42.9%) had a positive PCR result. Nine of 11 patients with TE (81.8%) had multiple lesions. Analysis of the sites of TE lesions did not reveal a difference in site predilection between TE and brain lymphoma. Uptake was negative in all 9 patients who underwent 201TI SPECT. The study findings suggest that toxoplasma serostatus and PCR may be used to discriminate TE from brain lymphoma. No focal accumulation of 201TI is strongly suggestive of TE in patients with AIDS in Japan. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
• Difference from Bile Duct Cancer and Relationship between Bile Duct Wall Thickness And Serum IgG/IgG4 Levels in IgG4-Related Sclerosing Cholangitis

  Masaki Kuwatani, Hiroshi Kawakami, Yoh Zen, Kazumichi Kawakubo, Taiki Kudo, Yoko Abe, Kimitoshi Kubo, Naoya Sakamoto

  HEPATO-GASTROENTEROLOGY 61 (135) 1852 - 1856 0172-6390 2014/10 [Refereed][Not invited]
   

  Background/Aims: IgG4-related sclerosing cholangitis (IgG4-SC) is a newly established entity The purpose of this study was to investigate the differences in intraductal ultrasonography (IDUS) findings between IgG4-SC and bile duct (BD) cancer (BDC) as well as the relationship among BD wall thickness, serological and pathological findings in IgG4-SC. Methodology: Based on the diagnostic criteria of IgG4-SC, we reviewed patients in our hospital between April 2005 and June 2013, and analyzed the data obtained from 32 patients with IgG4-SC and 40 patients with BDC. Results: Regarding IDUS findings, significantly more cases in BDC indicated rigid/papillary inner margin than in IgG4-SC, while biopsy was more efficient. There were no significant correlations between BD wall thickness and serum I IgG/IgG4 levels or the number of IgG4-positive cells of the BD specimens. All the IgG4-SC patients without steroid treatment revealed discordant results in the shifts of IgG, IgG4 and BD wall thickness between the 1st and 2nd examinations, while all patients with steroid had completely concordant results of the shifts. Conclusions: IDUS findings alone are insufficient for differ entiation between IgG4-SC and BDC. BD wall thickness, serum IgG and IgG4 proportionally shift and reflect the effect of steroid on IgG4-SC after steroid treatment, not before it.
• Subjective adverse reactions to metronidazole in patients with amebiasis

  Kenji Ohnishi, Naoya Sakamoto, Ken-ichiro Kobayashi, Sentaro Iwabuchi, Fukumi Nakamura-Uchiyama, Atsushi Ajisawa, Yuko Yamauchi, Nozomi Takeshita, Yasuyuki Yamamoto, Takafumi Tsunoda, Yukihiro Yoshimura, Natsuo Tachikawa, Tomoko Uehira

  PARASITOLOGY INTERNATIONAL 63 (5) 698 - 700 1383-5769 2014/10 [Refereed][Not invited]
   

  Subjective adverse reactions to metronidazole were analyzed in 111 patients with amebiasis. Metronidazole was administered to 36 patients at a daily dose of 2250 mg and 75 patients at daily doses lower than 2250 mg. The reactions reported included nausea without vomiting in 11(9.9%) patients, nausea with vomiting in 2 (1.8%), dysgeusia in 2 (1.8%), diarrhea in 1 (0.9%), headache in 1 (0.9%), numbness in 1 (0.9%), dizziness in 1 (0.9%), urticaria in 1 (0.9%), exanthema in 1 (0.9%), and discomfort in 1 (0.9%). Nausea was reported by 28% (10/36) of the patients receiving metronidazole at a daily dose of 2250 mg and 4% (3/75) of the patients receiving lower daily doses. The duration of the metronidazole administration in days was not associated with the appearance of nausea. No life-threatening adverse reactions were identified, and good clinical therapeutic effects were observed in 96% (107/111) of the patients. While metronidazole appears to be a safe anti-protozoal agent for patients with amebiasis, our results indicate that a daily metronidazole dose of 2250 mg is excessive for amebiasis, as it often induces nausea. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
• FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia

  Junko Iwasaki, Takeshi Kondo, Stephanie Darmanin, Makoto Ibata, Masahiro Onozawa, Daigo Hashimoto, Naoya Sakamoto, Takanori Teshima

  ANNALS OF HEMATOLOGY 93 (9) 1473 - 1481 0939-5555 2014/09 [Refereed][Not invited]
   

  FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia.
• The J6JFH1 Strain of Hepatitis C Virus Infects Human B-Cells with Low Replication Efficacy

  Masato Nakai, Tsukasa Seya, Misako Matsumoto, Kunitada Shimotohno, Naoya Sakamoto, Hussein H. Aly

  VIRAL IMMUNOLOGY 27 (6) 285 - 294 0882-8245 2014/08 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) infection is a serious health problem worldwide that can lead to hepatocellular carcinoma or end-stage liver disease. Current treatment with pegylated interferon, ribavirin, and NS3/4A protease inhibitor would lead to a good prognosis in a large population of patients, but there is still no effective vaccine for HCV. HCV robustly infects hepatocytes in the liver. However, extrahepatic manifestations such as mixed cryoglobulinemia, a systemic immune complex-mediated disorder characterized by B-cell proliferation, which may evolve into overt B-cell non-Hodgkin's lymphoma, have been demonstrated. HCV-RNA is often found to be associated with peripheral blood lymphocytes, suggesting a possible interaction with peripheral blood mononuclear cells (PBMCs), especially B-cells with HCV. B-cell HCV infection was a matter of debate for a long time, and the new advance in HCV in vitro infectious systems suggest that exosome can transmit HCV genome to support "infection." We aimed to clarify the susceptibility of primary B-cells to HCV infection, and to study its functional effect. In this article, we found that the recombinant HCV J6JFH1 strain could infect human B-cells isolated from the peripheral blood of normal volunteers by the detection of both HCV-negative-strand RNA by reverse transcription polymerase chain reaction, and NS5A protein. We also show the blocking of HCV replication by type I interferon after B-cell HCV infection. Although HCV replication in B-lymphocytes showed lower efficiency, in comparison with hepatocyte line (Huh7) cells, our results clearly demonstrate that human B-lymphocytes without other non-B-cells can actually be infected with HCV, and that this interaction leads to the induction of B-cells' innate immune response, and change the response of these cells to apoptosis.
• Identification of PRL1 as a novel diagnostic and therapeutic target for castration-resistant prostate cancer by the Escherichia coli ampicillin secretion trap (CAST) method

  Shunsuke Shinmei, Kazuhiro Sentani, Tetsutaro Hayashi, Naoya Sakamoto, Keisuke Goto, Htoo Zarni Oo, Yutaka Naito, Jun Teishima, Akio Matsubara, Naohide Oue, Hiroki Kuniyasu, Wataru Yasui

  UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 32 (6) 769 - 778 1078-1439 2014/08 [Refereed][Not invited]
   

  Objectives: Although chemotherapy for castration-resistant prostate cancer (CRPC) has been applied clinically in recent years, the effects are not sufficient. It is urgently necessary to develop novel therapeutics for CRPC. We previously generated Escherichia coli ampicillin secretion trap libraries of 2 prostate cancer (PCa) cell lines and normal prostate. By comparing the E. coli ampicillin secretion trap libraries of CRPC cell lines with those of androgen-sensitive PCa cell lines and normal prostate, we focused on the protein-tyrosine-phosphatase of regenerating liver 1 (PRL1) gene and analyzed its expression and biological function. Materials and methods: The expression of PRL1 was examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in clinical PCa samples. The effects of PRL1 on PCa cells were evaluated by cell growth, migration, and invasion assays. To investigate the effect of PRL1 on epidermal growth factor receptor (EGFR) signaling, PRL1 knockdown PC3 cells were examined by Western blot and immunohistochemical analyses. Results: Quantitative reverse transcription polymerase chain reaction revealed that PRL1 was expressed much more highly in PCa than in nonneoplastic prostate samples. High expression of PRL1 detected by immunohistochemistry correlated with poor prognosis after prostatectomy and combined androgen blockade therapy. Functional analysis indicated that PRL1 stimulated cell growth, migration, and invasion in PCa cell lines. Expression EGFR and matrix metalloproteinase 9 was reduced by knockdown of PRL1 in the PC3 cell line. Conclusions: PRL1 regulates expression of EGFR and modulates downstream targets. PRL1 has potential as a therapeutic target in PCa including CRPC. (C) 2014 Elsevier Inc. All rights reserved.
• ヘリコバクターの現状・今後 病態との関連 ヘリコバクター・ピロリ胃炎に対する飲水超音波検査を用いた病態評価

  工藤 俊彦, 加藤 元嗣, 西田 睦, 坂本 直哉

  胃病態機能研究会誌 (株)勁草書房コミュニケーション事業部 46 17 - 17 1880-3652 2014/07
• Pyoderma gangrenosum successfully treated with antiretroviral therapy alone in a human immunodeficiency virus-infected individual

  Naoya Sakamoto, Naoki Yanagisawa, Noritaka Sekiya, Akihiko Suganuma, Akifumi Imamura, Atsushi Ajisawa

  JOURNAL OF INFECTION AND CHEMOTHERAPY 20 (7-8) 502 - 505 1341-321X 2014/07 [Refereed][Not invited]
   

  We report a case of a 60-year-old man infected with human immunodeficiency virus (HIV) who was transferred to our hospital for management of multiple non-healing, painful ulcers on the lower extremities. The histological findings of the biopsy specimen were compatible with the diagnosis of pyoderma gangrenosum (PG). An association between HIV infection and the development of PG was considered after a thorough investigation. Antiretroviral therapy without the use of adjunctive immunosuppressive agents resulted in clinical improvement. Our case implies that antiretroviral therapy alone could heal PG in untreated HIV-infected patients. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
• Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer

  Htoo Zarni Oo, Kazuhiro Sentani, Naoya Sakamoto, Katsuhiro Anami, Yutaka Naito, Naohiro Uraoka, Takashi Oshima, Kazuyoshi Yanagihara, Naohide Oue, Wataru Yasui

  ONCOLOGY REPORTS 32 (1) 403 - 410 1021-335X 2014/07 [Refereed][Not invited]
   

  Scirrhous type gastric cancer is highly aggressive and has a poorer prognosis than many other types of gastric carcinoma, due to its characteristic rapid cancer cell infiltration and proliferation, extensive stromal fibrosis, and frequent peritoneal dissemination. The aim of the present study was to identify novel prognostic markers or therapeutic targets for scirrhous type gastric cancer. We reviewed a list of genes with upregulated expression in scirrhous type gastric cancer and compared their expression with that in normal stomach from our previous Escherichia coli (E. coli) ampicillin secretion-trap (CAST) analysis. We focused on the ZDHHC14 gene, which encodes zinc finger, DHHC-type containing 14 protein. qRT-PCR analysis of ZDHHC14 in 41 gastric cancer cases revealed that compared to mRNA levels in normal non-neoplastic gastric mucosa, ZDHHC14 mRNA was overexpressed in 27% of gastric cancer tissue samples. The overexpression of ZDHHC14 was significantly associated with depth of tumor invasion, undifferentiated histology and scirrhous pattern. The invasiveness of ZDHHC14-knockdown HSC-44PE and 44As3 gastric cancer cells was decreased in comparison with that of the negative control siRNA-transfected cells, together with downregulation of MMP-17 mRNA. Integrins alpha 5 and beta 31 were also downregulated in ZDHHC14-knockdown 44As3 cells. Forced expression of ZDHHC14 activated gastric cancer cell migration and invasion in vitro. These results indicate that ZDHHC14 is involved in tumor progression in patients with scirrhous type gastric cancer.
• Endoscopic Ultrasound-Guided Transluminal Drainage for Peripancreatic Fluid Collections: Where Are We Now?

  Hiroshi Kawakami, Takao Itoi, Naoya Sakamoto

  GUT AND LIVER 8 (4) 341 - 355 1976-2283 2014/07 [Refereed][Not invited]
   

  Endoscopic drainage for pancreatic and peripancreatic fluid collections (PFCs) has been increasingly used as a minimally invasive alternative to surgical or percutaneous drainage. Recently, endoscopic ultrasound-guided transluminal drainage (EUS-TD) has become the standard of care and a safe procedure for nonsurgical PFC treatment. EUS-TD ensures a safe puncture, avoiding intervening blood vessels. Single or multiple plastic stents (combined with a nasocystic catheter) were used for the treatment of PFCs for EUS-TD. More recently, the use of covered self-expandable metallic stents (CSEMSs) has provided a safer and more efficient approach route for internal drainage. We focused our review on the best approach and stent to use in endoscopic drainage for PFCs. We reviewed studies of EUS-TD for PFCs based on the original Atlanta Classification, including case reports, case series, and previous review articles. Data on clinical outcomes and adverse events were collected retrospectively. A total of 93 patients underwent EUS-TD of pancreatic pseudocysts using CSEMSs. The treatment success and adverse event rates were 94.6% and 21.1%, respectively. The majority of complications were of mild severity and resolved with conservative therapy. A total of 56 patients underwent EUS-TD using CSEMSs for pancreatic abscesses or infected walled-off necroses. The treatment success and adverse event rates were 87.8% and 9.5%, respectively. EUS-TD can be performed safely and efficiently for PFC treatment. Larger diameter CSEMSs without additional fistula tract dilation for the passage of a standard scope are needed to access and drain for PFCs with solid debris.
• Gender Difference Influences Food Intake Under an Emotional Stress via 5-HT2CR Activation in Aged Mice

  Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chihiro Yamada, Yayoi Saegusa, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda

  GASTROENTEROLOGY 146 (5) S498 - S499 0016-5085 2014/05 [Refereed][Not invited]
  
• Association of Abnormal Ghrelin Dynamics With Delayed Gastric Emptying in Acute Restraint-Stressed Mice

  Hiroshi Takeda, Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Naoya Sakamoto

  GASTROENTEROLOGY 146 (5) S658 - S658 0016-5085 2014/05 [Refereed][Not invited]
  
• The Possibility of Rikkunshito As a Treatment for Anorexia: a Proposal From a Basic Research Perspective

  Hiroshi Takeda, Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Naoya Sakamoto

  GASTROENTEROLOGY 146 (5) S899 - S899 0016-5085 2014/05 [Refereed][Not invited]
  
• EGFR Inhibitors Eliminate Esophageal Cancer Stem Cells by Suppressing Epithelial-Mesenchymal Transition

  Mitsuteru Natsuizaka, Bongani Kaimila, Yoshimasa Kubota, Yutaka Hatanaka, Katsuji Marukawa, Katsumi Terashita, Fumiyuki Satou, Shunsuke Ohnishi, Goki Suda, Shinya Ohashi, Shingo Kagawa, Kelly A. Whelan, Anil K. Rustgi, Hiroshi Nakagawa, Naoya Sakamoto

  GASTROENTEROLOGY 146 (5) S821 - S821 0016-5085 2014/05 [Refereed][Not invited]
  
• Rikkunshito, a Traditional Japanese Kampo Medicine, Ameliorates the Decrease in Feeding Behavior in Aged Mice Exposed to Stress via Enhancement of Endogenous Ghrelin Production

  Shuichi Muto, Shunsuke Ohnishi, Koji Nakagawa, Chihiro Yamada, Yayoi Saegusa, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda

  GASTROENTEROLOGY 146 (5) S848 - S849 0016-5085 2014/05 [Refereed][Not invited]
  
• Safety and Utility of Single-Session Endoscopic Ultrasonography and Endoscopic Retrograde Cholangiopancreatography for the Evaluation of Pancreatobiliary Diseases

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Shin Haba, Taiki Kudo, Yoko Abe, Shuhei Kawahata, Manabu Onodera, Nobuyuki Ehira, Hiroaki Yamato, Kazunori Eto, Naoya Sakamoto

  GUT AND LIVER 8 (3) 329 - 332 1976-2283 2014/05 [Refereed][Not invited]
   

  Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are essential for diagnosing and treating pancreatobiliary diseases. Single-session EUS and ERCP are considered to be essential in reducing the duration of hospital stays; however, complications are a primary concern. The aim of this study was to evaluate the safety and efficacy of single-session EUS and ERCP. Sixty-eight patients underwent single-session EUS and ERCP at a tertiary referral center between June 2008 and December 2012. We retrospectively reviewed patient data from a prospectively maintained EUS-ERCP database and evaluated the procedural characteristics and complications. Thirty-eight patients (56%) underwent diagnostic EUS, and 30 patients (44%) underwent EUS fine-needle aspiration, which had an overall accuracy of 100%. Sixty patients (89%) underwent therapeutic ERCP, whereas the remaining eight procedures were diagnostic. Thirteen patients underwent biliary stone extraction, and 48 underwent biliary drainage. The median total procedural time was 75 minutes. Complications were observed in seven patients (10%). Six complications were post-ERCP pancreatitis,,which were resolved using conservative management. One patient developed Mallory-Weiss syndrome, which required endoscopic hemostasis. No sedation-related cardiopulmonary complications were observed. Single-session EUS and ERCP provided accurate diagnosis and effective management with a minimal complication rate.
• [Future perspectives of hepatitis C therapeutics].

  Sakamoto N

  [Hokkaido igaku zasshi] The Hokkaido journal of medical science 89 (1) 13 - 15 0367-6102 2014/05 [Refereed][Not invited]
  
• Endoscopic diagnosis of early neoplasia of the esophagus with narrow band imaging: Correlations among background coloration and iodine staining findings

  Masakazu Takahashi, Yuichi Shimizu, Masayoshi Ono, Mio Suzuki, Saori Omori, Takeshi Yoshida, Yasuaki Mori, Manabu Nakagawa, Shouko Ono, Soichi Nakagawa, Katsuhiro Mabe, Mototsugu Kato, Kanako Hatanaka, Masahiro Asaka, Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 29 (4) 762 - 768 0815-9319 2014/04 [Refereed][Not invited]
   

  Background and AimIt was previously reported that high-grade intraepithelial neoplasia of the esophagus turns pink within a few minutes after iodine staining (pink-color sign; PCS); however, iodine staining is uncomfortable. By using narrow band imaging (NBI), color change in the area between the intraepithelial papillary capillary loop (background coloration; BGC) is often observed within the brownish area. The diagnostic usefulness of BGC findings for differentiating high-grade intraepithelial neoplasia from low-grade intraepithelial neoplasia was evaluated. MethodsIn a prospective observational study from September 2010 to August 2012, 285 patients who were in a high-risk group for esophageal squamous cell carcinoma underwent endoscopic examination. Lesions with both endoscopic findings of dilated intraepithelial papillary capillary loop on NBI and iodine-unstained areas were studied, in which endoscopic biopsy or endoscopic resection was subsequently performed. The esophageal background mucosa was also evaluated on the basis of the iodine staining pattern (uniform type: Group U, scattered type: Group S). ResultsOne hundred three esophageal lesions in 87 patients were studied. When BGC was used as the differentiation index, sensitivity was 93.8%, specificity was 88.2%, and accuracy was 91.3%. When PCS was used, sensitivity was 97.9%, specificity was 88.2%, and accuracy was 93.2% (P=0.79). In Group U (n=54), BGC had an accuracy of 93.8%, and PCS had an accuracy of 92.3% (P=1.0). On the other hand, in Group S (n=33), BGC had an accuracy of 86.8%, while PCS had an accuracy of 94.7% (P=0.27). ConclusionsDiagnosis using BGC on NBI may substitute for diagnosis based on PCS in many patients.
• Influence of the safety and diagnostic accuracy of preoperative endoscopic ultrasound-guided fine-needle aspiration for resectable pancreatic cancer on clinical performance

  Taiki Kudo, Hiroshi Kawakami, Masaki Kuwatani, Kazunori Eto, Shuhei Kawahata, Yoko Abe, Manabu Onodera, Nobuyuki Ehira, Hiroaki Yamato, Shin Haba, Kazumichi Kawakubo, Naoya Sakamoto

  WORLD JOURNAL OF GASTROENTEROLOGY 20 (13) 3620 - 3627 1007-9327 2014/04 [Refereed][Not invited]
   

  AIM: To evaluate the safety and diagnostic accuracy of endoscopic ultrasound- guided fine- needle aspiration (EUS-FNA) in a cohort of pancreatic cancer patients. METHODS: Of 213 patients with pancreatic cancer evaluated between April 2007 and August 2011, 82 were thought to have resectable pancreatic cancer on the basis of cross-sectional imaging findings. Of these, 54 underwent EUS-FNA before surgery (FNA+ group) and 28 underwent surgery without preoperative EUSFNA (FNA-group). RESULTS: All 54 lesions were visible on EUS, and all 54 attempts at FNA were technically successful. The diagnostic accuracy according to cytology and histology findings was 98.1% (53/54) and 77.8% (42/54), respectively, and the total accuracy was 98.1% (53/54). One patient developed mild pancreatitis after EUS-FNA but was successfully treated by conservative therapy. No severe complications occurred after EUS-FNA. In the FNA+ and FNA-groups, the median relapse-free survival (RFS) was 742 and 265 d, respectively (P = 0.0099), and the median overall survival (OS) was 1042 and 557 d, respectively (P = 0.0071). RFS and OS were therefore not inferior in the FNA+ group. These data indicate that the use of EUS-FNA did not influence RFS or OS, nor did it increase the risk of peritoneal recurrence. CONCLUSION: In patients with resectable pancreatic cancer, preoperative EUS-FNA is a safe and accurate diagnostic method. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
• 脂肪組織と石灰化成分を内部に含有した胆嚢癌の1例

  桑谷 将城, 河上 洋, 川久保 和道, 工藤 大樹, 阿部 容子, 羽場 真, 田中 栄一, 平野 聡, 三橋 智子, 坂本 直哉

  胆道 日本胆道学会 28 (1) 73 - 80 0914-0077 2014/03 [Not refereed][Not invited]
   

  症例は71歳、男性。近医における腹部超音波検査で2年前より指摘されていた胆嚢底部の腫瘤性病変の増大がみられたため、精査目的に当科に紹介となった。各種画像診断により、腫瘤性病変は約20mm大であり、辺縁はほぼ平滑で、内部には脂肪成分が含まれていることが明らかとなった。良性病変も示唆されたが、表面に不整な顆粒状粘膜を伴い、増大傾向にある亜有茎性の腫瘤性病変であり、漿膜側に腫瘤内部への引きつれを伴うことから、胆嚢癌を第一に考え、胆嚢摘出術を施行した。腫瘍内部には脂肪組織と石灰化成分を含有し、腫瘍中心の不整な癌性腺管の周囲には著明な線維化と毛細血管の増生やフィブリンの析出がみられた。胆嚢底部には、炎症性変化に伴う漿膜下脂肪織の引きつれがみられ、その結果、腫瘍内部に脂肪組織を含有したものと考えられた。脂肪組織および石灰化成分を含有する胆嚢癌は非常にまれであり、術前の診断を困難にする要因であった。(著者抄録)
• Leptospirosis in a Japanese urban area: A case report and literature review

  Yukiko Shimizu, Naoya Sakamoto, Yusuke Ainoda, Mayu Hikone, Kenichiro Kobayashi, Sentaro Iwabuchi, Nobuo Koizumi, Kenji Ohnishi

  JOURNAL OF INFECTION AND CHEMOTHERAPY 20 (3-4) 278 - 281 1341-321X 2014/03 [Refereed][Not invited]
   

  Leptospirosis is not a major disease in urban areas of japan. We describe a 49-year-old man with leptospirosis, who lived in an urban area and had no history of living in endemic area of leptospirosis. As he worked at a fish market infested with rats, he was suspected of having contracted leptospirosis and received antimicrobial agent treatment. Serum and urinary tests confirmed the diagnosis of leptospirosis. Although it took six days from the onset until treatment initiation, the patient improved in response to receiving ceftriaxone for seven days. Analyzing past reports of Japanese patients with leptospirosis who had no history of overseas travel, we identified 90 patients with courses similar to that of our patient, and the period from onset to treatment initiation was about six days on average (described in 46 cases). Health care providers as well as patients need to recognize that even people with no history of being in an endemic area of leptospirosis may still be at risk of developing this disease depending on occupations and activities. (C) 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
• MicroRNA-148a is downregulated in gastric cancer, targets MMP7, and indicates tumor invasiveness and poor prognosis

  Naoya Sakamoto, Yutaka Naito, Naohide Oue, Kazuhiro Sentani, Naohiro Uraoka, Htoo Zarni Oo, Kazuyoshi Yanagihara, Kazuhiko Aoyagi, Hiroki Sasaki, Wataru Yasui

  CANCER SCIENCE 105 (2) 236 - 243 1349-7006 2014/02 [Refereed][Not invited]
   

  Gastric cancer (GC) develops through deregulation of gene expression and accumulation of epigenetic abnormalities, leading to tumor cell acquisition of malignant features. MicroRNAs (miRNAs) play a critical role in cancer development where they can act as oncogenes or oncosuppressors. To identify miRNAs that are associated with some clinicopathologic features of GC and/or participate in tumor progression, miRNA expression in 20 GC tissues and five corresponding non-neoplastic gastric mucosa was examined by miRNA microarray. Oligonucleotide array analysis was carried out for miRNA target prediction. The functions of candidate miRNAs and their target genes were also analyzed by quantitative RT-PCR, Western blotting, reporter gene assay, and cell invasion assay. Comparison of miRNA expression profiles revealed that downregulation of miR-148a was identified in most of the GC tissues. Downregulation of miR-148a was significantly correlated with an advanced clinical stage, lymph node metastasis, and poor clinical outcome. Custom oligonucleotide array analysis revealed that MMP7 expression was markedly downregulated in miR-148a-overexpressing GC cells; MMP7 was found to be a direct and functional target of miR-148a, participating in cell invasion. These results suggest that miR-148a contributes to the maintenance of homeostasis in normal stomach tissue and plays an important role in GC invasion by regulating MMP7 expression.
• MicroRNA-143 regulates collagen type III expression in stromal fibroblasts of scirrhous type gastric cancer

  Yutaka Naito, Naoya Sakamoto, Naohide Oue, Masakazu Yashiro, Kazuhiro Sentani, Kazuyoshi Yanagihara, Kosei Hirakawa, Wataru Yasui

  CANCER SCIENCE 105 (2) 228 - 235 1349-7006 2014/02 [Refereed][Not invited]
   

  Gastric cancer (GC) is one of the most common malignancies worldwide. In particular, scirrhous type GC is highly metastatic and is characterized clinically by rapid disease progression and poor prognosis. MicroRNAs (miRNAs) play crucial roles in cancer development and progression. In the present study, we identified several miRNAs that are expressed at higher levels in scirrhous type GC than in non-scirrhous type GC by miRNA microarray analysis. Among these, microRNA-143 (miR-143) expression was higher in scirrhous type GC than in non-scirrhous types of GC. In situ hybridization and quantitative RT-PCR analysis showed that miR-143 is expressed by stromal fibroblasts but not by cancer cells. In stromal cells, miR-143 enhanced collagen type III expression in normal gastric fibroblasts and cancer-associated fibroblasts through activation of transforming growth factor-)/SMAD signaling. Furthermore, high miR-143 expression in GC was associated with worse cancer-specific mortality (P=0.0141). Multivariate analysis revealed that miR-143 was an independent prognostic factor. Treatment of GC cell lines with 5-aza-2-deoxycytidine restored the expression of miR-143, and precursor miR-143 caused the inhibition of cancer cell invasion. These data suggest that miR-143 regulates fibrosis of scirrhous type GC through induction of collagen expression in stromal fibroblasts and that miR-143 expression serves as a prognostic marker of GC.
• Transpapillary dilation of refractory severe biliary stricture or main pancreatic duct by using a wire-guided diathermic dilator (with video)

  Hiroshi Kawakami, Masaki Kuwatani, Kazumichi Kawakubo, Kazunori Eto, Shin Haba, Taiki Kudo, Yoko Abe, Shuhei Kawahata, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 79 (2) 338 - 343 0016-5107 2014/02 [Refereed][Not invited]
  
• Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor-B/mitogen-activated protein kinase

  Makoto Chuma, Naoya Sakamoto, Akira Nakai, Shuhei Hige, Mitsuru Nakanishi, Mitsuteru Natsuizaka, Goki Suda, Takuya Sho, Kanako Hatanaka, Yoshihiro Matsuno, Hideki Yokoo, Toshiya Kamiyama, Akinobu Taketomi, Gen Fujii, Kosuke Tashiro, Yoko Hikiba, Mitsuaki Fujimoto, Masahiro Asaka, Shin Maeda

  CARCINOGENESIS 35 (2) 272 - 281 0143-3334 2014/02 [Refereed][Not invited]
   

  Heat shock factor 1 (HSF1), a major transactivator of stress responses, has been implicated in carcinogenesis in various organs. However, little is known about the biological functions of HSF1 in the development of hepatocellular carcinoma (HCC). To clarify the functional role of HSF1 in HCC, we established HSF1-knockdown (HSF1 KD) KYN2 HCC cells by stably expressing either small hairpin RNA (shRNA) against HSF1 (i.e. HSF1 KD) or control shRNA (HSF1 control). Tumorigenicity was significantly reduced in orthotopic mice with HSF1 KD cells compared with those with HSF1 control cells. Reduced tumorigenesis in HSF1 KD cells appeared attributable to increased apoptosis and decreased proliferation. Tumor necrosis factor--induced apoptosis was increased in HSF1 KD cells and HSF1(/) mouse hepatocytes compared with controls. Decreased expression of IB kinase , a positive regulator of nuclear factor-B, was also observed in HSF1 KD cells and HSF1(/) mouse hepatocytes. Furthermore, expression of bcl-2-associated athanogene domain 3 (BAG3) was dramatically reduced in HSF1 KD cells and HSF1(/) mouse hepatocytes. We also found that epidermal growth factor-stimulated mitogen-activated protein kinase signaling was impaired in HSF1 KD cells. Clinicopathological analysis demonstrated frequent overexpression of HSF1 in human HCCs. Significant correlations between HSF1 and BAG3 protein levels and prognosis were also observed. In summary, these results identify a mechanistic link between HSF1 and liver tumorigenesis and may provide as a potential molecular target for the development of anti-HCC therapies.
• Is wire-guided selective bile duct cannulation effective for prevention of post-ERCP pancreatitis by all endoscopists?

  Hiroshi Kawakami, Hiroyuki Isayama, Hiroyuki Maguchi, Masaki Kuwatani, Kazumichi Kawakubo, Taiki Kudo, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Kazuhiko Koike, Naoya Sakamoto

  ENDOSCOPY 46 (2) 163 - 163 0013-726X 2014/02 [Refereed][Not invited]
  
• Endoscopic ultrasound-guided rendezvous technique for difficult cannulation into the bile duct

  Kazumichi Kawakubo, Hiroshi Kawakami, Hiroyuki Isayama, Naoya Sakamoto

  Gastroenterological Endoscopy 56 (3) 504 - 514 0387-1207 2014 

  The endoscopic ultrasound (EUS)-guided rendezvous technique was reported to be a useful salvage method for patients with failed cannulation. In such patients, after bile duct puncture under EUS guidance, cholangiography was obtained. Then the guidewire was inserted through the needle into the bile duct and further antegradely advanced through the papilla into the duodenum. The echoendoscope was removed leaving the guidewire in place, followed by duodenoscope insertion. Finally, the bile duct was cannulated alongside of the guidewire or over the guidewire. The EUS-guided rendezvous technique is a complicated procedure and not yet standardized due to the absence of dedicated devices. However, the EUS-guided rendezvous technique allows reliable bile duct cannulation because of bile duct access under ultrasonographic guidance compared to conventional retrograde bile duct cannulation using the ERCP technique. However, the possibility of serious complications, such as bile leak or peritonitis, should be of concern due to bile duct access through the peritoneum or retroperitoneum. To gain familiarity with various approach routes in the EUS-guided rendezvous technique is essential for a successful procedure.
• Responses of living cells to hydrodynamic stimuli due to fluid flow

  Naoya Sakamoto

  Lecture Notes in Computational Vision and Biomechanics 12 165 - 180 2212-9413 2014 [Refereed][Not invited]
   

  Cells, the basic units of our body, are constantly exposed to fluiddynamic stimuli. Typical examples are the epithelial cells of tubular organs, including blood and lymphatic vessels and renal tubes, which are in direct contact with flowing fluid. In addition, other cell types such as smooth muscle cells, fibroblasts, articular chondrocytes, and bone cells are subjected to interstitial fluid flow, which is the movement of fluid through the extracellular matrix of tissues elicited by differences in hydrostatic pressure and deformation of tissues. Fluiddynamic stimuli can modulate cell alignment, proliferation, differentiation, migration, and cytokine secretion. These morphological and functional responses of cells play important roles not only in the maintenance of physiological functions of tissues but also in the development and progression of disease. Many attempts have been made to understand the effect of fluid-dynamic stimuli on cells. This chapter summarizes cellular responses induced by such stimuli, mainly focusing on the effect of shear stress on vascular cells, which have been extensively investigated in vitro over the last three decades. In addition, the possible mechanisms by which cells sense shear stress are also introduced briefly.
• Oligophrenin-1 Is Associated with Cell Adhesion and Migration in Prostate Cancer

  Keisuke Goto, Naohide Oue, Tetsutaro Hayashi, Shunsuke Shinmei, Naoya Sakamoto, Kazuhiro Sentani, Jun Teishima, Akio Matsubara, Wataru Yasui

  PATHOBIOLOGY 81 (4) 190 - 198 1015-2008 2014 [Refereed][Not invited]
   

  Objective: We performed Escherichia coli ampicillin secretion trap (CAST) analysis in prostate cancer (PCa) to identify novel biomarkers. We show here that OPHN1, which encodes oligophrenin-1 protein, is upregulated in PCa. OPHN1 was first determined to be one of the genes associated with X-linked mental retardation; however, neither the gene's function nor the link between its expression and survival of patients has been investigated. Methods: We investigate the expression of oligophrenin-1 in 141 PCa tissue samples by immunohistochemistry and perform functional analysis using RNA interference. Results: lrnmunohistochemical analysis of oligophrenin-1 demonstrated that 60 (43%) PCa cases were positive for oligophrenin-1. Positive oligophrenin-1 expression was significantly correlated with a high Gleason score (p = 0.0198). Furthermore, patients with oligophrenin-1-positive PCa had a worse biochemical recurrence-free survival rate than patients with oligophrenin-1-negative PCa (p = 0.0079). Cell adhesion to fibronectin was significantly reduced in OPHN1 small interfering (si)RNA-transfected LNCaP and PC3 cells in comparison to negative-control siRNA-transfected cells. Knockdown of OPHN1 reduced the expression of ITGA5 and stress fiber formation in LNCaP and PC3 cells. Conclusion: These results suggest that oligophrenin-1 is involved in tumor progression in PCa. (C) 2014 S. Karger AG, Basel
• NRD1, which encodes nardilysin protein, promotes esophageal cancer cell invasion through induction of MMP2 and MMP3 expression

  Naohiro Uraoka, Naohide Oue, Naoya Sakamoto, Kazuhiro Sentani, Htoo Zarni Oo, Yutaka Naito, Tsuyoshi Noguchi, Wataru Yasui

  CANCER SCIENCE 105 (1) 134 - 140 1349-7006 2014/01 [Refereed][Not invited]
   

  Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. In the present study, to identify novel prognostic markers or therapeutic targets for ESCC, we reviewed a list of genes with upregulated expression in ESCC compared with normal esophagus, as identified by our serial analysis of gene expression (SAGE) analysis. We focused on the NRD1 gene, which encodes the nardilysin protein. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 34 ESCC tissue samples revealed that mRNA expression of NRD1 was upregulated in 56% of ESCC tissue samples. Immunohistochemical analysis of nardilysin in 109 ESCC tissue samples demonstrated that 43 (39%) ESCC cases were positive for nardilysin. Nardilysin-positive ESCC cases were more advanced in terms of T classification (P=0.0007), N classification (P=0.0164), and tumor stage (P<0.0001) than nardilysin-negative ESCC cases. Furthermore, nardilysin expression was significantly associated with poorer prognosis (P=0.0258). Univariate and multivariate analyses revealed that nardilysin expression is an independent prognostic classifier of patients with ESCC. The invasiveness of NRD1-knockdown TE1 and TE5 esophageal cancer cell lines was less than that of the negative control siRNA-transfected cell lines. Expression of MMP2 and MMP3 mRNA was significantly lower in NRD1-knockdown TE5 cells than in negative control siRNA-transfected cells. These results suggest that nardilysin is involved in tumor progression, and is an independent prognostic classifier in patients with ESCC.
• A pivotal role of KLF5 in regulation of cancer stem-like cells in hepatocellular carcinoma

  Mitsuteru Natsuizaka, Osamu Maehara, Fumiyuki Sato, Yoshimasa Kubota, Goki Suda, Jun Itoh, Seiji Tsunematsu, Yoko Tsukuda, Katsumi Terashita, Masato Nakai, Takuya Sho, Koji Ogawa, Shunsuke Ohnishi, Naoya Sakamoto

  HEPATOLOGY 60 825A - 825A 0270-9139 2014 [Refereed][Not invited]
  
• Hepatosplenic Gamma-delta T-cell Lymphoma Associated with Epstein-Barr Virus

  Seiji Tsunematsu, Mitsuteru Natsuizaka, Hiromi Fujita, Noriyuki Otsuka, Katsumi Terashita, Fumiyuki Sato, Tomoe Kobayashi, Masato Nakai, Yoko Tsukuda, Hiromasa Horimoto, Takuya Sho, Goki Suda, Mitsuru Nakanishi, Satoshi Hashino, Makoto Chuma, Naoya Sakamoto

  INTERNAL MEDICINE 53 (18) 2079 - 2082 0918-2918 2014 [Refereed][Not invited]
   

  Hepatosplenic gamma-delta T-cell lymphoma (HSTCL) is a rare, aggressive subset of peripheral T-cell lymphoma. It has been reported that Epstein-Barr virus (EBV) infection can cause HSTCL; however, such cases are extremely rare, with only a few cases having been reported to date. We herein report an autopsy case of HSTCL associated with EBV infection. The presence of EBV infection was confirmed in serum EBV DNA and on in-situ hybridization, and cytotoxic molecules, such as granzyme B, perforin and T-cell intracytoplasmic antigen (TIA)-1, were all positive in lymphoma cells. These findings indicate that stimulation of persistent EBV infection may have caused HSTCL in this patient.
• Candy-like sign during endoscopic ultrasound-guided choledochoduodenostomy as an indication of the long distance between the bile duct and duodenal wall

  Hiroshi Kawakami, Masaki Kuwatani, Kazumichi Kawakubo, Taiki Kudo, Yoko Abe, Kimitoshi Kubo, Yoshimasa Kubota, Naoya Sakamoto

  ENDOSCOPY 46 E406 - E407 0013-726X 2014 [Refereed][Not invited]
  
• Rendezvous biliary recanalization combining percutaneous and endoscopic techniques using a diathermic dilator for bile duct obstruction

  Hiroshi Kawakami, Daisuke Abo, Kazumichi Kawakubo, Masaki Kuwatani, Yuki Yoshino, Yoshimasa Kubota, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Yusuke Sakuhara, Hiroki Shirato, Naoya Sakamoto

  ENDOSCOPY 46 E460 - E461 0013-726X 2014 [Refereed][Not invited]
  
• Endoscopic ultrasonography-guided antegrade diathermic dilation for the treatment of complete obstruction of a pancreaticogastrostomy

  Hiroshi Kawakami, Masaki Kuwatani, Kazumichi Kawakubo, Yoshimasa Kubota, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 46 E517 - E518 0013-726X 2014 [Refereed][Not invited]
  
• Endoscopic placement of a fully covered self-expandable metallic stent to treat an arteriobiliary fistula

  Hiroshi Kawakami, Munenori Okamoto, Masaki Kuwatani, Yoshimasa Kubota, Kazumichi Kawakubo, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 46 E566 - E567 0013-726X 2014 [Refereed][Not invited]
  
• Endoscopic ultrasonography-guided liver abscess drainage using a dedicated, wide, fully covered self-expandable metallic stent with flared-ends

  Hiroshi Kawakami, Kazumichi Kawakubo, Masaki Kuwatani, Yoshimasa Kubota, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 46 E982 - E983 0013-726X 2014 [Refereed][Not invited]
  
• Endoscopic ultrasound-guided antegrade diathermic dilation followed by self-expandable metallic stent placement for anastomotic stricture after hepaticojejunostomy (with video)

  Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 26 (1) 121 - 122 0915-5635 2014/01 [Refereed][Not invited]
  
• Roadmap to eliminate gastric cancer with Helicobacter pylori eradication and consecutive surveillance in Japan

  Masahiro Asaka, Mototsugu Kato, Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY 49 (1) 1 - 8 0944-1174 2014/01 [Refereed][Not invited]
   

  In Japan, the annual number of deaths from gastric cancer is approximately 50,000 and there has been no change over the last 50 years. So far, all efforts have been directed toward improving the detection of early gastric cancer by barium X-ray and endoscopy, since early cancer has a good prognosis, resulting in Japan having the best diagnostic capability for early gastric cancer worldwide. The 5-year survival rate of gastric cancer patients exceeds 60 % in Japan and is much higher than that in Europe and the US (20 %) because of this superior diagnosis of early gastric cancer. In February 2013, national health insurance coverage for Helicobacter pylori eradication therapy to treat H. pylori-associated chronic gastritis became available in Japan. H. pylori-associated gastritis leads to development of gastric and duodenal ulcers and gastric polyps. Therefore, providing treatment for gastritis is likely to substantially decrease the prevalence of both gastric and duodenal ulcers and polyps. Because treatment for H. pylori-associated gastritis, which leads to atrophic gastritis and gastric cancer, is now covered by health insurance in Japan, a strategy to eliminate gastric cancer-related deaths by taking advantage of this innovation was planned. According to this strategy, patients with gastritis will be investigated for H. pylori infection and those who are positive will receive eradication therapy followed by periodic surveillance. If this strategy is implemented, deaths from gastric cancer in Japan will decrease dramatically after 10-20 years.
• A "resect and watch" strategy with endoscopic resection for pharyngeal cancer with massive subepithelial invasion would not be rational

  Yuichi Shimizu, Masakazu Takahashi, Takeshi Yoshida, Shouko Ono, Katsuhiro Mabe, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 79 (1) 178 - 179 0016-5107 2014/01 [Refereed][Not invited]
  
• Bilateral Facial Nerve Palsy and Appendicitis Occurring during Acute Retroviral Syndrome

  Hiroshi Morioka, Naoya Sakamoto, Sentaro Iwabuchi, Kenji Ohnishi

  INTERNAL MEDICINE 53 (2) 155 - 158 0918-2918 2014 [Refereed][Not invited]
   

  We herein report the case of 41-year-old homosexual man who presented to our hospital with typical acute retroviral syndrome. Complications of bilateral facial nerve palsy and appendicitis appeared eight days after admission. The bilateral facial nerve palsy spontaneously recovered one month later; however, the appendicitis required surgical intervention. To our knowledge, this is the first reported case of appendicitis related to acute retroviral syndrome.
• Acute pancreatitis caused by Anisakis

  Hiroaki Yamato, Hiroshi Kawakami, Kikuko Takagi, Koji Ogawa, Kazuteru Hatanaka, Yoshiya Yamamoto, Hirohito Naruse, Kazumichi Kawakubo, Naoya Sakamoto

  Gastrointestinal Endoscopy 79 (4) 676 - 678 1097-6779 2014 [Refereed][Not invited]
  
• Endoscopic salvage technique for spontaneous dislocation and tumor ingrowth of a partially covered, self-expandable metallic stent after endoscopic ultrasound-guided choledochoduodenostomy

  Hiroshi Kawakami, Masaki Kuwatani, Kazumichi Kawakubo, Taiki Kudo, Yoko Abe, Kimitoshi Kubo, Naoya Sakamoto

  ENDOSCOPY 46 E58 - E59 0013-726X 2014/01 [Refereed][Not invited]
  
• Multiple Ring-enhancing Lesions in the Brain of a Patient with AIDS

  Kenichiro Kobayashi, Naoya Sakamoto, Sentaro Iwabuchi, Kenji Ohnishi

  INTERNAL MEDICINE 53 (6) 641 - 641 0918-2918 2014 [Refereed][Not invited]
  
• Human intestinal spirochetosis is significantly associated with sessile serrated adenomas/polyps

  Saori Omori, Katsuhiro Mabe, Kanako Hatanaka, Masayoshi Ono, Mio Matsumoto, Masakazu Takahashi, Takeshi Yoshida, Shoko Ono, Yuichi Shimizu, Nozomi Sugai, Akira Suzuki, Shinichi Katsuki, Takahiro Fujii, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  PATHOLOGY RESEARCH AND PRACTICE 210 (7) 440 - 443 0344-0338 2014 [Refereed][Not invited]
   

  It remains unclear whether or not human intestinal spirochetosis (HIS) has any associated symptoms or lesions. In this study, we assessed the prevalence of HIS in sessile serrated adenomas/polyps (SSA/Ps) and their possible association. Following identification of early cecal cancer with SSA/P accompanied by a colonization of HIS, we went on to conduct a retrospective case-control study using endoscopically resected SSA/P specimens to examine the frequency of HIS infection in SSA/Ps. Nineteen SSA/P cases and 172 controls were obtained. The rate of HIS infection was significantly higher at 52.6% (10/19) in the SSA/P cases compared to the controls at 8.1% (14/172). Our SSA/P series were associated with a remarkably higher rate of HIS than controls or than previously reported. This is the first report to provide evidence for potential association between HIS and SSA/Ps. (C) 2014 Elsevier GmbH. All rights reserved.
• Endoscopic ultrasound-guided antegrade diathermic dilation followed by self-expandable metal stent placement for malignant distal biliary stricture

  Hiroshi Kawakami, Masaki Kuwatani, Kazumichi Kawakubo, Taiki Kudo, Yoko Abe, Kimitoshi Kubo, Yoshimasa Kubota, Naoya Sakamoto

  ENDOSCOPY 46 E328 - 9 0013-726X 2014 [Refereed][Not invited]
  
• Inhibitory Effects of Caffeic Acid Phenethyl Ester Derivatives on Replication of Hepatitis C Virus

  Hui Shen, Atsuya Yamashita, Masamichi Nakakoshi, Hiromasa Yokoe, Masashi Sudo, Hirotake Kasai, Tomohisa Tanaka, Yuusuke Fujimoto, Masanori Ikeda, Nobuyuki Kato, Naoya Sakamoto, Hiroko Shindo, Shinya Maekawa, Nobuyuki Enomoto, Masayoshi Tsubuki, Kohji Moriishi

  PLOS ONE 8 (12) e82299  1932-6203 2013/12 [Refereed][Not invited]
   

  Caffeic acid phenethyl ester (CAPE) has been reported as a multifunctional compound. In this report, we tested the effect of CAPE and its derivatives on hepatitis C virus (HCV) replication in order to develop an effective anti-HCV compound. CAPE and CAPE derivatives exhibited anti-HCV activity against an HCV replicon cell line of genotype 1b with EC50 values in a range from 1.0 to 109.6 mu M. Analyses of chemical structure and antiviral activity suggested that the length of the n-alkyl side chain and catechol moiety are responsible for the anti-HCV activity of these compounds. Caffeic acid n-octyl ester exhibited the highest anti-HCV activity among the tested derivatives with an EC50 value of 1.0 mu M and an SI value of 63.1 by using the replicon cell line derived from genotype 1b strain Con1. Treatment with caffeic acid n-octyl ester inhibited HCV replication of genotype 2a at a similar level to that of genotype 1b irrespectively of interferon signaling. Caffeic acid n-octyl ester could synergistically enhance the anti-HCV activities of interferon-alpha 2b, daclatasvir, and VX-222, but neither telaprevir nor danoprevir. These results suggest that caffeic acid n-octyl ester is a potential candidate for novel anti-HCV chemotherapy drugs.
• Low-level shear stress induces human mesenchymal stem cell migration through the SDF-1/CXCR4 axis via MAPK signaling pathways

  Lin Yuan, Naoya Sakamoto, Guanbin Song, Masaaki Sato

  Stem Cells and Development 22 (17) 2384 - 2393 1547-3287 2013/09/01 [Refereed][Not invited]
   

  Mesenchymal stem cells (MSCs) are able to home and migrate into damaged tissues and are thus, considered an optimal therapeutic strategy for clinical use. We previously demonstrated that higher shear stress (> 2 Pa) hindered human MSC (hMSC) migration, whereas lower shear stress (0.2 Pa) induced cell migration through mitogen-activated protein kinase (MAPK) pathways. Here the mechanisms underlying shear stress-induced hMSC migration have been studied further. An MSC monolayer was mechanically wounded and subsequently exposed to low-level shear stress of 0.2 Pa. Image analysis was performed to quantify cell migration speeds under both flow and static conditions. hMSCs along both upstream- and downstream edges of the wound migrated at a similar speed to cover the wounded area under static conditions, whereas shear stress induced cells along the downstream edge of the wound to migrate significantly faster than those along the upstream edge. We also found that shear stress upregulated the secretion of stromal-derived factor-1 (SDF-1), which stimulated its receptor CXCR4 expression in hMSCs until the cells covered the wounded area. A CXCR4 antagonist repressed both cell migration and activation of c-Jun N-terminal kinase (JNK) and p38 MAPK but did not affect extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. When MAPK activation in upstream- and downstream hMSCs was evaluated separately, ERK1/2 was activated earlier in downstream than in upstream cells. These results indicate that the SDF-1/CXCR4 axis mediates shear stress-induced hMSC migration through JNK and p38 MAPK pathways and that the difference in migration speeds between upstream- and downstream cells may be due to ERK1/2 activation. © Mary Ann Liebert, Inc.
• Pathophysiologic basis of anorexia: Focus on the interaction between ghrelin dynamics and the serotonergic system

  Hiroshi Takeda, Koji Nakagawa, Naoto Okubo, Mie Nishimura, Shuichi Muto, Shunsuke Ohnishi, Naoya Sakamoto, Hidetaka Hosono, Masahiro Asaka

  Biological and Pharmaceutical Bulletin 36 (9) 1401 - 1405 0918-6158 2013/09 [Refereed][Not invited]
   

  Anorexia is an important issue in the management of elderly patients with cancer because it contributes to the development of malnutrition, increases morbidity and mortality, and negatively affects patients' quality of life. This review summarizes the potential mechanisms of the development of anorexia in three animal models that mimic the situations commonly seen in elderly patients receiving chemotherapy. Cisplatin-induced anorexia is attributable to a decrease in peripheral and central ghrelin secretion caused by the stimulation of serotonin (5-hydroxytryptamine 5-HT)2B and 5-HT2C receptors via 5-HT secretion. Age-associated anorexia is caused by an increase in plasma leptin, which results from disturbed reactivity of ghrelin in the hypothalamus and regulation of ghrelin secretion. Environmental change causes the activation of central 5-HT1B and 5-HT2C receptors and the melanocortin-4 receptor system, resulting in a decrease in circulating ghrelin levels which lowers food intake. New therapeutic approaches based on these pathophysiological mechanisms are warranted for the treatment of anorexia in cancer patients, especially elderly ones. © 2013 The Pharmaceutical Society of Japan.
• [Case report: focal adenocarcinoma arising from sessile serrated adenoma/polyp with intestinal spirochetosis, report of a case].

  Omori S, Mabe K, Ono M, Suzuki M, Takahashi M, Ono S, Simizu Y, Kato M, Hatanaka K, Sakamoto N

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 102 (8) 2046 - 2049 0021-5384 2013/08 [Refereed][Not invited]
  
• Diagnostic ability and factors affecting accuracy of endoscopic ultrasound-guided fine needle aspiration for pancreatic solid lesions: Japanese large single center experience

  Shin Haba, Kenji Yamao, Vikram Bhatia, Nobumasa Mizuno, Kazuo Hara, Susumu Hijioka, Hiroshi Imaoka, Yasumasa Niwa, Masahiro Tajika, Shinya Kondo, Tsutomu Tanaka, Yasuhiro Shimizu, Yasushi Yatabe, Waki Hosoda, Hiroshi Kawakami, Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY 48 (8) 973 - 981 0944-1174 2013/08 [Refereed][Not invited]
   

  Several studies have investigated the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for pancreatic lesions, but they have included only limited patient populations. This study aimed to clarify the diagnostic accuracy of EUS-FNA in a large number of pancreatic lesions, and to describe the factors that influence it. From March 1997 to May 2010, 944 consecutive patients who had undergone EUS-FNA for pancreatic solid lesions were evaluated retrospectively. Factors affecting EUS-FNA accuracy were then analyzed. A total of 996 solid pancreatic lesions were sampled by EUS-FNA. The overall sampling adequacy and diagnostic accuracy of these lesions were 99.3 % (989/996) and 91.8 % (918/996), respectively. The sensitivity and specificity for differentiating malignant from benign lesions were 91.5 % (793/867) and 97.7 % (126/129), respectively. The diagnostic performance was significantly higher when both cytological and cell-block examinations were carried out than with only cytological examination. In multivariate analysis, final diagnosis, location of lesion, lesion size, availability of on-site cytopathological evaluation, and experience of EUS-FNA procedure were independent factors affecting the accuracy of EUS-FNA. On-site cytopathological evaluation and lesion size were found to be the most weighted factors affecting diagnostic accuracy. EUS-FNA for pancreatic solid lesions yielded a high accuracy and low complication rate. Both cytological and cell-block preparations and on-site cytopathological evaluation contributed to improve the accuracy. The diagnostic ability of EUS-FNA was less for smaller lesions, and repeated procedures may be needed if malignancy is suspected.
• Therapeutic effect of praziquantel against taeniasis asiatica

  Kenji Ohnishi, Naoya Sakamoto, Ken-ichiro Kobayashi, Sentaro Iwabuchi, Fukumi Nakamura-Uchiyama

  INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES 17 (8) E656 - E657 1201-9712 2013/08 [Refereed][Not invited]
   

  Eight Japanese adult patients infected with Taenia asiatica were treated with a single 600 mg dose of praziquantel. The patients' body weights ranged from 47 to 87 kg (mean 67.1 +/- 12.7 kg). All patients expelled the strobila after taking praziquantel, and all of them were free from proglottids the day after praziquantel administration, hence all patients were considered to be cured. No side effects due to praziquantel were noted. Although the number of patients is small, our results indicate that praziquantel is a drug of choice for the treatment of taeniasis asiatica and that a single dose of 7-13 mg/kg (9.3 +/- 1.9 mg/kg) is effective. (C) 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
• Endoscopic in vivo cellular imaging of superficial squamous cell carcinoma of the head and neck by using an integrated endocytoscopy system (with video)

  Yuichi Shimizu, Masakazu Takahashi, Takeshi Yoshida, Shouko Ono, Katsuhiro Mabe, Mototsugu Kato, Masahiro Asaka, Kanako Hatanaka, Naoya Sakamoto

  Gastrointestinal Endoscopy 78 (2) 351 - 358 0016-5107 2013/08 [Refereed][Not invited]
   

  Background: Recently, some patients have been found to have superficial squamous cell carcinoma (SCC) of the head and neck region during GI endoscopy however, endoscopic biopsy from a lesion in the head and neck region is troublesome. An endocytoscopy system has been reported to enable optical biopsy of an esophageal lesion. Objective: To evaluate the feasibility of in vivo cellular imaging with an integrated endocytoscopy system for patients with superficial SCC of the head and neck. Design: Experimental pilot study. Setting: University hospital. Patients: This study involved 12 patients who were found to have superficial SCC of the head and neck during GI endoscopy. Intervention: Endocytoscopic images were taken of each lesion and of the surrounding mucosa. The images were later reviewed by 1 pathologist and 2 endoscopists who were unaware of any other findings. Main Outcome Measurements: Correlation between endocytoscopy diagnosis and histologic diagnosis. Results: Adequate endocytoscopic images could be obtained in 11 of the 12 patients (15 of 16 lesions). For endocytoscopic images of 15 lesions and 12 areas of surrounding mucosa, the overall accuracy of endocytoscopic diagnosis in differentiating between nonmalignant and malignant histopathology by the pathologist, endoscopist 1, and endoscopist 2 were 96%, 96%, and 96%, respectively. The kappa value for interobserver agreement was 0.77. Limitations: Single-center experience, small number of patients. Conclusion: An endocytoscopy system has the potential to be used as an optical biopsy for superficial head and neck lesions.
• [After endoscopic treatment of early stage gastric cancer].

  Kato M, Ono S, Mabe K, Sakamoto N, Asaka M

  Nihon rinsho. Japanese journal of clinical medicine 71 (8) 1429 - 1435 0047-1852 2013/08 [Refereed][Not invited]
  
• Endoscopic ultrasound-guided rendezvous procedure for unidentifiable papilla and non-dilated pancreatic duct (with video)

  Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 25 (4) 466 - 466 0915-5635 2013/07 [Refereed][Not invited]
  
• Synthesis of ¹⁸O-labeled RNA for application to kinetic studies and imaging.

  Tomohiro Hamasaki, Takahiro Matsumoto, Naoya Sakamoto, Akiko Shimahara, Shiori Kato, Ayumi Yoshitake, Ayumi Utsunomiya, Hisayoshi Yurimoto, Esteban C Gabazza, Tadaaki Ohgi

  Nucleic acids research 41 (12) e126  0305-1048 2013/07 [Refereed][Not invited]
   

  Radioisotopes and fluorescent compounds are frequently used for RNA labeling but are unsuitable for clinical studies of RNA drugs because of the risk from radiation exposure or the nonequivalence arising from covalently attached fluorophores. Here, we report a practical phosphoramidite solid-phase synthesis of (18)O-labeled RNA that avoids these disadvantages, and we demonstrate its application to quantification and imaging. The synthesis involves the introduction of a nonbridging (18)O atom into the phosphate group during the oxidation step of the synthetic cycle by using (18)O water as the oxygen donor. The (18)O label in the RNA was stable at pH 3-8.5, while the physicochemical and biological properties of labeled and unlabeled short interfering RNA were indistinguishable by circular dichroism, melting temperature and RNA-interference activity. The (18)O/(16)O ratio as measured by isotope ratio mass spectrometry increased linearly with the concentration of (18)O-labeled RNA, and this technique was used to determine the blood concentration of (18)O-labeled RNA after administration to mice. (18)O-labeled RNA transfected into human A549 cells was visualized by isotope microscopy. The RNA was observed in foci in the cytoplasm around the nucleus, presumably corresponding to endosomes. These methodologies may be useful for kinetic and cellular-localization studies of RNA in basic and pharmaceutical studies.
• Hypoxia-Inducible Factors Activate CD133 Promoter through ETS Family Transcription Factors

  Shunsuke Ohnishi, Osamu Maehara, Koji Nakagawa, Ayano Kameya, Kanako Otaki, Hirotoshi Fujita, Ryosuke Higashi, Kikuko Takagi, Masahiro Asaka, Naoya Sakamoto, Masanobu Kobayashi, Hiroshi Takeda

  PLoS ONE 8 (6) e66255  1932-6203 2013/06/20 [Refereed][Not invited]
   

  CD133 is a cellular surface protein that has been reported to be a cancer stem cell marker, and thus it is considered to be a potential target for cancer treatment. However, the mechanism regulating CD133 expression is not yet understood. In this study, we analyzed the activity of five putative promoters (P1-P5) of CD133 in human embryonic kidney (HEK) 293 cells and colon cancer cell line WiDr, and found that the activity of promoters, particularly of P5, is elevated by overexpression of hypoxia-inducible factors (HIF-1α and HIF-2α). Deletion and mutation analysis identified one of the two E-twenty six (ETS) binding sites (EBSs) in the P5 region as being essential for its promoter activity induced by HIF-1α and HIF-2α. In addition, a chromatin imunoprecipitation assay demonstrated that HIF-1α and HIF-2α bind to the proximal P5 promoter at the EBSs. The immunoprecipitation assay showed that HIF-1α physically interacts with Elk1 however, HIF-2α did not bind to Elk1 or ETS1. Furthermore, knockdown of both HIF-1α and HIF-2α resulted in a reduction of CD133 expression in WiDr. Taken together, our results revealed that HIF-1α and HIF-2α activate CD133 promoter through ETS proteins. © 2013 Ohnishi et al.
• High-level shear stress stimulates endothelial differentiation and VEGF secretion by human mesenchymal stem cells

  Lin Yuan, Naoya Sakamoto, Guanbin Song, Masaaki Sato

  Cellular and Molecular Bioengineering 6 (2) 220 - 229 1865-5025 2013/06 [Refereed][Not invited]
   

  Growing experimental evidence suggests that mechanical stimulation play important roles in determining the proliferation, migration, and apoptosis of human mesenchymal stem cells (hMSCs). Here, we show that shear stress stimulates hMSCs toward an EC phenotype in the absence of chemical induction. Most importantly, fluorescence microscopy clearly demonstrated for the first time that the distributions of endothelial-specific markers, vascular endothelial (VE)-cadherin and CD31, in hMSCs were similar to those of ECs at cell-cell adhesion sites after exposing hMSCs to a shear stress of 2 Pa for 2 days with subsequent static culture for 5 days. Western blot analysis proved that shear stress of 2 Pa significantly induced protein expression of von Willebrand factor (vWF), VE-cadherin, and CD31. However, an unclear expression of the endothelial-specific markers was observed in the 0.2 Pa shear stress group. In addition, there was a cumulative production of vascular endothelial growth factor (VEGF), which is known to induce endothelial differentiation of MSCs. By exerting shear stress of 2 Pa on hMSCs for 2 days with subsequent culture for 5 days, the production level of approximately 2-fold compared with that of the control group was achieved. Our findings suggest that high-level shear stress can induce VEGF production and EC differentiation from hMSCs. This may provide a means for addressing the cell sourcing issue for effective tissue engineering. © 2013 Biomedical Engineering Society.
• Wnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells in mice

  Kei Kiyohashi, Sei Kakinuma, Akihide Kamiya, Naoya Sakamoto, Sayuri Nitta, Hideto Yamanaka, Kouhei Yoshino, Junko Fujiki, Miyako Murakawa, Akiko Kusano-Kitazume, Hiromichi Shimizu, Ryuichi Okamoto, Seishin Azuma, Mina Nakagawa, Yasuhiro Asahina, Naoki Tanimizu, Akira Kikuchi, Hiromitsu Nakauchi, Mamoru Watanabe

  Hepatology 57 (6) 2502 - 2513 0270-9139 2013/06 [Refereed][Not invited]
   

  The molecular mechanisms regulating differentiation of fetal hepatic stem/progenitor cells, called hepatoblasts, which play pivotal roles in liver development, remain obscure. Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. Although a β-catenin-independent noncanonical Wnt pathway is essential for cell adhesion and polarity, the physiological functions of noncanonical Wnt pathways in liver development are unknown. Here we describe a functional role for Wnt5a, a noncanonical Wnt ligand, in the differentiation of mouse hepatoblasts. Wnt5a was expressed in mesenchymal cells and other cells of wild-type (WT) midgestational fetal liver. We analyzed fetal liver phenotypes in Wnt5a-deficient mice using a combination of histological and molecular techniques. Expression levels of Sox9 and the number of hepatocyte nuclear factor (HNF)1β+HNF4α- biliary precursor cells were significantly higher in Wnt5a-deficient liver relative to WT liver. In Wnt5a-deficient fetal liver, in vivo formation of primitive bile ductal structures was significantly enhanced relative to WT littermates. We also investigated the function of Wnt5a protein and downstream signaling molecules using a three-dimensional culture system that included primary hepatoblasts or a hepatic progenitor cell line. In vitro differentiation assays showed that Wnt5a retarded the formation of bile duct-like structures in hepatoblasts, leading instead to hepatic maturation of such cells. Whereas Wnt5a signaling increased steady-state levels of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in fetal liver, inhibition of CaMKII activity resulted in the formation of significantly more and larger-sized bile duct-like structures in vitro compared with those in vehicle-supplemented controls. Conclusion: Wnt5a-mediated signaling in fetal hepatic stem/progenitor cells suppresses biliary differentiation. These findings also suggest that activation of CaMKII by Wnt5a signaling suppresses biliary differentiation. © 2013 American Association for the Study of Liver Diseases.
• Expression of olfactomedin 4 and claudin-18 in serrated neoplasia of the colorectum: A characteristic pattern is associated with sessile serrated lesion

  Kazuhiro Sentani, Naoya Sakamoto, Fumio Shimamoto, Katsuhiro Anami, Naohide Oue, Wataru Yasui

  Histopathology 62 (7) 1018 - 1027 0309-0167 2013/06 [Refereed][Not invited]
   

  Aims: Olfactomedin 4 is a useful marker for stem cells in the intestine and is an independent prognostic molecule for survival in patients with colorectal cancer (CRC). Claudin-18, a component of tight junctions, correlates with poor survival in patients with CRC and is associated with the gastric phenotype. We investigated the possible usefulness of these molecules in serrated neoplasia of the colorectum. Methods and results: We performed immunohistochemical analysis of colorectal polyps, including hyperplastic polyps (HP), sessile serrated lesions (SSL), traditional serrated adenomas (TSA) and conventional adenomas (CA). We also investigated the association between expression of these molecules and clinicopathological parameters in serrated adenocarcinoma (SAC) and non-SAC of the colorectum. Olfactomedin 4 expression was not detected or was decreased in SSL compared with the other polyp types. Claudin-18 expression was higher in SSL than in the other types. Similarly, positivity for olfactomedin 4 in SAC was significantly lower than that in non-SAC, and positivity for claudin-18 in SAC was significantly higher than that in non-SAC. Furthermore, claudin-18-positive SAC showed more advanced N grade and stage than claudin-18-negative SAC. Conclusions: Reduced expression of olfactomedin 4 and ectopic expression of claudin-18 might be useful markers in the differential diagnosis of serrated polyps. © 2013 Blackwell Publishing Ltd.
• Wnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells in mice

  Kei Kiyohashi, Sei Kakinuma, Akihide Kamiya, Naoya Sakamoto, Sayuri Nitta, Hideto Yamanaka, Kouhei Yoshino, Junko Fujiki, Miyako Murakawa, Akiko Kusano-Kitazume, Hiromichi Shimizu, Ryuichi Okamoto, Seishin Azuma, Mina Nakagawa, Yasuhiro Asahina, Naoki Tanimizu, Akira Kikuchi, Hiromitsu Nakauchi, Mamoru Watanabe

  HEPATOLOGY 57 (6) 2502 - 2513 0270-9139 2013/06 [Refereed][Not invited]
   

  The molecular mechanisms regulating differentiation of fetal hepatic stem/progenitor cells, called hepatoblasts, which play pivotal roles in liver development, remain obscure. Wnt signaling pathways regulate the development and differentiation of stem cells in various organs. Although a -catenin-independent noncanonical Wnt pathway is essential for cell adhesion and polarity, the physiological functions of noncanonical Wnt pathways in liver development are unknown. Here we describe a functional role for Wnt5a, a noncanonical Wnt ligand, in the differentiation of mouse hepatoblasts. Wnt5a was expressed in mesenchymal cells and other cells of wild-type (WT) midgestational fetal liver. We analyzed fetal liver phenotypes in Wnt5a-deficient mice using a combination of histological and molecular techniques. Expression levels of Sox9 and the number of hepatocyte nuclear factor (HNF)1+HNF4- biliary precursor cells were significantly higher in Wnt5a-deficient liver relative to WT liver. In Wnt5a-deficient fetal liver, in vivo formation of primitive bile ductal structures was significantly enhanced relative to WT littermates. We also investigated the function of Wnt5a protein and downstream signaling molecules using a three-dimensional culture system that included primary hepatoblasts or a hepatic progenitor cell line. In vitro differentiation assays showed that Wnt5a retarded the formation of bile duct-like structures in hepatoblasts, leading instead to hepatic maturation of such cells. Whereas Wnt5a signaling increased steady-state levels of phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) in fetal liver, inhibition of CaMKII activity resulted in the formation of significantly more and larger-sized bile duct-like structures in vitro compared with those in vehicle-supplemented controls. Conclusion: Wnt5a-mediated signaling in fetal hepatic stem/progenitor cells suppresses biliary differentiation. These findings also suggest that activation of CaMKII by Wnt5a signaling suppresses biliary differentiation. (HEPATOLOGY 2013;)
• What is an adequate management strategy for pharyngeal low-grade dysplasia?

  Yuichi Shimizu, Masakazu Takahashi, Takeshi Yoshida, Shouko Ono, Katsuhiro Mabe, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 77 (6) 972 - 973 0016-5107 2013/06 [Refereed][Not invited]
  
• Involvement of Ghrelin Signaling Dysfunction in Acute Restraint Stress-Induced Delayed Gastric Emptying

  Shunsuke Ohnishi, Shuichi Muto, Koji Nakagawa, Chiharu Sadakane, Yayoi Saegusa, Miwa Nahata, Chihiro Yamada, Tomohisa Hattori, Masahiro Asaka, Naoya Sakamoto, Hiroshi Takeda

  GASTROENTEROLOGY 144 (5) S542 - S542 0016-5085 2013/05 [Refereed][Not invited]
  
• Transplantaion of Human Fetal Membrane-Derived Mesenchymal Stem Cells Improves Severe Colitis Induced by Dextran Sulfate Sodium in Rats

  Reizo Onishi, Shunsuke Ohnishi, Ryosuke Higashi, Michiko Watari, Waka Kobayashi, Takehiko Katsurada, Hiroshi Takeda, Naoya Sakamoto

  GASTROENTEROLOGY 144 (5) S811 - S812 0016-5085 2013/05 [Refereed][Not invited]
  
• MicroRNA-155 is a predictive marker for survival in patients with clear cell renal cell carcinoma

  Shunsuke Shinmei, Naoya Sakamoto, Keisuke Goto, Kazuhiro Sentani, Katsuhiro Anami, Tetsutaro Hayashi, Jun Teishima, Akio Matsubara, Naohide Oue, Yasuhiko Kitadai, Wataru Yasui

  International Journal of Urology 20 (5) 468 - 477 0919-8172 2013/05 [Refereed][Not invited]
   

  Objectives: To investigate the clinical significance of micro-ribonucleic acid-155 in clear cell renal cell carcinoma, in particular focusing on the association of expression levels of micro-ribonucleic acid-155 with clinicopathological factors, cancer-specific survival and therapeutic outcomes in clear cell renal cell carcinoma patients. Methods: Quantitative reverse transcription polymerase chain reaction of micro-ribonucleic acid-155 was carried out on 137 clear cell renal cell carcinoma cases, containing 77 matched pairs of clear cell renal cell carcinoma and normal adjacent kidney tissues from the same patients. Results: Significant overexpression of micro-ribonucleic acid-155 was found in clear cell renal cell carcinoma compared with normal kidney tissue. Expression of micro-ribonucleic acid-155 was not associated with prognosis in all stage groups. However, in 43 patients with stageIII and IV clear cell renal cell carcinoma, low expression levels of micro-ribonucleic acid-155 correlated with a poor prognosis. Regarding cancer-free survival of 26 patients with stageIII and IV clear cell renal cell carcinoma who received curative resection and cancer-specific survival of 31 patients who received postoperative therapy with interferon-α after radical nephrectomy, low expression levels of micro-ribonucleic acid-155 correlated with poor clinical outcomes in these two groups. Conclusions: Low expression of micro-ribonucleic acid-155 represents a valuable marker of poor clinical outcomes in patients with stageIII and IV clear cell renal cell carcinoma. © 2012 The Japanese Urological Association.
• Hepatobiliary alveolar echinococcosis infiltration of the hepatic hilum diagnosed by endoscopic ultrasonography-guided fine-needle aspiration

  Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 25 (3) 339 - 340 0915-5635 2013/05 [Refereed][Not invited]
  
• Hepatitis C Virus Replication Is Modulated by the Interaction of Nonstructural Protein NS5B and Fatty Acid Synthase

  Jing-Tang Huang, Ching-Ping Tseng, Mei-Huei Liao, Shao-Chun Lu, Wei-Zhou Yeh, Naoya Sakamoto, Chuan-Mu Chen, Ju-Chien Cheng

  JOURNAL OF VIROLOGY 87 (9) 4994 - 5004 0022-538X 2013/05 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) that acts as a key player in the HCV replication complex. Understanding the interplay between the viral and cellular components of the HCV replication complex could provide new insight for prevention of the progression of HCV-associated hepatocellular carcinoma (HCC). In this study, the NS5B protein was used as the bait in a pulldown assay to screen for NS5B-interacting proteins that are present in Huh7 hepatoma cell lysates. After mass spectrophotometric analysis, fatty acid synthase (FASN) was found to interact with NS5B. Coimmunoprecipitation and double staining assays further confirmed the direct binding between NS5B and FASN. The domain of NS5B that interacts with FASN was also determined. Moreover, FASN was associated with detergent-resistant lipid rafts and colocalized with NS5B in active HCV replication complexes. In addition, overexpression of FASN enhanced HCV expression in Huh7/Rep-Feo cells, while transfection of FASN small interfering RNA (siRNA) or treatment with FASN-specific inhibitors decreased HCV replication and viral production. Notably, FASN directly increased HCV NS5B RdRp activity in vitro. These results together indicate that FASN interacts with NS5B and modulates HCV replication through a direct increase of NS5B RdRp activity. FASN may thereby serve as a target for the treatment of HCV infection and the prevention of HCV-associated HCC progression.
• New stent exchange technique following endoscopic ultrasound-guided nasobiliary drainage (with video)

  Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 25 (3) 343 - 344 0915-5635 2013/05 [Refereed][Not invited]
  
• NX-PVKA assay, a conventional but refined prognostic biomarker for hepatocellular carcinoma

  Naoya Sakamoto

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 28 (5) 755 - 756 0815-9319 2013/05 [Refereed][Not invited]
  
• Human equilibrative nucleoside transporter 1 and Notch3 can predict gemcitabine effects in patients with unresectable pancreatic cancer

  K. Eto, H. Kawakami, M. Kuwatani, T. Kudo, Y. Abe, S. Kawahata, A. Takasawa, M. Fukuoka, Y. Matsuno, M. Asaka, N. Sakamoto

  British Journal of Cancer 108 (7) 1488 - 1494 0007-0920 2013/04/16 [Refereed][Not invited]
   

  Background:Pancreatic ductal carcinoma (PDC) is one of the most lethal human carcinomas. Expression patterns of some genes may predict gemcitabine (GEM) treatment efficacy. We examined predictive indicators of survival in GEM-treated patients by quantifying the expression of several genes in pre-treatment endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples from patients with PDC.Methods:The expressions of human equilibrative nucleoside transporter 1 (hENT1), deoxycitidine kinase, ribonucleoside reductase 1, ribonucleoside reductase 2 and Notch3 in EUS-FNA tissue samples from 71 patients with unresectable PDC were quantified using real-time reverse transcription-polymerase chain reactions and examined for correlations with GEM sensitivity.Results:The log-rank test detected no significant differences in overall survival between GEM-treated patients with low and high mRNA levels of all genes examined. However, low Notch3 mRNA expression was significantly associated with longer overall survival in a multivariate analysis for survival (P=0.0094). High hENT1 expression level was significantly associated with a longer time to progression (P=0.039). Interaction tests for GEM administration and hENT1 or Notch3 mRNA expression were statistically significant (P=0.0054 and 0.0047, respectively).Conclusion:hENT1 and Notch3 mRNA expressions in EUS-FNA specimens were the key predictive biomarkers of GEM effect and GEM sensitivity in patients with unresectable PDC. © 2013 Cancer Research UK. All rights reserved.
• IL-28B (IFN-λ3) and IFN-α synergistically inhibit HCV replication

  H. Shindo, S. Maekawa, K. Komase, M. Miura, M. Kadokura, R. Sueki, N. Komatsu, K. Shindo, F. Amemiya, Y. Nakayama, T. Inoue, M. Sakamoto, A. Yamashita, K. Moriishi, N. Enomoto

  Journal of Viral Hepatitis 20 (4) 281 - 289 1352-0504 2013/04 [Refereed][Not invited]
   

  Genetic variation in the IL-28B (interleukin-28B interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon-α and ribavirin. However, the mechanisms by which polymorphisms in the IL-28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN-λs and IFN-α on HCV RNA replication. The anti-HCV effect of IFN-λ3 and IFN-α in combination was also assessed. Changes in gene expression induced by IFN-λ3 and IFN-α were compared using cDNA microarray analysis. IFN-λs at concentrations of 1 ng/mL or more exhibited concentration- and time-dependent HCV inhibition. In combination, IFN-λ3 and IFN-α had a synergistic anti-HCV effect however, no synergistic enhancement was observed for interferon-stimulated response element (ISRE) activity or upregulation of interferon-stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN-λ3-induced gene expression occurred later and lasted longer than that induced by IFN-α. In addition, although the genes upregulated by IFN-α and IFN-λ3 were similar to microarray analysis, interferon-stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN-α and IFN-λ3 in combination showed synergistic anti-HCV activity in vitro. Differences in time-dependent upregulation of these genes might contribute to the synergistic antiviral activity. © 2012 Blackwell Publishing Ltd.
• Nicotine reduced MMP-9 expression in the primary porcine tenocytes exposed to cyclic stretch

  Taku Hatta, Hirotaka Sano, Naoya Sakamoto, Koshi N. Kishimoto, Masaaki Sato, Eiji Itoi

  Journal of Orthopaedic Research 31 (4) 645 - 650 0736-0266 2013/04 [Refereed][Not invited]
   

  Nicotine is one of the major chemical components of the cigarette smoke, which has been known as a risk factor for tendon ruptures including rotator cuff tears. This study investigated the effect of nicotine on tenocytes under cyclic-stretched condition. Particularly, we focused on the morphologic changes of tenocytes and their expression of MMPs. Primary porcine tenocytes were obtained from the infraspinatus tendon. The cells were cultured on elastic chambers under static or cyclic-stretched condition for 24 h in the existence of nicotine (0, 1, 10, and 100 μM). Cell shape, gene expression of collagen type I and III, MMPs (-1, -2, -3, -9, and -13) and TIMPs (-1, -2, and -3) and enzyme activity of MMP-9 were analyzed using immunohistochemistry, RT-PCR, and zymography. Tenocytes exposed to nicotine represented significantly decreased gene expressions in MMP-9 (p < 0.001) and TIMP-3 (p < 0.05) under the cyclic stretch. Enzymatic activity of MMP-9 was also reduced by nicotine exposure in a dose-dependent manner (p < 0.001). The down-regulation of MMP and TIMP expression by nicotine shown in our in vitro experiment might deteriorate normal metabolism of the tendon. These mechanisms might affect the mechanical properties of the extracellular matrix of the rotator cuff tendon. Copyright © 2012 Orthopaedic Research Society.
• Expression of miR-486 is a potential prognostic factor after nephrectomy in advanced renal cell carcinoma.

  Keisuke Goto, Naohide Oue, Shunsuke Shinmei, Kazuhiro Sentani, Naoya Sakamoto, Yutaka Naito, Tetsutaro Hayashi, Jun Teishima, Akio Matsubara, Wataru Yasui

  Molecular and clinical oncology 1 (2) 235 - 240 2049-9450 2013/03 

  Renal cell carcinoma is the most frequently occurring neoplasm in the adult kidney, leading to poor prognosis. Therefore novel biomarkers are required for the prediction of early metastasis following nephrectomy. The aim of the present study was to investigate whether or not expression levels of miR-486, detected in RNA isolated from formalin-fixed paraffin-embedded tissue sections, can predict prognosis for patients with renal cell carcinoma (RCC). Expression levels of miR-486 were measured by quantitative reverse transcriptase-polymerase chain reaction in 150 RCC cases. Expression of miR-486 in RCC samples was ∼2.7-fold higher than in corresponding non-neoplastic kidney samples (P<0.0001). In stage III and IV RCC cases (n=46), a high miR-486 expression in tumors was associated with worse cancer-specific mortality, independent of clinical covariates, including TNM staging (P=0.0064). In addition, miR-486 expression tended to be associated with cancer-specific mortality in stage III and IV RCC patients who were not treated with interferon-α (Kaplan-Meier analysis, n=14, P=0.0574). These results suggest that miR-486 is a promising biomarker to identify poor prognosis in RCC patients. As expression of miR-486 was measured from formalin-fixed paraffin-embedded (FFPE) samples, this study demonstrated that measurement of miR-486 may be readily translated into clinical applications.
• Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C

  Masayuki Kurosaki, Yasuhito Tanaka, Nao Nishida, Naoya Sakamoto, Nobuyuki Enomoto, Kentaro Matsuura, Yasuhiro Asahina, Mina Nakagawa, Mamoru Watanabe, Minoru Sakamoto, Shinya Maekawa, Katsushi Tokunaga, Masashi Mizokami, Namiki Izumi

  JOURNAL OF MEDICAL VIROLOGY 85 (3) 449 - 458 0146-6615 2013/03 [Refereed][Not invited]
   

  This study aimed to develop a model for predicting anemia using the inosine triphosphatase (ITPA) genotype and to evaluate its relationship with treatment outcome. Patients with genotype 1b chronic hepatitis C (n?=?446) treated with peg-interferon alpha and ribavirin (RBV) for 48 weeks were genotyped for the ITPA (rs1127354) and IL28B (rs8099917) genes. Data mining analysis generated a predictive model for anemia (hemoglobin (Hb) concentration <10?g/dl); the CC genotype of ITPA, baseline Hb <14.0?g/dl, and low creatinine clearance (CLcr) were predictors of anemia. The incidence of anemia was highest in patients with Hb <14.0?g/dl and CLcr <90?ml/min (76%), followed by Hb <14.0?g/dl and ITPA CC (57%). Patients with Hb =14.0?g/dl and ITPA AA/CA had the lowest incidence of anemia (17%). Patients with two predictors (high-risk) had a higher incidence of anemia than the others (64% vs. 28%, P?<?0.0001). At baseline, the IL28B genotype was a predictor of a sustained virological response [adjusted odds ratio 9.88 (95% confidence interval 5.0119.48), P?<?0.0001]. In patients who achieved an early virological response, the IL28B genotype was not associated with a sustained virological response, while a high risk of anemia was a significant negative predictor of a sustained virological response [0.47 (0.240.91), P?=?0.026]. For high-risk patients with an early virological response, giving >80% of the planned RBV dose increased sustained virological responses by 24%. In conclusion, a predictive model incorporating the ITPA genotype could identify patients with a high risk of anemia and reduced probability of sustained virological response. J. Med. Virol. 85:449458, 2013. (c) 2013 Wiley Periodicals, Inc.
• Association of ITPA gene variation and serum ribavirin concentration with a decline in blood cell concentrations during pegylated interferon-alpha plus ribavirin therapy for chronic hepatitis C

  Mina Nakagawa, Naoya Sakamoto, Takako Watanabe, Yuki Nishimura-Sakurai, Izumi Onozuka, Seishin Azuma, Sei Kakinuma, Sayuri Nitta, Kei Kiyohashi, Akiko Kusano-Kitazume, Miyako Murakawa, Kohei Yoshino, Yasuhiro Itsui, Yasuhito Tanaka, Masashi Mizokami, Mamoru Watanabe

  HEPATOLOGY INTERNATIONAL 7 (1) 153 - 161 1936-0533 2013/03 [Refereed][Not invited]
   

  Genetic variation leading to inosine triphosphatase (ITPA) deficiency protects chronic hepatitis C patients receiving ribavirin against hemolytic anemia. The relationship between ITPA gene variation and serum ribavirin concentration was analyzed in association with a reduction in blood cells and dose reduction of pegylated interferon (PEG-IFN) or ribavirin. A total of 300 hepatitis C patients treated with PEG-IFN plus ribavirin were analyzed. Genetic polymorphisms were determined in ITPA and the quantitative reduction in blood cells from the baseline was analyzed every 4 weeks for the duration of treatment and after the end of therapy. The decline in hemoglobin (Hb) or platelet (PLT) level at week 4 compared to baseline was also assessed according to ribavirin concentrations. Patients with the ITPA-CA/AA genotypes showed a lower degree of Hb reduction throughout therapy than those with the ITPA-CC genotype and a marked difference in mean Hb reduction was found at week 4 (CA/AA -1.0 vs. CC -2.8, p < 0.001). The ITPA-CC genotype had significantly less reduction in the mean platelet count than the ITPA-CA/AA genotypes early during treatment (p < 0.001 for weeks 4 and 8). Patients with the ITPA-CA/AA genotypes were less likely to develop anemia, regardless of the concentration of ribavirin. Patients with baseline PLT counts below 130 x 10(3)/mu l had a significantly lower tendency to achieve sustained virological response (SVR), especially those with the ITPA-CA/AA genotypes. ITPA gene variation was not extracted by multivariable analysis as an important predictor of SVR. Despite the fact that ITPA variants were less likely to develop anemia, patients with low baseline PLT counts were difficult to treat, especially those with the ITPA-CA/AA genotype. These results may give a valuable pharmacogenetic diagnostic tool for the tailoring of dosing to minimize drug-induced adverse events.
• Carbon dioxide insufflation for endoscopic retrograde cholangiopancreatography: Is this beneficial for all patients?

  Masaki Kuwatani, Hiroshi Kawakami, Naoya Sakamoto

  DIGESTIVE ENDOSCOPY 25 (2) 205 - 205 0915-5635 2013/03 [Refereed][Not invited]
  
• Endoscopic resection (endoscopic mucosal resection/endoscopic submucosal dissection) for superficial esophageal squamous cell carcinoma: Current status of various techniques

  Yuichi Shimizu, Masakazu Takahashi, Takeshi Yoshida, Shouko Ono, Katsuhiro Mabe, Mototsugu Kato, Masahiro Asaka, Naoya Sakamoto

  Digestive Endoscopy 25 (1) 13 - 19 0915-5635 2013/03 [Refereed][Not invited]
   

  Endoscopic resection (ER) has been widely accepted as an effective and minimally invasive treatment for patients with superficial esophageal squamous cell carcinoma (SCC). Techniques of conventional endoscopic mucosal resection (EMR) were first developed for ER. There are three representative methods of conventional EMR: endoscopic esophageal mucosal resection (EEMR)-tube method, EMR using a cap-fitted endoscope (EMRC) method and two-channel EMR method. In the past decade, techniques of endoscopic submucosal dissection (ESD) have become established as standard methods of ER. ESD allows en bloc resection of a lesion, irrespective of the size and shape of the lesion. Recently, results of retrospective cohort studies confirming that ESD is superior to EMR as a curative treatment for superficial esophageal SCC have been reported. Representative knives that are now frequently used in esophageal ESD include Hook knife, Triangle tip knife, IT knife nano, Flush knife-BT, Dual knife, SB knife, and so on. Although there are various knives developed for ESD, the basic techniques for safe and effective ESD are the same. © 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.
• Add-on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C

  Motoyuki Kohjima, Munechika Enjoji, Tsuyoshi Yoshimoto, Ryoko Yada, Tatsuya Fujino, Yoko Aoyagi, Nobuyoshi Fukushima, Kunitaka Fukuizumi, Naohiko Harada, Masayoshi Yada, Masaki Kato, Kazuhiro Kotoh, Manabu Nakashima, Naoya Sakamoto, Yasuhito Tanaka, Makoto Nakamuta

  JOURNAL OF MEDICAL VIROLOGY 85 (2) 250 - 260 0146-6615 2013/02 [Refereed][Not invited]
   

  Despite the use of pegylated-interferon (peg-IFN) plus ribavirin combination therapy, many patients infected with hepatitis C virus (HCV)-1b remain HCV-positive. To determine whether addition of pitavastatin and eicosapentaenoic acid (EPA) is beneficial, the add-on therapy option (add-on group) was compared retrospectively with unmodified peg-IFN/ribavirin therapy (standard group). Association of host- or virus-related factors with sustained virological response was assessed. In HCV replicon cells, the effects of pitavastatin and/or EPA on HCV replication and expression of innate-immunity- and lipid-metabolism-associated genes were investigated. In patients infected with HCV-1b, sustained virological response rates were significantly higher in the add-on than standard group. In both groups, sustained virological response rates were significantly higher in patients with genotype TT of IL-28B (rs8099917) than in those with non-TT genotype. Among the patients with non-TT genotype, sustained virological response rates were markedly higher in the add-on than standard group. By multivariate analysis, genome variation of IL28B but not add-on therapy remained as a predictive factor of sustained virological response. In replicon cells, pitavastatin and EPA suppressed HCV replication. Activation of innate immunity was obvious in pitavastatin-treated cells and EPA suppressed the expression of sterol regulatory element binding protein-1c and low-density lipoprotein receptor. Addition of pitavastatin and EPA to peg-IFN/ribavirin treatment improved sustained virological response in patients infected with HCV-1b. Genotype variation of IL-28B is a strong predictive factor in add-on therapy. J. Med. Virol. 85:250260, 2013. (c) 2012 Wiley Periodicals, Inc.
• Serum pepsinogen and gastric cancer risk

  Katsuhiro Mabe, Mototsugu Kato, Naoya Sakamoto, Masahiro Asaka

  Journal of Japanese Society of Gastroenterology 110 (2) 218 - 224 0446-6586 2013/02 [Refereed][Not invited]
  
• Development of Novel Flow Chamber to Study Endothelial Cell Morphology: Effects of Shear Flow with Uniform Spatial Gradient on Distribution of Focal Adhesion*

  Daisuke Yoshino, Naoya Sakamoto, Keita Takahashi, Eri Inoue, Masaaki Sato

  Journal of Biomechanical Science and Engineering 8 (3) 233 - 243 1880-9863 2013 [Refereed][Not invited]
   

  Fluid shear stress (SS) is well known to cause morphological changes in vascular endothelial cells (ECs) accompanied by alteration in actin cytoskeletal structure and distribution of focal adhesions. Recent studies have shown that spatial SS gradient also has effects on EC morphology, but the detailed mechanisms of EC responses to SSG remain unclear. In the present study, we sought morphological responses of ECs under SS and uniform SSG condition using a newly developed flow chamber. Confluent ECs were exposed to SS with SSG for 24 hours. Focal adhesions of the EC under SS without SSG were localized in the cell periphery. In contrast, focal adhesions were expressed not only in the periphery but also in interior portion of cells after exposure to SS with SSG. Unlike ECs exposure to SS developed thick actin filaments aligned to the direction of flow no development of thick actin filaments but thin and short filaments were observed in ECs after 24-hour exposure to SS with SSG. Since the distribution of focal adhesion is of critical importance for development of actin filaments and cell morphological changes, these results suggest that SSG suppresses redistribution of focal adhesions, resulting in the inhibition of EC morphological changes and development of thick actin filaments in responseto flow. © 2013 by JSME.
• Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type I interferon-dependent innate immunity

  Sayuri Nitta, Naoya Sakamoto, Mina Nakagawa, Sei Kakinuma, Kako Mishima, Akiko Kusano-Kitazume, Kei Kiyohashi, Miyako Murakawa, Yuki Nishimura-Sakurai, Seishin Azuma, Megumi Tasaka-Fujita, Yasuhiro Asahina, Mitsutoshi Yoneyama, Takashi Fujita, Mamoru Watanabe

  Hepatology 57 (1) 46 - 58 0270-9139 2013/01 [Not refereed][Not invited]
   

  Hepatitis C virus (HCV) infection blocks cellular interferon (IFN)-mediated antiviral signaling through cleavage of Cardif by HCV-NS3/4A serine protease. Like NS3/4A, NS4B protein strongly blocks IFN-β production signaling mediated by retinoic acid-inducible gene I (RIG-I) however, the underlying molecular mechanisms are not well understood. Recently, the stimulator of interferon genes (STING) was identified as an activator of RIG-I signaling. STING possesses a structural homology domain with flaviviral NS4B, which suggests a direct protein-protein interaction. In the present study, we investigated the molecular mechanisms by which NS4B targets RIG-I-induced and STING-mediated IFN-β production signaling. IFN-β promoter reporter assay showed that IFN-β promoter activation induced by RIG-I or Cardif was significantly suppressed by both NS4B and NS3/4A, whereas STING-induced IFN-β activation was suppressed by NS4B but not by NS3/4A, suggesting that NS4B had a distinct point of interaction. Immunostaining showed that STING colocalized with NS4B in the endoplasmic reticulum. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrated that NS4B specifically bound STING. Intriguingly, NS4B expression blocked the protein interaction between STING and Cardif, which is required for robust IFN-β activation. NS4B truncation assays showed that its N terminus, containing the STING homology domain, was necessary for the suppression of IFN-β promoter activation. NS4B suppressed residual IFN-β activation by an NS3/4A-cleaved Cardif (Cardif1-508), suggesting that NS3/4A and NS4B may cooperate in the blockade of IFN-β production. Conclusion: NS4B suppresses RIG-I-mediated IFN-β production signaling through a direct protein interaction with STING. Disruption of that interaction may restore cellular antiviral responses and may constitute a novel therapeutic strategy for the eradication of HCV. © 2012 American Association for the Study of Liver Diseases.
• Rikkunshito, a Japanese Kampo Medicine, Ameliorates Decreased Feeding Behavior via Ghrelin and Serotonin 2B Receptor Signaling in a Novelty Stress Murine Model

  Chihiro Yamada, Yayoi Saegusa, Koji Nakagawa, Shunsuke Ohnishi, Shuichi Muto, Miwa Nahata, Chiharu Sadakane, Tomohisa Hattori, Naoya Sakamoto, Hiroshi Takeda

  BIOMED RESEARCH INTERNATIONAL 2013 792940  2314-6133 2013 [Refereed][Not invited]
   

  We investigated the effects of rikkunshito (RKT), a ghrelin signal enhancer, on the decrease in food intake after exposure to novelty stress in mice. RKT administration (500 mg/kg, per os) improved the decrease in 6 h cumulative food intake. In control mice, the plasma acylated ghrelin levels significantly increased by 24 h fasting. In contrast, the acylated ghrelin levels did not increase by fasting in mice exposed to the novelty stress. RKT administration to the novelty stress mice showed a significant increase in the acylated ghrelin levels compared with that in the distilled-water-treated control mice. Food intake after administering serotonin 2B (5-HT2B) receptor antagonists was evaluated to clarify the role of 5-HT2B receptor activation in the decrease in feeding behavior after novelty stress. SB215505 and SB204741, 5-HT2B receptor antagonists, significantly improved the decrease in food intake after exposure to novelty stress. A component of RKT, isoliquiritigenin, prevented the decrease in 6 h cumulative food intake. Isoliquiritigenin showed 5-HT2B receptor antagonistic activity in vitro. In conclusion, the results suggested that RKT improves the decrease in food intake after novelty stress probably via 5-HT2B receptor antagonism of isoliquiritigenin contained in RKT.
• Large Solid-pseudopapillary Neoplasm of the Pancreas with Aberrant Protein Expression and Mutation of beta-Catenin: A Case Report and Literature Review of the Distribution of beta-Catenin Mutation

  Takahiko Kobayashi, Mariko Ozasa, Kencho Miyashita, Akiyoshi Saga, Kimiaki Miwa, Makoto Saito, Masanobu Morioka, Motoya Takeuchi, Nobuo Takenouchi, Takashi Yabiku, Hiromi Kanno, Sayaka Yuzawa, Mishie Tanino, Shinya Tanaka, Hiroshi Kawakami, Masahiro Asaka, Naoya Sakamoto

  INTERNAL MEDICINE 52 (18) 2051 - 2056 0918-2918 2013 [Refereed][Not invited]
   

  Solid-pseudopapillary neoplasms (SPN) are rare pancreatic tumors. The etiology of SPN involves mutations in the gene that encodes beta-catenin (CTNNB1). We herein report the case of a 23-year-old woman with a large SPN with proliferating tumor cells that displayed both solid and pseudo-papillary patterns. The simultaneous nuclear accumulation and loss of membrane localization of beta-catenin and E-cadherin was specifically observed in the tumor cells. Further, the tumor cells were shown to harbor a missense mutation in exon 3 of CTNNB1. We also present a review of the literature describing the clustering of CTNNB1 mutations in patients with SPN.
• Hypoxia suppresses stretch-induced elongation and orientation of macrophages

  Koki Oya, Naoya Sakamoto, Masaaki Sato

  BIO-MEDICAL MATERIALS AND ENGINEERING 23 (6) 463 - 471 0959-2989 2013 [Refereed][Not invited]
   

  BACKGROUND: Cells in the arterial wall are normally subjected to approximately 10% cyclic stretch due to pulsatile blood flow. In addition, cells in the walls of abdominal aortic aneurysms (AAA) experience hypoxic conditions caused by the accumulation of intraluminal thrombus. Such combined stimulation by hypoxia and stretch can induce abnormal functions in macrophages that infiltrate into the AAA walls; however, the details of these effects are unknown. OBJECTIVE: The aim of this study is to know the influence of a combination of cyclic stretch and hypoxia on the macrophage morphology. METHODS: Morphological changes, such as aspect ratio and orientation, in macrophages exposed to 10% cyclic stretch and 2.2% O-2 hypoxia during 24 h were evaluated with usage of ImageJ software. We also assessed expression of hypoxia-inducible factor-alpha (HIF-1 alpha), an intracellular signaling factor, in macrophages by western blotting. RESULTS: The results indicate that hypoxia significantly suppresses stretch-induced orientation in the direction of the stretch and elongation of macrophages. We also found that the combination of cyclic stretch and hypoxia significantly increased HIF-1 alpha expression. CONCLUSIONS: These results suggest that hypoxia suppresses morphological responses of macrophages to cyclic stretch by elevating HIF-1 alpha expression.
• Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type I interferon-dependent innate immunity

  Sayuri Nitta, Naoya Sakamoto, Mina Nakagawa, Sei Kakinuma, Kako Mishima, Akiko Kusano-Kitazume, Kei Kiyohashi, Miyako Murakawa, Yuki Nishimura-Sakurai, Seishin Azuma, Megumi Tasaka-Fujita, Yasuhiro Asahina, Mitsutoshi Yoneyama, Takashi Fujita, Mamoru Watanabe

  HEPATOLOGY 57 (1) 46 - 58 0270-9139 2013/01 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) infection blocks cellular interferon (IFN)-mediated antiviral signaling through cleavage of Cardif by HCV-NS3/4A serine protease. Like NS3/4A, NS4B protein strongly blocks IFN-beta production signaling mediated by retinoic acidinducible gene I (RIG-I); however, the underlying molecular mechanisms are not well understood. Recently, the stimulator of interferon genes (STING) was identified as an activator of RIG-I signaling. STING possesses a structural homology domain with flaviviral NS4B, which suggests a direct protein-protein interaction. In the present study, we investigated the molecular mechanisms by which NS4B targets RIG-Iinduced and STING-mediated IFN-beta production signaling. IFN-beta promoter reporter assay showed that IFN-beta promoter activation induced by RIG-I or Cardif was significantly suppressed by both NS4B and NS3/4A, whereas STING-induced IFN-beta activation was suppressed by NS4B but not by NS3/4A, suggesting that NS4B had a distinct point of interaction. Immunostaining showed that STING colocalized with NS4B in the endoplasmic reticulum. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrated that NS4B specifically bound STING. Intriguingly, NS4B expression blocked the protein interaction between STING and Cardif, which is required for robust IFN-beta activation. NS4B truncation assays showed that its N terminus, containing the STING homology domain, was necessary for the suppression of IFN-beta promoter activation. NS4B suppressed residual IFN-beta activation by an NS3/4A-cleaved Cardif (Cardif1-508), suggesting that NS3/4A and NS4B may cooperate in the blockade of IFN-beta production. Conclusion: NS4B suppresses RIG-Imediated IFN-beta production signaling through a direct protein interaction with STING. Disruption of that interaction may restore cellular antiviral responses and may constitute a novel therapeutic strategy for the eradication of HCV. (HEPATOLOGY 2013;57:46-58)
• Severe Murine Typhus With Shock and Acute Respiratory Failure in a Japanese Traveler After Returning From Thailand

  Naoya Sakamoto, Fukumi Nakamura-Uchiyama, Ken-ichiro Kobayashi, Tomohiko Takasaki, Yumiko Ogasawara, Shuji Ando, Sentaro Iwabuchi, Kenji Ohnishi

  JOURNAL OF TRAVEL MEDICINE 20 (1) 50 - 53 1195-1982 2013/01 [Refereed][Not invited]
   

  We treated a case of severe murine typhus in a Japanese traveler after returning from Thailand. Although the disease is typically self-limited or mild, the patient showed shock and multiple organ failure including acute respiratory distress syndrome. Then the patient fully recovered following intensive care and administration of antirickettsial medicines.
• A multicenter survey of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan

  Tsugiko Oze, Naoki Hiramatsu, Eiji Mita, Norio Akuta, Naoya Sakamoto, Hiroaki Nagano, Yoshito Itoh, Shuichi Kaneko, Namiki Izumi, Hideyuki Nomura, Norio Hayashi, Tetsuo Takehara

  HEPATOLOGY RESEARCH 43 (1) 35 - 43 1386-6346 2013/01 [Refereed][Not invited]
   

  Aim: This study aimed to clarify the factors associated the efficacy of re-treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. Methods: One hundred and forty-three patients who had previously shown relapse (n = 79), non-response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re-treated with PEG IFN plus ribavirin. Results: Twenty-five patients with intolerance to previous treatment completed re-treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re-treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re-treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin-28B major genotype responded significantly better and earlier to re-treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Conclusion: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re-treatment for HCV genotype 1 patients. Re-treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re-treatment.
• Duplicated Wirsung duct.

  Kawakubo K, Kawakami H, Sakamoto N

  Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 13 (1) 98  1424-3903 2013/01 [Refereed][Not invited]
  
• The search for secreted proteins in prostate cancer by the escherichia coli ampicillin secretion trap: Expression of NBL1 is highly restricted to the prostate and is related to cancer progression

  Tetsutaro Hayashi, Kazuhiro Sentani, Naohide Oue, Shinya Ohara, Jun Teishima, Katsuhiro Anami, Naoya Sakamoto, Akio Matsubara, Wataru Yasui

  Pathobiology 80 (2) 60 - 69 1015-2008 2012/11 [Refereed][Not invited]
   

  Aims: Genes expressed only in cancer tissue or specific organs will be useful molecular markers. To identify genes that encode secreted proteins present in prostate cancer (PCa), we generated Escherichia coli ampicillin secretion trap (CAST) libraries from PCa and normal prostate (NP). Methods and Results: We identified 15 candidate genes that encode secreted proteins present in PCa and NP. Quantitative RT-PCR analysis revealed that MSMB, NBL1 and AZGP1 were expressed with much higher specificity in PCa and NP than in 14 other kinds of normal tissue. We focused on NBL1, which was originally identified as a putative tumor suppressor gene. Western blot analysis revealed that NBL1 protein was highly expressed in both cell lysate and culture media of the DU145 PCa cell line. Immunohistochemical analysis showed that NBL1 expression was highly detected in and restricted to NP and PCa and was significantly down-regulated in PCa. NBL1 expression was significantly reduced according to the tumor stage, Gleason grade and preoperative prostate-specific antigen (PSA) value. Conclusion: NBL1 is a secreted protein that is highly restricted to the prostate. Underexpression of NBL1 correlated with PCa progression. NBL1 might be a candidate tumor marker for PCa in addition to PSA. Copyright © 2012 S. Karger AG, Basel.
• Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C

  Tomoe Kobayashi, Shuhei Hige, Katsumi Terashita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuru Nakanishi, Koji Ogawa, Makoto Chuma, Naoya Sakamoto, Masahiro Asaka

  JOURNAL OF GASTROENTEROLOGY 47 (11) 1228 - 1237 0944-1174 2012/11 [Refereed][Not invited]
   

  An inosine triphosphatase (ITPA) single-nucleotide polymorphism (SNP) is associated with anemia induced by pegylated interferon and ribavirin (RBV) combination therapy in patients with chronic hepatitis C (CHC). However, there are very few reports on the hematological effects of RBV monotherapy. Here, hematological changes were monitored in patients with CHC who received RBV monotherapy, and the mechanism of these changes was investigated. Patients with CHC (n = 30) received RBV monotherapy for 4 weeks. The RBV dose was determined on the basis of body weight. Complete blood count, and serum erythropoietin (EPO) and thrombopoietin (TPO) levels were assessed. The associations between these parameters and the ITPA SNP (rs1127354) were analyzed. Over the 4 weeks, the median hemoglobin level of all patients decreased significantly, from 13.6 (10.5-16.6) to 11.7 (9.4-14.9) g/dl (P < 0.001), and the platelet counts increased, from 14.0 x 10(4) (8.9-37.4 x 10(4)) to 15.8 x 10(4) (10.2-40.6 x 10(4)) /mm(3) (P = 0.003). At week 4, hemoglobin levels differed between patients with the ITPA CC genotype and those with the AA or AC genotypes [11.1 (9.4-13.5) vs. 12.9 (12.5-14.9) g/dl, P = 0.001]. The platelet change ratio (i.e., platelet count at week 4/platelet count at baseline) in the patients with developing anemia was correlated with the increase in the serum EPO level over 4 weeks (r = 0.88, P = 0.002), but not with the increase in the serum TPO level over 4 weeks. RBV monotherapy induced anemia and affected thrombocytosis in patients with CHC. Elevated endogenous EPO may stimulate platelet production.
• Reg IV Is a Direct Target of Intestinal Transcriptional Factor CDX2 in Gastric Cancer

  Yutaka Naito, Naohide Oue, Takao Hinoi, Naoya Sakamoto, Kazuhiro Sentani, Hideki Ohdan, Kazuyoshi Yanagihara, Hiroki Sasaki, Wataru Yasui

  PLOS ONE 7 (11) e47545  1932-6203 2012/11 [Refereed][Not invited]
   

  REG4, which encodes Reg IV protein, is a member of the calcium-dependent lectin superfamily and potent activator of the epidermal growth factor receptor/Akt/activator protein-1 signaling pathway. Several human cancers overexpress Reg IV, and Reg IV expression is associated with intestinal phenotype differentiation. However, regulation of REG4 transcription remains unclear. In the present study, we investigated whether CDX2 regulates Reg IV expression in gastric cancer (GC) cells. Expression of Reg IV and CDX2 was analyzed by Western blot and quantitative reverse transcription-polymerase chain reaction in 9 GC cell lines and 2 colon cancer cell lines. The function of the 5'-flanking region of the REG4 gene was characterized by luciferase assay. In 9 GC cell lines, endogenous Reg IV and CDX2 expression were well correlated. Using an estrogen receptor-regulated form of CDX2, rapid induction of Reg IV expression was observed in HT-29 cells. Reporter gene assays revealed an important role in transcription for consensus CDX2 DNA binding elements in the 5'-flanking region of the REG4 gene. Chromatin immunoprecipitation assays showed that CDX2 binds directly to the 5'-flanking region of REG4. These results indicate that CDX2 protein directly regulates Reg IV expression.
• Inhibition of Both Protease and Helicase Activities of Hepatitis C Virus NS3 by an Ethyl Acetate Extract of Marine Sponge Amphimedon sp.

  Yuusuke Fujimoto, Kazi Abdus Salam, Atsushi Furuta, Yasuyoshi Matsuda, Osamu Fujita, Hidenori Tani, Masanori Ikeda, Nobuyuki Kato, Naoya Sakamoto, Shinya Maekawa, Nobuyuki Enomoto, Nicole J. de Voogd, Masamichi Nakakoshi, Masayoshi Tsubuki, Yuji Sekiguchi, Satoshi Tsuneda, Nobuyoshi Akimitsu, Naohiro Noda, Atsuya Yamashita, Junichi Tanaka, Kohji Moriishi

  PLOS ONE 7 (11) e48685  1932-6203 2012/11 [Refereed][Not invited]
   

  Combination therapy with ribavirin, interferon, and viral protease inhibitors could be expected to elicit a high level of sustained virologic response in patients infected with hepatitis C virus (HCV). However, several severe side effects of this combination therapy have been encountered in clinical trials. In order to develop more effective and safer anti-HCV compounds, we employed the replicon systems derived from several strains of HCV to screen 84 extracts from 54 organisms that were gathered from the sea surrounding Okinawa Prefecture, Japan. The ethyl acetate-soluble extract that was prepared from marine sponge Amphimedon sp. showed the highest inhibitory effect on viral replication, with EC50 values of 1.5 and 24.9 mu g/ml in sub-genomic replicon cell lines derived from genotypes 1b and 2a, respectively. But the extract had no effect on interferon-inducing signaling or cytotoxicity. Treatment with the extract inhibited virus production by 30% relative to the control in the JFH1-Huh7 cell culture system. The in vitro enzymological assays revealed that treatment with the extract suppressed both helicase and protease activities of NS3 with IC50 values of 18.9 and 10.9 mu g/ml, respectively. Treatment with the extract of Amphimedon sp. inhibited RNA-binding ability but not ATPase activity. These results suggest that the novel compound(s) included in Amphimedon sp. can target the protease and helicase activities of HCV NS3.
• Guidewire cannulation: friend or foe Response

  Hiroshi Kawakami, Hiroyuki Isayama, Hiroyuki Maguchi, Masaki Kuwatani, Yousuke Nakai, Kazumichi Kawakubo, Shin Haba, Taiki Kudo, Yoko Abe, Kazuhiko Koike, Naoya Sakamoto

  GASTROINTESTINAL ENDOSCOPY 76 (4) 920 - 921 0016-5107 2012/10 [Refereed][Not invited]
  
• Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients

  Hiroaki Saito, Kiyoaki Ito, Masaya Sugiyama, Teppei Matsui, Yoshihiko Aoki, Masatoshi Imamura, Kazumoto Murata, Naohiko Masaki, Hideyuki Nomura, Hiroshi Adachi, Shuhei Hige, Nobuyuki Enomoto, Naoya Sakamoto, Masayuki Kurosaki, Masashi Mizokami, Sumio Watanabe

  HEPATOLOGY RESEARCH 42 (10) 958 - 965 1386-6346 2012/10 [Refereed][Not invited]
   

  Aim: IL28B polymorphisms serve to predict response to pegylated interferon plus ribavirin therapy (PEG IFN/RBV) in Japanese patients with chronic hepatitis C (CHC) very reliably. However, the prediction by the IL28B polymorphism contradicted the virological response to PEG IFN/RBV in some patients. Here, we aimed to investigate the factors responsible for the discrepancy between the IL28B polymorphism prediction and virological responses. Methods: CHC patients with genotype 1b and high viral load were enrolled in this study. In a casecontrol study, clinical and virological factors were analyzed for 130 patients with rs8099917 TT genotype and 96 patients with rs8099917 TG or GG genotype who were matched according to sex, age, hemoglobin level and platelet count. Results: Higher low-density lipoprotein (LDL) cholesterol, lower ?-glutamyltransferase and the percentage of wild-type phenotype at amino acids 70 and 91 were significantly associated with the rs8099917 TT genotype. Multivariate analysis showed that rs8099917 TG or GG genotype, older age and lower LDL cholesterol were independently associated with the non-virological responder (NVR) phenotype. In patients with rs8099917 TT genotype (predicted as virological responder [VR]), multivariate analysis showed that older age was independently associated with NVR. In patients with rs8099917 TG or GG genotype (predicted as NVR), multivariate analysis showed that younger age was independently associated with VR. Conclusion: Patient age gave rise to the discrepancy between the prediction by IL28B polymorphism and the virological responses, suggesting that patients should be treated at a younger age.
• [The effect of H. pylori eradication against prevention of gastric cancer].

  Mabe K, Kato M, Ono S, Asaka M, Sakamoto N

  Nihon rinsho. Japanese journal of clinical medicine 日本臨床社 70 (10) 1726 - 1730 0047-1852 2012/10 [Refereed][Not invited]
  
• Migration of human mesenchymal stem cells under low shear stress mediated by mitogen-activated protein kinase signaling

  Lin Yuan, Naoya Sakamoto, Guanbin Song, Masaaki Sato

  Stem Cells and Development 21 (13) 2520 - 2530 1547-3287 2012/09/01 [Refereed][Not invited]
   

  Human mesenchymal stem cells (hMSCs) are attractive candidates for cell-based tissue repair approaches and have been used as vectors for delivering therapeutic genes to sites of injury. It is believed that hMSCs are able to detect and respond to shear stress due to blood and interstitial fluid flow through mechanotransduction pathways after transplantation. However, information regarding hMSC migration under shear stress and its mechanism is still limited. In this study, we examined the effect of shear stress on hMSC migration and the role of mitogen-activated protein kinases (MAPKs) in their migration. Shear stress between 0.2 and 10 Pa, which was produced by the flow medium, was exerted on fluorescently labeled hMSCs. Cell migration was evaluated using the scratch wound assay, and images were captured using a microscope equipped with a digital 3CCD camera. The results showed that hMSCs subjected to a shear stress of 0.2 Pa caused notably faster wound closure than statically cultured hMSCs, while migration in the 0.5- and 1-Pa shear stress group did not differ significantly from that in the control group. Shear stress > 2 Pa markedly inhibited hMSC migration. hMSCs subjected to a shear stress of 0.2 Pa displayed an increase in extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 MAPK activation for up to 60 min, while a shear stress of 2 Pa abrogated the activation. JNK and p38 MAPK inhibitors completely abolished the effect of shear stress on hMSC migration, while significant differences were observed between the ERK1/2 inhibitor-treated static control and shear stress groups. Taken together, these results demonstrate that low shear stress effectively induces hMSC migration and that JNK and p38 MAPK play more prominent roles in shear stress-induced migration than ERK1/2. Copyright © 2012, Mary Ann Liebert, Inc. 2012.
• Liver-intestine cadherin induction by epidermal growth factor receptor is associated with intestinal differentiation of gastric cancer

  Naoya Sakamoto, Naohide Oue, Kazuhiro Sentani, Katsuhiro Anami, Naohiro Uraoka, Yutaka Naito, Htoo Zarni Oo, Takao Hinoi, Hideki Ohdan, Kazuyoshi Yanagihara, Kazuhiko Aoyagi, Hiroki Sasaki, Wataru Yasui

  CANCER SCIENCE 103 (9) 1744 - 1750 1347-9032 2012/09 [Refereed][Not invited]
   

  Gastric cancer (GC) is one of the most common malignancies worldwide. The epidermal growth factor receptor (EGFR) molecule is very important in GC progression. To examine the correlation between EGFR and GC-related genes, we analyzed gene expression profiles of HT-29 cells treated with EGFR ligands and identified six genes upregulated by epidermal growth factor (EGF) and transforming growth factor (TGF)-a treatment. Among these, we focused on cadherin 17 (CDH17) encoding liverintestine cadherin (LI-cadherin). Expression of LI-cadherin was induced by both EGF and TGF-a, as detected by quantitative RT-PCR and Western blot analysis. A luciferase assay showed that LI-cadherin promoter activity was enhanced by EGF or TGF-a in both HT-29 cells and MKN-74 GC cells. Immunohistochemical analysis of 152 GC cases showed that out of 58 LI-cadherin-positive cases, 24 (41%) cases were also positive for EGFR, whereas out of 94 LI-cadherin-negative cases, only 9 (10%) cases were positive for EGFR (P similar to<similar to 0.0001). Double-immunofluorescence staining revealed that EGFR and LI-cadherin were coexpressed. Significant correlation was found between LI-cadherin expression and advanced T grade and N grade. Both EGFR and LI-cadherin expression were more frequently found in GC cases with an intestinal mucin phenotype than in cases with a gastric mucin phenotype. These results indicate that, in addition to the known intestinal transcription factor caudal type homeobox 2, EGFR activation induces LI-cadherin expression and participates in intestinal differentiation of GC.
• Decrease of Peripheral and Intestinal NKG2A-Positive T Cells in Patients with Ulcerative Colitis

  Takehiko Katsurada, Waka Kobayashi, Utano Tomaru, Tomohisa Baba, Shigeru Furukawa, Akihiro Ishizu, Kazuyoshi Takeda, Naoya Sakamoto, Masahiro Asaka, Hiroshi Takeda, Masanori Kasahara

  PLOS ONE 7 (9) e44113  1932-6203 2012/09 [Refereed][Not invited]
   

  To investigate the role of inhibitory natural killer receptors (iNKRs) in inflammatory bowel disease (IBD), we analyzed the expression of NKG2A, one of the iNKRs, on T cells in a mouse colitis model and human IBD. During the active phase of dextran sulfate sodium (DSS)-induced mouse colitis, the frequency of NKG2A+ T cells was significantly decreased in the peripheral blood, and increased in the intestine, suggesting the mobilization of this T cell subset to the sites of inflammation. Administration of anti-NKG2A antibody increased the number of inflammatory foci in DSS-induced colitis, suggesting the involvement of NKG2A+ T cells in this colitis model. In ulcerative colitis (UC) patients, the frequency of peripheral blood NKG2A+ T cells was significantly decreased, compared with Crohn's disease (CD) patients and healthy controls, regardless of clinical conditions such as treatment modalities and disease activity. Notably, in sharp contrast to the DSS-induced mouse colitis model, the frequency of NKG2A+ cells among intestinal T cells was also decreased in UC patients. These results suggest that inadequate local infiltration of NKG2A+ T cells may be involved in the pathogenesis of UC.
• Medial Regeneration Using a Biodegradable Felt as a Scaffold Preserves Integrity and Compliance of a Canine Dissected Aorta

  Mitsuru Sato, Shunsuke Kawamoto, Mika Watanabe, Naoya Sakamoto, Masaaki Sato, Yasuhiko Tabata, Yoshikatsu Saiki

  CIRCULATION 126 (11) S102 - + 0009-7322 2012/09 [Refereed][Not invited]
   

  Background-Repair of a dissected aorta involves reattaching the media with synthetic glue and/or reinforcement with nonbiodegradable felt. Late complications specific to each aspect of this procedure have been reported. We attempted to regenerate the media by using biodegradable felt. Methods and Results-We created a canine model of descending thoracic aortic dissection and compared 4 modes of aortic repair: biodegradable polyglycolic acid (PGA) felt in the media; PGA with basic fibroblast growth factor (bFGF) in the media; PGA with bFGF in the media plus external reinforcement with expanded polytetrafluoroethylene; and primary suture closure of the dissected lumen (control). Repaired aortic stumps were quantitatively tested for suture pull-out strength. Failure force improved 4-fold in all 3 medial reinforcement groups compared with controls. Additionally, animals were kept alive for histological examination and compliance testing 6 months after repair. Compliance of the aortic wall at the anastomotic sites was not essentially affected in the long term except in the group with concomitant external reinforcement (55.9 +/- 4.5% reduction; P < 0.05). In this group, elastic fiber in the media and collagen fiber in the adventitia tended to diminish relative to the other groups. Regarding vessel density in the repaired false lumen, this external reinforced group had a significantly decreased number. Histological derangement was not observed in control or medial reinforcement groups. Basic FGF, applied with PGA in the dissected lumen, failed to yield additional modifications in this model. Conclusions-Medial reinforcement provides sufficient augmented strength for aortic surgical repair. Medial regeneration using biodegradable felt as a scaffold preserves histological integrity and compliance in the canine dissected aorta. (Circulation. 2012;126[suppl 1]:S102-S109.)
• Infantile adenomyoma subclinically excreted into the patient's diaper

  Katsuhiro Anami, Kazuhiro Sentani, Naoya Sakamoto, Naohiro Uraoka, Naohide Oue, Wataru Yasui

  PATHOLOGY INTERNATIONAL 62 (8) 532 - 537 1320-5463 2012/08 [Refereed][Not invited]
   

  Adenomyoma is a rare condition of the gastrointestinal tract, consisting of glandular structures lined by columnar or cuboidal epithelium and surrounded by smooth muscle bundles. The vast majority of adenomyomas of gastrointestinal tract have been reported to be located at the propyloric segment of the stomach and their localization in the bowel of infantile patients is considered rare. A review of the literature showed that 13 cases of infantile adenomyoma in the bowel have been reported. In the previous cases, intussusception was the most common complication of adenomyoma in the bowel and all cases underwent laparotomy. Here we describe an extremely rare case of infantile adenomyoma subclinically eliminated in the diaper. In addition, we performed immunohistochemical analysis to speculate on the origin of the adenomyoma.
• Let-7b is a novel regulator of hepatitis C virus replication

  Ju-Chien Cheng, Yung-Ju Yeh, Ching-Ping Tseng, Sheng-Da Hsu, Yu-Ling Chang, Naoya Sakamoto, Hsien-Da Huang

  CELLULAR AND MOLECULAR LIFE SCIENCES 69 (15) 2621 - 2633 1420-682X 2012/08 [Refereed][Not invited]
   

  The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cell-based systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5'-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7b-mediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFN alpha-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy.
• Role of nesprin-1 in nuclear deformation in endothelial cells under static and uniaxial stretching conditions

  Toshiro Anno, Naoya Sakamoto, Masaaki Sato

  Biochemical and Biophysical Research Communications 424 (1) 94 - 99 0006-291X 2012/07/20 [Refereed][Not invited]
   

  The linker of nucleus and cytoskeleton (LINC) complex, including nesprin-1, has been suggested to be crucial for many biological processes. Previous studies have shown that mutations in nesprin-1 cause abnormal cellular functions and diseases, possibly because of insufficient force transmission to the nucleus through actin filaments (F-actin) bound to nesprin-1. However, little is known regarding the mechanical interaction between the nucleus and F-actin through nesprin-1. In this study, we examined nuclear deformation behavior in nesprin-1 knocked-down endothelial cells (ECs) subjected to uniaxial stretching by evaluating nuclear strain from lateral cross-sectional images. The widths of nuclei in nesprin-1 knocked-down ECs were smaller than those in wild-type cells. In addition, nuclear strain in nesprin-1 knocked-down cells, which is considered to be compressed by the actin cortical layer, increased compared with that in wild-type cells under stretching condition. These results indicate that nesprin-1 knockdown releases the nucleus from the tension of F-actin bound to the nucleus, thereby increasing allowance for deformation before stretching, and that F-actin bound to the nucleus through nesprin-1 causes sustainable force transmission to the nucleus. © 2012 Elsevier Inc.
• Cytokeratin 7 is a Predictive Marker for Survival in Patients with Esophageal Squamous Cell Carcinoma

  Naohide Oue, Tsuyoshi Noguchi, Katsuhiro Anami, Seigo Kitano, Naoya Sakamoto, Kazuhiro Sentani, Naohiro Uraoka, Kazuhiko Aoyagi, Teruhiko Yoshida, Hiroki Sasaki, Wataru Yasui

  ANNALS OF SURGICAL ONCOLOGY 19 (6) 1902 - 1910 1068-9265 2012/06 [Refereed][Not invited]
   

  Patients diagnosed with stage II and III esophageal squamous cell carcinoma (ESCC) have variable prognosis. This group would benefit greatly from the discovery of prognostic markers that are capable of identifying individuals for whom adjuvant treatment would be advantageous. The aim of this study was to investigate the impact of immunohistochemically detected cytokeratin 7 (CK7) expression on disease-free survival, overall survival (OS), or therapeutic outcome in patients with ESCC. Immunohistochemical analysis of CK7 was performed on 225 surgically resected specimens of stage 0-III ESCC. In total, 20 (9%) of 225 ESCC cases were positive for CK7. In stage 0-III ESCC patients, CK7 expression was statistically significantly associated with OS, independent of clinical covariates, including tumor, node, metastasis system stage. In stage II and III ESCC patients ( = 124), CK7 expression was significantly associated with poorer OS ( = 0.0377). Furthermore, in stage II and III ESCC patients who did not receive adjuvant chemotherapy ( = 73), CK7 expression was significantly associated with poorer OS ( = 0.0003). CK7 expression was not associated with therapeutic outcome in patients with stage II and III ESCC who received adjuvant chemotherapy. In patients with CK7-positive ESCC ( = 16), receipt of adjuvant chemotherapy tended to be beneficial for patients with stage II and III ESCC ( = 0.0654). Immunohistochemical analysis of CK7 will help to identify high-risk patients.
• Suppression of hepatitis C virus replicon by adenovirus vector-mediated expression of tough decoy RNA against miR-122a

  Fuminori Sakurai, Norihisa Furukawa, Maiko Higuchi, Sayuri Okamoto, Kaori Ono, Takeshi Yoshida, Masuo Kondoh, Kiyohito Yagi, Naoya Sakamoto, Kazufumi Katayama, Hiroyuki Mizuguchi

  VIRUS RESEARCH 165 (2) 214 - 218 0168-1702 2012/05 [Refereed][Not invited]
   

  Recent studies have demonstrated that the liver-specific microRNA (miRNA) miR-122a plays an important role in the replication of hepatitis C virus (HCV). Antisense nucleotides against miR-122a, including locked nucleic acid (LNA), have shown promising results for suppression of HCV replication; however, a liver-specific delivery system of antisense nucleotides has not been fully developed. In this study, an adenovirus (Ad) vector that expresses tough decoy (TuD)-RNA against miR-122a (TuD-122a) was developed to suppress the HCV replication in the liver hepatocytes. Ad vectors have been well established to exhibit a marked hepatotropism following systemic administration. An in vitro reporter gene expression assay demonstrated that Ad vector-mediated expression of TuD-122a efficiently blocked the miR-122a in Huh-7 cells. Furthermore, transduction with the Ad vector expressing TuD-122a in HCV replicon-expressing cells resulted in significant reduction in the HCV replicon levels. These results indicate that Ad vector-mediated expression of TuD-122a would be a promising tool for treatment of HCV infection. (C) 2012 Elsevier B.V. All rights reserved.
• Inhibition of Hepatitis C Virus Replication and Viral Helicase by Ethyl Acetate Extract of the Marine Feather Star Alloeocomatella polycladia

  Atsuya Yamashita, Kazi Abdus Salam, Atsushi Furuta, Yasuyoshi Matsuda, Osamu Fujita, Hidenori Tani, Yoshihisa Fujita, Yuusuke Fujimoto, Masanori Ikeda, Nobuyuki Kato, Naoya Sakamoto, Shinya Maekawa, Nobuyuki Enomoto, Masamichi Nakakoshi, Masayoshi Tsubuki, Yuji Sekiguchi, Satoshi Tsuneda, Nobuyoshi Akimitsu, Naohiro Noda, Junichi Tanaka, Kohji Moriishi

  MARINE DRUGS 10 (4) 744 - 761 1660-3397 2012/04 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) is a causative agent of acute and chronic hepatitis, leading to the development of hepatic cirrhosis and hepatocellular carcinoma. We prepared extracts from 61 marine organisms and screened them by an in vitro fluorescence assay targeting the viral helicase (NS3), which plays an important role in HCV replication, to identify effective candidates for anti-HCV agents. An ethyl acetate-soluble fraction of the feather star Alloeocomatella polycladia exhibited the strongest inhibition of NS3 helicase activity, with an IC50 of 11.7 mu g/mL. The extract of A. polycladia inhibited interaction between NS3 and RNA but not ATPase of NS3. Furthermore, the replication of the replicons derived from three HCV strains of genotype 1b in cultured cells was suppressed by the extract with an EC50 value of 23 to 44 mu g/mL, which is similar to the IC50 value of the NS3 helicase assay. The extract did not induce interferon or inhibit cell growth. These results suggest that the unknown compound(s) included in A. polycladia can inhibit HCV replication by suppressing the helicase activity of HCV NS3. This study may present a new approach toward the development of a novel therapy for chronic hepatitis C.
• Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication

  Akiko Kusano-Kitazume, Naoya Sakamoto, Yukiko Okuno, Yuko Sekine-Osajima, Mina Nakagawa, Sei Kakinuma, Kei Kiyohashi, Sayuri Nitta, Miyako Murakawa, Seishin Azuma, Yuki Nishimura-Sakurai, Masatoshi Hagiwara, Mamoru Watanabe

  Antimicrobial Agents and Chemotherapy 56 (3) 1315 - 1323 0066-4804 2012/03 [Not refereed][Not invited]
   

  To identify novel compounds that possess antiviral activity against hepatitis C virus (HCV), we screened a library of small molecules with various amounts of structural diversity using an HCV replicon-expressing cell line and performed additional validations using the HCV-JFH1 infectious-virus cell culture. Of 4,004 chemical compounds, we identified 4 novel compounds that suppressed HCV replication with 50% effective concentrations of ranging from 0.36 to 4.81μM. N′-(Morpholine-4-carbonyloxy)-2-(naphthalen-1-yl) acetimidamide (MCNA) was the most potent and also produced a small synergistic effect when used in combination with alpha interferon. Structure-activity relationship (SAR) analyses revealed 4 derivative compounds with antiviral activity. Further SAR analyses revealed that the N-(morpholine-4-carbonyloxy) amidine moiety was a key structural element for antiviral activity. Treatment of cells with MCNA activated nuclear factor κB and downstream gene expression. In conclusion, N-(morpholine-4-carbonyloxy) amidine and other related morpholine compounds specifically suppressed HCV replication and may have potential as novel chemotherapeutic agents. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
• Inhibition of hepatitis C virus NS5B polymerase by S-trityl-L-cysteine derivatives

  Daniel B. Nichols, Guy Fournet, K. R. Gurukumar, Amartya Basu, Jin-Ching Lee, Naoya Sakamoto, Frank Kozielski, Ira Musmuca, Benoit Joseph, Rino Ragno, Neerja Kaushik-Basu

  EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 49 191 - 199 0223-5234 2012/03 [Refereed][Not invited]
   

  Structure-based studies led to the identification of a constrained derivative of S-trityl-c-cysteine (STLC) scaffold as a candidate inhibitor of hepatitis C virus (HCV) NS5B polymerase. A panel of STLC derivatives were synthesized and investigated for their activity against HCV NS5B. Three STLC derivatives, 9, F-3070, and F-3065, were identified as modest HCV NS5B inhibitors with IC50 values between 22.3 and 39.7 mu M. F-3070 and F-3065 displayed potent inhibition of intracellular NS5B activity in the BHK-NS5B-FRLuc reporter and also inhibited HCV RNA replication in the Huh7/Rep-Feo1b reporter system. Binding mode investigations suggested that the STLC scaffold can be used to develop new NS5B inhibitors by further chemical modification at one of the trityl phenyl group. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C

  Masayuki Kurosaki, Naoki Hiramatsu, Minoru Sakamoto, Yoshiyuki Suzuki, Manabu Iwasaki, Akihiro Tamori, Kentaro Matsuura, Sei Kakinuma, Fuminaka Sugauchi, Naoya Sakamoto, Mina Nakagawa, Namiki Izumi

  JOURNAL OF HEPATOLOGY 56 (3) 602 - 608 0168-8278 2012/03 [Refereed][Not invited]
   

  Background & Aims: Assessment of the risk of hepatocellular carcinoma (HCC) development is essential for formulating personalized surveillance or antiviral treatment plan for chronic hepatitis C. We aimed to build a simple model for the identification of patients at high risk of developing HCC. Methods: Chronic hepatitis C patients followed for at least 5 years (n = 1003) were analyzed by data mining to build a predictive model for HCC development. The model was externally validated using a cohort of 1072 patients (472 with sustained virological response (SVR) and 600 with nonSVR to PEG-interferon plus ribavirin therapy). Results: On the basis of factors such as age, platelet, albumin, and aspartate aminotransferase, the HCC risk prediction model identified subgroups with high-, intermediate-, and low-risk of HCC with a 5-year HCC development rate of 20.9%, 6.3-7.3%, and 0-1.5%, respectively. The reproducibility of the model was confirmed through external validation (r(2) = 0.981). The 10-year HCC development rate was also significantly higher in the high- and intermediate-risk group than in the low-risk group (24.5% vs. 4.8%; p<0.0001). In the high-and intermediate-risk group, the incidence of HCC development was significantly reduced in patients with SVR compared to those with nonSVR (5-year rate, 9.5% vs. 4.5%; p = 0.040). Conclusions: The HCC risk prediction model uses simple and readily available factors and identifies patients at a high risk of HCC development. The model allows physicians to identify patients requiring HCC surveillance and those who benefit from IFN therapy to prevent HCC. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
• Identification of Novel N-(Morpholine-4-Carbonyloxy) Amidine Compounds as Potent Inhibitors against Hepatitis C Virus Replication

  Akiko Kusano-Kitazume, Naoya Sakamoto, Yukiko Okuno, Yuko Sekine-Osajima, Mina Nakagawa, Sei Kakinuma, Kei Kiyohashi, Sayuri Nitta, Miyako Murakawa, Seishin Azuma, Yuki Nishimura-Sakurai, Masatoshi Hagiwara, Mamoru Watanabe

  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 56 (3) 1315 - 1323 0066-4804 2012/03 [Refereed][Not invited]
   

  To identify novel compounds that possess antiviral activity against hepatitis C virus (HCV), we screened a library of small molecules with various amounts of structural diversity using an HCV replicon-expressing cell line and performed additional validations using the HCV-JFH1 infectious-virus cell culture. Of 4,004 chemical compounds, we identified 4 novel compounds that suppressed HCV replication with 50% effective concentrations of ranging from 0.36 to 4.81 mu M. N'-(Morpholine-4-carbonyloxy)-2-(naphthalen-1-yl) acetimidamide (MCNA) was the most potent and also produced a small synergistic effect when used in combination with alpha interferon. Structure-activity relationship (SAR) analyses revealed 4 derivative compounds with antiviral activity. Further SAR analyses revealed that the N-(morpholine-4-carbonyloxy) amidine moiety was a key structural element for antiviral activity. Treatment of cells with MCNA activated nuclear factor kappa B and downstream gene expression. In conclusion, N-(morpholine-4-carbonyloxy) amidine and other related morpholine compounds specifically suppressed HCV replication and may have potential as novel chemotherapeutic agents.
• Role of paxillin in the early phase of orientation of the vascular endothelial cells exposed to cyclic stretching

  Wenjing Huang, Naoya Sakamoto, Ryotaro Miyazawa, Masaaki Sato

  Biochemical and Biophysical Research Communications 418 (4) 708 - 713 0006-291X 2012/02/24 [Refereed][Not invited]
   

  Paxillin, a structural and signaling scaffold molecule in focal adhesions (FAs), is considered to be important in intracellular signaling transduction and the cell shape changes in response to cyclic stretching. However, the detailed role of paxillin in stretch-induced morphological changes of endothelial cells (ECs) has not fully determined until date. In this study, in order to understand the role of paxillin in the orientation of ECs exposed to cyclic stretching, we examined the time course of changes in the shape and distribution of FA proteins of paxillin knockdown ECs. Non-treated ECs subjected to 20% cyclic stretching at 0.5. Hz oriented perpendicularly to the direction of stretching after 10. min of exposure. On the other hand, the orientation of paxillin knockdown ECs was abolished at 10. min, but it was observed after 60. min of cyclic stretching exposure. Immunofluorescent microscopy revealed that accumulation and redistribution of FA proteins, including focal adhesion kinase (FAK) and integrin β1, were observed at 10. min of exposure to cyclic stretching in non-treated ECs. The accumulation of FAK and integrin β1 was not prominent in paxillin knockdown ECs under static conditions and after 10. min of exposure to cyclic stretching. However, we found that accumulation of FA proteins in paxillin knockdown ECs at 30 and 60. min was similar to that in non-transfected ECs. Because paxillin is an adaptor protein offering binding sites for FAK and integrin β1, which are critical molecules for the early signaling events of focal adhesion formation in ECs, these results suggest that paxillin is required for the early phase of EC orientation in response to cyclic stretching by scaffolding for accumulation of FA proteins. © 2012 Elsevier Inc..
• Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer

  Yuta Wakamatsu, Naoya Sakamoto, Htoo Zarni Oo, Yutaka Naito, Naohiro Uraoka, Katsuhiro Anami, Kazuhiro Sentani, Naohide Oue, Wataru Yasui

  PATHOLOGY INTERNATIONAL 62 (2) 112 - 119 1320-5463 2012/02 [Refereed][Not invited]
   

  Gastric cancer (GC) is one of the most common malignancies worldwide. Recently, cancer stem cells (CSCs) in tumors were found to possess the ability to sustain tumor self-renewal, initiate tumor progression, and possibly also contribute to cancer metastasis. We immunohistochemically examined expression and distribution of representative CSC markers ALDH1, CD44, and CD133 in primary tumors and lymph node metastasis of GC. Among 190 GC primary tumors, 104 (55%) were positive for ALDH1, 117 (62%) were positive for CD44, and 18 (9%) were positive for CD133. Expression of these three CSC markers was significantly associated with advanced clinicopathologic factors. Patients with CD44- and CD133-positive GC had a poorer survival rate than patients with CD44- and CD133-negative GC (CD44: P < 0.001, CD133: P= 0.006). Univariate and multivariate Cox proportional hazards analysis revealed tumor node metastasis stage, CD44 expression, and CD133 expression to be independent predictors of survival in patients with GC. Comparison of CSC markers in primary and metastatic sites showed ALDH1 positivity to be significantly higher in diffuse-type lymph node metastasis than in the primary tumor (P < 0.001). These results indicate that these CSC markers are important in tumor invasion and metastasis and may be good markers indicating long-term survival in patients with GC.
• Migration of human mesenchymal stem cells is stimulated by low shear stress via mapk signaling

  Lin Yuan, Naoya Sakamoto, Guanbin Song, Masaaki Sato

  ASME 2012 Summer Bioengineering Conference, SBC 2012 675 - 676 2012 [Refereed][Not invited]
  
• Cytokeratin Expression Profiling in Gastric Carcinoma: Clinicopathologic Significance and Comparison with Tumor-Associated Molecules

  Hokuto Takami, Kazuhiro Sentani, Miho Matsuda, Naohide Oue, Naoya Sakamoto, Wataru Yasui

  PATHOBIOLOGY 79 (3) 154 - 161 1015-2008 2012 [Refereed][Not invited]
   

  Objective: The expressions of cytokeratin (CK) 7 and 20 have been studied in various primary and metastatic carcinomas, and their determination may help distinguish the site of origin of metastatic carcinomas. However, little is known about the molecular basis that determines variations in CK patterns in gastric cancers (GCs). The aim of the present study was to analyze the CK expression patterns in a large number of GCs and to investigate how the CK patterns correlate with clinicopathologic parameters, histology, mucin phenotype or several tumor-related molecules. Methods and Results: We immunohistochemically examined the CK7/CK20 patterns, mucin expression profiles (MUC5AC, MUC6, MUC2 and CD10), and the cancer-related molecules (CDX2, p53, EGFR and beta-catenin), using a tissue microarray with 870 GCs. The GCs were divided into four patterns; 17% of CK7+/CK20+, 57% of CK7+/CK20-, 9% of CK7-/CK20+ and 17% of CK7-/CK20. GCs with the CK7-/CK20- pattern demonstrated a close relation to undifferentiated adenocarcinoma. CK7 expression was significantly correlated with the expression of MUC5AC and MUC6, while CK20 expression was correlated with MUC2 and CDX2. There were statistically significant associations between CK expression patterns and mucin phenotypes. Conclusion: These results indicate that the CK7/CK20 expression patterns in GCs demonstrated different clinicopathologic features and molecular signatures. Copyright (C) 2012 S. Karger AG, Basel
• alpha-Bridged BODIPY oligomers with switchable near-IR photoproperties by external-stimuli-induced foldamer formation and disruption

  Naoya Sakamoto, Chusaku Ikeda, Masaki Yamamura, Tatsuya Nabeshima

  CHEMICAL COMMUNICATIONS 48 (40) 4818 - 4820 1359-7345 2012 [Refereed][Not invited]
   

  We designed and synthesized a series of new alpha-bridged linear BODIPY oligomers, which exhibited strong absorption and high fluorescence efficiency in the near infrared region. The oligomers can be reversibly converted to the first NIR emissive BODIPY foldamers upon selective complexation with Cs+.
• Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response

  Yasuhiro Asahina, Kaoru Tsuchiya, Masaru Muraoka, Keisuke Tanaka, Yuichiro Suzuki, Nobuharu Tamaki, Yoshihide Hoshioka, Yutaka Yasui, Tomoji Katoh, Takanori Hosokawa, Ken Ueda, Hiroyuki Nakanishi, Jun Itakura, Yuka Takahashi, Masayuki Kurosaki, Nobuyuki Enomoto, Sayuri Nitta, Naoya Sakamoto, Namiki Izumi

  HEPATOLOGY 55 (1) 20 - 29 0270-9139 2012/01 [Refereed][Not invited]
   

  Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon alpha(PEG-IFN alpha) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFN alpha-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFN?). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (approximate to 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (approximate to 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. Conclusion: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNa/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR. (Hepatology 2012)
• Age and total ribavirin dose are independent predictors of relapse after interferon therapy in chronic hepatitis C revealed by data mining analysis

  Masayuki Kurosaki, Naoki Hiramatsu, Minoru Sakamoto, Yoshiyuki Suzuki, Manabu Iwasaki, Akihiro Tamori, Kentaro Matsuura, Sei Kakinuma, Fuminaka Sugauchi, Naoya Sakamoto, Mina Nakagawa, Hiroshi Yatsuhashi, Namiki Izumi

  ANTIVIRAL THERAPY 17 (1) 35 - 43 1359-6535 2012 [Refereed][Not invited]
   

  Background: This study aimed to define factors associated with relapse among responders to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy in chronic hepatitis C. Methods: A cohort of genotype 1b chronic hepatitis C patients treated with PEG-IFN plus RBV and who had an undetectable HCV RNA by week 12 (n = 951) were randomly assigned to model derivation (n = 636) or internal validation (n = 315) groups. An independent cohort (n = 598) were used for an external validation. A decision tree model for relapse was explored using data mining analysis. Results: The data mining analysis defined five subgroups of patients with variable rates of relapse ranging from 13% to 52%. The reproducibility of the model was confirmed by internal and external validations (r(2) = 0.79and 0.83, respectively). Patients with undetectable HCV RNA at week 4 had the lowest risk of relapse (13%), followed by patients <60 years with undetectable HCV RNA at week 5-12 who received >= 3.0 g/kg of body weight of RBV (16%). Older patients with a total RBV dose <3.0 g/kg had the highest risk of relapse (52%). Higher RBV dose beyond 3.0 g/kg was associated with further decrease of relapse rate among patients <60 years (up to 11%) but not among older patients whose relapse rate remained stable around 30%. Conclusions: Data mining analysis revealed that time to HCV RNA negativity, age and total RBV dose was associated with relapse. To prevent relapse, >= 3.0 g/kg of RBV should be administered. Higher dose of RBV may be beneficial in patients <60 years.
• Use of human hepatocyte-like cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection

  Takeshi Yoshida, Kazuo Takayama, Masuo Kondoh, Fuminori Sakurai, Hideki Tani, Naoya Sakamoto, Yoshiharu Matsuura, Hiroyuki Mizuguchi, Kiyohito Yagi

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 416 (1-2) 119 - 124 0006-291X 2011/12 [Refereed][Not invited]
   

  Host tropism of hepatitis C virus (HCV) is limited to human and chimpanzee. HCV infection has never been fully understood because there are few conventional models for HCV infection. Human induced pluripotent stem cell-derived hepatocyte-like (iPS-Hep) cells have been expected to use for drug discovery to predict therapeutic activities and side effects of compounds during the drug discovery process. However, the suitability of iPS-Hep cells as an experimental model for HCV research is not known. Here, we investigated the entry and genomic replication of HCV in iPS-Hep cells by using HCV pseudotype virus (HCVpv) and HCV subgenomic replicons, respectively. We showed that iPS-Hep cells, but not iPS cells, were susceptible to infection with HCVpv. The iPS-Hep cells expressed HCV receptors, including CD81, scavenger receptor class B type I (SR-BI), claudin-1, and occludin; in contrast, the iPS cells showed no expression of SR-BI or claudin-1. HCV RNA genome replication occurred in the iPS-Hep cells. Anti-CD81 antibody, an inhibitor of HCV entry, and interferon, an inhibitor of HCV genomic replication, dose-dependently attenuated HCVpv entry and HCV subgenomic replication in iPS-Hep cells, respectively. These findings suggest that iPS-Hep cells are an appropriate model for HCV infection. (C)2011 Elsevier Inc. All rights reserved.
• Development of an endothelial-smooth muscle cell coculture model using phenotype-controlled smooth muscle cells

  Naoya Sakamoto, Takuya Kiuchi, Masaaki Sato

  Annals of Biomedical Engineering 39 (11) 2750 - 2758 0090-6964 2011/11 [Refereed][Not invited]
   

  A coculture of endothelial cells (ECs) and smooth muscle cells (SMCs), which mimics cellular interactions appearing in vivo, has been performed in studies on the relationship between atherogenesis and fluid shear stress conditions. Although healthy arteries in vivo consist of contractile phenotype SMCs, cultured cells used in many studies normally exhibit a synthetic phenotype. Here, we developed an EC-SMC coculture model to investigate the interactions between ECs and contractile SMCs, and examined the effect of shear stress applied to ECs on SMC phenotypes. Cultured human umbilical artery SMCs were differentiated into contractile states by arresting cell growth using a serum-free medium. Western blotting confirmed that SMC expression of contractile protein markers, α-smooth muscle actin (SMA) and calponin, increased to levels similar to those observed in arterial cells. After coculturing contractile SMCs with ECs separated by a collagen gel layer, the expression of α-SMA decreased under static conditions, indicating that the SMC phenotype tended to be synthetic by coculturing with ECs, but shear stress applied to cocultured ECs maintained the level of α-SMA expression in SMCs. The coculture model constructed in the present study will be a useful tool to investigate interactions between ECs and contractile SMCs under shear conditions. © 2011 Biomedical Engineering Society.
• Suppression of Hath1 Gene Expression Directly Regulated by Hes1 Via Notch Signaling Is Associated with Goblet Cell Depletion in Ulcerative Colitis

  Xiu Zheng, Kiichiro Tsuchiya, Ryuichi Okamoto, Michiko Iwasaki, Yoshihito Kano, Naoya Sakamoto, Tetsuya Nakamura, Mamoru Watanabe

  INFLAMMATORY BOWEL DISEASES 17 (11) 2251 - 2260 1078-0998 2011/11 [Refereed][Not invited]
   

  Background: The transcription factor Atoh1/Hath1 plays crucial roles in the differentiation program of human intestinal epithelium cells (IECs). Although previous studies have indicated that the Notch signal suppresses the differentiation program of IEC, the mechanism by which it does so remains unknown. This study shows that the undifferentiated state is maintained by the suppression of the Hath1 gene in human intestine. Methods: To assess the effect of Notch signaling, doxycycline-induced expression of Notch intracellular domain (NICD) and Hes1 cells were generated in LS174T. Hath1 gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Hath1 promoter region targeted by HES1 was determined by both reporter analysis and ChIP assay. Expression of Hath1 protein in ulcerative colitis (UC) was examined by immunohistochemistry. Results: Hath1 mRNA expression was increased by Notch signal inhibition. However, Hath1 expression was suppressed by ectopic HES1 expression alone even under Notch signal inhibition. Suppression of the Hath1 gene by Hes1, which binds to the 50 promoter region of Hath1, resulted in suppression of the phenotypic gene expression for goblet cells. In UC, the cooperation of aberrant expression of HES1 and the disappearance of caudal type homeobox 2 (CDX2) caused Hath1 suppression, resulting in goblet cell depletion. Conclusions: The present study suggests that Hes1 is essential for Hath1 gene suppression via Notch signaling. Moreover, the suppression of Hath1 is associated with goblet cell depletion in UC. Understanding the regulation of goblet cell depletion may lead to the development of new therapy for UC. (Inflamm Bowel Dis 2011;17:2251-2260)
• A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors

  Daisuke Takaya, Atsuya Yamashita, Kazue Kamijo, Junko Gomi, Masahiko Ito, Shinya Maekawa, Nobuyuki Enomoto, Naoya Sakamoto, Yoshiaki Watanabe, Ryoichi Arai, Hideaki Umeyama, Teruki Honma, Takehisa Matsumoto, Shigeyuki Yokoyama

  BIOORGANIC & MEDICINAL CHEMISTRY 19 (22) 6892 - 6905 0968-0896 2011/11 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) is an etiologic agent of chronic liver disease, and approximately 170 million people worldwide are infected with the virus. HCV NS3-4A serine protease is essential for the replication of this virus, and thus has been investigated as an attractive target for anti-HCV drugs. In this study, we developed our new induced-fit docking program (GENIUS), and applied it to the discovery of a new class of NS3-4A protease inhibitors (IC(50) = 1-10 mu M including high selectivity index). The new inhibitors thus identified were modified, based on the docking models, and revealed preliminary structure-activity relationships. Moreover, the GENIUS in silico screening performance was validated by using an enrichment factor. We believe our designed scaffold could contribute to the improvement of HCV chemotherapy. (C) 2011 Elsevier Ltd. All rights reserved.
• NIK-333(非環式レチノイド)は自然免疫系やISG15システムを介してC型肝炎ウイルスの増殖を抑制する

  中牟田 誠, 国府島 庸之, 矢田 雅佳, 坂本 直哉, 後藤 和人, 吉本 剛志, 福嶋 伸良, 福泉 公仁隆, 河邉 顕, 水谷 孝弘, 原田 直彦, 武冨 紹信, 前原 喜彦, 遠城寺 宗近

  肝臓 (一社)日本肝臓学会 52 (Suppl.2) A587 - A587 0451-4203 2011/09 [Refereed][Not invited]
  
• Role of intercellular junctions in redistribution of focal adhesions and orientation of vascular endothelial cells exposed to cyclic stretching

  Wenjing Huang, Naoya Sakamoto, Kazuhiko Hanamura, Ryotaro Miyazawa, Masaaki Sato

  Cellular and Molecular Bioengineering 4 (3) 368 - 378 1865-5025 2011/09 [Refereed][Not invited]
   

  The redistribution of focal adhesions (FAs) containing integrin b1 and paxillin plays an important role in the cyclic stretching-induced morphological changes of endothelial cells (ECs). In addition to focal adhesion kinase (FAK), known to be a primary regulator for FA redistribution, intercellular junctions (IJs) have recently been reported to be involved in signaling upstream of FAs. Here, we addressed the role of IJs in the morphological changes and redistribution of FAs in ECs exposed to cyclic stretching. Both confluent and sparse ECs were oriented nearly perpendicularly to the stretch direction after 10 min of exposure. Orientation of sparse ECs, but not confluent ECs, was suppressed by treatment with a phospho-FAK inhibitor. FAK inhibitor blocked integrin b1 redistribution in ECs, which was observed in non-inhibited cells after 10-min stretch exposure. However, paxillin redistribution in confluent ECs was observed regardless of FAK inhibitor treatment after 2-min stretch exposure. When we blocked signals from IJs with an inhibitor of Src homology 2 domain-containing tyrosine phosphatase-2, the percentage of oriented ECs decreased and paxillin redistribution, but not integrin b1, was suppressed. These findings suggest that IJs are involved in the orientation of ECs subjected to cyclic stretching through signaling pathways other than FAK. © 2011 Biomedical Engineering Society.
• Pretreatment prediction of anemia progression by pegylated interferon alpha-2b plus ribavirin combination therapy in chronic hepatitis C infection: decision-tree analysis.

  Naoki Hiramatsu, Masayuki Kurosaki, Naoya Sakamoto, Manabu Iwasaki, Minoru Sakamoto, Yoshiyuki Suzuki, Fuminaka Sugauchi, Akihiro Tamori, Sei Kakinnuma, Kentaro Matsuura, Namiki Izumi

  Journal of gastroenterology 46 (9) 1111 - 9 1435-5922 2011/09 [Refereed][Not invited]
   

  BACKGROUND: This study aimed to develop a model to predict the development of severe anemia during pegylated interferon alpha-2b plus ribavirin combination therapy. METHODS: Data were collected from 1081 genotype 1b chronic hepatitis C patients who were treated at 6 hospitals in Japan. These patients were randomly assigned to a model-building group (n = 691) or an internal validation group (n = 390). Factors predictive of severe anemia (hemoglobin, Hb < 8.5 g/dl) were explored using data-mining analysis. RESULTS: Hb values at baseline, creatinine clearance (Ccr), and an Hb concentration decline by 2 g/dl at week 2 were used to build a decision-tree model, in which the patients were divided into 5 subgroups based on variable rates of severe anemia ranging from 0.4 to 11.8%. The reproducibility of the model was confirmed by the internal validation group (r² = 0.96). The probability of severe anemia was high in patients whose Hb value was <14 g/dl before treatment (6.5%), especially (a) in those whose Ccr was <80 ml/min (11.8%) and (b) those whose Ccr was ≥ 80 ml/min but whose Hb concentration decline at week 2 was ≥ 2 g/dl (11.5%). The probability of severe anemia was low in the other patients (0.4-2.5%). CONCLUSIONS: The decision-tree model that included Hb values at baseline, Ccr, and an Hb concentration decline by 2 g/dl at week 2 was useful for predicting the probability of severe anemia, and has the potential to support clinical decisions regarding early dose reduction of ribavirin.
• Combined stimulation with cyclic stretching and hypoxia increases production of matrix metalloproteinase-9 and cytokines by macrophages

  Koki Oya, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 412 (4) 678 - 682 0006-291X 2011/09 [Refereed][Not invited]
   

  Macrophages in the vessel wall of advanced abdominal aortic aneurysms (AAAs) are subjected to cyclic stretching and hypoxia because of pulsatile blood flow and intraluminal thrombi, respectively. It is possible that these conditions induce abnormal changes in macrophage functions, such as increased production of matrix metalloproteinase-2 (MMP-2), MMP-9, and inflammatory cytokines, leading to weakening of the aortic wall through excessive extracellular matrix disruption. Here we show the effects of cyclic stretching and hypoxia on the production of MMP-9 and inflammatory cytokines by macrophages. Gelatin zymography revealed that MMP-9 production by macrophages was significantly increased by 5% and 10% cyclic stretching under hypoxia (2.2% O-2). Using enzyme-linked immunosorbent assay, we also evaluated the production of 12 different inflammatory cytokines and found that there was a tendency toward higher expressions of interleukin-8 and tumor necrosis factor-alpha by macrophages subjected to 10% cyclic stretching under normoxia and hypoxia. Next, we evaluated apoptosis of smooth muscle cells (SMCs) in medium conditioned by macrophages cultured under the 2 conditions described above. SMC apoptosis increased significantly when exposed to media harvested from macrophages subjected to 10% cyclic stretching under normoxia and hypoxia. On the basis of these results, we believe that macrophages produce cytokines that induce SMC apoptosis. Our results suggest that the combination of cyclic stretching and hypoxia stimulates MMP-9 and cytokine production in macrophages, which may result in weakening of AAA walls. (C) 2011 Elsevier Inc. All rights reserved.
• Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy

  Makoto Kadokura, Shinya Maekawa, Ryota Sueki, Mika Miura, Kazuki Komase, Hiroko Shindo, Fumitake Amemiya, Tomoyoshi Uetake, Taisuke Inoue, Minoru Sakamoto, Mina Nakagawa, Naoya Sakamoto, Mamoru Watanabe, Nobuyuki Enomoto

  HEPATOLOGY INTERNATIONAL 5 (3) 789 - 799 1936-0533 2011/09 [Refereed][Not invited]
   

  Purpose A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome. Methods The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored. Results Patients with SVR (n = 58) and with non-SVR (n = 20) differed significantly in pretreatment HCV RNA level (p = 0.002), fibrosis score (p = 0.047), and cumulative RBV dosage (p = 0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p = 0.01 for group 1, p = 0.004 for group 2, and p = 5E-05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258-2306 region were significantly high in SVR compared to non-SVR patients (p = 0.01 for group 1, p = 0.006 for group 2, and p = 0.0006 for combined). Multivariate analyses revealed that core aa 110 (p = 0.02), NS5A aa 2258-2306 (p = 0.03), and cumulative RBV dosage (p = 0.02) were identified as independent variables associated with the final outcome. Conclusions The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.
• Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C

  Yasuhito Tanaka, Masayuki Kurosaki, Nao Nishida, Masaya Sugiyama, Kentaro Matsuura, Naoya Sakamoto, Nobuyuki Enomoto, Hiroshi Yatsuhashi, Shuhei Nishiguchi, Keisuke Hino, Shuhei Hige, Yoshito Itoh, Eiji Tanaka, Satoshi Mochida, Masao Honda, Yoichi Hiasa, Asako Koike, Fuminaka Sugauchi, Shuichi Kaneko, Namiki Izumi, Katsushi Tokunaga, Masashi Mizokami

  HUMAN MOLECULAR GENETICS 20 (17) 3507 - 3516 0964-6906 2011/09 [Refereed][Not invited]
   

  Hematologic abnormalities during current therapy with pegylated interferon and ribavirin (PEG-IFN/RBV) for chronic hepatitis C (CHC) often necessitate dose reduction and premature withdrawal from therapy. The aim of this study was to identify host factors associated with IFN-induced thrombocytopenia by genome-wide association study (GWAS). In the GWAS stage using 900K single-nucleotide polymorphism (SNP) microarrays, 303 Japanese CHC patients treated with PEG-IFN/RBV therapy were genotyped. One SNP (rs11697186) located on DDRGK1 gene on chromosome 20 showed strong associations in the minor-allele-dominant model with the decrease of platelet counts in response to PEG-IFN/RBVtherapy [P = 8.17 x 10(-9); odds ratio (OR) = 4.6]. These associations were replicated in another sample set (n = 391) and the combined P-values reached 5.29 x 10(-17) (OR = 4.5). Fine mapping with 22 SNPs around DDRGK1 and ITPA genes showed that rs11697186 at the GWAS stage had a strong linkage disequilibrium with rs1127354, known as a functional variant in the ITPA gene. The ITPA-AA/CA genotype was independently associated with a higher degree of reduction in platelet counts at week 4 (P < 0.0001), as well as protection against the reduction in hemoglobin, whereas the CC genotype had significantly less reduction in the mean platelet counts compared with the AA/CA genotype (P < 0.0001 for weeks 2, 4, 8, 12), due to a reactive increase of the platelet count through weeks 1-4. Our present results may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events.
• Pretreatment prediction of anemia progression by pegylated interferon alpha-2b plus ribavirin combination therapy in chronic hepatitis C infection: decision-tree analysis

  Naoki Hiramatsu, Masayuki Kurosaki, Naoya Sakamoto, Manabu Iwasaki, Minoru Sakamoto, Yoshiyuki Suzuki, Fuminaka Sugauchi, Akihiro Tamori, Sei Kakinnuma, Kentaro Matsuura, Namiki Izumi

  JOURNAL OF GASTROENTEROLOGY 46 (9) 1111 - 1119 0944-1174 2011/09 [Refereed][Not invited]
   

  Background This study aimed to develop a model to predict the development of severe anemia during pegylated interferon alpha-2b plus ribavirin combination therapy. Methods Data were collected from 1081 genotype 1b chronic hepatitis C patients who were treated at 6 hospitals in Japan. These patients were randomly assigned to a model-building group (n = 691) or an internal validation group (n = 390). Factors predictive of severe anemia (hemoglobin, Hb < 8.5 g/dl) were explored using data-mining analysis. Results Hb values at baseline, creatinine clearance (Ccr), and an Hb concentration decline by 2 g/dl at week 2 were used to build a decision-tree model, in which the patients were divided into 5 subgroups based on variable rates of severe anemia ranging from 0.4 to 11.8%. The reproducibility of the model was confirmed by the internal validation group (r(2) = 0.96). The probability of severe anemia was high in patients whose Hb value was <14 g/dl before treatment (6.5%), especially (a) in those whose Ccr was <80 ml/min (11.8%) and (b) those whose Ccr was >= 80 ml/min but whose Hb concentration decline at week 2 was >= 2 g/dl (11.5%). The probability of severe anemia was low in the other patients (0.4-2.5%). Conclusions The decision-tree model that included Hb values at baseline, Ccr, and an Hb concentration decline by 2 g/dl at week 2 was useful for predicting the probability of severe anemia, and has the potential to support clinical decisions regarding early dose reduction of ribavirin.
• Analysis of the Complete Open Reading Frame of Genotype 2b Hepatitis C Virus in Association with the Response to Peginterferon and Ribavirin Therapy

  Makoto Kadokura, Shinya Maekawa, Ryota Sueki, Mika Miura, Kazuki Komase, Hiroko Shindo, Fumitake Amemiya, Tomoyoshi Uetake, Taisuke Inoue, Minoru Sakamoto, Mina Nakagawa, Naoya Sakamoto, Mamoru Watanabe, Nobuyuki Enomoto

  PLOS ONE 6 (9) e24514  1932-6203 2011/09 [Refereed][Not invited]
   

  Background and Aims: Patients infected with genotype 2b hepatitis C virus (HCV) generally can achieve favorable responses to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV). However, a proportion of patients show poorer responses and the correlation between viral sequence variation and treatment outcome remains unclear. Methods: The pretreatment complete open reading frame (ORF) sequences of genotype 2b HCV determined by direct sequencing were investigated for correlation with the final outcome in a total of 60 patients. Results: In this study group, 87.5% (14/16) of non-sustained virological response (non-SVR) patients (n = 16) were relapsers. Compared to sustained virological response (SVR) patients (n = 44), non-SVR patients were older and could not achieve prompt viral clearance after the therapy induction. Comparing each viral protein between the two groups, viral sequences were more diverse in SVR patients and that diversity was found primarily in the E1, p7, and NS5A proteins. In searching for specific viral regions associated with the final outcome, several regions in E2, p7, NS2, NS5A, and NS5B were extracted. Among these regions, part of the interferon sensitivity determining region (ISDR) was included. In these regions, amino acid substitutions were associated with the final outcome in an incremental manner, depending upon the number of substitutions. Conclusions: Viral sequences are more diverse in SVR patients than non-SVR patients receiving PEG-IFN/RBV therapy for genotype-2b HCV infection. Through systematic comparison of viral sequences, several specific regions, including part of the ISDR, were extracted as having significant correlation with the final outcome.
• Oxygen isotopic compositions of asteroidal materials returned from Itokawa by the Hayabusa mission.

  Hisayoshi Yurimoto, Ken-ichi Abe, Masanao Abe, Mitsuru Ebihara, Akio Fujimura, Minako Hashiguchi, Ko Hashizume, Trevor R Ireland, Shoichi Itoh, Juri Katayama, Chizu Kato, Junichiro Kawaguchi, Noriyuki Kawasaki, Fumio Kitajima, Sachio Kobayashi, Tatsuji Meike, Toshifumi Mukai, Keisuke Nagao, Tomoki Nakamura, Hiroshi Naraoka, Takaaki Noguchi, Ryuji Okazaki, Changkun Park, Naoya Sakamoto, Yusuke Seto, Masashi Takei, Akira Tsuchiyama, Masayuki Uesugi, Shigeyuki Wakaki, Toru Yada, Kosuke Yamamoto, Makoto Yoshikawa, Michael E Zolensky

  Science (New York, N.Y.) 333 (6046) 1116 - 9 0036-8075 2011/08/26 [Refereed][Not invited]
   

  Meteorite studies suggest that each solar system object has a unique oxygen isotopic composition. Chondrites, the most primitive of meteorites, have been believed to be derived from asteroids, but oxygen isotopic compositions of asteroids themselves have not been established. We measured, using secondary ion mass spectrometry, oxygen isotopic compositions of rock particles from asteroid 25143 Itokawa returned by the Hayabusa spacecraft. Compositions of the particles are depleted in (16)O relative to terrestrial materials and indicate that Itokawa, an S-type asteroid, is one of the sources of the LL or L group of equilibrated ordinary chondrites. This is a direct oxygen-isotope link between chondrites and their parent asteroid.
• Effect of initial orientation of vascular endothelial cells on activation of RhoGTPases induced by fluid shear stress

  Kazuma Nishio, Yosuke Ueki, Naoya Sakamoto, Masaaki Sato

  Cellular and Molecular Bioengineering 4 (2) 160 - 168 1865-5025 2011/06 [Refereed][Not invited]
   

  Vascular endothelial cells (ECs) exposed to fluid shear stress (FSS) become elongated and aligned to the direction of flow. However, the process of morphological change in individual cells is different depending of their initial shape. Rac1 and RhoA, members of the family of Rho GTPases, play important roles in cellular morphological changes but are thought to be activated differently in the process. Here, we measured changes in Rac1 and RhoA activities with a focus on the effect of cell orientation when exposed to FSS. In ECs initially oriented parallel to the direction of flow, RhoA and Rac1 were activated primarily in the upstream and the downstream regions of cells, respectively, accompanied by the formation of lamellipodia in the direction of flow. On the other hand, in cells oriented perpendicular to the direction of flow, FSS caused RhoA activation in the upstream region but did not change Rac1 activity. Furthermore, treatment with cytochalasin D inhibited the localization of Rac1 activation and suppressed RhoA activation by FSS. These results indicate that cell orientation affects the local activation of Rac1 and RhoA when induced by forces transmitted through the actin cytoskeleton under a FSS condition. © 2011 Biomedical Engineering Society.
• Inhibitory Effect of a Triterpenoid Compound, with or without Alpha Interferon, on Hepatitis C Virus Infection

  Takako Watanabe, Naoya Sakamoto, Mina Nakagawa, Sei Kakinuma, Yasuhiro Itsui, Yuki Nishimura-Sakurai, Mayumi Ueyama, Yusuke Funaoka, Akiko Kitazume, Sayuri Nitta, Kei Kiyohashi, Miyako Murakawa, Seishin Azuma, Kiichiro Tsuchiya, Shinya Oooka, Mamoru Watanabe

  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 55 (6) 2537 - 2545 0066-4804 2011/06 [Refereed][Not invited]
   

  A lack of patient response to alpha interferon (alpha-IFN) plus ribavirin (RBV) treatment is a major problem in eliminating hepatitis C virus (HCV). We screened chemical libraries for compounds that enhanced cellular responses to alpha-IFN and identified a triterpenoid, toosendanin (TSN). Here, we studied the effects and mechanisms of action of TSN on HCV replication and its effect on alpha-IFN signaling. We treated HCV genotype 1b replicon-expressing cells and HCV-J6/JFH-infected cells with TSN, with or without alpha-IFN, and the level of HCV replication was quantified. To study the effects of TSN on alpha-IFN signaling, we detected components of the interferon-stimulated gene factor 3 (ISGF3), phosphorylated signal transducer and activator of transcription 1 (STAT1), and STAT2 by Western blotting analysis; expression levels of mRNA of interferon regulatory factor 9 using real-time reverse transcription-PCR (RT-PCR); and interferon-stimulated response element reporter activity and measured the expression levels of interferon-inducible genes for 2',5'-oligoadenylate synthetase, MxA, protein kinase R, and p56 using real-time RT-PCR. TSN alone specifically inhibited expression of the HCV replicon (50% effective concentration = 20.6 nM, 50% cytotoxic concentration > 3 mu M, selectivity index > 146). Pretreatment with TSN prior to alpha-IFN treatment was more effective in suppressing HCV replication than treatment with either drug alone. Although TSN alone did not activate the alpha-IFN pathway, it significantly enhanced the alpha-IFN-induced increase of phosphorylated STATs, interferon-stimulated response element activation, and interferon-stimulated gene expression. TSN significantly increased baseline expression of interferon regulatory factor 9, a component of interferon-stimulated gene factor 3. Antiviral effects of treatment with alpha-IFN can be enhanced by pretreatment with TSN. Its mechanisms of action could potentially be important to identify novel molecular targets to treat HCV infection.
• Analysis of Interferon Signaling by Infectious Hepatitis C Virus Clones with Substitutions of Core Amino Acids 70 and 91

  Yusuke Funaoka, Naoya Sakamoto, Goki Suda, Yasuhiro Itsui, Mina Nakagawa, Sei Kakinuma, Takako Watanabe, Kako Mishima, Mayumi Ueyama, Izumi Onozuka, Sayuri Nitta, Akiko Kitazume, Kei Kiyohashi, Miyako Murakawa, Seishin Azuma, Kiichiro Tsuchiya, Mamoru Watanabe

  JOURNAL OF VIROLOGY 85 (12) 5986 - 5994 0022-538X 2011/06 [Refereed][Not invited]
   

  Substitution of amino acids 70 and 91 in the hepatitis C virus (HCV) core region is a significant predictor of poor responses to peginterferon-plus-ribavirin therapy, while their molecular mechanisms remain unclear. Here we investigated these differences in the response to alpha interferon (IFN) by using HCV cell culture with R70Q, R70H, and L91M substitutions. IFN treatment of cells transfected or infected with the wild type or the mutant HCV clones showed that the R70Q, R70H, and L91M core mutants were significantly more resistant than the wild type. Among HCV-transfected cells, intracellular HCV RNA levels were significantly higher for the core mutants than for the wild type, while HCV RNA in culture supernatant was significantly lower for these mutants than for the wild type. IFN-induced phosphorylation of STAT1 and STAT2 and expression of the interferon-inducible genes were significantly lower for the core mutants than for the wild type, suggesting cellular unresponsiveness to IFN. The expression level of an interferon signal attenuator, SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type. Interleukin 6 (IL-6), which upregulates SOCS3, was significantly higher for the R70Q, R70H, and L91M mutants than for the wild type, suggesting interferon resistance, possibly through IL-6-induced, SOCS3-mediated suppression of interferon signaling. Expression levels of endoplasmic reticulum (ER) stress proteins were significantly higher in cells transfected with a core mutant than in those transfected with the wild type. In conclusion, HCV R70 and L91 core mutants were resistant to interferon in vitro, and the resistance may be induced by IL-6-induced upregulation of SOCS3. Those mechanisms may explain clinical interferon resistance of HCV core mutants.
• Adenovirus vector-mediated assay system for hepatitis C virus replication

  Takeshi Yoshida, Masuo Kondoh, Manabu Ojima, Hiroyuki Mizuguchi, Yoshiaki Yamagishi, Naoya Sakamoto, Kiyohito Yagi

  NUCLEIC ACIDS RESEARCH 39 (10) e64  0305-1048 2011/05 [Refereed][Not invited]
   

  The efficient delivery of the hepatitis C virus (HCV) RNA subgenomic replicon into cells is useful for basic and pharmaceutical studies. The adenovirus (Ad) vector is a convenient and efficient tool for the transduction of foreign genes into cells in vitro and in vivo. However, an Ad vector expressing the HCV replicon has never been developed. In the present study, we developed Ad vector containing an RNA polymerase (pol) I-dependent expression cassette and a tetracycline-controllable RNA pol I-dependent expression system. We prepared a hybrid promoter from the tetracycline-responsive element and the RNA pol I promoter. Ad vector particles coding the hybrid promoter-driven HCV replicon could be amplified, and interferon, an inhibitor of HCV replication, reduced HCV replication in cells transduced with the Ad vector coding HCV replicon. This is the first report of the development of an Ad vector-mediated HCV replicon system.
• Association between lipid accumulation and the cannabinoid system in Huh7 cells expressing HCV genes

  Mako Toyoda, Akira Kitaoka, Kazuyuki Machida, Takuya Nishinakagawa, Ryoko Yada, Motoyuki Kohjima, Masaki Kato, Kazuhiro Kotoh, Naoya Sakamoto, Goshi Shiota, Makoto Nakamuta, Manabu Nakashima, Munechika Enjoji

  INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 27 (5) 619 - 624 1107-3756 2011/05 [Refereed][Not invited]
   

  Evidence from clinical and laboratory studies has accumulated indicating that the activation of the cannabinoid system is crucial for steatosis, especially in non-alcoholic fatty liver disease. However, the association between hepatitis C virus (HCV) infection and the cannabinoid system has not been well investigated and it is unclear whether steatosis in chronic hepatitis C develops via activation of the endocannabinoid/cannabinoid receptor signaling pathway. In this study, we examined the expression of a cannabinoid receptor (CBI.) and the lipid accumulation in the hepatic Huh7 cell line, expressing HCV genes. We utilized Huh7/Rep-Feo-lb cells stably expressing HCV non-structural proteins (NS) 3, NS4, NS5A, and NS5B, as well as Tet-On Core-2 cells, in which the HCV core protein expression is inducible. Significantly higher levels of stored triglycerides were found in Huh7/Rep-Feo-lb cells compared to Huh7 cells. Also, triglyceride accumulation and CBI receptor expression were down-regulated in Huh7/Rep-Teo-lb cells after HCV reduction by IFN alpha. Moreover, lipid accumulation appeared to increase after CBI agonist treatment, while it decreased after CBI antagonist treatment, although significant differences were not found compared to untreated cells. In Tet-On Core-2 cells, induction of HCV core protein expression did not affect CB1 expression or triglyceride accumulation. The results of this study in cultured cells suggest that HCV infection may activate the cannabinoid system and precede steatosis, but the core protein by itself may not have any effect on the cannabinoid system.
• Association of IL28B Variants With Response to Pegylated-Interferon Alpha Plus Ribavirin Combination Therapy Reveals Intersubgenotypic Differences Between Genotypes 2a and 2b

  Naoya Sakamoto, Mina Nakagawa, Yasuhito Tanaka, Yuko Sekine-Osajima, Mayumi Ueyama, Masayuki Kurosaki, Nao Nishida, Akihiro Tamori, Nishimura-Sakurai Yuki, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Shuhei Hige, Yoshito Itoh, Eiji Tanaka, Yoichi Hiasa, Namiki Izumi, Katsushi Tokunaga, Masashi Mizokami, Mamoru Watanabe

  JOURNAL OF MEDICAL VIROLOGY 83 (5) 871 - 878 0146-6615 2011/05 [Refereed][Not invited]
   

  Genetic polymorphisms of the interleukin 28B (IL28B) locus are associated closely with outcomes of pegylated-interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. The aim of this study was to investigate the relationship between IL28B polymorphism and responses to therapy in patients infected with genotype 2. One hundred twenty-nine chronic hepatitis C patients infected with genotype 2, 77 patients with genotype 2a and 52 patients with genotype 2b, were analyzed. Clinical and laboratory parameters, including genetic variation near the IL28B gene (rs8099917), were assessed. Drug adherence was monitored in each patient. Univariate and multivariate statistical analyses of these parameters and clinical responses were carried out. Univariate analyses showed that a sustained virological response was correlated significantly with IL28B polymorphism, as well as age, white blood cell and neutrophil counts, adherence to RBV, and rapid virological response. Subgroup analysis revealed that patients infected with genotype 2b achieved significantly lower rapid virological response rates than those with genotype 2a. Patients with the IL28B-major allele showed higher virus clearance rates at each time point than those with the IL28B-minor allele, and the differences were more profound in patients infected with genotype 2b than those with genotype 2a. Furthermore, both rapid and sustained virological responses were associated significantly with IL28B alleles in patients with genotype 2b. IL28B polymorphism was predictive of PEG-IFN plus RBV combination treatment outcomes in patients infected with genotype 2 and, especially, with genotype 2b. In conclusion, IL-28B polymorphism affects responses to PEG-IFN-based treatment in difficult-to-treat HCV patients. J. Med. Virol. 83:871-878, 2011. (C) 2011 Wiley-Liss, Inc.
• [Mechanism of hepatitis C virus (HCV) RNA replication and HCV genetic variability].

  Sekine-Osajima Y, Nakagawa M, Sakamoto N

  Nihon rinsho. Japanese journal of clinical medicine 日本臨床社 69 Suppl 4 52 - 58 0047-1852 2011/05 [Refereed][Not invited]
  
• Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice

  Izumi Onozuka, Sei Kakinuma, Akihide Kamiya, Masato Miyoshi, Naoya Sakamoto, Kei Kiyohashi, Takako Watanabe, Yusuke Funaoka, Mayumi Ueyama, Mina Nakagawa, Naohiko Koshikawa, Motoharu Seiki, Hiromitsu Nakauchi, Mamoru Watanabe

  Biochemical and Biophysical Research Communications 406 (1) 134 - 140 0006-291X 2011/03/04 [Not refereed][Not invited]
   

  Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice toxin (carbon tetrachloride, CCl4)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wild-type mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP-2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor β, platelet-derived growth factor receptor and MMP-14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up-regulation during liver fibrosis. © 2011 Elsevier Inc.
• Clinicopathological significance of nuclear factor-kappa B activation in hepatocellular carcinoma

  Hideki Yokoo, Jun Yasuda, Kazuaki Nakanishi, Makoto Chuma, Toshiya Kamiyama, Satoru Todo, Setsuo Hirohashi, Michiie Sakamoto

  HEPATOLOGY RESEARCH 41 (3) 240 - 249 1386-6346 2011/03 [Refereed][Not invited]
   

  Aim: Nuclear factor-kappa B (NF-kappa B) is a critical signaling mediator in inflammation, apoptosis resistance and oncogenesis. It has been reported that NF-kappa B is activated in several cancers, including hepatocellular carcinoma (HCC). Studies of genetic disruptions in mice also suggest that NF-kappa B plays critical roles in hepatocarcinogenesis. The aim of the present study is to characterize NF-kappa B activation and correlate it with the degree of malignancy in HCC. Methods: To examine the correlation between the positivity of the nuclear p50 subunit and HCC recurrence, we analyzed immunostaining of the NF-kappa B p50 subunit in two groups of HCC samples with known prognosis and Akt phosphorylation status: 49 patients showing early recurrence within 6 months (group A) and 50 patients who were recurrence-free for at least for 3 years (group B). Results: In group A, positive nuclear staining of p50 was shown in 18 cases (36.7%), whereas only one case (2.0%) in group B had positive nuclear staining of p50 (P = 2.48839 x 10-5). This suggests a positive relationship between nuclear p50 and early recurrence and advanced HCC in humans. The presence of phosphorylated Akt correlated with nuclear staining of p50 in HCCs in group A (R2 = 0.213, P < 0.001). Conclusion: Our results indicate that nuclear staining of p50 was clearly associated with early recurrent HCC, and the Akt pathway might play a role in NF-kappa B activation in a subset of early recurrent HCC.
• Serum concentration and expression of Reg IV in patients with esophageal cancer: Age-related elevation of serum Reg IV concentration

  Naohide Oue, Tsuyoshi Noguchi, Katsuhiro Anami, Kazuhiro Sentani, Naoya Sakamoto, Naohiro Uraoka, Yuta Wakamatsu, Hiroki Sasaki, Wataru Yasui

  ONCOLOGY LETTERS 2 (2) 235 - 239 1792-1074 2011/03 [Refereed][Not invited]
   

  Regenerating islet-derived family, member 4 (REG4, which encodes Reg IV) is a marker for cancer and inflammatory bowel disease. This study aimed to investigate the diagnostic utility of Reg IV measurement in sera from esophageal cancer patients. Reg IV expression was examined in 269 esophageal cancer samples by immunostaining and the Reg IV levels in sera were measured from 65 patients with esophageal squamous cell carcinoma (SCC) by enzyme-linked immunosorbent assay. No Reg IV staining was detected in 255 SCC and 4 small cell carcinoma samples, whereas Reg IV was stained in 4 of 10 (40%) adenocarcinoma samples. Serum Reg IV concentration in esophageal SCC patients was significantly higher compared to that of the control subjects (P=0.0003). A significant correlation between serum Reg IV concentration and age was found in control subjects (P<0.0001). When serum Reg IV concentration was analyzed according to age, the distribution of serum Reg IV concentration in patients with esophageal SCC was similar to that of the control subjects. These results suggest that Reg IV expression is highly specific for adenocarcinoma of the esophagus. Further investigation is required. to clarify whether Reg IV serves as a serum tumor marker for esophageal cancer.
• Pretreatment prediction of response to peginterferon plus ribavirin therapy in genotype 1 chronic hepatitis C using data mining analysis

  Masayuki Kurosaki, Naoya Sakamoto, Manabu Iwasaki, Minoru Sakamoto, Yoshiyuki Suzuki, Naoki Hiramatsu, Fuminaka Sugauchi, Hiroshi Yatsuhashi, Namiki Izumi

  JOURNAL OF GASTROENTEROLOGY 46 (3) 401 - 409 0944-1174 2011/03 [Refereed][Not invited]
   

  This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C. Data from 800 genotype 1b chronic hepatitis C patients with high viral load (> 100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (n = 506) or an internal validation (n = 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis. Age (< 50 years), alpha-fetoprotein (AFP) (< 8 ng/mL), platelet count (a parts per thousand yen120 x 10(9)/l), gamma-glutamyltransferase (GGT) (< 40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (r (2) = 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group. A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy.
• Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors

  Masayuki Kurosaki, Yasuhito Tanaka, Nao Nishida, Naoya Sakamoto, Nobuyuki Enomoto, Masao Honda, Masaya Sugiyama, Kentaro Matsuura, Fuminaka Sugauchi, Yasuhiro Asahina, Mina Nakagawa, Mamoru Watanabe, Minoru Sakamoto, Shinya Maekawa, Akito Sakai, Shuichi Kaneko, Kiyoaki Ito, Naohiko Masaki, Katsushi Tokunaga, Namiki Izumi, Masashi Mizokami

  JOURNAL OF HEPATOLOGY 54 (3) 439 - 448 0168-8278 2011/03 [Refereed][Not invited]
   

  Background & Aims: Pegylated interferon and ribavirin (PEG-IFN/RBV) therapy for chronic hepatitis C virus (HCV) genotype 1 infection is effective in 50% of patients. Recent studies revealed an association between the IL28B genotype and treatment response. We aimed to develop a model for the pre-treatment prediction of response using host and viral factors. Methods: Data were collected from 496 patients with HCV genotype 1 treated with PEG-IFN/RBV at five hospitals and universities in Japan. IL28B genotype and mutations in the core and IFN sensitivity determining region (ISDR) of HCV were analyzed to predict response to therapy. The decision model was generated by data mining analysis. Results: The IL28B polymorphism correlated with early virological response and predicted null virological response (NVR) (odds ratio = 20.83, p <0.0001) and sustained virological response (SVR) (odds ratio = 7.41, p <0.0001) independent of other covariates. Mutations in the ISDR predicted relapse and SVR independent of IL28B. The decision model revealed that patients with the minor IL28B allele and low platelet counts had the highest NVR (84%) and lowest SVR (7%), whereas those with the major IL28B allele and mutations in the ISDR or high platelet counts had the lowest NVR (0-17%) and highest SVR (61-90%). The model had high reproducibility and predicted SVR with 78% specificity and 70% sensitivity. Conclusions: The IL28B polymorphism and mutations in the ISDR of HCV were significant pre-treatment predictors of response to PEG-IFN/RBV. The decision model, including these host and viral factors may support selection of optimum treatment strategy for individual patients. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
• Sequences in the Interferon Sensitivity-Determining Region and Core Region of Hepatitis C Virus Impact Pretreatment Prediction of Response to PEG-Interferon Plus Ribavirin: Data Mining Analysis

  Masayuki Kurosaki, Naoya Sakamoto, Manabu Iwasaki, Minoru Sakamoto, Yoshiyuki Suzuki, Naoki Hiramatsu, Fuminaka Sugauchi, Akihiro Tamori, Mina Nakagawa, Namiki Izumi

  JOURNAL OF MEDICAL VIROLOGY 83 (3) 445 - 452 0146-6615 2011/03 [Refereed][Not invited]
   

  The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity-determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG-IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P= 0.01) predicted sustained virological response independent of other covariates. The decision-tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0-1) but was 83% in selected subgroups of younger patients (<60 years), wild-type sequence at Core70, and higher level of low-density lipoprotein cholesterol (LDL-C) (>= 120 mg/dl). Reproducibility of the model was validated (r(2) = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG-IFN plus RBV therapy. A decision-tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response. J. Med. Virel. 83:445-452,2011. (C) 2011 Wiley-Liss, Inc.
• Studies on virus kinetics using infectious fluorescence-tagged hepatitis C virus cell culture

  Machi Yamamoto, Naoya Sakamoto, Tetsuya Nakamura, Yasuhiro Itsui, Mina Nakagawa, Yuki Nishimura-Sakurai, Sei Kakinuma, Seishin Azuma, Kiichiro Tsuchiya, Takanobu Kato, Takaji Wakita, Mamoru Watanabe

  HEPATOLOGY RESEARCH 41 (3) 258 - 269 1386-6346 2011/03 [Refereed][Not invited]
   

  Aim: Studies of the complete hepatitis C virus (HCV) life cycle have become possible with the development of a HCV-JFH1 cell culture system. Methods: In this study, we constructed two fluorescence protein-tagged recombinant JFH1 virus clones, JFH1-EYFP and JFH1-AsRed, as well as two corresponding clones with adaptive mutations, JFH1-EYFP mutant and JFH1-AsRed mutant, that and were as effective as JFH1 in producing infectious virus particles, and investigated their viral infection life cycles. Results: After infection of the fluorescence-tagged mutant viruses, infected cells increased exponentially. In cells, EYFP or AsRed and NS5A were expressed as a fusion protein and co-localized in core proteins. The rate of the cell-cell spread was dependent on the cell densities with a maximum of 102.5/day. Treatment of cells with interferon or a protease inhibitor suppressed expansion of virus-positive cells. Conclusion: Taken together, these results indicate that fluorescence-tagged HCV is a useful tool to study virus infection life cycles and to assist in the search for novel antiviral compounds.
• Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice

  Izumi Onozuka, Sei Kakinuma, Akihide Kamiya, Masato Miyoshi, Naoya Sakamoto, Kei Kiyohashi, Takako Watanabe, Yusuke Funaoka, Mayumi Ueyama, Mina Nakagawa, Naohiko Koshikawa, Motoharu Seiki, Hiromitsu Nakauchi, Mamoru Watanabe

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 406 (1) 134 - 140 0006-291X 2011/03 [Refereed][Not invited]
   

  Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice; toxin (carbon tetrachloride, CC14)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wildtype mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor p, platelet-derived growth factor receptor and MMP-14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up-regulation during liver fibrosis. (C) 2011 Elsevier Inc. All rights reserved.
• Longitudinal cell formation in the entire human small intestine is correlated with the localization of Hath1 and Klf4

  Michiko Iwasaki, Kiichiro Tsuchiya, Ryuichi Okamoto, Xiu Zheng, Yoshihito Kano, Eiko Okamoto, Eriko Okada, Akihiro Araki, Shinji Suzuki, Naoya Sakamoto, Keisuke Kitagaki, Takumi Akashi, Yoshinobu Eishi, Tetsuya Nakamura, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY 46 (2) 191 - 202 0944-1174 2011/02 [Refereed][Not invited]
   

  Double balloon endoscopy (DBE) enables the observation and collection of viable specimens from the entire intestine, thereby allowing more detailed investigation of how the structure and function of the human small intestine are regulated. The present study aimed to elucidate the regulation of cell formation in the human small intestine using biopsy specimens collected from an entire individual small intestine by DBE. The expression and the localization of representative genes for the differentiation program were analyzed in the entire small intestine of 10 patients. The functional correlation between Hath1 and Klf4 was analyzed in an intestinal cell line by using a Tet-On system. In longitudinal cell formation in the small intestine, it was shown that goblet cells, but not Paneth cells, increased toward the ileum in each individual small intestine. Immunohistochemistry showed that Hath1-expressing cells migrated from the base of the crypt to the top of the villi in the terminal ileum, while Klf4-expressing cells migrated from the top of the villus, resulting in the colocalization of Hath1 and Klf4 in the terminal ileum. Coexpression of Hath1 and Klf4 upregulated the expression of phenotypic genes for goblet cells following the downregulation of those for Paneth cells. Using mapping biopsy by DBE, we have demonstrated, for the first time, the molecular basis of the villus structure in the entire human small intestine in vivo. The present study showed that longitudinal cell formation was regulated by the colocalization of Hath1 and Klf4 that converted Paneth cell differentiation into goblet cell differentiation.
• Intercellular junctions play an important role in orientation of vascular endothelial cells exposed to cyclic stretch

  Wenjing Huang, Naoya Sakamoto, Kazuhiko Hanamura, Ryotaro Miyazawa, Masaaki Sato

  ASME 2011 Summer Bioengineering Conference, SBC 2011 1153 - 1154 2011 [Refereed][Not invited]
  
• Identification of Transmembrane Protein in Prostate Cancer by the Escherichia coli Ampicillin Secretion Trap: Expression of CDON Is Involved in Tumor Cell Growth and Invasion

  Tetsutaro Hayashi, Naohide Oue, Naoya Sakamoto, Katsuhiro Anami, Htoo Zarni Oo, Kazuhiro Sentani, Shinya Ohara, Jun Teishima, Akio Matsubara, Wataru Yasui

  PATHOBIOLOGY 78 (5) 277 - 284 1015-2008 2011 [Refereed][Not invited]
   

  Aims: Prostate cancer (PCa) is one of the most common malignancies worldwide. Genes expressed only in cancer tissue, and especially related to proteins located on the cell membrane, will be useful molecular markers for diagnosis and may also be good therapeutic targets. The aim of this study was to identify genes that encode transmembrane proteins present in PCa. Methods and Results: We generated Escherichia coli ampicillin secretion trap (CAST) libraries from 2 PCa cell lines and normal prostate tissues. By sequencing 3,264 colonies from CAST libraries, we identified 18 candidate genes that encode transmembrane proteins present in PCa. Quantitative RT-PCR analysis of these candidates revealed that STEAP1, ADAM9 and CDON were expressed much more highly in PCa than in 15 kinds of normal tissues. Among the candidates, CDON encodes the CDO protein, which is an orphan cell surface receptor of the immunoglobulin superfamily. Additional quantitative RT-PCR revealed that 83% of PCa tissues showed CDON overexpression. Knockdown of CDON in DU145 cells induced 5-fluorouracil-induced apoptosis and inhibited invasion ability. Conclusion: These results suggest that CDON has a high potential as a therapeutic target for PCa. Copyright (C) 2011 S. Karger AG, Basel
• Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection with pegylated-interferon-alpha 2b plus ribavirin

  Mayumi Ueyama, Mina Nakagawa, Naoya Sakamoto, Izumi Onozuka, Yusuke Funaoka, Takako Watanabe, Sayuri Nitta, Kei Kiyohashi, Akiko Kitazume, Miyako Murakawa, Yuki Nishimura-Sakurai, Yuko Sekine-Osajima, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe

  ANTIVIRAL THERAPY 16 (7) 1081 - 1091 1359-6535 2011 [Refereed][Not invited]
   

  Background: Interleukin (IL)-6, a pleiotropic cytokine, is increased in various types of chronic liver disease, including chronic hepatitis C (CHC). It was reported recently that IL-6 is associated with insulin resistance, iron metabolism and interferon resistance, which may affect the outcome of antiviral treatment. In this study, we investigated the association of serum IL-6 levels with outcomes of pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. Methods: We included 149 CHC patients and measured serum IL-6 levels at baseline and at 4, 8 and 12 weeks, and the end of treatment in 49 patients. We performed univariate and multivariate regression analyses for the association of IL-6 levels and clinical and laboratory parameters and treatment responses. Results: Serum IL-6 levels were significantly higher in CHC patients than healthy subjects. Pretreatment IL-6 levels of male patients were inversely correlated with sustained virological response (SVR) in univariate analysis (P=0.012). In male patients with SVR, serum IL-6 levels decreased significantly at 4 weeks of treatment (P=0.029) and remained significantly lower than those of non-SVR patients after 4, 8 and 12 weeks of PEG-IFN plus RBV therapy. Conclusions: Our results suggest that baseline levels of IL-6, as well as their decrease during treatment, are correlated to outcomes of PEG-IFN plus RBV therapy in male patients. Further analyses of IL-6 may provide new strategies for difficult-to-treat CHC patients and prevention of hepatocarcinogenesis.
• IL-6-mediated intersubgenotypic variation of interferon sensitivity in hepatitis C virus genotype 2a/2b chimeric clones

  Goki Suda, Naoya Sakamoto, Yasuhiro Itsui, Mina Nakagawa, Megumi Tasaka-Fujita, Yusuke Funaoka, Takako Watanabe, Sayuri Nitta, Kei Kiyohashi, Seishin Azuma, Sei Kakinuma, Kiichiro Tsuchiya, Michio Imamura, Nobuhiko Hiraga, Kazuaki Chayama, Mamoru Watanabe

  VIROLOGY 407 (1) 80 - 90 0042-6822 2010/11 [Refereed][Not invited]
   

  Mechanisms of difference in interferon sensitivity between hepatitis C virus (HCV) strains have yet to be clarified. Here, we constructed an infectious genotype2b clone and analyzed differences in interferon-alpha sensitivity between HCV-2b and 2a-JFH1 clones using intergenotypic homologous recombination. The HCV-2b/JFH1 chimeric virus able to infect Huh7.5.1 cells and was significantly more sensitive to IFN than JFH1. IFN-induced expression of MxA and 25-OAS was significantly lower in JFH1 than in 2b/JFH1-infected cells. In JFH1-infected cells, expression of SOCS3 and its inducer, IL-6, was significantly higher than in 2b/JFH1-infected cells. The IFN-resistance of JFH1 cells was negated by siRNA-knock down of SOCS3 expression and by pretreatment with anti-IL6 antibody. In conclusion, intergenotypic differences of IFN sensitivity of HCV may be attributable to the sequences of HCV structural proteins and can be determined by SOCS3 and IL-6 expression levels. (C) 2010 Elsevier Inc. All rights reserved.
• ITPA gene variant protects against anemia induced by pegylated interferon-alpha and ribavirin therapy for Japanese patients with chronic hepatitis C

  Naoya Sakamoto, Yasuhito Tanaka, Mina Nakagawa, Hiroshi Yatsuhashi, Shuhei Nishiguchi, Nobuyuki Enomoto, Seishin Azuma, Yuki Nishimura-Sakurai, Sei Kakinuma, Nao Nishida, Katsushi Tokunaga, Masao Honda, Kiyoaki Ito, Masashi Mizokami, Mamoru Watanabe

  HEPATOLOGY RESEARCH 40 (11) 1063 - 1071 1386-6346 2010/11 [Refereed][Not invited]
   

  Aim: Host genetic variants leading to inosine triphosphatase (ITPA) deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in chronic hepatitis C patients receiving ribavirin. In this study, we evaluated the clinical significance of ITPA variants in Japanese hepatitis C patients who were treated with pegylated interferon plus ribavirin. Methods: In this multicenter retrospective cross-sectional study, 474 hepatitis C patients were enrolled who were treated with pegylated interferon plus ribavirin in four geographically different hospitals in Japan. Patients were grouped according to hemoglobin decline of more than 3 g/dL at week 4. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs6051702, rs1127354) were genotyped. Results: A functional SNP, rs1127354, within the ITPA exon was strongly associated with protection against anemia with only one (0.8%) in 129 patients with the ITPA minor variant A developing severe anemia (P = 5.9 x 10-20). For rs6051702, which had significant association in European-Americans, significant but weak association with severe hemoglobin reduction was found in Japanese (P = 0.009). In patients excluding genotype 1b and high viral load, those with the ITPA minor variant A achieved significantly higher sustained viral response rate than those with the major variant (CC) (96% vs 70%, respectively, P = 0.0066). Conclusion: ITPA SNP, rs1127354, is confirmed to be a useful predictor of ribavirin-induced anemia in Japanese patients. Patients with the ITPA minor variant A (similar to 27%) have an advantage in pegylated interferon plus ribavirin-based therapies, due to expected adherence of ribavirin doses, resulting in a higher viral clearance rate.
• Cell culture and in vivo analyses of cytopathic hepatitis C virus mutants

  Kako Mishima, Naoya Sakamoto, Yuko Sekine-Osajima, Mina Nakagawa, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Kei Kiyohashi, Akiko Kitazume, Kiichiro Tsuchiya, Michio Imamura, Nobuhiko Hiraga, Kazuaki Chayama, Takaji Wakita, Mamoru Watanabe

  VIROLOGY 405 (2) 361 - 369 0042-6822 2010/09 [Refereed][Not invited]
   

  HCV-JFH1 yields subclones that develop cytopathic plaques (Sekine-Osajima Y, et al., Virology 2008; 371:71). Here, we investigated viral amino acid substitutions in cytopathic mutant HCV-JFH1 clones and their characteristics in vitro and in vivo. The mutant viruses with individual C2441S, P29385 or R2985P signature substitutions, and with all three substitutions, showed significantly higher intracellular replication efficiencies and greater cytopathic effects than the parental JFH1 in vitro. The mutant HCV-inoculated mice showed significantly higher serum HCV RNA and higher level of expression of ER stress-related proteins in early period of infection. At 8 weeks post inoculation, these signature mutations had reverted to the wild type sequences. HCV-induced cytopathogenicity is associated with the level of intracellular viral replication and is determined by certain amino acid substitutions in HCV-NS5A and NS5B regions. The cytopathic HCV clones exhibit high replication competence in vivo but may be eliminated during the early stages of infection. (C) 2010 Elsevier Inc. All rights reserved.
• IL-2 is positively involved in the development of colitogenic CD4(+) IL-7R alpha(high) memory T cells in chronic colitis

  Kaori Kameyama, Yasuhiro Nemoto, Takanori Kanai, Tamako Shinohara, Ryuichi Okamoto, Kuechiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Teruji Totsuka, Toshifumi Hibi, Mamoru Watanabe

  EUROPEAN JOURNAL OF IMMUNOLOGY 40 (9) 2423 - 2436 0014-2980 2010/09 [Refereed][Not invited]
   

  IL-2 and IL-7 share a common gamma-chain receptor and are critical for T-cell homeostasis. We aimed to clarify the reciprocal roles of IL-2 and IL-7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL-2(-/-) CD4(+) CD45RB(high) T cells into RAG-2(-/-) mice and assessed the role of IL-2 in the induction of IL-7R alpha on colitogenic CD4(+) T cells and the development of chronic colitis. RAG-2(-/-) mice transferred with WT but not with IL-2(-/-) CD4(+)CD45RB(high) T cells developed Th1/Th17-mediated colitis. Consistently, re-expression of IL-7R alpha was severely impaired on IL-2(-/-) but not on WT CD4(+) T cells from the transferred mice. To exclude a contribution of the preclinical autoimmunity of IL-2(-/-) mice, WT Ly5.1(broken vertical bar) or IL-2(-/-) Ly5.2(broken vertical bar) CD4(broken vertical bar) CD45RB(high) T cells from GFP mice previously transplanted with the same number of WT and IL-2(-/-) BM cells were transferred into RAG-2(-/-) mice. RAG-2(-/-) mice transferred with IL-2(-/-) -derived CD4(+) CD45RB(high) T cells did not develop colitis, but their splenic CD4(+) T cells changed from effector-memory to central-memory type. These results show that IL-2 is critically involved in the establishment and maintenance of IL-7-dependent colitogenic memory CD4(+)IL-7R alpha(high) T cells.
• Inhibition of Hepatitis C Virus Replication by a Specific Inhibitor of Serine-Arginine-Rich Protein Kinase

  Yuko Karakama, Naoya Sakamoto, Yasuhiro Itsui, Mina Nakagawa, Megumi Tasaka-Fujita, Yuki Nishimura-Sakurai, Sei Kakinuma, Masaya Oooka, Seishin Azuma, Kiichiro Tsuchiya, Hiroshi Onogi, Masatoshi Hagiwara, Mamoru Watanabe

  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 54 (8) 3179 - 3186 0066-4804 2010/08 [Refereed][Not invited]
   

  Splicing of messenger RNAs is regulated by site-specific binding of members of the serine-arginine-rich (SR) protein family, and SR protein kinases (SRPK) 1 and 2 regulate overall activity of the SR proteins by phosphorylation of their RS domains. We have reported that specifically designed SRPK inhibitors suppressed effectively several DNA and RNA viruses in vitro and in vivo. Here, we show that an SRPK inhibitor, SRPIN340, suppressed in a dose-dependent fashion expression of a hepatitis C virus (HCV) subgenomic replicon and replication of the HCV-JFH1 clone in vitro. The inhibitory effects were not associated with antiproliferative or nonspecific cytotoxic effects on the host cells. Overexpression of SRPK1 or SRPK2 resulted in augmentation of HCV replication, while small interfering RNA (siRNA) knockdown of the SRPKs suppressed HCV replication significantly. Immunocytochemistry showed that SRPKs and the HCV core and NS5A proteins colocalized to some extent in the perinuclear area. Our results demonstrate that SRPKs are host factors essential for HCV replication and that functional inhibitors of these kinases may constitute a new class of antiviral agents against HCV infection.
• Search for transmembrane protein in gastric cancer by the Escherichia coli ampicillin secretion trap: expression of DSC2 in gastric cancer with intestinal phenotype

  Katsuhiro Anami, Naohide Oue, Tsuyoshi Noguchi, Naoya Sakamoto, Kazuhiro Sentani, Tetsutaro Hayashi, Takao Hinoi, Masazumi Okajima, Jonathan M. Graff, Wataru Yasui

  JOURNAL OF PATHOLOGY 221 (3) 275 - 284 0022-3417 2010/07 [Refereed][Not invited]
   

  Gastric cancer (GC) is one of the most common malignancies worldwide. Genes expressed only in cancer tissue, and especially on the cell membrane, will be useful molecular markers for diagnosis and may also be good therapeutic targets. To identify genes that encode transmembrane proteins present in GC, we generated Escherichia coli ampicillin secretion trap (CAST) libraries from two GC cell lines and normal stomach. By sequencing 4320 colonies from CAST libraries, we identified 30 candidate genes that encode transmembrane proteins present in GC. Quantitative reverse transcription-polymerase chain reaction analysis of these candidates revealed that ZDHHC14, BST2, DRAM2, and DSC2 were expressed much more highly in GC than in 14 kinds of normal tissues. Among these, DSC2 encodes desmocollin 2, which is one of three known desmocollins. Immunohistochemical analysis demonstrated that 22 (28%) of 80 GC cases were positive for desmocollin 2, and desmocollin 2 expression was observed frequently in GC with the intestinal mucin phenotype. Furthermore, desmocollin 2 expression was correlated with CDX2 expression. These results suggest that expression of desmocollin 2, induced by CDX2, may be a key regulator for GC with the intestinal mucin phenotype. Our results provide a list of genes that have high potential as a diagnostic and therapeutic target for GC. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
• Role of p120-catenin in the morphological changes of endothelial cells exposed to fluid shear stress

  Naoya Sakamoto, Kei Segawa, Makoto Kanzaki, Toshiro Ohashi, Masaaki Sato

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 398 (3) 426 - 432 0006-291X 2010/07 [Refereed][Not invited]
   

  p120-Catenin is known to play important roles in cell-cell adhesion stability by binding to cadherin and morphological changes of cells by regulating small RhoGTPase activities. Although the expression and binding states of p120-catenin are thought to dynamically change due to morphological adaptation of endothelial cells (ECs) to fluid shear stress, these dynamics remain to be explored. In the present study, we examined the time course of changes in p120-catenin expression and its binding to vascular endothelial (VE)-cadherin in ECs exposed to shear stress. Human umbilical vein ECs began to change their morphologies at 3-6 h, and became elongated and oriented to the direction of flow at 24 h after exposure to a shear stress of 1.5 Pa. Binding and co-localization of p120-catenin with VE-cadherin at the foci of cell-cell adhesions were retained in ECs during exposure to shear stress, indicating that VE-cadherin was stabilized in the plasma membrane. In contrast, cytoplasmic p120-catenin that was dissociated from VE-cadherin was transiently increased at 3-6 h after the flow onset. These results suggest that the transient increase of cytoplasmic p120-catenin may stimulate RhoGTPase activities and act as a switch for the morphological changes in ECs in response to shear stress. (C) 2010 Elsevier Inc. All rights reserved.
• Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection

  Mina Nakagawa, Naoya Sakamoto, Mayumi Ueyama, Kaoru Mogushi, Satoshi Nagaie, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Hiroshi Tanaka, Nobuyuki Enomoto, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY 45 (6) 656 - 665 0944-1174 2010/06 [Refereed][Not invited]
   

  Pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin (RBV) therapy is currently the de-facto standard treatment for hepatitis C virus (HCV) infection. The aims of this study were to analyze the clinical and virological factors associated with a higher rate of response in patients with HCV genotype 1b infection treated with combination therapy. We analyzed, retrospectively, 239 patients with chronic hepatitis C-1b infection who received 48 weeks of combination therapy. We assessed clinical and laboratory parameters, including age, gender, pretreatment hemoglobin, platelet counts, HCV RNA titer, liver histology, the number of interferon sensitivity determining region (ISDR) mutations and substitutions of the core amino acids 70 and 91. Drug adherence was monitored in each patient. We carried out univariate and multivariate statistical analyses of these parameters and clinical responses. On an intention-to-treat (ITT) analysis, 98 of the 239 patients (41%) had sustained virological responses (SVRs). Patients with more than two mutations in the ISDR had significantly higher SVR rates (P < 0.01). Univariate analyses showed that stage of fibrosis, hemoglobin, platelet counts, ISDR mutations, serum HCV RNA level, and adherence to PEG-IFN plus RBV were significantly correlated with SVR rates. Multivariate analysis in subjects with good drug adherence extracted the number of ISDR mutations (two or more: odds ratio [OR] 5.181). The number of mutations in the ISDR sequence of HCV-1b (a parts per thousand yen2) is the most effective parameter predicting a favorable clinical outcome of 48-week PEG-IFN plus RBV therapy in patients with HCV genotype 1b infection.
• Measurements of strain on single stress fibers in living endothelial cells induced by fluid shear stress

  Yosuke Ueki, Yuhei Uda, Naoya Sakamoto, Masaaki Sato

  Biochemical and Biophysical Research Communications 395 (3) 441 - 446 0006-291X 2010/05/07 [Refereed][Not invited]
   

  Fluid shear stress (FSS) acting on the apical surface of endothelial cells (ECs) can be sensed by mechano-sensors in adhesive protein complexes found in focal adhesions and intercellular junctions. This sensing occurs via force transmission through cytoskeletal networks. This study quantitatively evaluated the force transmitted through cytoskeletons to the mechano-sensors by measuring the FSS-induced strain on SFs using live-cell imaging for actin stress fibers (SFs). FSS-induced bending of SFs caused the SFs to align perpendicular to the direction of the flow. In addition, the displacement vectors of the SFs were detected using image correlation and the FSS-induced axial strain of the SFs was calculated. The results indicated that FSS-induced strain on SFs spanned the range 0.01-0.1% at FSSs ranging from 2 to 10 Pa. Together with the tensile property of SFs reported in a previous study, the force exerted on SFs was estimated to range from several to several tens of pN. © 2010 Elsevier Inc. All rights reserved.
• Comparison of HCV-associated gene expression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells

  Yuki Nishimura-Sakurai, Naoya Sakamoto, Kaoru Mogushi, Satoshi Nagaie, Mina Nakagawa, Yasuhiro Itsui, Megumi Tasaka-Fujita, Yuko Onuki-Karakama, Goki Suda, Kako Mishima, Machi Yamamoto, Mayumi Ueyama, Yusuke Funaoka, Takako Watanabe, Seishin Azuma, Yuko Sekine-Osajima, Sei Kakinuma, Kiichiro Tsuchiya, Nobuyuki Enomoto, Hiroshi Tanaka, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY 45 (5) 523 - 536 0944-1174 2010/05 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) replication is affected by several host factors. Here, we screened host genes and molecular pathways that are involved in HCV replication by comprehensive analyses using two genotypes of HCV replicon-expressing cells, their cured cells and na < ve Huh7 cells. Huh7 cell lines that stably expressed HCV genotype 1b or 2a replicon were used. The cured cells were established by treating HCV replicon cells with interferon-alpha. Expression of 54,675 cellular genes was analyzed by GeneChip DNA microarray. The data were analyzed by using the KEGG Pathway database. Hierarchical clustering analysis showed that the gene-expression profiles of each cell group constituted clear clusters of na < ve, HCV replicon-expressed, and cured cell lines. The pathway process analysis between the replicon-expressing and the cured cell lines identified significantly altered pathways, including MAPK, steroid biosynthesis and TGF-beta signaling pathways, suggesting that these pathways were affected directly by HCV replication. Comparison of cured and na < ve Huh7 cells identified pathways, including steroid biosynthesis and sphingolipid metabolism, suggesting that these pathways were required for efficient HCV replication. Cytoplasmic lipid droplets were obviously increased in replicon-expressing and cured cells as compared to na < ve cells. HCV replication was significantly suppressed by peroxisome proliferator-activated receptor (PPAR)-alpha agonists but augmented by PPAR-gamma agonists. Comprehensive gene expression and pathway analyses show that lipid biosynthesis pathways are crucial to support proficient virus replication. These metabolic pathways could constitute novel antiviral targets against HCV.
• Effect of spatial gradient in fluid shear stress on morphological changes in endothelial cells in response to flow

  Naoya Sakamoto, Naoki Saito, Xiaobo Han, Toshiro Ohashi, Masaaki Sato

  Biochemical and Biophysical Research Communications 395 (2) 264 - 269 0006-291X 2010/04/30 [Refereed][Not invited]
   

  Arterial bifurcations are common sites for development of cerebral aneurysms. Although this localization of aneurysms suggests that high shear stress (SS) and high spatial SS gradient (SSG) occurring at the bifurcations may be crucial factors for endothelial dysfunction involved in aneurysm formation, the details of the relationship between the hemodynamic environment and endothelial cell (EC) responses remain unclear. In the present study, we sought morphological responses of ECs under high-SS and high-SSG conditions using a T-shaped flow chamber. Confluent ECs were exposed to SS of 2-10 Pa with SSG of up to 34 Pa/mm for 24 and 72 h. ECs exposed to SS without spatial gradient elongated and oriented to the direction of flow at 72 h through different processes depending on the magnitude of SS. In contrast, cells did not exhibit preferred orientation and elongation under the combination of SS and SSG. Unlike cells aligned to the flow by exposure to only SS, development of actin stress fibers was not observed in ECs exposed to SS with SSG. These results indicate that SSG suppresses morphological changes of ECs in response to flow. © 2010 Elsevier Inc. All rights reserved.
• Direct measurement of shear strain in adherent vascular endothelial cells exposed to fluid shear stress

  Yosuke Ueki, Naoya Sakamoto, Masaaki Sato

  Biochemical and Biophysical Research Communications 394 (1) 94 - 99 0006-291X 2010/03/26 [Refereed][Not invited]
   

  Functional and morphological responses of endothelial cells (ECs) to fluid shear stress are thought to be mediated by several mechanosensitive molecules. However, how the force due to fluid shear stress applied to the apical surface of ECs is transmitted to the mechanosensors is poorly understood. In the present paper, we performed an analysis of an intracellular mechanical field by observation of the deformation behaviors of living ECs exposed to shear stress with a novel experimental method. Lateral images of human umbilical vein ECs before and after the onset of flow were obtained by confocal microscopy, and image correlation and finite element analysis were performed for quantitative analyses of subcellular strain due to shear stress. The shear strain of the cells changed from 1.06 ± 1.09% (mean ± SD) to 4.67 ± 1.79% as the magnitude of the shear stress increased from 2 to 10 Pa. The nuclei of ECs also exhibited shear deformation, which was similar to that observed in cytoplasm, suggesting that nuclei transmit forces from apical to intracellular components, as well as cytoskeletons. The obtained strain-stress relation resulted in a mean shear modulus of 213 Pa for adherent ECs. These results provide a mechanical perspective on the investigation of flow-sensing mechanisms of ECs. © 2010 Elsevier Inc. All rights reserved.
• Inhibition of hepatitis C virus replication by chloroquine targeting virus-associated autophagy

  Tomokazu Mizui, Shunhei Yamashina, Isei Tanida, Yoshiyuki Takei, Takashi Ueno, Naoya Sakamoto, Kenichi Ikejima, Tsuneo Kitamura, Nobuyuki Enomoto, Tatsuo Sakai, Eiki Kominami, Sumio Watanabe

  JOURNAL OF GASTROENTEROLOGY 45 (2) 195 - 203 0944-1174 2010/02 [Refereed][Not invited]
   

  Autophagy has been reported to play a pivotal role on the replication of various RNA viruses. In this study, we investigated the role of autophagy on hepatitis C virus (HCV) RNA replication and demonstrated anti-HCV effects of an autophagic proteolysis inhibitor, chloroquine. Induction of autophagy was evaluated following the transfection of HCV replicon to Huh-7 cells. Next, we investigated the replication of HCV subgenomic replicon in response to treatment with lysosomal protease inhibitors or pharmacological autophagy inhibitor. The effect on HCV replication was analyzed after transfection with siRNA of ATG5, ATG7 and light-chain (LC)-3 to replicon cells. The antiviral effect of chloroquine and/or interferon-alpha (IFN alpha) was evaluated. The transfection of HCV replicon increased the number of autophagosomes to about twofold over untransfected cells. Pharmacological inhibition of autophagic proteolysis significantly suppressed expression level of HCV replicon. Silencing of autophagy-related genes by siRNA transfection significantly blunted the replication of HCV replicon. Treatment of replicon cells with chloroquine suppressed the replication of the HCV replicon in a dose-dependent manner. Furthermore, combination treatment of chloroquine to IFN alpha enhanced the antiviral effect of IFN alpha and prevented re-propagation of HCV replicon. Protein kinase R was activated in cells treated with IFN alpha but not with chloroquine. Incubation with chloroquine decreased degradation of long-lived protein leucine. The results of this study suggest that the replication of HCV replicon utilizes machinery involving cellular autophagic proteolysis. The therapy targeted to autophagic proteolysis by using chloroquine may provide a new therapeutic option against chronic hepatitis C.
• Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway

  KyeongJin Kim, Kook Hwan Kim, Hye Young Kim, Hyun Kook Cho, Naoya Sakamoto, JaeHun Cheong

  FEBS LETTERS 584 (4) 707 - 712 0014-5793 2010/02 [Refereed][Not invited]
   

  A polyphenolic compound from the curry spice turmeric, curcumin, is known to show anti-viral activity against the influenza virus, adenovirus, coxsackievirus, and the human immunodeficiency virus. However, it remains to be determined whether curcumin can inhibit the replication of hepatitis C virus (HCV). In this study, we showed that curcumin decreases HCV gene expression via suppression of the Akt-SREBP-1 activation, not by NF-kappa B pathway. The combination of curcumin and IFN alpha exerted profound inhibitory effects on HCV replication. Collectively, our results indicate that curcumin can suppress HCV replication in vitro and may be potentially useful as novel anti-HCV reagents. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
• Modification of the descending thoracic aortic anastomotic site using biodegradable felt: Study in a canine model with or without basic fibroblast growth factor

  Hidenori Fujiwara, Yoshikatsu Saiki, Mitsuru Sato, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato, Yasuhiko Tabata, Koichi Tabayashi

  Journal of Vascular Surgery 51 (1) 194 - 202 0741-5214 2010/01 [Refereed][Not invited]
   

  Objectives: We investigated the outcomes of reinforcing anastomotic sites using (1) nonbiodegradable polytetrafluoroethylene (PTFE) felt, (2) biodegradable polyglycolic acid (PGA) felt, and (3) PGA felt with basic fibroblast growth factor (bFGF) in a canine descending thoracic aortic replacement model. Methods: Thirty-seven beagles underwent descending thoracic aorta replacement using a prosthetic graft with one of the above-mentioned reinforcements or no reinforcement for controls. Histologic evaluations were carried out 1 month and 3 months after surgery. The biomechanical strength of the anastomosis was assessed along the longitudinal axis of the aortic segments using a tensile tester. Local compliance at the anastomotic site was also evaluated in the circumferential direction. Results: The media was significantly thinner in the PTFE group than in the control group (65.8% ± 5.1% vs 95.0% ± 9.3% of normal thickness P < .05). Relative to the control group, the adventitial layer was significantly thinner in the PTFE group (42.3% ± 8.2% of control P < .05) but significantly thicker in the PGA and the PGA + bFGF groups (117.2% ± 11.3% and 134.1% ± 14.2% of control, respectively P < .05). There were more vessels in the adventitial layer in the PGA + bFGF group than in the control, PTFE, and PGA groups (29.2 ± 2.1/mm2 vs 13.8 ± 0.8, 5.4 ± 0.7, 17.0 ± 1.3/mm2, respectively P < .01). There were no significant differences between the four groups in the failure force at anastomotic sites. Local compliance at the anastomotic site was higher in the PGA group than that in the PTFE group (11.6 ± 1.6 10-6 m2/N vs 5.6 ± 1.9 10-6 m2/N P < .05). Conclusion: Reinforcement of the experimental aortic wall with PTFE felt resulted in thinning of the media and adventitia and fewer vessels at the anastomotic site. These histologic changes were not observed when biodegradable felt was used. The bFGF failed to augment the modification of the aortic wall with the exception of increased adventitial vessel number. Biomechanical strength of the anastomosis along the longitudinal axis was comparable in all four groups however, local vascular compliance was better in the biodegradable PGA felt group. © 2010 Society for Vascular Surgery.
• Olfactomedin 4 (GW112, hGC-1) is an independent prognostic marker for survival in patients with colorectal cancer

  Naotsugu Seko, Naohide Oue, Tsuyoshi Noguchi, Kazuhiro Sentani, Naoya Sakamoto, Takao Hinoi, Masazumi Okajima, Wataru Yasui

  EXPERIMENTAL AND THERAPEUTIC MEDICINE 1 (1) 73 - 78 1792-0981 2010/01 [Refereed][Not invited]
   

  Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide We previously performed Serial Analysis of Gene Expression (SAGE) on four primary gastric cancer samples and identified several gastric cancer-specific genes Of these genes, olfactomedin 4 (OLFM4, also known as GW112 or hGC-1) 1, a candidate gene for cancer-specific expression In the present study, we examined the expression and distribution of olfactomedin 4 in CRC by immunohistochemistry Of the 176 CRC cases, 59 (34%) were positive for cytoplasmic staining of olfactomedin 4 Olfactomedin 4-positive CRC cases showed earlier T classification (P=0 0180), N classification (P=0 0149) and stage (P=0 0144) than olfactomedin 4-negative CRC cases In the 176 CRC patients, those with olfactomedin 4-positive CRC had a better survival rate than patients with olfactomedin 4-negative CRC (P=0 0092) Multivariate analysis indicated that T classification, M classification and negative olfactomedin 4 expression were independent predictors of survival in patients with CRC In addition to cytoplasmic staining of olfactomedin 4, stromal staining at the invasive front was observed In total, 29 (16%) of the 176 CRC eases were positive for stromal olfactomedin 4, however, stromal olfactomedin 4 staining was not correlated with any clinicopathologic characteristic or with patient survival These results indicate that olfactomedin 4 is a valuable marker for long-term survival in patients with CRC
• 診断に難渋した小腸腫瘍の1例

  平尾龍彦, 荒木昭博, 鈴木伸治, 岡田英理子, 藤井俊光, 櫻井幸, 松本浩之, 小田柿智之, 岡本英子, 岩嵜美智子, 長堀正和, 長沼誠, 東正新, 大岡真也, 土屋輝一郎, 岡本隆一, 中村哲也, 秋山純子, 坂本直哉, 渡辺守

  Progress of Digestive Endoscopy 77 (1) 106  2010 [Not refereed][Not invited]
  
• 【C型肝炎ウイルスの感染・増殖メカニズムと臨床応用】 SR蛋白リン酸化酵素阻害剤によるHCV増殖抑制効果の解析

  唐鎌優子, 坂本直哉, 井津井康浩, 中川美奈, 藤田めぐみ, 櫻井幸, 柿沼晴, 大岡真也, 東正新, 土屋輝一郎, 小野木博, 萩原正敏, 渡辺守

  消化器内科 51 (6) 632 - 635 2010 [Not refereed][Not invited]
  
• IL-2 is positively involved in the development of colitogenic CD4 + IL-7Rαhigh memory T cells in chronic colitis

  Kaori Kameyama, Yasuhiro Nemoto, Takanori Kanai, Tamako Shinohara, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Teruji Totsuka, Toshifumi Hibi, Mamoru Watanabe

  European Journal of Immunology 40 (9) 2423 - 2436 1521-4141 2010 [Refereed][Not invited]
   

  IL-2 and IL-7 share a common γ-chain receptor and are critical for T-cell homeostasis. We aimed to clarify the reciprocal roles of IL-2 and IL-7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL-2-/- CD4+CD45RBhigh T cells into RAG-2-/- mice and assessed the role of IL-2 in the induction of IL-7Rα on colitogenic CD4+ T cells and the development of chronic colitis. RAG-2-/- mice transferred with WT but not with IL-2-/- CD4+CD45RBhigh T cells developed Th1/Th17-mediated colitis. Consistently, re-expression of IL-7Rα was severely impaired on IL-2-/- but not on WT CD4+ T cells from the transferred mice. To exclude a contribution of the preclinical autoimmunity of IL-2-/-mice, WT Ly5.1+ or IL-2 -/- Ly5.2+ CD4+CD45RBhigh T cells from GFP mice previously transplanted with the same number of WT and IL-2 -/- BM cells were transferred into RAG-2-/- mice. RAG-2-/- mice transferred with IL-2-/--derived CD4 + CD45RBhigh T cells did not develop colitis, but their splenic CD4+ T cells changed from effector-memory to central-memory type. These results show that IL-2 is critically involved in the establishment and maintenance of IL-7-dependent colitogenic memory CD4+IL- 7Rαhigh T cells. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
• Cation recognition and pseudorotaxane formation of tris-dipyrrin BF2 macrocycles

  Naoya Sakamoto, Chusaku Ikeda, Tatsuya Nabeshima

  CHEMICAL COMMUNICATIONS 46 (36) 6732 - 6734 1359-7345 2010 [Refereed][Not invited]
   

  Macrocyclic planar tris-dipyrrin BF2 complexes exhibit strong alkali-metal recognition and pseudorotaxane formation ability with a secondary ammonium salt through BF2-cation interactions.
• Upregulation of Connexin 30 in Intestinal Phenotype Gastric Cancer and Its Reduction during Tumor Progression

  Kazuhiro Sentani, Naohide Oue, Naoya Sakamoto, Katsuhiro Anami, Yutaka Naito, Kazuhiko Aoyagi, Hiroki Sasaki, Wataru Yasui

  PATHOBIOLOGY 77 (5) 241 - 248 1015-2008 2010 [Refereed][Not invited]
   

  Aims: The mucin phenotype is associated with clinicopathological findings and tumorigenesis in gastric cancer (GC). The aim was to search for a novel marker regulating the intestinal phenotype of GC. Methods and Results: We performed microarray analyses, and GJB6 (encoding connexin 30) was identified as a gene associated with the intestinal phenotype. Immunostaining of connexin 30 in 169 GC cases revealed that 47 (28%) cases were positive for connexin 30, while connexin 30 was negative in nonneoplastic gastric tissue. Connexin 30-negative GC cases showed more advanced T grade, N grade, and tumor stage than connexin 30-positive GC cases. Six (13%) GC cases positive for connexin 30 were histologically of the differentiated type. In addition, the expression of gastric and intestinal phenotypes of GC was examined by immunostaining for MUC5AC, MUC6, MUC2, and CD10. Connexin 30 expression occurred more frequently in the intestinal phenotype (48%) than in other phenotypes (21%) of GC. Conclusion: These results indicate that the expression of connexin 30 is a novel differentiation marker mediating the biological behavior of intestinal phenotype GC. Copyright (C) 2010 S. Karger AG, Basel
• Antiviral Effects of the Interferon-Induced Protein Guanylate Binding Protein 1 and Its Interaction with the Hepatitis C Virus NS5B Protein

  Yasuhiro Itsui, Naoya Sakamoto, Sei Kakinuma, Mina Nakagawa, Yuko Sekine-Osajima, Megumi Tasaka-Fujita, Yuki Nishimura-Sakurai, Gokui Suda, Yuko Karakama, Kako Mishima, Machi Yamamoto, Takako Watanabe, Mayumi Ueyama, Yusuke Funaoka, Seishin Azuma, Mamoru Watanabe

  HEPATOLOGY 50 (6) 1727 - 1737 0270-9139 2009/12 [Refereed][Not invited]
   

  Interferons (IFNs) and the interferon-stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We have reported previously that ISGs, including guanylate binding protein 1 (GBP-1), interferon alpha inducible protein (IFI)-6-16, and IFI-27, inhibit HCV subgenomic replication. In this study we investigated the effects of these ISGs against HCV in cell culture and their direct molecular interaction with viral proteins. HCV replication and virus production were suppressed significantly by overexpression of GBP-1, IFI-6-16, or IFI-27. Knockdown of the individual ISGs enhanced HCV RNA replication markedly. A two-hybrid panel of molecular interaction of the ISGs with HCV proteins showed that GBP-1 bound HCV-NS5B directly. A protein truncation assay showed that the guanine binding domain of GBP-1 and the finger domain of NS5B were involved in the interaction. Binding of NS5B with GBP-1 inhibited its guanosine triphosphatase GTPase activity, which is essential for its antiviral effect. Taken together, interferon-induced GBP-1 showed antiviral activity against HCV replication. Conclusion: Binding of the HCV-NS5B protein to GBP-1 countered the antiviral effect by inhibition of its GTPase activity. These mechanisms may contribute to resistance to innate, IFN-mediated antiviral defense and to the clinical persistence of HCV infection. (HEPATOLOGY 2009;50:1727-1737.)
• Serum olfactomedin 4 (GWI 12, hGC4) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients

  Naohide Oue, Kazuhiro Sentani, Tsuyoshi Noguchi, Shinya Ohara, Naoya Sakamoto, Tetsutaro Hayashi, Katsuhirio Anami, Junichi Motoshita, Masanori Ito, Shinji Tanaka, Kazuhiro Yoshida, Wataru Yasui

  INTERNATIONAL JOURNAL OF CANCER 125 (10) 2383 - 2392 0020-7136 2009/11 [Refereed][Not invited]
   

  Gastric cancer (GC) is 1 of the most common human cancers. Early defection remains the most promising approach to improving long-term survival of patients with GC. We previously performed Serial Analysis of Gene Expression (SAGE) oil 4 primary GCs and identified several GC-specific genes including Reg IV. Of these genes, olfactomedin 4 (OLFM4, also knonwn as GW112 or hGC-1) is a candidate gene for cancer-specific expression. In this study, we examined the expression of olfactomedin 4 in human GC by immunohistochemistry. We also assessed serum olfactomedin 4 levels in GC patients by enzyme-linked immunosorbent assay. 94 (56%) of 167 GC cases were positive for olfactomedin 4 by immunostaining. Olfactomedin 4 staining was observed more frequently in stage I/II cases than in stage III/IV cases. The serum olfactomedin 4 concentration in presurgical GC patients (n = 123, mean +/- SE, 36.3 +/- 3.5 ng/mL) was significantly higher than that in healthy individuals (n = 76, 16.6 +/- 1.6 ng/mL). In patients with stage 1 GC, the sensitivity of serum olfactomedin 4 (25%) and Reg IV (35%) was superior to that of CA19-9 (5%) or CEA (3%). Furthermore, in patients with stage I GC. the combination of olfactomedin 4 and Reg IV elevated the diagnostic Sensitivity to These results suggest that serum olfactomedin 4 is it useful marker for GC and its measurement alone or in combination with Reg IV has utility in the early defection of GC. (C) 2009 UICC
• Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice

  Masahiro Ohira, Kohei Ishiyama, Yuka Tanaka, Marlen Doskali, Yuka Igarashi, Hirotaka Tashiro, Nobuhiko Hiraga, Michio Imamura, Naoya Sakamoto, Toshimasa Asahara, Kazuaki Chayama, Hideki Ohdan

  JOURNAL OF CLINICAL INVESTIGATION 119 (11) 3226 - 3235 0021-9738 2009/11 [Refereed][Not invited]
   

  After liver transplantation in HCV-infected patients, the virus load inevitably exceeds pre-transplantation levels. This phenomenon reflects suppression of the host-effector immune responses that control HCV replication by the immunosuppressive drugs used to prevent rejection of the transplanted liver. Here, we describe an adoptive immunotherapy approach, using lymphocytes extracted from liver allograft perfusate (termed herein liver allograft-derived lymphocytes), which includes an abundance of NK/NKT cells that mounted an anti-HCV response in HCV-infected liver transplantation recipients, despite the immunosuppressive environment. This therapy involved intravenously injecting patients 3 days after liver transplantation with liver allograft-derived lymphocytes treated with IL-2 and the CD3-specific mAb OKT3. During the first month after liver transplantation, the HCV RNA titers in the sera of recipients who received immunotherapy were markedly lower than those in the sera of recipients who did not receive immunotherapy. We further explored these observations in human hepatocyte-chimeric mice, in which mouse hepatocytes were replaced by human hepatocytes. These mice unfailingly developed HCV infections after inoculation with HCV-infected human serum. However, injection of human liver-derived lymphocytes treated with IL-2/OKT3 completely prevented HCV infection. Furthermore, an in vitro study using genomic HCV replicon-containing hepatic cells revealed that IFN-gamma-secreting cells played a pivotal role in such anti-HCV responses. Thus, our study presents what we believe to be a novel paradigm for the inhibition of HCV replication in HCV-infected liver transplantation recipients.
• IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitis

  Takayuki Tomita, Takanori Kanai, Teruji Totsuka, Yasuhiro Nemoto, Ryuichi Okamoto, Kiichiro Tsuchiya, Naoya Sakamoto, Toshiaki Ohteki, Toshifumi Hibi, Mamoru Watanabe

  European Journal of Immunology 39 (10) 2737 - 2747 0014-2980 2009/10 [Refereed][Not invited]
   

  We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4 +CD45RBhigh T cells into IL-7-/- x RAG-1 +/+ mice did not induce colitis and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7-/- x RAG-1-/- mice parabiosed with colitic CD4+CD45RB high T-cell-transferred RAG-1-/- mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4+ T cells by surgically separating these parabionts. Surprisingly, the separated IL-7-/- x RAG-1-/- mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7-/- x RAG-1-/- partners. CD4+ T cells isolated from the separated RAG-1-/- or IL-7-/- x RAG-1-/- mice were then transferred into new RAG-1-/- or IL-7-/- x RAG-1-/- mice. Regardless of the source of donor cells, RAG-1-/- recipients developed colitis, whereas IL-7 -/- x RAG-1-/- recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
• IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) memory T cells in chronic colitis

  Takayuki Tomita, Takanori Kanai, Teruji Totsuka, Yasuhiro Nemoto, Ryuichi Okamoto, Kiichiro Tsuchiya, Naoya Sakamoto, Toshiaki Ohteki, Toshifumi Hibi, Mamoru Watanabe

  EUROPEAN JOURNAL OF IMMUNOLOGY 39 (10) 2737 - 2747 0014-2980 2009/10 [Refereed][Not invited]
   

  We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4(+)CD45RB(high) T cells into IL-7(-/-) x RAG-1(-/-) mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7(-/-) x RAG-1(-/-) mice parabiosed with colitic CD4(+)CD45RB(high) T-cell-transferred RAG-1(-/-) mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4(+) T cells by surgically separating these parabionts. Surprisingly, the separated IL-7(-/-) x RAG-1(-/-) mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7(-/-) x RAG-1(-/-) partners. CD4(+) T cells isolated from the separated RAG(-/-) or IL-7(-/-) x RAG-1(-/-) mice were then transferred into new RAG-1(-/-) or IL-7(-/-) x RAG-1(-/-) mice. Regardless of the source of donor cells, RAG-1(-/-) recipients developed colitis, whereas IL-7(-/-) x RAG-1(-/-) recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases.
• Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C

  Yasuhito Tanaka, Nao Nishida, Masaya Sugiyama, Masayuki Kurosaki, Kentaro Matsuura, Naoya Sakamoto, Mina Nakagawa, Masaaki Korenaga, Keisuke Hino, Shuhei Hige, Yoshito Ito, Eiji Mita, Eiji Tanaka, Satoshi Mochida, Yoshikazu Murawaki, Masao Honda, Akito Sakai, Yoichi Hiasa, Shuhei Nishiguchi, Asako Koike, Isao Sakaida, Masatoshi Imamura, Kiyoaki Ito, Koji Yano, Naohiko Masaki, Fuminaka Sugauchi, Namiki Izumi, Katsushi Tokunaga, Masashi Mizokami

  NATURE GENETICS 41 (10) 1105 - U81 1061-4036 2009/10 [Refereed][Not invited]
   

  The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).
• Long-Lived Colitogenic CD4(+) Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis

  Yasuhiro Nemoto, Takanori Kanai, Kaori Kameyama, Tamako Shinohara, Naoya Sakamoto, Teruji Totsuka, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Tetsuo Sudo, Satoshi Matsumoto, Mamoru Watanabe

  JOURNAL OF IMMUNOLOGY 183 (8) 5059 - 5068 0022-1767 2009/10 [Refereed][Not invited]
   

  To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4(+) T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4(+) T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4(+) T cells from colitic CD4(+)CD45RB(high) T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4(+) T cells have a characteristic CD44(high)CD62L(-)IL-7R alpha(high) effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GF -> GF), and the other was transferred into SPF conditions (GF -> SPF). GF -> SPF but not GF -> GF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4(+) effector-memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GF -> GF SCID recipients. Consistent with this, GF -> SPF but not GF -> GF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4(+) cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4(+) cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease. The Journal of Immunology, 2009, 183: 5059-5068.
• Hepatitis C virus NS5A protein increases hepatic lipid accumulation via induction of activation and expression of PPARgamma

  KyeongJin Kim, Kook Hwan Kim, Eunsin Ha, Jin Young Park, Naoya Sakamoto, JaeHun Cheong

  FEBS LETTERS 583 (17) 2720 - 2726 0014-5793 2009/09 [Refereed][Not invited]
   

  Steatosis is an established risk factor for disease progression in cases of chronic hepatitis C. Recently it was demonstrated that Hepatitis C virus (HCV) core and non-structural (NS)2 proteins (NS2) induce lipid accumulation in hepatic cells. However, it has yet to be determined whether other HCV proteins are associated with lipid metabolism. The NS5A augmented the transcriptional activity and gene expression of PPAR gamma. Furthermore, NS5A increased the ability to recruit the transcriptional coactivator PGC-1s to the PPRE with PPAR gamma, as well as the interaction with PPAR gamma 2 and PGC-1 alpha. Our results indicate that NS5A may exploit multiple strategies that enhance PPAR gamma-induced lipid accumulation. Structured summary: MINT-7229685: PPAR gamma 2 (uniprotkb: P37231-2) physically interacts (MI: 0914) with PGC1 alpha (uniprotkb: Q9UBK2) by pull down (MI: 0096) MINT-7229712: PPAR gamma 2 (uniprotkb: P37231-2) physically interacts (MI: 0914) with NS5A (uniprotkb: P26662) by pull down ( MI: 0096) MINT-7229698: PPAR gamma 2 (uniprotkb: P37231-2) physically interacts (MI: 0914) with PGC1 alpha (uniprotkb: Q9UBK2) by anti tag coimmunoprecipitation ( MI: 0007) MINT-7229731: PPAR gamma 2 (uniprotkb: P37231-2) physically interacts (MI: 0914) with NS5A (uniprotkb: P26662) by anti tag coimmunoprecipitation (MI: 0007) (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
• Inhibition of intracellular hepatitis C virus replication by nelfinavir and synergistic effect with interferon-α

  S. Toma, T. Yamashiro, S. Arakaki, J. Shiroma, T. Maeshiro, K. Hibiya, N. Sakamoto, F. Kinjo, M. Tateyama, J. Fujita

  Journal of Viral Hepatitis 16 (7) 506 - 512 1352-0504 2009/07 [Refereed][Not invited]
   

  Summary. Liver diseases associated with hepatitis C virus (HCV) infection have become the major cause of mortality in patients with human immunodeficiency virus (HIV) infection since the introduction of highly active anti-retroviral therapy. HCV-related liver disease is more severe in HIV-infected patients than in non-HIV-infected patients, but the standard therapies used to treat chronic hepatitis C in HCV/HIV coinfected patients are the same as those for patients infected with HCV alone. HIV protease inhibitors might have potential to down-regulate HCV load of HCV/HIV coinfected patients. In this study, we evaluated the effects of nelfinavir on intracellular HCV replication using the HCV replicon system. We constructed an HCV replicon expressing a neomycin-selectable chimeric firefly luciferase reporter protein. Cytotoxicity and apoptosis induced by nelfinavir were assessed and synergism between nelfinavir and interferon (IFN) was calculated using CalcuSyn analysis. Nelfinavir dose-dependently repressed HCV replication at low concentrations (IC50, 9.88 μmol/L). Nelfinavir failed to induce cytotoxicity or apoptosis at concentrations that inhibited HCV replication. Clinical concentrations of nelfinavir (5 μmol/L) combined with IFN showed synergistic inhibition of HCV replication in our replicon model. Our results suggest that the direct effects of nelfinavir on the HCV subgenome and its synergism with IFN could improve clinical responses to IFN therapy in HCV/HIV coinfected patients. © 2009 Blackwell Publishing Ltd.
• Bioactivity-guided screening identifies pheophytin a as a potent anti-hepatitis C virus compound from Lonicera hypoglauca Miq.

  Sheng-Yang Wang, Ching-Ping Tseng, Keng-Chang Tsai, Chia-Fan Lin, Ching-Ya Wen, Hsin-Sheng Tsaye, Naoya Sakamoto, Chin-Hsiao Tseng, Ju-Chien Cheng

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 385 (2) 230 - 235 0006-291X 2009/07 [Refereed][Not invited]
   

  Chronic hepatitis C virus (HCV) infection is a worldwide public issue. In this study, we performed bioactivity-guided screening of the Lonicera hypoglauca Miq. crude extracts to find for naturally chemical entities with anti-HCV activity. Pheophytin a was identified from the ethano-soluble fraction of L. hypoglauca that elicited dose-dependent inhibition of HCV vital proteins and RNA expression in both replicon cells and cell culture infectious system. Computational modeling revealed that pheophytin a can bind to the active site of HCV-NS3, suggesting that NS3 is a potent molecular target of pheophytin a. Biochemical analysis further revealed that pheophytin a inhibited NS3 serine protease activity with IC(50) = 0.89 mu M. Notably, pheophytin a and IFN alpha-2a elicited synergistic anti-HCV activity in replicon cells with no significant cytotoxicity. This study thereby demonstrates for the first time that pheophytin a is a potent HCV-NS3 protease inhibitor and offers insight for development of novel anti-HCV regimens. (C) 2009 Elsevier Inc. All rights reserved.
• New therapeutic approaches to hepatitis C virus

  Naoya Sakamoto, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY 44 (7) 643 - 649 0944-1174 2009/07 [Refereed][Not invited]
   

  Year 201X will see a huge battle against hepatitis C virus (HCV) infection. HCV, a leading cause of end stage diseases and hepatocellular malignancies, is a negative legacy of the past in many regions worldwide, and has long been refractory to conventional treatments. The most effective peginterferons and ribavirin-based antiviral therapies can eliminate the virus in only half of patients treated, and the treatments are often poorly tolerated. Recently, the development of an HCV cell culture system has become a turning point of basic research. At present, novel therapeutic agents with different mechanisms of action are under development or on clinical trials. Some of these drugs have been proven to be effective when used with the conventional treatments, and may constitute antiviral therapies without being used in combination with interferons. This article reviews the current status of preclinical drug development, ongoing clinical trials, and near future perspectives in the field of HCV therapeutics.
• Rank-rankl signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis

  Teruji Totsuka, Takanori Kanai, Yasuhiro Nemoto, Takayuki Tomita, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Hisaya Akiba, Ko Okumura, Hideo Yagita, Mamoru Watanabe

  Journal of Immunology 182 (10) 6079 - 6087 0022-1767 2009/05/15 [Refereed][Not invited]
   

  It is now clear that functional CD4+CD25+ regulatory T (TR) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4+CD25+ TR cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4+CD25+ T R cells in the intestine. We first found that RANKL was preferentially expressed on both CD4+CD25+ TR cells and colitogenic CD4+ T cells, whereas RANK was expressed on dendritic cells. Although neutralizing anti-RANKL mAb did not affect T R activity of CD4+CD25+ TR cells to suppress the proliferation of CD4+ responder cells in vitro, in vivo administration of anti-RANKL mAb abrogated CD4+CD25+ TR cell-mediated suppression of colitis induced by adoptive transfer of CD4+CD45RBhigh T cells into SCID mice. Interestingly, an adoptive transfer experiment using Ly5.1+CD4 +CD45RBhigh cells and Ly5.2+CD4 +CD25+ TR cells revealed that the ratio of CD4+CD25+ TR cells in total CD4+ T cells in inflamed mucosa was significantly decreased by anti-RANKL mAb treatment. Consistent with this, the expression of RANK on lamina propria CD11c+ cells from colitic mice was significantly increased as compared with that from normal mice, and in vitro treatment with anti-RANKL mAb suppressed the expansion of CD4+Foxp3+ TR cells in culture with colitic lamina propria CD11c+ cells. Together, these results suggest that the RANK-RANKL signaling pathway is critically involved in regulating the function of CD4+CD25+ TR cells in colitis. Copyright © 2009 by The American Association of Immunologists, Inc.
• h-prune Is an Independent Prognostic Marker for Survival in Esophageal Squamous Cell Carcinoma

  Tsuyoshi Noguchi, Naohide Oue, Shinsuke Wada, Kazuhiro Sentani, Naoya Sakamoto, Akira Kikuchi, Wataru Yasui

  ANNALS OF SURGICAL ONCOLOGY 16 (5) 1390 - 1396 1068-9265 2009/05 [Refereed][Not invited]
   

  The human homologue of Drosophila prune (PRUNE, which encodes h-prune) protein interacts with glycogen synthase kinase 3 and promotes cell motility. The aim of our study was to investigate the impact of immunohistochemically detected h-prune expression on the survival of patients with esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining of h-prune was performed for 205 surgically resected specimens of ESCC. In total, 43 (21%) of 205 ESCC cases were positive for h-prune. h-prune-positive ESCC cases showed a more-advanced T stage (P < 0.0001), N stage (P < 0.0001), and tumor stage (P < 0.0001) than h-prune-negative ESCC cases. In the group of 116 stage II and III ESCC cases, recurrence of ESCC was frequently found in h-prune-positive cases. In patients with lung recurrence, the tumors were more likely to be h-prune positive than h-prune negative. Univariate analysis revealed that T stage (P < 0.0001), N stage (P < 0.0001), tumor stage (P < 0.0001), and h-prune staining (P < 0.0001) were significant prognostic factors for survival. Multivariate analysis indicated that N stage (P = 0.0182) and h-prune staining (P < 0.0001) were independent predictors for survival. These results indicate that immunostaining of h-prune is useful to identify patients at high risk for recurrence or poor prognosis associated with ESCC.
• RANK-RANKL Signaling Pathway Is Critically Involved in the Function of CD4(+)CD25(+) Regulatory T Cells in Chronic Colitis

  Teruji Totsuka, Takanori Kanai, Yasuhiro Nemoto, Takayuki Tomita, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Hisaya Akiba, Ko Okumura, Hideo Yagita, Mamoru Watanabe

  JOURNAL OF IMMUNOLOGY 182 (10) 6079 - 6087 0022-1767 2009/05 [Refereed][Not invited]
   

  It is now clear that functional CD4(+)CD25(+) regulatory T (T(R)) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4(+)CD25(+) T(R) cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4(+)CD25(+) T(R) cells in the intestine. We first found that RANKL was preferentially expressed on both CD4(+)CD25(+) T(R) cells and colitogenic CD4(+) T cells, whereas RANK was expressed on dendritic cells. Although neutralizing anti-RANKL mAb did not affect T(R) activity of CD4(+)CD25(+) T(R) cells to suppress the proliferation of CD4(+) responder cells in vitro, in vivo administration of anti-RANKL mAb abrogated CD4(+)CD2(+) T(R) cell-mediated suppression of colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells into SCID mice. Interestingly, an adoptive transfer experiment using Ly5.1(+)CD4(+)CD45RB(high) cells and Ly5.2(+)CD4(+)CD25(+) T(R) cells revealed that the ratio of CD4(+)CD25(+) T(R) cells in total CD4(+) T cells in inflamed mucosa was significantly decreased by anti-RANKL mAb treatment. Consistent with this, the expression of RANK on lamina propria CD11c(+) cells from colitic mice was significantly increased as compared with that from normal mice, and in vitro treatment with anti-RANKL mAb suppressed the expansion of CD4(+)Foxp3(+) T(R) cells in culture with colitic lamina propria CD11c(+) cells. Together, these results suggest that the RANK-RANKL, signaling pathway is critically involved in regulating the function of CD4(+)CD25(+) T(R) cells in colitis. The Journal of Immunology, 2009, 182: 6079-6087.
• Signaling pathway via TNF-alpha/NF-kappa B in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis

  Michio Onizawa, Takashi Nagaishi, Takanori Kanai, Ken-ichi Nagano, Shigeru Oshima, Yasuhiro Nemoto, Atsushi Yoshioka, Teruji Totsuka, Ryuichi Okamoto, Tetsuya Nakamura, Naoya Sakamoto, Kiichiro Tsuchiya, Kazuhiro Aoki, Keiichi Ohya, Hideo Yagita, Mamoru Watanabe

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 296 (4) G850 - G859 0193-1857 2009/04 [Refereed][Not invited]
   

  Treatment with anti-TNF-alpha MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-alpha signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-alpha MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-kappa B pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-kappa B activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-kappa B activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-alpha MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-kappa B inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-alpha MAb may prevent the development of CAC in patients with long-standing IBD.
• Musashi-1 suppresses expression of Paneth cell-specific genes in human intestinal epithelial cells

  Minekazu Murayama, Ryuichi Okamoto, Kiichiro Tsuchiya, Junko Akiyama, Tetsuya Nakamura, Naoya Sakamoto, Takanori Kanai, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY 44 (3) 173 - 182 0944-1174 2009/03 [Refereed][Not invited]
   

  Musashi-1 (Msi-1) is a RNA-binding protein, known as a putative marker of intestinal stem cells (ISCs). However, little is known about the function of Msi-1 within human intestinal epithelial cells (IECs). Thus, the present study aimed to clarify the role of Msi-1 in differentiation and proliferation of IECs. A human intestinal epithelial cell line stably expressing Msi-1 was established. Proliferation of the established cell lines was measured by bromodeoxyuridine incorporation, whereas differentiation were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of lineage-specific genes. Activities of the Notch and Wnt pathways were examined either by reporter assays or expression of downstream target genes. The distribution of Msi-1 and PLA2G2A expression in vivo was determined by immunohistochemistry. Constitutive expression of Msi-1 in IECs had no significant effect on cell proliferation, but suppressed expression of Paneth cell-specific genes, including PLA2G2A. Msi-1 appeared to suppress expression of the PLA2G2A gene at the mRNA level. Analysis of Notch and Wnt pathway activity, however, revealed no significant change upon Msi-1 expression. The expression of Msi-1 and PLA2G2A in vivo was restricted to IECs residing at the lowest part of the human intestinal crypt, but was clearly separated to within basal columnar cells or mature Paneth cells, respectively. Msi-1 suppresses expression of Paneth cell-specific genes in IECs, presumably through a pathway independent from Notch or Wnt. These findings suggest Msi-1 is a negative regulator of Paneth cell differentiation, an may contribute to maintain the undifferentiated phenotype of ISCs.
• A Functional Genomic Screen Identifies Cellular Cofactors of Hepatitis C Virus Replication

  Andrew W. Tai, Yair Benita, Lee F. Peng, Sun-Suk Kim, Naoya Sakamoto, Ramnik J. Xavier, Raymond T. Chung

  CELL HOST & MICROBE 5 (3) 298 - 307 1931-3128 2009/03 [Refereed][Not invited]
   

  Hepatitis C virus (HCV) chronically infects 3% of the world's population, and complications from HCV are the leading indication for liver transplantation. Given the need for better anti-HCV therapies, one strategy is to identify and target cellular cofactors of the virus lifecycle. Using a genome-wide si RNA library, we identified 96 human genes that support HCV replication, with a significant number of them being involved in vesicle organization and biogenesis. Phosphatidylinositol 4-kinase PI4KA and multiple subunits of the COPI vesicle coat complex were among the genes identified. Consistent with this, pharmacologic inhibitors of COPI and PI4KA blocked HCV replication. Targeting hepcidin, a peptide critical for iron homeostasis, also affected HCV replication, which may explain the known dysregulation of iron homeostasis in HCV infection. The host cofactors for HCV replication identified in this study should serve as a useful resource in delineating new targets for anti-HCV therapies.
• Novel image analysis for trajectory of microtubules gliding on kinesins with Tip detection

  Shukei Sugita, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  Journal of Biomechanical Science and Engineering 4 (3) 404 - 414 1880-9863 2009 [Refereed][Not invited]
   

  Control of the gliding directions of kinesin-driven microtubules (MTs) in vitro has good feasibility for the development of nano-scale transport systems. A requirement for the control of transporters in these systems includes detecting the positions of gliding MTs however, no studies have reported on the monitoring of the positions of gliding MTs. Here, we suggest an algorithm to detect tip coordinates of gliding MTs by binarization, skeletonization, and filtration of fluorescent images of MTs. The algorithm was first applied to artificially drawn segments with given lengths (10-80 pixels), widths (1-10 pixels), and curvature radii (20-120 pixels) to verify the effect of the sizes of MTs on accuracy of tip coordinates extracted by the algorithm, and error was estimated by referring to the true coordinates. The estimated errors were as small as 2 pixels in the width and were not affected by the length and the curvature radius, indicating that our algorithm is useful to extract the tips of MTs. The algorithm was subsequently applied to images of gliding MTs. Since distances from the trajectories of the MTs to the centers of gravity of the MTs (3.7 ± 2.1 pixels) were significantly larger than those to the tips (1.9 ± 0.5 pixels), the use of the tips as representative points of gliding MTs was verified. A detection method using tips of MTs, as suggested in this study, may be a useful technique for monitoring each MT in nanoscale transport systems.
• Two flavonoids extracts from Glycyrrhizae radix inhibit in vitro hepatitis C virus replication

  Yuko Sekine-Osajima, Naoya Sakamoto, Mina Nakagawa, Yasuhiro Itsui, Megumi Tasaka, Yuki Nishimura-Sakurai, Cheng-Hsin Chen, Goki Suda, Kako Mishima, Yuko Onuki, Machi Yamamoto, Shinya Maekawa, Nobuyuki Enomoto, Takanori Kanai, Kiichiro Tsuchiya, Mamoru Watanabe

  HEPATOLOGY RESEARCH 39 (1) 60 - 69 1386-6346 2009/01 [Refereed][Not invited]
   

  Traditional herbal medicines have been used for several thousand years in China and other Asian countries. In this study we screened herbal drugs and their purified compounds, using the Feo replicon system, to determine their effects on in vitro HCV replication. We screened herbal drugs and their purified extracts for the activities to suppress hepatitis C virus (HCV) replication using an HCV replicon system that expressed chimeric firefly luciferase reporter and neomycin phosphotransferase (Feo) genes. We tested extracts and 13 purified compounds from the following herbs: Glycyrrhizae radix; Rehmanniae radix; Paeoniae radix; Artemisiae capillari spica; and Rhei rhizoma. The HCV replication was significantly and dose-dependently suppressed by two purified compounds, isoliquiritigenin and glycycoumarin, which were from Glycyrrhizae radix. Dose-effect analyses showed that 50% effective concentrations were 6.2 +/- 1.0 mu g/mL and 15.5 +/- 0.8 mu g/mL for isoliquiritigenin and glycycoumarin, respectively. The MTS assay did not show any effect on cell growth and viability at these effective concentrations, indicating that the effects of the two compounds were specific to HCV replication. These two compounds did not affect the HCV IRES-dependent translation nor did they show synergistic action with interferon-alpha. Two purified herbal extracts, isoliquiritigenin and glycycoumarin, specifically suppressed in vitro HCV replication. Further elucidation of their mechanisms of action and evaluation of in vivo effects and safety might constitute a new anti-HCV therapeutics.
• Colitogenic CD4(+) Effector-memory T Cells Actively Recirculate in Chronic Colitic Mice

  Takayuki Tomita, Takanori Kanai, Yasuhiro Nemoto, Toshimitsu Fujii, Kengo Nozaki, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Teruji Totsuka, Mamoru Watanabe

  INFLAMMATORY BOWEL DISEASES 14 (12) 1630 - 1640 1078-0998 2008/12 [Refereed][Not invited]
   

  Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4(+) T cells continuously recirculate in peripheral blood during the chronic phase of colitis. Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adope tive transfer of CD4(+) CD45RB(high) cells into SCID mice in combination with a parabiosis system. Results: In colitic SCID recipients, first, almost all CD4(+) CD45RB(high) donor cells were converted to CD4(+) CD44(high) CD62L(-) IL-7R alpha(high) effector-memory T (T(EM)) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes. thoracic duct, peripheral blood, spleen, and bone marrow. Second, SCID mice retransferred with the colitic peripheral blood CD4(+) T cells developed colitis that is identical to the original colitis. Third, CD4(+) cells in parabionts between established colitic RAG-2(-/-) mice induced by adoptive transfer of Ly5.1(+) or Lv5.2(+) CD4(+) CD45RB(high) T cells were well mixed in almost equal proportions at various sites 2 weeks after parabiosis Surgery, and the redistribution of Ly5.1(+) and Ly5.2(+) CD4(+) T cells was significantly suppressed in FTY720-treated parabionts. Conclusions: Together. these findings indicate that colitogenic CD4(+) T(EM) cells continuously recirculate in established colitic mice, suggesting that therapeutic approaches targeting systemic CD4+ T(EM) cells, such as bone marrow transplantation, rather than those targeting only intestinal CD(4+) T cells, may be feasible for the treatment of IBD.
• FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4(+) T cells in bone marrow

  Toshimitsu Fujii, Takayuki Tomita, Takanori Kanai, Yasuhiro Nemoto, Teruji Totsuka, Naoya Sakamoto, Tetsuya Nakamura, Kiichiro Tsuchiya, Ryuichi Okamoto, Mamoru Watanabe

  EUROPEAN JOURNAL OF IMMUNOLOGY 38 (12) 3290 - 3303 0014-2980 2008/12 [Refereed][Not invited]
   

  2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized. (SPX) lymphotoxin-alpha(-/-) (LT-alpha(-/-)) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-alpha(-/-) mice. In a short-term transfer experiment, the cell number of transferred Ly5.1(+)CD4(+) T cells recovered from host FTY720-treated SPX LT-alpha(-/-) mice (Ly5.2(+)) was markedly decreased in PB, but conversely increased in BM. Notably, FTY720 treatment prevented the development of colitis that is otherwise induced in untreated SPX LT-alpha(-/-) x RAG-2(-/-) mice upon transfer of colitic lamina propria CD4(+) T cells. In such mice, the number of CD4(+) T cells in PB or lamina propria of FTY720-treated SPX LT-alpha(-/-) x RAG-2(-/-) recipients was significantly reduced, but that in the BM was significantly increased as compared with untreated control mice. Altogether, the present results indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4(+) T cells in BM, resulting in the prevention of colitis.
• Negative Feedback Regulation of Colitogenic CD4(+) T Cells by Increased Granulopoiesis

  Yosuhiro Nemoto, Takanori Kanai, Shuji Tohda, Teruji Totsuka, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Tetsuya Fukuda, Osamu Miura, Hideo Yagita, Mamoru Watanabe

  INFLAMMATORY BOWEL DISEASES 14 (11) 1491 - 1503 1078-0998 2008/11 [Refereed][Not invited]
   

  Background: Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery. We have recently demonstrated that colitogenic CD4(+) memory T cells reside in BM of colitic CD4(+)CD45RB(high) T-cell-transferred SCID mice. Based on this background we here investigate whether granulocytes promote or Suppress the expansion of colitogenic CD4(+) T cells. Methods: First, we show that Gr-1(high) CD11b(+) granulocytes were significantly increased in colitic BM along with a significant increase of peripheral granulocytes. Consistently, the colony-forming unit (CFU) assay revealed that granulocyte colony formation was dominantly induced by supernatants front anti-CD3-stimulated colitic BM CD4(+) T cells. Results: Administration of granulocyte-depleting anti-Gr-1 mAb to colitic mice did not ameliorate the colitis, but exacerbated the wasting disease with an increased expansion of systemic, but not lamina propria, CD4(+) T cells with activated phenotype. Conclusions: These results suggest that the. increased granulopoiesis by colitogenic BM CD4(+) T cells represent a negative feedback mechanism to control systemic inflammation.
• Griseofulvin, an oral antifungal agent, suppresses hepatitis C virus replication in vitro

  Haofan Jin, Atsuya Yamashita, Shinya Maekawa, Pinting Yang, Limin He, Satoru Takayanagi, Takaji Wakita, Naoya Sakamoto, Nobuyuki Enomoto, Masahiko Ito

  HEPATOLOGY RESEARCH 38 (9) 909 - 918 1386-6346 2008/09 [Refereed][Not invited]
   

  Aim: Hepatitis C virus (HCV), which infects an estimated 170 million people worldwide, is a major cause of chronic liver disease. The current standard therapy for chronic hepatitis C is based on pegylated interferon (IFN)alpha in combination with ribavirin. However, the success rate remains at approximately 50%. Therefore, alternative agents are needed for the treatment of HCV infection. Methods: Using an HCV-1b subgenomic replicon cell culture system (Huh7/Rep-Feo), we found that griseofulvin, an oral antifungal agent, suppressed HCV-RNA replication and protein expression in a dose-dependent manner. We also found that griseofulvin suppressed the replication of infectious HCV JFH-1. A combination of IFN alpha and griseofulvin exhibited a synergistic inhibitory effect in Huh7/Rep-Feo cells. Results: We found that griseofulvin blocked the cell cycle at the G(2)/M phase in the HCV subgenomic replicon cells, but did not inhibit HCV internal ribosome entry site-dependent translation. Conclusion: Our results suggest that griseofulvin may represent a new approach to the development of a novel therapy for HCV infection.
• Inhibition of hepatitis C virus infection and expression in vitro and in vivo by recombinant adenovirus expressing short hairpin RNA

  Naoya Sakamoto, Yoko Tanabe, Takanori Yokota, Kenichi Satoh, Yuko Sekine-Osajima, Mina Nakagawa, Yasuhiro Itsui, Megumi Tasaka, Yuki Sakurai, Chen Cheng-Hsin, Masahiko Yano, Shogo Ohkoshi, Yutaka Aoyagi, Shinya Maekawa, Nobuyuki Enomoto, Michinori Kohara, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 23 (9) 1437 - 1447 0815-9319 2008/09 [Refereed][Not invited]
   

  Background and Aim: We have reported previously that synthetic small interfering RNA (siRNA) and DNA-based siRNA expression vectors efficiently and specifically suppress hepatitis C virus (HCV) replication in vitro. In this study, we investigated the effects of the siRNA targeting HCV-RNA in vivo. Methods: We constructed recombinant retrovirus and adenovirus expressing short hairpin RNA (shRNA), and transfected into replicon-expressing cells in vitro and transgenic mice in vivo. Results: Retroviral transduction of Huh7 cells to express shRNA and subsequent transfection of an HCV replicon into the cells showed that the cells had acquired resistance to HCV replication. Infection of cells expressing the HCV replicon with an adenovirus expressing shRNA resulted in efficient vector delivery and expression of shRNA, leading to suppression of the replicon in the cells by similar to 10(-3). Intravenous delivery of the adenovirus expressing shRNA into transgenic mice that can be induced to express HCV structural proteins by the Cre/loxP switching system resulted in specific suppression of virus protein synthesis in the liver. Conclusion: Taken together, our results support the feasibility of utilizing gene targeting therapy based on siRNA and/or shRNA expression to counteract HCV replication, which might prove valuable in the treatment of hepatitis C.
• Immunohistochemical staining of Reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma

  Kazuhiro Sentani, Naohide Oue, Takashi Tashiro, Naoya Sakamoto, Takashi Nishisaka, Toshiyuki Fukuhara, Kiyorni Taniyama, Hiroo Matsuura, Koji Arihiro, Atsushi Ochiai, Wataru Yasui

  AMERICAN JOURNAL OF SURGICAL PATHOLOGY 32 (8) 1182 - 1189 0147-5185 2008/08 [Refereed][Not invited]
   

  Signet-ring cell carcinoma (SRCC) is a unique subtype of adenocarcinoma that is characterized by abundant intracellular mucin accumulation and a crescent-shaped nucleus displaced toward one end of the cell. Identification of an SRCC's primary site is important for better planning of patient management because the treatment and prognosis differs markedly depending on the origin of the SRCC. In the present study, we analyzed the immunohistochemical characteristics of 94 cases of SRCC, including 21 cases of gastric SRCC, 16 of colorectal SRCC, 10 of breast SRCC, and 47 of pulmonary SRCC, with antibodies against Reg IV and claudin-18, which we previously identified as gastric cancer-related genes. We also tested known markers cytokeratin 7, cytokeratin 20, MUC2, MUC5AC, caudal-related homeobox gene 2 (CDX2), thyroid transcription factor-1, mammaglobin, gross cystic disease fluid protein 15, and estrogen receptor. All 21 cases of gastric SRCC and 16 cases of colorectal SRCC were positive for Reg IV, and the remaining SRCCs were negative. Eighteen of 21 (86%) gastric SRCCs and 6 of 16 (38%) colorectal SRCCs were positive for claudin-18, whereas another SRCCs were negative. in conclusion, Reg IV staining and claudin-18 staining can aid in diagnosis of gastrointestinal SRCC.
• Continuous generation of colitogenic CD4(+) T cells in persistent colitis

  Takayuki Tomita, Takanori Kanai, Toshimitsu Fujii, Yasuhiro Nemoto, Ryuichi Okamoto, Kiichiro Tsuchiya, Teruji Totsuka, Naoya Sakamoto, Mamoru Watanabe

  EUROPEAN JOURNAL OF IMMUNOLOGY 38 (5) 1264 - 1274 0014-2980 2008/05 [Refereed][Not invited]
   

  inflammatory bowel diseases take chronic courses due to the expansion of colitogenic CD4(+) cells. However, it is unclear whether the persistent disease is driven by continuous reactivation of colitogenic memory CD4(+) cells to generate effector CD4(+) cells or by continuous generation of effector CD4(+) cells from naive cells. To clarify this issue, we performed a series of sequential adoptive transfers of Ly5.2(+) and Ly5.1(+) CD4(+)CD45RB high cells into RAG-2(-/-) mice at different time points. We show here that the secondarily transferred CD4(+)CD45RB high cells can be converted to CD4(+)CD44(high) CD62L(-)IL-7R alpha(high) effector-memory T cells even in the presence of pre-existing effector-memory CD4(+) cells. Although the total cell numbers of CD4(+) cells in established colitic mice were consistently equivalent irrespective of the number of primarily transferred cells, the ratio of primarily and secondarily transferred cells was dependent on the ratio of the transferred cell numbers, but not on the order of the transfer. Of note, we found that primarily transferred CD4(+) cells produced significantly lower amounts of IFN-gamma and IL-17 than CD4(+) cells arising from secondary transfer. In conclusion, the continuous generation of colitogenic CD4(+) cells that compensate for exhausted CD4(+) cells may be one of the mechanisms involved in the persistence of colitis.
• Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis

  Teruji Totsuka, Takanori Kanai, Yasuhiro Nemoto, Takayuki Tomita, Kiichiro Tsuchiya, Naoya Sakamoto, Ryuichi Okamoto, Mamoru Watanabe

  EUROPEAN JOURNAL OF IMMUNOLOGY 38 (5) 1275 - 1286 0014-2980 2008/05 [Refereed][Not invited]
   

  Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4(+) cells. However, it remains unknown whether colitogenic CD4(+) cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4(+) cells, we performed sequential transfers of LP CD4(+) cells from colitic CD4(+)CD45RB(high) cell-transferred SCID mice into new SCID mice. Although SCID mice transferred with colitic LP CD4(+) cells stably developed colitis until at least the sixth transfer, the interval to the development of colitis gradually lengthened as the number of transfers increased. The incidence of colitis gradually decreased after the seventh transfer. Furthermore, non-colitic LP CD4(+) cells from mice transferred over seven times expressed significantly higher levels of PD-1 and produced significantly lower amounts of IFN-gamma, TNF-alpha, and IL-17 than colitic LP CD4(+) cells recovered after the first transfer. Most notably, we found that re-transfer of non-colitic LP CD4(+) cells recovered after multiple transfers prevented the development of colitis in SCID mice co-transferred with CD4(+)CD45RB(high) cells. Thus, colitogenic LP CD4(+) cells may be exhausted over time, become non-functional, convert to regulatory cells, and finally suppress colitis in the process of immunosenescence.
• Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response

  Yasuhiro Asahina, Namiki Izumi, Itsuko Hirayama, Tomohiro Tanaka, Mitsuaki Sato, Yutaka Yasui, Nobutoshi Komatsu, Naoki Umeda, Takanori Hosokawa, Ken Ueda, Kaoru Tsuchiya, Hiroyuki Nakanishi, Jun Itakura, Masayuki Kurosaki, Nobuyuki Enomoto, Megumi Tasaka, Naoya Sakamoto, Shozo Miyake

  GASTROENTEROLOGY 134 (5) 1396 - 1405 0016-5085 2008/05 [Refereed][Not invited]
   

  Background & Aims: Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). Methods: We conducted a human study in 74 CH-C patients treated with pegylated interferon a-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. Results: Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with non-hepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDAS, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVP. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). Conclusions: NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR.
• Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer

  Mikayo Aragaki, Kiichiro Tsuchiya, Ryuichi Okamoto, Sanae Yoshioka, Tetsuya Nakamura, Naoya Sakamoto, Takanori Kanai, Mamoru Watanabe

  Biochemical and Biophysical Research Communications 368 (4) 923 - 929 0006-291X 2008/04/18 [Refereed][Not invited]
   

  Atoh1 plays a crucial role in intestinal cell differentiation. We have demonstrated that its human homolog Hath1 protein is targeted by the Wnt-GSK3 axis, resulting in the proteasomal degradation in human colon cancer. However, the contribution of Hath1 degradation to the undifferentiated state of colon cancer remains unknown. In this study, we demonstrated that both constitutive expression of mutant Hath1 and stabilization of Hath1 protein by a GSK3 inhibitor in colon cancer cells increased the expression of MUC2 known as a representative function of differentiated goblet cells. This means that Hath1 protein degradation may be required for maintaining the undifferentiated state of colon cancers, and that GSK3 inhibitors have potential for use in cancer therapy. © 2008 Elsevier Inc. All rights reserved.
• Gene expression profiling with microarray and SAGE identifies PLUNC as a marker for hepatoid adenocarcinoma of the stomach

  Kazuhiro Sentani, Naohide Oue, Naoya Sakamoto, Koji Arihiro, Kazuhiko Aoyagi, Hiroki Sasaki, Wataru Yasui

  MODERN PATHOLOGY 21 (4) 464 - 475 0893-3952 2008/04 [Refereed][Not invited]
   

  Gastric cancer is one of the most common malignancies worldwide. In this study, we screened for genes upregulated in gastric cancer by comparing gene expression profiles from serial analysis of gene expression and microarray and identified the palate, lung, and nasal epithelium carcinoma-associated protein (PLUNC) gene. Immunostaining for PLUNC in 140 gastric cancer cases revealed strong and extensive staining of PLUNC in hepatoid adenocarcinoma of the stomach, whereas 7% of conventional gastric cancer cases showed focal immunostaining of PLUNC. Gastric hepatoid adenocarcinoma is an extrahepatic tumor characterized by morphologic similarities to hepatocellular carcinoma. To investigate the utility of PLUNC immunostaining in the diagnosis of gastric hepatoid adenocarcinoma, six cases of gastric hepatoid adenocarcinoma (six primary tumors and two associated liver metastases) were studied further. PLUNC staining was observed in all six primary hepatoid adenocarcinomas. PLUNC staining was observed in both the hepatoid adenocarcinoma and tubular/papillary adenocarcinoma components of primary tumors, although PLUNC staining was preferentially localized in tubular/papillary adenocarcinoma components. Staining of PLUNC was also detected in both liver metastases. PLUNC staining was not observed in 52 cases of primary hepatocellular carcinoma or in normal adult or fetal liver. These results indicate that PLUNC is a novel marker that distinguishes gastric hepatoid adenocarcinoma from primary hepatocellular carcinoma.
• Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer

  Mikayo Aragaki, Kiichiro Tsuchiya, Ryuichi Okamoto, Sanae Yoshioka, Tetsuya Nakamura, Naoya Sakamoto, Takanorl Kanai, Mamoru Watanabe

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 368 (4) 923 - 929 0006-291X 2008/04 [Refereed][Not invited]
   

  Atoh1 plays a crucial role in intestinal cell differentiation. We have demonstrated that its human homolog Hath1 protein is targeted by the Wnt-GSK3 axis, resulting in the proteasomal degradation in human colon cancer. However, the contribution of Hath1 degradation to the undifferentiated state of colon cancer remains unknown. In this study, we demonstrated that both constitutive expression of mutant Hath1 and stabilization of Hath1 protein by a GSK3 inhibitor in colon cancer cells increased the expression of MUC2 known as a representative function of differentiated goblet cells. This means that Hath1 protein degradation may be required for maintaining the undifferentiated state of colon cancers, and that GSK3 inhibitors have potential for use in cancer therapy. (C) 2008 Elsevier Inc. All rights reserved.
• MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis.

  Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M

  Journal of immunology (Baltimore, Md. : 1950) 180 (8) 5291 - 5299 0022-1767 2008/04 [Refereed][Not invited]
  
• Development of plaque assays for hepatitis C virus-JFH1 strain and isolation of mutants with enhanced cytopathogenicity and replication capacity

  Yuko Sekine-Osajima, Naoya Sakamoto, Kako Mishima, Mina Nakagawa, Yasuhiro Itsui, Megumi Tasaka, Yuki Nishimura-Sakurai, Cheng-Hsin Chen, Takanori Kanai, Kiiehiro Tsuchiya, Takaji Wakita, Nobuyuki Enomoto, Mamoru Watanabe

  VIROLOGY 371 (1) 71 - 85 0042-6822 2008/02 [Refereed][Not invited]
   

  HCV culture in vitro results in massive cell death, which suggests the presence of HCV-induced cytopathic effects. Therefore, we investigated its mechanisms and viral nucleotide sequences involved in this effect using HCV-JFH1 cell culture and a newly developed HCV plaque assay technique. The plaque assay developed cytopathic plaques, depending on the titer of the inoculum. In the virus-infected cells, the ER stress markers, GR-P78 and phosphorylated eIF2-alpha, were overexpressed. Cells in the plaques were strongly positive for an apoplosis marker, annexin V Isolated virus subclones from individual plaque showed greater replication efficiency and cytopathogenicity than the parental virus. The plaque-purified virus had 9 amino acid substitutions, of which 5 were clustered in the C terminal of the NS5B region. Taken together, the cytopathic effect of HCV infection involves ER-stress-induced apoptotic cell death. Certain HCV genomic structures may determine the viral replication capacity and cytopathogenicity. (c) 2007 Elsevier Inc. All rights reserved.
• Targeting lipid metabolism in the treatment of hepatitis C virus infection

  Fumitake Amemiya, Shinya Maekawa, Yoshie Itakura, Asuka Kanayama, Akira Matsui, Shinichi Takano, Tatsuya Yamaguchi, Jun Itakura, Takatoshi Kitamura, Taisuke Inoue, Minoru Sakamoto, Kozue Yamauchi, Shunichi Okada, Atsuya Yamashita, Naoya Sakamoto, Masahiko Itoh, Nobuyuki Enomoto

  JOURNAL OF INFECTIOUS DISEASES 197 (3) 361 - 370 0022-1899 2008/02 [Refereed][Not invited]
   

  Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called "lipid rafts") have been considered to act as a scaffold for the hepatitis C virus(HCV) replication complex. Using the HCV cell culture system, we investigated the effect of myriocin, a sphingomyelin synthesis inhibitor, on HCV replication. We also investigated the combined effect of myriocin with interferon (IFN) and myriocin with simvastatin. Myriocin suppressed replication of both a genotype 1b subgenomic HCV replicon (Huh7/Rep-Feo) and genotype 2a infectious HCV (JFH-1 HCV) in a dose-dependent manner (for subgenomic HCV-1b, maximum of 79% at 1000 nmol/L; for genomic HCV-2a, maximum of 40% at 1000 nmol/L). Combination treatment with myriocin and IFN or myriocin and simvastatin attenuated HCV RNA replication synergistically in Huh7/Rep-Feo cells. Our data demonstrate that the sphingomyelin synthesis inhibitor strongly suppresses replication of both the subgenomic HCV-1b replicon and the JFH-1 strain of genotype 2a infectious HCV, indicating that lipid metabolism could be a novel target for HCV therapy.
• 2. Progression of Type C Chronic Hepatitis and Resistance to Treatment 1) From a Viewpoint of Viral Mutation

  Sakamoto Naoya

  Nihon Naika Gakkai Kaishi The Japanese Society of Internal Medicine 97 (1) 64 - 68 0021-5384 2008/01/10 

  C型肝炎ウイルス（HCV）は変位速度が速く，慢性持続感染の機構のひとつと考えられる．日本に多いゲノタイプ1型は2型に比べインターフェロン治療抵抗性である．ウイルスゲノムのコア領域·NS5A領域にインターフェロン治療の感受性を規定する部位が存在する．今後ウイルス蛋白を標的とした治療薬が登場するがウイルス耐性変異の克服が課題となる．
  
• Remodeling of Endothelial Cell Nucleus Exposed to Three Different Mechanical Stimuli

  Toshiro Ohashi, Kazuhiko Hanamura, Daisaku Azuma, Naoya Sakamoto, Masaaki Sato

  Journal of Biomechanical Science and Engineering 3 (2) 63 - 74 1880-9863 2008 [Refereed][Not invited]
   

  Cell Nuclei play a critical role in controlling gene expression and replicating DNA, and is known to deform in association with cell shape changes in response to external forces. This study dealed with morphological analysis to quantitatively assess the effect of three different mechanical stimuli including fluid shear stress, cyclic stretching, and hydrostatic pressure on nucleus morphology. Fluorescence images showed that fluid shear stress and cyclic stretching induced cell elongation and orientation very specifically to the direction of flow and stretch, respectively. In contrast, hydrostatic pressure induced cell elongation at non-preferred orientation. The nuclei were also found to deform in the same manner as that of the cells, which was, in particular, dependent on the type of mechanical stimuli, possibly suggesting the direct mechanical linkages between cell surface receptors, cytoskeletal meshworks, and nuclei. It was also shown that cytoskeletal meshworks may contribute to pre-existing strain of the nuclei. © 2008, The Japan Society of Mechanical Engineers. All rights reserved.
• Characterization of Motility Properties of Kinesin-Driven Microtubules Towards NanoScale Transporter: Focusing on Length of Microtubules and Kinesin Density

  Shukei Sugita, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  Journal of Biomechanical Science and Engineering 3 (4) 510 - 519 1880-9863 2008 [Refereed][Not invited]
   

  Kinesins, biomolecular motors moving along microtubules (MTs) in cells, can potentially be utilized as NanoScale transport systems with an inverted gliding assay, in which the MTs glide on a kinesin-coated surface. Although the key requirements include controls of gliding direction and velocity of MTs, the details of motility properties of MTs have not been well known. In this study, we quantitatively measured angular and gliding velocities, particularly focusing on the effects of MT length and kinesin density. The gliding assay of MTs of up to 20 μm in length was performed on a substrate coated with the kinesin density of 7.5, 38, and 75 ug/ml that resulted in the kinesin spacing of 7.8, 4.2, and 3.1 μm, respectively. The angular velocity for MTs shorter than kinesin spacings significantly decreased with increasing their length, and that for MTs longer than kinesin spacings was not affected by their length. Moreover, the angular velocity was substantially higher at lower kinesin density. These results suggest that both the number of associated kinesins with MTs and the kinesin spacings may contribute to the gliding direction. In contrast, the gliding velocity was independent of the MT length, ranging from 0.3 to 0.5 μm/s with decreasing the kinesin density. This may potentially imply the existence of an underlying mechanism with respect to the number of kinesins per the unit length of MTs. Towards development of high throughput NanoScale transport systems, long MTs and low kinesin densities would be effective for high directionality and high velocity, respectively. © 2008, The Japan Society of Mechanical Engineers. All rights reserved.
• Blockade of NKG2D signaling prevents the development of murine CD4(+) T cell-mediated colitis

  Y. Ito, T. Kanai, T. Totsuka, R. Okamoto, K. Tsuchiya, Y. Nemoto, A. Yoshioka, T. Tomita, T. Nagaishi, N. Sakamoto, T. Sakanishi, K. Okumura, H. Yagita, M. Watanabe

  AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 294 (1) G199 - G207 0193-1857 2008/01 [Refereed][Not invited]
   

  It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8(+) T cells, and gamma delta T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4(+) CD45RB(high) T cells is characterized by significant increase of CD4(+)NKG2D(+) T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c(+) dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4(+)CD45RB(high) T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-gamma by lamina propria CD4(+) T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4(+) T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases.
• Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis

  Yasuhiro Nemoto, Takanori Kanai, Shuji Tohda, Teruji Totsuka, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Tetsuya Fukuda, Osamu Miura, Hideo Yagita, Mamoru Watanabe

  Inflammatory Bowel Diseases 14 (11) 1491 - 1503 1078-0998 2008 [Refereed][Not invited]
   

  Background: Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery. We have recently demonstrated that colitogenic CD4+ memory T cells reside in BM of colitic CD4+CD45RBhigh T-cell-transferred SCID mice. Based on this background we here investigate whether granulocytes promote or suppress the expansion of colitogenic CD4+ T cells. Methods: First, we show that Gr-1highCD11b+ granulocytes were significantly increased in colitic BM along with a significant increase of peripheral granulocytes. Consistently, the colony-forming unit (CFU) assay revealed that granulocyte colony formation was dominantly induced by supernatants from anti-CD3-stimulated colitic BM CD4+ T cells. Results: Administration of granulocyte-depleting anti-Gr-1 mAb to colitic mice did not ameliorate the colitis, but exacerbated the wasting disease with an increased expansion of systemic, but not lamina propria, CD4+ T cells with activated phenotype. Conclusions: These results suggest that the increased granulopoiesis by colitogenic BM CD4+ T cells represent a negative feedback mechanism to control systemic inflammation. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.
• Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice

  Takayuki Tomita, Takanori Kanai, Yasuhiro Nemoto, Toshimitsu Fujii, Kengo Nozaki, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Teruji Totsuka, Mamoru Watanabe

  Inflammatory Bowel Diseases 14 (12) 1630 - 1640 1078-0998 2008 [Refereed][Not invited]
   

  Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4+ T cells continuously recirculate in peripheral blood during the chronic phase of colitis. Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4+CD45RBhigh cells into SCID mice in combination with a parabiosis system. Results: In colitic SCID recipients, first, almost all CD4+ CD45RBhigh donor cells were converted to CD4+CD44highCD62L- IL-7Rα high effector-memory T (TEM) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow. Second, SCID mice retransferred with the colitic peripheral blood CD4+ T cells developed colitis that is identical to the original colitis. Third, CD4+ cells in parabionts between established colitic RAG-2-/- mice induced by adoptive transfer of Ly5.1+ or Ly5.2+ CD4+CD45RBhigh T cells were well mixed in almost equal proportions at various sites 2 weeks after parabiosis surgery, and the redistribution of Ly5.1+ and Ly5.2+ CD4+ T cells was significantly suppressed in FTY720-treated parabionts. Conclusions: Together, these findings indicate that colitogenic CD4+ TEM cells continuously recirculate in established colitic mice, suggesting that therapeutic approaches targeting systemic CD4+ TEM cells, such as bone marrow transplantation, rather than those targeting only intestinal CD4+ T cells, may be feasible for the treatment of IBD. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.
• FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow

  Toshimitsu Fujii, Takayuki Tomita, Takanori Kanai, Yasuhiro Nemoto, Teruji Totsuka, Naoya Sakamoto, Tetsuya Nakamura, Kiichiro Tsuchiya, Ryuichi Okamoto, Mamoru Watanabe

  European Journal of Immunology 38 (12) 3290 - 3303 0014-2980 2008 [Refereed][Not invited]
   

  2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4+ T cells in splenectomized (SPX) lymphotoxin-α-/- (LT-α -/-) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-α -/- mice. In a short-term transfer experiment, the cell number of transferred Ly5.1+CD4+ T cells recovered from host FTY720-treated SPX LT-α-/- mice (Ly5.2+) was markedly decreased in PB, but conversely increased in BM. Notably, FTY720 treatment prevented the development of colitis that is otherwise induced in untreated SPX LT-α -/- x RAG-2-/- mice upon transfer of colitic lamina propria CD4+ T cells. In such mice, the number of CD4+ T cells in PB or lamina propria of FTY720-treated SPX LT-α-/- x RAG-2-/- recipients was significantly reduced, but that in the BM was significantly increased as compared with untreated control mice. Altogether, the present results indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4+ T cells in BM, resulting in the prevention of colitis. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.
• Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis.

  Tomita T, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Sakamoto N, Watanabe M

  Journal of immunology (Baltimore, Md. : 1950) 180 (1) 383 - 390 0022-1767 2008/01 [Refereed][Not invited]
  
• Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response

  Megumi Tasaka, Naoya Sakamoto, Mina Nakagawa, Yasuhiro Itsui, Yuko Sekine-Osajima, Yuki Nishimura-Sakurai, Cheng-Hsin Chen, Mitsutoshi Yoneyama, Takashi Fujita, Takaji Wakita, Shinya Maekawa, Nobuyuki Enomoto, Mamoru Watanabe

  JOURNAL OF GENERAL VIROLOGY 88 (Pt 12) 3323 - 3333 0022-1317 2007/12 [Refereed][Not invited]
   

  Viral infections activate cellular expression of type I interferons (IFNs). These responses are partly triggered by RIG-I and mediated by Cardif, TBK1, IKK epsilon and IRF-3. This study analysed the mechanisms of dsRNA-induced IFN responses in various cell lines that supported subgenomic hepatitis C virus (HCV) replication. Transfection of dsRNA into Huh7, HeLa and HEK293 cells induced an IFN expression response as shown by IRF-3 dimerization, whilst these responses were abolished in corresponding cell lines that expressed HCV replicons. Similarly, RIG-I-dependent activation of the IFN-stimulated response element (ISRE) was significantly suppressed by cells expressing the HCV replicon and restored in replicon-eliminated cells. Overexpression analyses of individual HCV non-structural proteins revealed that NS4B, as well as NS34A, significantly inhibited RIG-I-triggered ISRE activation. Taken together, HCV replication and protein expression substantially blocked the dsRNA-triggered, RIG-I-mediated IFN expression response and this blockade was partly mediated by HCV NS4B, as well as NS34A. These mechanisms may contribute to the clinical persistence of HCV infection and could constitute a novel antiviral therapeutic target.
• Identification of novel epoxide inhibitors of hepatitis C virus replication using a high-throughput screen

  Lee F. Peng, Sun Suk Kim, Sirinya Matchacheep, Xiaoguang Lei, Shun Su, Wenyu Lin, Weerawat Runguphan, Won-Hyeok Choe, Naoya Sakamoto, Masanori Ikeda, Nobuyuki Kato, Aaron B. Beeler, John A. Porco, Stuart L. Schreiber, Raymond T. Chung

  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 51 (10) 3756 - 3759 0066-4804 2007/10 [Refereed][Not invited]
   

  Using our high-throughput hepatitis C replicon assay to screen a library of over 8,000 novel diversity-oriented synthesis (DOS) compounds, we identified several novel compounds that regulate hepatitis C virus (HCV) replication, including two libraries of epoxides that inhibit HCV replication (best 50% effective concentration, < 0.5 mu M). We then synthesized an analog of these compounds with optimized activity.
• Bone morphogenetic protein-7 and interferon-alpha synergistically suppress hepatitis C virus replicon

  Naoya Sakamoto, Mika Yoshimura, Tomomi Kimura, Keisuke Toyama, Yuko Sekine-Osajima, Mamoru Watanabe, Masaaki Muramatsu

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 357 (2) 467 - 473 0006-291X 2007/06 [Refereed][Not invited]
   

  Various cytokines contribute to control hepatitis C virus (HCV) viral replication. HCV subgenomic replicon systems have been developed, and cell-cycle-dependent replication has been reported. But the molecules involved in this processes is not totally elucidated. The aim of this study is to investigate the involvement of the bone morphogenetic protein (BMP)-7, a member of TGF-beta superfamily, to the in vitro HCV replication. BMP-7 dose-dependently suppressed the replication and protein expression from the HCV replicon in Huh7/Rep-Feo cells and was associated with cell-cycle arrest at the G1 phase. These results were consistent with the effect of TGF-beta in a previous study. Combination of BMP-7 and interferon-alpha showed a synergic decrease of HCV replication, and was more effective compared to the treatment with interferon-alpha alone. This synergistic effect was also present in HCV-JFH1 virus cell culture. While BMP-7 alone did not stimulate expression of the interferon-stimulated genes (ISGs), it augmented interferon-induced expression of the ISGs independently of the interferon-induced Jak/STAT pathway. Taken together, BMP-7 may constitute a novel molecule to suppress HCV replication. (c) 2007 Elsevier Inc. All rights reserved.
• Biomechanical role of intracellular structures in smooth muscle cells estimated by traction force measurements

  Toshiro Ohashi, Shouji Nakamura, Naoya Sakamoto, Masaaki Sato

  2007 International Symposium on Micro-NanoMechatronics and Human Science, MHS 400 - 405 2007 [Refereed][Not invited]
   

  This study addresses a technique to explore mechanical role of intracellular structures by using a triton cytoskeleton model (TC model) for traction force measurements. Inhibition of signaling pathways of myosin light chain phosphorylation, possibly being induced by disruption of mictotubules, is also performed. Traction forces for the TC model significantly decreased compared to control. In contrast, traction forces significantly increased from 10.3 ± 2.5 nN to 13.3 ± 3.7 nN after treatment of nocodazole, which is well consistent with previous studies. From these results, not only cytoskeletal structures but also other cellular components such as cytoplasm should be involved in cell mechanics. Separate fluorescence studies showed that microtubules disruption induced myosin light chain phosphorylation. Exposure to Y27632 showed that traction forces decreased by 80% compared to control within 15 min and the following treatment with nocodazole showed only 40% recovery from the priori decreased forces. This result indicates that microtubules disassembly may modulate the actomyosin mechanism leading to the increase in traction forces, mainly through the ROCK pathway. It can be concluded that contribution of microtubules should include not only a force balance but also a modulator of the actomyosin-based contractile system. ©2007 IEEE.
• Hydrostatic pressure influences morphology and expression of VE-cadherin of vascular endothelial cells

  Toshiro Ohashi, Yoshiaki Sugaya, Naoya Sakamoto, Masaaki Sato

  Journal of Biomechanics 40 (11) 2399 - 2405 0021-9290 2007 [Refereed][Not invited]
   

  Bovine aortic endothelial cells (BAECs) were exposed to hydrostatic pressures of 50, 100, and 150 mmHg and changes in morphology and expression of vascular endothelial (VE)-cadherin were studied. After exposure to hydrostatic pressure, BAECs exhibited elongated and tortuous shape without predominant orientation, together with the development of centrally located, thick stress fibers. Pressured BAECs also exhibited a multilayered structure unlike those under control conditions and showed a significant increase in proliferation compared with control cells. Western blot analysis demonstrated that protein level of VE-cadherin were significantly lower under pressure conditions than under control conditions. Inhibition of VE-cadherin expression, using an antibody to VE-cadherin, induced the formation of numerous randomly distributed intercellular gaps, elongated and tortuous shapes, and multilayering. These responses were similar to those of pressured BAECs. The exposure of BAECs to hydrostatic pressure may therefore downregulate the expression of VE-cadherin, resulting in loss of contact inhibition followed by increased proliferation and formation of a multilayered structure. © 2007 Elsevier Ltd. All rights reserved.
• Effects of frequency of pulsatile flow on morphology and integrin expression of vascular endothelial cells

  Kazushi Ito, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  Technology and Health Care 15 (2) 91 - 101 0928-7329 2007 [Refereed][Not invited]
   

  Endothelial cells are known to adapt their morphology and functions in response to different types of fluid flow. In vivo, endothelial cells are exposed to varying frequencies of pulsatile flow. Therefore, in this study, the effects of frequency of pulsatile flow on morphology and α vβ3 integrin expression of bovine aortic endothelial cells (BAEC) were investigated. A newly developed flow-system was used to apply pulsatile flow at frequencies of 0.5, 1.0, and 1.5 Hz to BAEC for 12 h. At 1.0 Hz, the expression of αvβ3 integrin was significantly higher at the central regions of cells than at the upstream regions. In contrast, at 0.5 and 1.5 Hz, the expression of α vβ3 integrin was significantly higher at the upstream regions than at the central regions. Morphological observation revealed that BAEC under pulsatile flow frequencies of 0.5 and 1.0 Hz exhibited elongated morphologies and oriented with the direction of flow. In addition, stress fibers developed parallel to the cell major axis. Similar results were obtained under steady flow conditions. In contrast, BAEC under 1.5 Hz elongated but with a random orientation. These results suggest that BAEC morphology and integrin expression may be modulated by the frequency of pulsatile flow. In particular, BAEC exposed to 1.5 Hz pulsatile flow may not be able to align with the direction of flow, possibly indicating the presence of a critical value for living systems. © 2007 - IOS Press and the authors. All rights reserved.
• ダブルバルーン小腸内視鏡(DBE)を用いて小腸ポリープを切除したPeutz-Jeghers syndromeの1例

  渡辺貴子, 玄世鋒, 植山真由美, 小野塚泉, 久保田大輔, 岡田英理子, 鈴木伸治, 陳正新, 長堀正和, 岡本隆一, 中川美奈, 戸塚輝治, 土屋輝一郎, 永石宇司, 中村哲也, 荒木昭博, 坂本直哉, 金井隆典, 渡辺守

  Progress of Digestive Endoscopy 72 (1) 107  2007 [Not refereed][Not invited]
  
• ダブルバルーン内視鏡で診断し治療後経過観察し得た、空腸follicular lymphomaの一例

  岡本英子, 岡田英理子, 荒木昭博, 土屋輝一郎, 小貫優子, 三島果子, 山本満千, 須田剛生, 松本智子, 久保田大輔, 陳正新, 大岡真也, 長堀正和, 吉岡早苗, 鈴木伸治, 坂本直哉, 金井隆典, 渡辺守

  Progress of Digestive Endoscopy 71 (1) 103  2007 [Not refereed][Not invited]
  
• A case of severe ulcerative colitis successfully with intravenous cyclosporine without high dose corticosteroid

  Daisuke Kubota, Takanori Kanai, Fumiro Yui, Tomoko Matsumoto, Takahiro Kawamura, Yasuhiro Itsui, Eriko Okada, Seishin Chin, Shinya Ooka, Masakazu Nagahori, Kiichiro Tsuchiya, Akihiro Araki, Naoya Sakamoto, Tatsuya Miyata, Mamoru Watanabe

  Japanese Journal of Gastroenterology 104 (1) 42 - 46 0446-6586 2007/01 [Not refereed][Not invited]
   

  A 44-year-old women developed marked myopathy one year earlier, when she was treated with intravenous prednisolone for acute severe exacerbation of ulcerative colitis. When she was admitted to our hospital for another severe exacerbation, intravenous cyclosporine A was administered as monotherapy because she could not tolerate corticosteroid. The treatment was successful and she obtained complete remission. Cyclosporine A monotherapy is considered to be a valuable alternative to proctocolectomy for severe ulcerative colitis patients who cannot tolerate corticosteroid.
• A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication

  Sun Suk Kim, Lee F. Peng, Wenyu Lin, Won-Hyeok Choe, Naoya Sakamoto, Stuart L. Schreiber, Raymond T. Chung

  GASTROENTEROLOGY 132 (1) 311 - 320 0016-5085 2007/01 [Refereed][Not invited]
   

  Background & Aims: Only half of patients with chronic hepatitis C virus (HCV) infection experience sustained virologic response to pegylated-interferon and ribavirin, which cause numerous side effects. Thus, the identification of more effective and better tolerated agents is a high priority. We applied chemical biology to screen small molecules that regulate HCV. Methods: We first optimized the Huh7/RepFeo replicon cell fine for the 384-well microplate format and used this line to screen a large library of well-characterized, known biologically active compounds using automated technology. After identifying several molecules capable of either stimulating or inhibiting HCV replication in this primary screen, we then validated our hit compounds using a full-length HCV replicon cell line in secondary screens. Results: We identified and validated a number of antiviral and proviral agents, including HMG-CoA reductase inhibitors (antiviral) and corticosteroids (proviral). The finding of increased replication associated with corticosteroids suggests that these agents directly promote viral replication independent of their suppressive effects on the immune response. The finding of antiviral activity associated with the HMG-CoA reductase inhibitors implies an important role for lipid metabolism in the viral life cycle. Conclusions: We have developed a simple, reproducible, and reliable cell-based high-throughput screening assay system using an HCV replicon model to identify small molecules that regulate HCV replication. This method can be used to identify not only putative antiviral agents, but also cellular regulators of viral replication.
• Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication

  Y. Itsui, N. Sakamoto, M. Kurosaki, N. Kanazawa, Y. Tanabe, T. Koyama, Y. Takeda, M. Nakagawa, S. Kakinuma, Y. Sekine, S. Maekawa, N. Enomoto, M. Watanabe

  JOURNAL OF VIRAL HEPATITIS 13 (10) 690 - 700 1352-0504 2006/10 [Refereed][Not invited]
   

  Type-I interferons (IFNs) and the interferon-stimulated genes (ISGs) play a major role in antivirus responses against hepatitis C virus (HCV) infection. In this study, we studied expression profiles of ISGs in cells supporting subgenomic HCV replication (Huh7/Rep), and screened their activities to suppress HCV replication. Real-time PCR analyses showed that the expression levels of 23 ISGs were significantly lower in Huh7/Rep than naive Huh7 cells due to transcriptional suppression of the interferon-stimulated response element (ISRE). Furthermore, the expression level of ISGs was also decreased in the cured Huh7 cells in which replicon had been eliminated (cHuh7), indicating adaptation of the cells to support HCV replication by downregulating ISGs. On the other hand, expression of HCV replicon was significantly suppressed by overexpression of several ISGs including PKR, MxA, IRF-9, GBP-1, IFI-6-16, IFI-27, 25OAS and IRF-1. Knock down of GBP-1, IFI-6-16 and IFI-27 by short hairpin RNA resulted in increase of HCV replication. Thus, we conclude that downregulation of ISG expression is required in the host cells supporting HCV replication and that several ISGs directly suppress HCV replication. The search for ISGs that regulate HCV replication may help to elucidate the cellular antiviral defence mechanisms against HCV infection.
• Site-specific mutation of the interferon sensitivity-determining region (ISDR) modulates hepatitis C virus replication

  T. Kohashi, S. Maekawa, N. Sakamoto, M. Kurosaki, H. Watanabe, Y. Tanabe, C. -H. Chen, N. Kanazawa, M. Nakagawa, S. Kakinuma, T. Yamashiro, Y. Itsui, T. Koyama, N. Enomoto, M. Watanabe

  JOURNAL OF VIRAL HEPATITIS 13 (9) 582 - 590 1352-0504 2006/09 [Refereed][Not invited]
   

  The number of amino acid substitutions in the interferon sensitivity-determining region (ISDR) in the nonstructural 5A (NS5A) gene of hepatitis C virus (HCV) is closely associated with the interferon (IFN) response and viral load. Several HCV replicon-based studies have reported that ISDR sequences had an influence on viral replication in vitro. However, it is unclear as to how different ISDR sequences affect HCV replication. Various clinically observed ISDR sequences were introduced into HCV replicons and their contribution to viral replication was investigated using a colony formation assay and/or a transient replication assay. A mapping study of the ISDR was performed to identify the amino acid positions that critically affect replication. While no colonies were formed in the colony formation assay using HCV replicons with few mutations (0, 1 and 3) in the ISDR, numerous colonies (> 200) appeared when using constructs with six mutations. Introduction of various distinct ISDR sequences with multiple mutations resulted in replication enhancement in transient assays. A mapping study identified several specific sites in the ISDR that critically affected replication, including codon 2209 which, in patients, was closely associated with a strong response to IFN. ISDR sequences associated with a clinical IFN response and viral load modulated the replication of HCV replicons, suggesting the importance of the ISDR sequence in HCV infection.
• A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient

  Daisuke Kubota, Chizuru Takishima, Ken-Ichi Ishii, Takahiro Kawamura, Tomoko Matsumoto, Yasuhiro Itsui, Eriko Okada, Seishin Chin, Shinya Oooka, Kiichiro Tsuchiya, Akihiro Araki, Naoya Sakamoto, Tatsuya Miyata, Takanori Kanai, Mamoru Watanabe

  Japanese Journal of Gastroenterology 103 (9) 1044 - 1049 0446-6586 2006/09 [Not refereed][Not invited]
   

  A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/μl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.
• Negative regulation of intracellular hepatitis C virus replication by interferon regulatory factor 3

  Tsuyoshi Yamashiro, Naoya Sakamoto, Masayuki Kurosaki, Nobuhiko Kanazawa, Yoko Tanabe, Mina Nakagawa, Cheng-Hsin Chen, Yasuhiro Itsui, Tomoyuki Koyama, Yoshie Takeda, Shinya Maekawa, Nobuyuki Enomoto, Hiroshi Sakugawa, Mamoru Watanabe

  JOURNAL OF GASTROENTEROLOGY 41 (8) 750 - 757 0944-1174 2006/09 [Refereed][Not invited]
   

  Backround. Interferon regulatory factor (IRF)-3 plays an important role in initiating cellular interferon-stimulated gene-mediated antiviral responses. In the present study, we evaluated the effects of IRF-3 expression and activation on intracellular hepatitis C virus (HCV) replication using an HCV replicon system. Methods. An HCV replicon was constructed that expressed a neomycin-selectable chimeric firefly luciferase reporter protein. A small interfering (si) RNA oligonucleotide directed against IRF-3 mRNA was designed and synthesized. A eukaryote expression plasmid vector was constructed that expressed IRF-3 mRNA under control of the cytomegalovirus early promoter/enhancer. To evaluate transcriptional activity of the interferon-stimulated genes, a reporter vector was used that expressed firefly luciferase under control of the interferon-stimulated response element (ISRE). Results. The baseline expression of IRF-3 did not significantly differ between cells with and without expression of the replicon. Transfection of an IRF-3 expression plasmid into the cells raised the ISRE-luciferase activities. The increase of ISRE activity was significantly more potent in the replicon-expressing cells than in cells without replicon expression. Concomitantly, the overexpression of IRF-3 suppressed HCV replication levels. In contrast, siRNA knockdown of IRF-3 suppressed ISRE activity by 38% +/- 2%. Interestingly, the suppression of IRF-3 resulted in a significant increase of HCV replication, by up to twofold, depending on the IRF-3 suppression levels. Conclusions. IRF-3 negatively regulated intracellular HCV replication, and was partially activated in cells that expressed the HCV replicon. Thus, IRF-3 is a key molecule controlling HCV replication through modulation of host interferon gene responses.
• Adhesive force of human hepatoma HepG2 cells to endothelial cells and expression of E-selectin

  Guanbin Song, Toshiro Ohashi, Naoya Sakamoto, Masaaki Sato

  MCB Molecular and Cellular Biomechanics 3 (2) 61 - 68 1556-5297 2006/06 [Refereed][Not invited]
   

  Expression of adhesion molecules may play an important role in the interaction of tumor cells with vascular endothelial cells during tumor invasion and metastasis. In this study, the adhesive force of human hepatoma HepG2 cells to human umbilical vein endothelial cells (HUVECs) was investigated using a micropipette aspiration technique. Expression of an adhesion molecule, E-selectin, was also observed by immunofluorescence, microscopy. In particular, the adhesive force after stimulation of HUVECs with recombinant human interleukin-1β (rhIL-1β) was examined. The results demonstrated that the adhesive force of HepG2 cells to stimulated HUVECs is significantly higher than that of unstimulated control cells, and that immunofluorescence of E-selectin in stimulated HUVECs showed a higher fluorescent intensity compared to control cells. Moreover, addition of monoclonal anti-human E-selectin decreased the adhesive force of HepG2 cells to stimulated HUVECs by 50%. These results suggest that endothelial E-selectin may be a main mediator of carcinoma metastasis of malignant tumor through blood circulation, possibly increasing the adhesive force of human hepatoma HepG2 cells to HUVECs in the early stage of metastases. Copyright © 2006 Tech Science Press.
• Effect of fluid shear stress on migration of vascular smooth muscle cells in cocultured model

  Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  Annals of Biomedical Engineering 34 (3) 408 - 415 0090-6964 2006/03 [Refereed][Not invited]
   

  Migration of smooth muscle cells (SMCs) in hyperplasia is thought to have a correlation with blood flow conditions. In this study, the effect of shear stress applied to endothelial cells (ECs) on SMC migration was examined using a newly designed EC-SMC coculture model (CM), in which bovine SMCs and ECs were separated by a collagen layer and a membrane filter. After exposing the CM to shear stresses of 0.5, 1.0, or 1.5 Pa for 48 h, the number of SMCs migrating into the collagen layer was counted. Under static conditions, the migration of SMCs in the CM increased compared with SMCs cultured alone. Shear stress of 1.5 Pa significantly suppressed the SMC migration (p < 0.05) compared with the static CM. Media conditioned with the CM exposed to shear stress of 1.0 Pa (p < 0.05) and 1.5 Pa (p < 0.005) exhibited reduction in activated matrix metalloproteinase-2 (MMP-2) compared with the static CM, as analyzed by zymography. Addition of an inhibitor of nitric oxide (NO) synthase, N ω-nitro-L-arginine methyle ester, to the media inhibited the effect of 1.5 Pa shear stress on SMC migration but MMP-2 activity was unaffected. These results suggest that physiological shear stress has protective roles in atherosclerogenesis. © 2006 Biomedical Engineering Society.
• The wrapping method using biodegradable felt strips has a preventive effect on the thinning of the aortic wall: Experimental study in the canine aorta

  Hidenori Fujiwara, Katsuhiko Oda, Yoshikatsu Saiki, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato, Yasuhiko Tabata, Koichi Tabayashi

  Journal of Vascular Surgery 43 (2) 349 - 356 0741-5214 2006/02 [Refereed][Not invited]
   

  Objectives: Wrapping methods have been widely used to reinforce the anastomotic site in vascular surgery however, postoperative changes in the aortic wall wrapped by nonbiodegradable felt have not been well characterized. The purposes of this investigation are to elucidate the sequelae of wrapping with nonbiodegradable felt on the aortic wall and to modify those changes by using biodegradable felt with or without basic fibroblast growth factor (bFGF). Methods: The descending thoracic aortas of 15 beagles were wrapped with three different materials: nonbiodegradable polytetrafluoroethylene (PTFE) felt, biodegradable polyglycol acid (PGA) material, and PGA with 100 μg bFGF (n = 5 in each group). The descending thoracic aorta was resected after 3 months. The thickness of the aortic wall, vessel density in the media and the adventitia, and the wall strength were assessed. Untreated native aortic wall served as a normal control. Results: The thickness of the media of the PTFE group was lower than that of the PGA + bFGF group (66% ± 5% vs 85% ± 6% of control, P < .05). The adventitia-media ratio in the PTFE group decreased compared with controls (59.1% of normal, P < 0.05), whereas those in the PGA and PGA + bFGF groups increased (172.1% and 189.6% of normal, respectively, P < .01). The collagen-smooth muscle ratio in the media was higher in the PTFE group than in the controls (0.14 ± 0.02 vs 0.07 ± 0.01, P < .01). The number of vessels in the adventitia was higher in the PGA + bFGF group than those in PTFE or PGA groups (29.6 ± 2.5/mm 2 vs 6.4 ± 0.8/mm 2, 19.0 ± 1.1/mm 2, P < .01). The PGA + bFGF group demonstrated larger failure force than the PTFE group (4.0 ± 0.3 kgf vs 1.6 ± 0.3 kgf, P < .01). The failure stress in the PGA and PGA + bFGF groups was larger than that in PTFE group (PTFE:PGA + bFGF = 5.3 ± 0.9 ×10 2 kPa:11.7 ± 1.7 × 10 2 kPa, P < .01 PTFE:PGA = 5.3 ± 0.9 × 10 2 kPa:11.2 ± 1.2 × 10 2 kPa, P < .05). Conclusion: The aortic wall wrapped with nonbiodegradable PTFE felt showed a reduced thickness and diminished vessels in the adventitia. Biodegradable felt (PGA), with or without bFGF, modified these histologic changes. The vessel-rich thickened adventitia, after wrapping by PGA with bFGF, was associated with increased aortic wall strength. Copyright © 2006 by The Society for Vascular Surgery.
• A case of sacroiliitis complicated by ulcerative colitis that was successfully treated with steroid

  Daisuke Kubota, Takanori Kanai, Tomoko Matsumoto, Takahiro Kawamura, Yasuhiro Itsui, Eriko Okada, Seishin Chin, Shinya Ohoka, Kiichiro Tsuchiya, Akihiro Araki, Naoya Sakamoto, Tatsuya Miyata, Mamoru Watanabe

  Japanese Journal of Gastroenterology 103 (8) 936 - 942 0446-6586 2006 [Not refereed][Not invited]
   

  A 23-year-old woman was admitted in November, 2002, complaining pain of the left side and buttock. She had ulcerative colitis when she was 16 and received medical treatment. Based on physical examination and findings of magnetic resonance imaging and bone scintigrapy, as sacroiliitis complicated by ulcerative colitis, was diagnosed Reports on sacroiliitis and ankylosing spondylitis complicated by inflammatory bowel diseases (IBD) are relatively rare in Japan, whereas they are common complications of IBD in Western countries. The efficacy of steroids on pain relief of sacroiliitis and ankylosing spondylitis is unclear.
• Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication

  T Koyama, N Sakamoto, Y Tanabe, M Nakagawa, Y Itsui, Y Takeda, S Kakinuma, Y Sekine, S Maekawa, Y Yanai, M Kurimoto, M Watanabe

  HEPATOLOGY RESEARCH 34 (1) 41 - 49 1386-6346 2006/01 [Refereed][Not invited]
   

  Backgrounds: Interferon (IFN)-alpha is represented by several structurally related subtypes that show different antiviral and anti-tumor effects. Here, we analyzed differential effects of IFN-alpha subtypes on intracellular hepatitis C virus (HCV) replication using HCV subgenomic replicon system as a model. Methods: Huh7 and HeLa cells supporting expression of HCV replicon were treated with various concentrations of five recombinant human IFN-alpha subtypes 1, 2, 5, 8, and 10, and with IFN-alpha con I. The effects of IFNs on various cell-signaling pathways were assayed by using ISRE-, GAS-, AP1-, NF-kappa B-, CRE-, and SRE-luciferase reporter plasmids. Results: Each IFN-alpha subtype suppressed HCV replication in a dose-dependent manner. Among them, IFN-alpha8 was the most effective, while IFN-alpha1 was the least effective with 50% inhibitory concentrations of 0.123 IU/ml versus 0.375 IU/ml, respectively. These differential effects against HCV replication did not correlate with levels of the IFN-responsive ISRE or GAS reporter activities, nor they did activate the other reporters, AP1, NF-kappa B, CRE and SRE. Conclusion: There were divergent effects of IFN-alpha subtypes against HCV replication that may be through JAK-STAT-independent pathways. Exploring further mechanisms of action may elucidate IFN-mediated cellular antiviral mechanisms. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
• Mutations in the NS5B region of the hepatitis C virus genome correlate with clinical outcomes of interferon-alpha plus ribavirin combination therapy

  K Hamano, N Sakamoto, N Enomoto, N Izumi, Y Asahina, M Kurosaki, E Ueda, Y Tanabe, S Maekawa, J Itakura, H Watanabe, S Kakinuma, M Watanabe

  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 20 (9) 1401 - 1409 0815-9319 2005/09 [Refereed][Not invited]
   

  Background and Aim: Combination treatments of interferon-alpha (IFN) and ribavirin (RBV) are more effective than those of IFN alone in hepatitis C virus (HCV) infection. However, mechanisms of the action of the combination regimen are not well understood. To elucidate the viral genetic basis of IFN plus RBV combination therapy, genetic variabilities of HCV-1b were analyzed. Methods: We performed pair-wise comparisons of full-length HCV genomic sequences in three patients' sera before and after initiation of IFN plus RBV treatment. Subsequently, we analyzed amino acid sequences of the NS5B region, which codes for the viral RNA-dependent RNA polymerase, and compared these with the outcomes of the therapy in 81 patients. Results: Analysis of the entire HCV sequence in patients who received IFN plus RBV therapy did not show consistent amino acid changes between before and after the initiation of the therapy. NS5B sequence analyses revealed that mutations at positions 300-358 of NS5B, including polymerase motif B to E, occurred more frequently in a group of patients exhibiting a sustained viral response (SVR) or an end-of-treatment response (ETR) compared with a group of patients exhibiting a non-response (NR). Closer examination revealed that mutations at aa 309, 333, 338 and 355 of NS5B occurred significantly more frequently in the SVR plus ETR group than in the NR group (P = 0.0004). Multivariate analysis showed that the number of mutations at these four sites was an independent predictor of SVR plus ETR versus NR. Conclusions: Particular amino acid changes in the NS5B region of HCV may correlate with outcomes of IFN plus RBV combination therapy. (C) 2005 Blackwell Publishing Asia Pty Ltd.
• Suppression of hepatitis C virus replication by cyclosporin A is mediated by blockade of cyclophilins

  M Nakagawa, N Sakamoto, Y Tanabe, T Koyama, Y Itsui, Y Takeda, CH Chen, S Kakinuma, S Oooka, S Maekawa, N Enomoto, M Watanabe

  GASTROENTEROLOGY 129 (3) 1031 - 1041 0016-5085 2005/09 [Refereed][Not invited]
   

  Background & Aims: Cyclosporin A specifically suppresses hepatitis C virus (HCV) replication in vitro at clinically achievable concentrations. In this study, we investigated the mechanisms of action of cyclosporin A against HCV replication. Methods: The in vitro effects of cyclosporin A on HCV replication were analyzed using an HCV replicon system that expresses chimeric luciferase reporter protein. Results: The significant effects of cyclosporin A on expression of an HCV replicon and the absence of such effects of FK506, which shares mechanisms of action with cyclosporin A, suggested the involvement of intracellular ligands of cyclosporin A, the cyclophilins. Transient and stable knockdown of the expression of cytoplasmic cyclophilins A, B, and C by short hairpin RNA-expressing vectors suppressed HCV replication significantly. A cyclosporin analogue, cyclosporin D, which lacks immunosuppressive activity but exhibits cyclophilin binding, induced a similar suppression of HCV replication. Furthermore, cyclosporin A treatment of Huh7 cells induced an unfolded protein response exemplified by expression of cellular BiP/GRP78. Treatment of cells with thapsigargin and mercaptoethanol, which induce the unfolded protein responses, suppressed HCV replication, suggesting that the cyclosporin-induced unfolded protein responses might contribute to the suppression of HCV protein processing and replication. Conclusions: The anti-HCV activity of cyclosporin A is mediated through a specific blockade of cyclophilins, and these molecules may constitute novel targets for anti-HCV therapeutics.
• Enhancement of mitochondrial gene expression in the liver of primary biliary cirrhosis

  CH Chen, K Nagayama, N Enomoto, Y Miyasaka, M Kurosaki, N Sakamoto, S Maekawa, S Kakinuma, T Ikeda, N Izumi, C Sato, M Watanabe

  HEPATOLOGY RESEARCH 31 (1) 24 - 30 1386-6346 2005/01 [Refereed][Not invited]
   

  Primary biliary cirrhosis (PBC) is one of the most important autoimmune liver diseases but the etiology and pathogenesis remain unknown. In this study, we analyzed differential mRNA expression in the liver of a patient with PBC using suppression subtractive hybridization to identify overexpressed genes. Overexpression of mRNA transcripts from mitochondrial DNA was observed in the PBC liver, compared to normal liver. To explore the mechanism of increased mitochondrial transcription, we investigated the mRNA levels of nuclear DNA-encoded regulator molecules of mitochondrial gene expression in 60 liver biopsy samples from various diseases, including PBC, using competitive RT-PCR. Increased expression of mitochondrial transcriptional factor A (mtTFA) and mitochondrial nuclear respiratory factor 1 (NRF-1) mRNA was demonstrated in PBC liver compared to other liver diseases, while NRF-1 coactivator 1, PGC-1 was suppressed. Mitochondrial DNA-encoded mRNA molecules are overexpressed in the PBC liver, and this is associated with up-regulation of mitochondrial transcription factor mtTFA and its transactivator NRF-1. Further studies are needed to focus on the relevance of this perturbation of mitochondrial gene expression in the pathogenesis of PBC. (C) 2004 Elsevier B.V. All rights reserved.
• ダブルバルーン内視鏡のみにて発見,および術前に確定診断し得た小腸がんの二例

  荒木昭博, 土屋輝一郎, 岡田英理子, 久保田大輔, 陳正新, 石井賢一, 柿沼晴, 大岡真也, 中村哲也, 坂本直哉, 宮田達也, 金井隆典, 渡辺守, 大貫和美, 金澤信彦

  Progress of Digestive Endoscopy 67 (1) 57  2005 [Not refereed][Not invited]
  
• ダブルバルーン小腸内視鏡を用いて全消化管を検索し得た好酸球性胃腸炎の一例

  高山啓, 土屋輝一郎, 荒木昭博, 岡田英理子, 久保田大輔, 陳正新, 石井賢一, 柿沼晴, 大岡真也, 中村哲也, 坂本直哉, 宮田達也, 金井隆典, 渡辺守

  Progress of Digestive Endoscopy 67 (1) 91  2005 [Not refereed][Not invited]
  
• Effect of shear stress on permeability of vascular endothelial monolayer cocultured with smooth muscle cells

  Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  JSME International Journal, Series C: Mechanical Systems, Machine Elements and Manufacturing 47 (4) 992 - 999 1344-7653 2004/12 [Refereed][Not invited]
   

  Effect of fluid shear stress on permeability of endothelial monolayer was investigated using an endothelial cell (EC) - smooth muscle cell (SMC) cocultured model (CM). Permeability of ECs to bovine serum albumin was measured after exposure to shear stress of 1.5 Pa for 48 hours. Morphology and VE-cadherin expression of ECs in CM was almost same as of ECs cultured alone (monocultured model, MM). Under static condition, EC permeability was 5.1 ± 3.0 × 10-6 cm/sec (mean ± SD) in MM and 6.5 ± 3.4 × 10-6 cm/sec in CM. After exposure to shear stress, EC permeability in CM (2.2 ± 1.9 × 10-6 cm/sec, p < 0.05) significantly decreased compared with the static model. However, EC permeability in MM (3.9 ± 3.2 × 10-6 cm/sec) did not significantly change compared with static cultured condition. These results suggested that cellular interactions between ECs and SMCs have important influences on EC permeability.
• Down-regulation of p27(Kip1) promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin d1 and CDK4-Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation

  M Tamamori-Adachi, K Hayashida, K Nobori, C Omizu, K Yamada, N Sakamoto, T Kamura, K Fukuda, S Ogawa, KI Nakayama, S Kitajima

  JOURNAL OF BIOLOGICAL CHEMISTRY 279 (48) 50429 - 50436 0021-9258 2004/11 [Refereed][Not invited]
   

  Mammalian cardiomyocytes lose their capacity to proliferate during terminal differentiation. We have previously reported that the expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and its partner cyclin-dependent kinase 4 (CDK4) induces proliferation of rat neonatal cardiomyocytes. Here we show that the D1NLS/CDK4 cells, after their entry into the cell cycle, accumulated cyclin-dependent kinase inhibitor p27 in the nuclei and decreased the cyclin-dependent kinase 2 (CDK2) activity, leading to early cell cycle arrest. Biochemical analysis demonstrated that Skp2-dependent p27 ubiquitylation was remarkably suppressed in cardiomyocytes, whereas Skp2, a component of Skp1-CullinF- box protein ubiquitin ligase, was more actively ubiquitylated compared with proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle. These data altogether indicate that the impaired Skp2-dependent p27 degradation is causally related to the loss of proliferation in cardiomyocytes. This provides a novel insight in understanding the molecular mechanism by which mammalian cardiomyocytes cease to proliferate during terminal differentiation.
• Regulation of hepatitis C virus replication by interferon regulatory factor 1

  N Kanazawa, M Kurosaki, N Sakamoto, N Enomoto, Y Itsui, T Yamashiro, Y Tanabe, S Maekawa, M Nakagawa, CH Chen, S Kakinuma, S Oshima, T Nakamura, T Kato, T Wakita, M Watanabe

  JOURNAL OF VIROLOGY 78 (18) 9713 - 9720 0022-538X 2004/09 [Refereed][Not invited]
   

  Cellular antiviral responses are mediated partly by the expression of interferon-stimulated genes, triggered by viral genomes, their transcripts and replicative intermediates. Persistent replication of a hepatitis C virus (HCV) replicon suggests that the replicon does not elicit cellular innate antiviral responses. In the present study, we investigated regulatory factors of the interferon-mediated antiviral system in cells expressing an HCV replicon. Luciferase reporter assays revealed that the baseline activity of the interferon-stimulated response element (ISRE) was significantly lower in cells harboring the replicon than in naive cells. Among the proteins involved in the IFN/jak/STAT pathway and in ISRE activity, the expression level of interferon regulatory factor 1 (IRF-1) was found to be significantly lower in cells harboring the replicon. Transfection of an IRF-1 expression construct into cells harboring the replicon caused an increase of ISRE activity, accompanied by suppression of expression of the HCV replicon. Moreover, in cured Huh7 cells from which the HCV replicon had been eliminated, the expression levels of IRF-1 and ISRE activity also were suppressed, demonstrating that the decrease of IRF-1 is attributable, not to active suppression by the viral proteins, but to adaptation of cells that enables replication of the HCV subgenome. The high permissiveness of the cured cells for the replicon was abolished by transgenic supplementation of IRF-1 expression. Taken together, IRF-1 is one of the key host factors that regulate intracellular HCV replication through modulation of interferon-stimulated-gene-mediated antiviral responses.
• Changes of HCV quasispecies during combination therapy with interferon and ribavirin.

  Ueda E, Enomoto N, Sakamoto N, Hamano K, Sato C, Izumi N, Watanabe M

  Hepatology research : the official journal of the Japan Society of Hepatology 29 (2) 89 - 96 1386-6346 2004/06 [Refereed][Not invited]
  
• Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon-alpha

  Y Tanabe, N Sakamoto, N Enomoto, M Kurosaki, E Ueda, S Maekawa, T Yamashiro, M Nakagawa, CH Chen, N Kanazawa, S Kakinuma, M Watanabe

  JOURNAL OF INFECTIOUS DISEASES 189 (7) 1129 - 1139 0022-1899 2004/04 [Refereed][Not invited]
   

  Treatment of hepatitis C virus (HCV) infection with interferon (IFN)-alpha and ribavirin combination therapy results in superior clinical antiviral responses than does monotherapy with IFN. To explore the virological basis of the effects of combination therapy, we analyzed the effects of IFN-alpha and ribavirin, singly and in combination, on intracellular HCV replication by use of an HCV replicon system. A new replicon that expressed a selectable chimeric reporter protein comprising firefly luciferase and neomycin phosphotransferase was constructed. The replicon was highly sensitive to IFN-alpha (50% inhibitory concentration [IC50], 0.5 U/mL). Therapy with ribavirin showed weak suppression of HCV replication at a lower concentration (IC50, 126 mumol/ L). The nucleotide sequence diversity of the replicon was increased significantly by therapy with ribavirin, suggesting that error-prone HCV replication was induced by the drug. Importantly, use of a clinically achievable concentration of ribavirin (similar to 10 mmol/ L) in combination with IFN showed strong synergistic inhibitory effects on HCV replication. Our results suggest that the direct effects of ribavirin on the genetic stability of the HCV subgenome and its synergistic action combined, with IFN-alpha, may explain the improved clinical responses to combination therapy.
• 放射線性腸炎による出血に対しアルゴンプラズマ凝固療法が有効であった特発性血小板減少性紫斑病の1例

  深山雄大, 土屋輝一郎, 荒木昭博, 岡田英理子, 久保田大輔, 陳正新, 石井賢一, 長堀正和, 柿沼晴, 大岡真也, 中村哲也, 坂本直哉, 宮田達也, 金井隆典, 渡辺守

  Progress of Digestive Endoscopy 66 (1) 68  2004 [Not refereed][Not invited]
  
• Specific inhibition of hepatitis C virus replication by cyclosporin A

  M Nakagawa, N Sakamoto, N Enomoto, Y Tanabe, N Kanazawa, T Koyama, M Kurosaki, S Maekawa, T Yamashiro, CH Chen, Y Itsui, S Kakinuma, M Watanabe

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 313 (1) 42 - 47 0006-291X 2004/01 [Refereed][Not invited]
   

  The difficulty in eradicating hepatitis C virus (HCV) infection is attributable to the limited treatment options against the virus. Recently, cyclosporin A (CsA), a widely used immunosuppressive drug, has been reported to be effective against HCV infection [J. Gastroenterol. 38 (2003) 567], although little is understood about the mechanism of its action against HCV. In this study, we investigated the anti-viral effects of CsA using an HCV replicon system. Human hepatoma Huh7 cells were transfected with an HCV replicon expressing a chimeric gene encoding a luciferase reporter and neomycin phosphotransferase (Huh7/Rep-Feo). Treatment of the Huh7/Rep-Feo cells with CsA resulted in suppression of the replication of the HCV replicon in a dose-dependent manner, with an IC50 of similar to0.5 mug/ml. There were no changes in the rate of cell growth or viability, suggesting that the effect of CsA against HCV is specific and not due to cytotoxicity. In contrast, FK506, another immunosuppressive drug, did not suppress HCV replication. CsA did not activate interferon-stimulated gene responses, suggesting that its action is independent of that of interferon. In conclusion, CsA inhibits HCV replication in vitro specifically at clinical concentrations. Further defining its mode of action against HCV replication potentially may be important for identifying novel molecular targets to treat HCV infection. (C) 2003 Elsevier Inc. All rights reserved.
• Hepatitis C virus nonstructural protein 5A inhibits tumor necrosis factor-alpha-mediated apoptosis in Huh7 cells

  Y Miyasaka, N Enomoto, M Kurosaki, N Sakamoto, N Kanazawa, T Kohashi, E Ueda, S Maekawa, H Watanabe, N Izumi, C Sato, M Watanabe

  JOURNAL OF INFECTIOUS DISEASES 188 (10) 1537 - 1544 0022-1899 2003/11 [Refereed][Not invited]
   

  To analyze the influence of hepatitis C virus nonstructural protein 5A ( NS5A) on apoptosis, we established Huh7 cells that stably express NS5A, and induced apoptosis using tumor necrosis factor ( TNF) - alpha. The viability of control Huh7 cells was reduced to 40%, compared with untreated cells, after TNF- alpha treatment, whereas that of Huh7- NS5A cells was reduced only to 80%. DNA fragmentation also decreased to < 50% in Huh7-NS5A compared with control cells. Nuclear factor - κB activation was the same in both cell types, whereas caspase- 8, - 9, and - 3 activity was decreased in Huh7- NS5A cells, compared with control cells, which indicates that the inhibition of caspase- 8 activation is responsible for the antiapoptotic effect of the NS5A protein. The coexpression of NS5A did not inhibit apoptosis induced by caspase- 8 or Fas- associating death domain protein expression. These findings suggest that the NS5A protein inhibits the apoptotic effect of TNF- α upstream of caspase- 8 in the apoptosis cascade.
• Inhibition of intracellular hepatitis C virus replication by synthetic and vector-derived small interfering RNAs

  T Yokota, N Sakamoto, N Enomoto, Y Tanabe, M Miyagishi, S Maekawa, L Yi, M Kurosaki, K Taira, M Watanabe, H Mizusawa

  EMBO REPORTS 4 (6) 602 - 608 1469-221X 2003/06 [Refereed][Not invited]
   

  Small interfering RNAs (siRNAs) efficiently inhibit gene expression by RNA interference. Here, we report efficient inhibition, by both synthetic and vector-derived siRNAs, of hepatitis C virus (HCV) replication, as well as viral protein synthesis, using an HCV replicon system. The siRNAs were designed to target the 5' untranslated region ( 5' UTR) of the HCV genome, which has an internal ribosomal entry site for the translation of the entire viral polyprotein. Moreover, the 5' UTR is the most conserved region in the HCV genome, making it an ideal target for siRNAs. Importantly, we have identified an effective site in the 5' UTR at which similar to80% suppression of HCV replication was achieved with concentrations of siRNA as low as 2.5 nM. Furthermore, DNA-based vectors expressing siRNA against HCV were also effective, which might allow the efficient delivery of RNAi into hepatocytes in vivo using viral vectors. Our results support the feasibility of using siRNA-based gene therapy to inhibit HCV replication, which may prove to be valuable in the treatment of hepatitis C.
• [Hepatitis C virus infection].

  Nakagawa M, Enomoto N, Sakamoto N

  Nihon rinsho. Japanese journal of clinical medicine 61 Suppl 3 627 - 633 0047-1852 2003/03 [Refereed][Not invited]
  
• Elongation and random orientation of bovine endothelial cells in response to hydrostatic pressure: Comparison with response to shear stress

  Yoshiaki Sugaya, Naoya Sakamoto, Toshiro Ohashi, Masaaki Sato

  JSME International Journal, Series C: Mechanical Systems, Machine Elements and Manufacturing 46 (4) 1248 - 1255 1344-7653 2003 [Refereed][Not invited]
   

  Morphological responses of cultured bovine endothelial cells (ECs) exposed to hydrostatic pressure were investigated. ECs were exposed to physiological blood pressure under a hydrostatic head of culture medium for 24 hours. Pressured ECs exhibited marked elongation and orientation with the random direction, together with development of centrally located, thick stress fibers. Pressured ECs also exhibited multilayered structure unlike under control conditions. The area and the shape index value significantly decreased after exposure to hydrostatic pressure, which were in good agreement with the results from conventional flow-imposed experiments. In contrast, a tortuosity index, which was newly introduced to represent cell shape tortuosity, significantly increased for pressured ECs, while sheared ECs had no difference in turtuosity index from control. In addition, pressured ECs aligned with no predominant direction, while sheared ECs aligned in the flow direction. These results indicate that ECs can respond very specifically to the type of imposed mechanical stimuli such as hydrostatic pressure and fluid shear stress.
• Oxygen tension modulates Ca2+ response to flow stimulus in endothelial cells exposed to hydrostatic pressure

  Toshiro Ohashi, Naoya Sakamoto, Akiyo Iwao, Masaaki Sato

  Technology and Health Care 11 (4) 263 - 274 0928-7329 2003 [Refereed][Not invited]
   

  The effects of oxygen gas tensions and hydrostatic pressure on intracellular calcium, [Ca2+]i, response to a flow stimulus in endothelial cells were investigated. Cultured bovine aortic endothelial cells (BAECs) were exposed to a hydrostatic pressure of 100 mmHg under low oxygen gas tensions and were subsequently subjected to a 1 minute mechanical stimulation of fluid shear stress of 20 dynes/cm2. The [Ca2+]i response in BAECs was measured using a fluorescent indicator, Calcium Green-1. The maximum intensity for low oxygen tension was significantly lower than that for normal oxygen tension, which provides evidence that low oxygen tension regulates cellular functions downward. Moreover, preloading of hydrostatic pressure also reduced the increases in [Ca2+]i. These results suggest that BAECs in venous system, where oxygen tension and hydrostatic pressure are lower than those in arterial system, may be less sensitive to fluid flow. A separate observation showed that low oxygen tension did not significantly affect the cell morphology. In constrast, BAECs exposed to hydrostatic pressure showed marked elongation with no predominant orientation and the F-actin filament distributions were rearranged, indicating centrally located thick stress fibers. For better understanding of endothelial cell physiology, it is very important to elucidate the effect of oxygen gas tensions together with mechanical environment on endothelial cell responses.
• Role of sarcolemmal K-ATP channels in cardioprotection against ischemia/reperfusion injury in mice

  M Suzuki, N Sasaki, T Miki, N Sakamoto, Y Ohmoto-Sekine, M Tamagawa, S Seino, E Marban, H Nakaya

  JOURNAL OF CLINICAL INVESTIGATION 109 (4) 509 - 516 0021-9738 2002/02 [Refereed][Not invited]
   

  Recently it has been postulated that mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels rather than sarcolemmal K-ATP (sarcK(ATP)) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC). To define the pathophysiological significance of sarcK(ATP) channels, we conducted functional experiments using Kir6.2-deficient (KO) mice. Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcK(ATP) current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice. MitoK(ATP) channel function was preserved in KO ventricular cells. In anesthetized mice, IPC reduced the infarct size in WT but not KO mice. Following global ischemia/reperfusion, the increase of left ventricular end-diastolic pressure during ischemia was more marked, and the recovery of contractile function was worse, in KO hearts than in WT hearts. Treatment with HMR1098, a sarcK(ATP) channel blocker, but not 5-hydroxydecanoate, a mitoK(ATP) channel blocker, produced a deterioration of contractile function in WT hearts comparable to that of KO hearts. These findings suggest that sarcK(ATP) channels figures prominently in modulating ischemia/reperfusion injury in the mouse. The rapid heart rate of the mouse (>600 beats per minute) may magnify the relative importance of sarcK(ATP) channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals.
• Overexpression of interferon gamma-inducible protein 10 in the liver of patients with type I autoimmune hepatitis identified by suppression subtractive hybridization.

  K Nagayama, N Enomoto, Y Miyasaka, M Kurosaki, C H Chen, N Sakamoto, M Nakagawa, C Sato, J Tazawa, T Ikeda, N Izumi, M Watanabe

  Am. J. Gastroenterol. 96 (7) 2211 - 2217 0002-9270 2001/07 [Refereed][Not invited]
  
• Comparison of the hypervariable region of hepatitis C virus genomes in plasma and liver

  Naoya Sakamoto, Nobuyuki Enomoto, Masayuki Kurosaki, Yasuhiro Asahina, Shinya Maekawa, Kazuhiko Koizumi, Ikuo Sakuma, Takeshi Murakami, Fumiaki Marumo, Chifumi Sato

  Journal of Medical Virology 46 (1) 7 - 11 1096-9071 1995 [Refereed][Not invited]
   

  Nucleotide sequences of the hypervariable region of hepatitis C virus genomes obtained from plasma change rapidly during the course of in fection and are believed to play a part in immunological escape and consequently in the development of persistent infection. It is not known, however, whether these changes also occur in the liver. To clarify this aspect, RNA was extracted from the plasma and liver tissue of eight patients with chronic hepatitis C. After cDNA synthesis, DNA fragments that included the hypervariable region were amplified by the polymerase chain reaction. Consensus nucleotide sequences were determined directly from the polymerase chain reaction products by the dideoxy chain termination method. The diversity of the hypervariable region was analyzed further by the polymerase chain reaction‐single strand conformation polymorphism analysis. Consensus nucleotide sequences of the hypervariable region were identical between the plasma and the liver in each patient. The polymerase chain reaction‐single strand conformation polymorphism analysis showed multiple DNA bands that represented different hypervariable region sequences. Comparison of the single strand conformation polymorphism patterns revealed that the number, the mobility, and the density of bands were the same between the plasma and the liver. It is concluded that the population and the diversity of hepatitis C virus quasispecies as detected by the hypervariable region sequence are the same between the plasma and the liver despite rapid mutations, indicating that rapid changes in the population of hepatitis C virus quasispecies also occur in the liver. © 1995 Wiley‐Liss, Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company

MISC

• 胆道疾患に対するInterventional EUSの現在、およびX線透視の活用—特集 低被ばく進むX線撮影装置

  川久保 和道, 桒谷 将城, 杉浦 諒, 永井 孝輔, 岸 法磨, 米村 洋輝, 野澤 俊一郎, 坂本 直哉  映像情報medical : a monthly journal of medical imaging and information  55-  (2)  12  -16  2023/02
• 核酸アナログによるHBs抗原消失—Hepatitis B surface antigen (HBsAg) seroclearance by nucleos(t)ide analogs treatment—特集 B型肝炎診療の進歩

  山田 錬, 森川 賢一, 中村 晃久, 出水 孝章, 梅村 真知子, 大原 正嗣, 中井 正人, 荘 拓也, 須田 剛生, 小川 浩司, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  12-  (2)  184  -192  2022/08
• B型肝炎治療オーバービュー—Overview of treatment for hepatitis B—特集 B型肝炎診療の進歩

  須田 剛生, 川岸 直樹, 大原 正嗣, 中井 正人, 荘 拓也, 小川 浩司, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  12-  (2)  172  -174  2022/08
• 閉塞性黄疸のドレナージ,何を考える?—特集 胆道・膵疾患を診る : 早期診断・早期治療のために ; 胆膵実地診療のコツ

  桒谷 将城, 岸 法磨, 永井 孝輔, 川久保 和道, 坂本 直哉  内科 = Internal medicine : 臨床雑誌  130-  (1)  41  -46  2022/07
• 肝疾患における核酸医薬開発—Development of nucleic acid medicine in liver diseases—特集 革新的技術が変える肝疾患診療

  須田 剛生, 小川 浩司, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  11-  (4)  489  -493  2022/04
• 減量・代謝改善手術後の膵β細胞機能改善に肝の脂肪化が関連する

  中村 昭伸, 大江 悠希, 久住 麻唯子, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 小川 浩司, 荘 拓也, 須田 剛生, 吉川 仁人, 阿保 大介, 西田 睦, 海老原 裕磨, 倉島 庸, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明  糖尿病  65-  (Suppl.1)  S  -153  2022/04
• 術前胆道ドレナージにおけるステント留置 : 適応と臨床成績—Preoperative endoscopic biliary stenting for malignant biliary obstruction : indication and clinical outcomes—特集 消化器ステント術のすべて ; 臓器別各論 ; 胆・膵

  桒谷 将城, 永井 孝輔, 平田 甫, 瀧新 悠之介, 古川 龍太郎, 川久保 和道, 坂本 直哉, 平野 聡  外科 = Surgery : 臨床雑誌  83-  (8)  917  -927  2021/07
• 【実地医家のためのNAFLD/NASH診療のポイント】実地医家のためのNAFLD/NASH診療のポイント 我が国における脂肪性肝疾患(NAFLD/NASH)の現状

  坂本 直哉, 森川 賢一  Vita  38-  (2)  2  -7  2021/04
• アルコール性肝障害・代謝性肝疾患の現状と課題 脂質異常症を合併する非アルコール性脂肪性肝疾患患者に対するペマフィブラート投与効果の検討

  久保 彰則, 森川 賢一, 坂本 直哉  肝臓  62-  (Suppl.1)  A150  -A150  2021/04
• NASHの病態解明と臨床応用 腸内細菌叢を標的としたNASH治療戦略の検討

  山田 錬, 森川 賢一, 坂本 直哉  肝臓  62-  (Suppl.1)  A222  -A222  2021/04
• LECSで切除した胃ESD瘢痕上の異時性胃癌の1例

  田中 一光, 小野 尚子, 西村 友佑, 久保 茉理奈, 霜田 佳彦, 井上 雅貴, 木脇 佐代子, 大野 正芳, 山本 桂子, 清水 勇一, 坂本 直哉, 篠原 良仁, 海老原 裕磨, 高桑 恵美  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  128回・122回-  51  -51  2021/03
• 早期慢性膵炎診断は慢性膵炎予備軍を正しく拾い上げているか—Can the diagnosis of early chronic pancreatitis lead to the diagnosis of definite chronic pancreatitis?—特集 膵炎診療update

  桒谷 将城, 川久保 和道, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  9-  (1)  99  -103  2021/01
• H.pylori除菌後異時性胃癌症例の臨床病理学的特徴

  田中一光, 小野尚子, 坂本直哉, 西村友佑, 久保茉理奈, 霜田佳彦, 井上雅貴, 木脇佐代子, 大野正芳, 山本桂子, 清水勇一  Gastroenterological Endoscopy (Web)  63-  (Supplement1)  2021
• Causes and Treatment of Iatrogenic Biliary Infection

  桑谷将城, 桑谷将城, 永井孝輔, 平田甫, 瀧新悠之介, 古川龍太郎, 川久保和道, 坂本直哉  臨床消化器内科  36-  (9)  2021
• Endoscopic transpapillary drainage for benign distal biliary stricture

  桑谷将城, 永井孝輔, 平田甫, 瀧新悠之介, 古川龍太郎, 川久保和道, 坂本直哉  消化器内視鏡  33-  (3)  2021
• Risk and Treatment of Postoperative Biliary Stricture After Resection of Gallbladder Cancer

  桑谷将城, 桑谷将城, 永井孝輔, 平田甫, 瀧新悠之介, 古川龍太郎, 川久保和道, 坂本直哉  胆と膵  42-  (7)  2021
• Intrahepatic arterio-venous shunt

  小川浩司, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  日本臨床  2021
• 各ゲノタイプにおけるDAA不成功例に対する治療—Retreatment for patients who failed to respond to DAAs according to HCV genotype—特集 最新C型肝炎治療up-to-date

  須田 剛生, 木村 恵, 北潟谷 隆, 重沢 拓, 鈴木 和治, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  8-  (1)  70  -75  2020/07
• Evolution and a promising role of EUS-FNA in gene and future analyses

  Masaki Kuwatani, Masaki Kuwatani, Naoya Sakamoto  Endoscopic Ultrasound  9-  (3)  151  -153  2020/05
• Annexin A10 is involved in the induction of pancreatic duodenal homeobox‑1 in gastric cancer tissue, cells and organoids.

  Akira Ishikawa, Naoya Sakamoto, Ririno Honma, Daiki Taniyama, Kaho Fukada, Takuya Hattori, Kazuhiro Sentani, Naohide Oue, Kazuyoshi Yanagihara, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui  Oncology reports  43-  (2)  581  -590  2020/02  [Not refereed][Not invited]
   

  Gastric cancer (GC) is the third most common cause of cancer‑related death in the world. Annexin A10 (ANXA10), a member of the Annexin family, is a calcium‑/phospholipid‑binding protein; however, little is known concerning its functions. It is still unclear what molecule is involved in the induction of ANXA10. In the present study, we performed immunohistochemistry to evaluate the expression of ANXA10, pancreatic and duodenal homeobox‑1 (PDX1) and mucin phenotype markers in 130 GC samples. ANXA10 was detected in 63 (48%) of the 130 GC cases and loss of ANXA10 was significantly correlated with disease progression and poor clinical outcomes in GC. PDX1 was significantly correlated with ANXA10 in GC cases and cell lines. Although PDX1 was not significantly correlated with the GC cases with any of the mucin phenotypes, ANXA10 was preferentially detected in the GC cases with the gastric mucin phenotype. As a further investigation, we generated organoids derived from human GC and identified the duplication of the mucin phenotypes of GC by immunohistochemistry. The repression effect on cell growth that was observed in the ANXA10‑knockdown cell lines was also clearly observed in the human gastric organoids. We demonstrated that the expression of ANXA10 was correlated with the gastric mucin phenotype and ANXA10 was involved in the induction of PDX1 expression in GC. We also provided evidence that GC organoids represent a powerful tool for scrutinizing the biology of GC, especially with regard to the mucin phenotype.
• 食道癌の治療中に横紋筋融解症を発症したことを契機に診断された甲状腺機能低下症の一例

  大江悠希, 亀田啓, 関崎知紀, 宮愛香, 野本博司, 曹圭龍, 中村昭伸, 原田一顕, 結城敏志, 小松嘉人, 坂本直哉, 三好秀明, 三好秀明, 渥美達也  日本内分泌学会雑誌  96-  (4 (Web))  976  -976  2020
• トルバプタン奏効後の再燃と炎症および尿L-FABP値の関連

  中井正人, 北潟谷隆, 山田錬, 重沢拓, 鈴木和治, 中村晃久, 梅村真知子, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  61-  (Supplement 1)  2020
• 肝性脳症の疫学

  中井正人, 小川浩司, 久保彰則, 得地祐匡, 北潟谷隆, 山田錬, 重沢拓, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  日本門脈圧亢進症学会雑誌  26-  (3)  2020
• HCC既往の無いC型肝炎SVR後の初発肝発癌の囲い込み因子としての肝弾性度の有用性

  中井正人, 山本義也, 馬場英, 古家乾, 北潟谷隆, 山田錬, 重沢拓, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  61-  (Supplement 2)  2020
• 免疫チェックポイント阻害剤関連肝炎の頻度,予測因子,臨床経過の検討

  北潟谷隆, 須田剛生, 中井正人, 荘拓也, 森川賢一, 小川浩司, 坂本直哉  肝臓  61-  (Supplement 2)  2020
• Comparative Glycomic Analysis by Aminolysis-SALSA method combined with Sialyl Linkage-specific Isotope Labeling.

  花松久寿, 西風隆司, 津元裕樹, 小川浩司, 横田育子, 森川賢一, 須田剛生, 荘拓也, 中井正人, 三浦信明, 関谷禎規, 岩本慎一, 三浦ゆり, 田中耕一, 坂本直哉, 古川潤一  日本糖質学会年会要旨集  39th-  2020
• 胃癌と低悪性度リンパ腫を合併した自己免疫性胃炎の1例

  石川麻倫, 小野尚子, 霜田佳彦, 田中一光, 井上雅貴, 木脇佐代子, 大野正芳, 高橋正和, 山本桂子, 森康明, 中川学, 中川宗一, 清水勇一, 三橋智子, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  126th-120th-  2020
• 生体ブタ全周性食道ESD施行後のバルーン拡張時の病理組織学的検討

  木脇佐代子, 清水勇一, 大西俊介, 大野正芳, 楊子健, 霜田佳彦, 井上雅貴, 田中一光, 石川麻倫, 山本桂子, 小野尚子, 坂本直哉  Gastroenterological Endoscopy (Web)  62-  (Supplement1)  2020
• 高齢者食道ESDの治療成績と予後解析

  霜田佳彦, 清水勇一, 坂本直哉, 石川麻倫, 田中一光, 井上雅貴, 木脇佐代子, 大野正芳, 山本桂子, 小野尚子  Gastroenterological Endoscopy (Web)  62-  (Supplement1)  2020
• 大腸EMRにおける抗凝固薬服用者の周術期管理と出血リスク

  田中一光, 小野尚子, 霜田佳彦, 井上雅貴, 木脇佐代子, 石川麻倫, 大野正芳, 山本桂子, 清水勇一, 坂本直哉  日本消化器病学会雑誌(Web)  117-  2020
• Helicobacter pylori除菌後SM浸潤癌の臨床病理学的特徴

  山本桂子, 霜田佳彦, 田中一光, 井上雅貴, 木脇佐代子, 石川麻倫, 大野正芳, 小野尚子, 清水勇一, 坂本直哉  日本消化器病学会雑誌(Web)  117-  2020
• 食道ESD中の鎮静薬と塩酸ペチジン併用の後ろ向き検討

  大野正芳, 霜田佳彦, 田中一光, 井上雅貴, 木脇佐代子, 石川麻倫, 山本桂子, 小野尚子, 清水勇一, 坂本直哉  Gastroenterological Endoscopy (Web)  62-  (Supplement2)  2020
• 子宮頸部・腟上皮内腫瘍における生体内細胞観察の診断能に関する検討-超拡大内視鏡は有用か-

  小野尚子, 松田可奈, 石川麻倫, 大野正芳, 木脇佐代子, 霜田佳彦, 田中一行, 井上雅貴, 山本桂子, 清水勇一, 坂本直哉  Gastroenterological Endoscopy (Web)  62-  (Supplement2)  2020
• 【肝胆膵の線維化up-to-date】肝臓の線維化 臨床・病理 新たな肝線維化マーカーの開発状況

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝・胆・膵  79-  (5)  891  -896  2019/11  [Not refereed][Not invited]
  
• CLIA法を用いたPIVKA-IIの臨床的有用性の評価

  小川 浩司, 鈴木 和治, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  60-  (11)  397  -404  2019/11  [Not refereed][Not invited]
   

  PIVKA-IIは肝細胞癌に特異性の高い腫瘍マーカーとして知られ、診断の補助や治療効果の判定などに用いられている。今回CLIA法を測定原理としたアーキテクト・PIVKA-IIを用いて、臨床症例における有用性を検討した。慢性肝疾患患者168例(慢性肝炎29例、肝硬変28例、肝細胞癌stage1 29例、stage2 29例、stage3 26例、stage4 27例)を対象とした。保存血清からアーキテクト・PIVKA-IIを測定し、診療時に測定したルミパルスPIVKA-IIおよびAFP値と比較検討を行った。両試薬ともに、肝細胞癌のstage進行に伴って上昇し、AFPとの組み合わせによる診断精度も同等であった。両試薬の測定値は高い相関性を示した。アーキテクト・PIVKA-IIは臨床検体において従来試薬と同等の診断精度を有しており、実臨床でも有用と考えられた。(著者抄録)
• NASHとASH、その診断と治療への対応 線維化早期NASH判別マーカーの検討

  中村 晃久, 森川 賢一, 坂本 直哉  肝臓  60-  (Suppl.3)  A800  -A800  2019/11  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブの奏功に寄与する因子と予備能変化についての検討

  山田 錬, 荘 拓也, 北潟谷 隆, 重沢 拓, 鈴木 和治, 中村 晃久, 中井 正人, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  60-  (Suppl.3)  A946  -A946  2019/11  [Not refereed][Not invited]
  
• MULTI-CENTER AND PROSPECTIVE COHORT STUDY OF 599 JAPANESE PATIENTS WITH HCV GENOTYPE 1 INFECTION REVEALS SUSTAINED VIROLOGICAL RESPONSE BY LEDIPASVIR/SOFOSBUVIR REDUCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA AS SAME AS PEG-INTERFERON PLUS RIBAVIRIN

  Masaaki Korenaga, Namiki Izumi, Nobuharu Tamaki, Osamu Yokosuka, Tatsuo Kanda, Tetsuo Takehara, Naoya Sakamoto, Goki Suda, Shuhei Nishiguchi, Hirayuiki Enomoto, Fusao Ikeda, Mikio Yanase, Hidenori Toyoda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Kazumi Yamasaki, Tatsuya Ide, Nobuo Toda, Kazushige Nirei, Yoshiyuki Ueno, Hiroaki Haga, Yohichi Nishigaki, Kunio Nakane, Masao Omata, Hitoshi Mochiduki, Tatsuya Kanto, Masashi Mizokami  HEPATOLOGY  70-  368A  -369A  2019/10
• TRI-ANTENNARY TRI-SIALYLATED MONO-FUCOSYLATED GLYCAN OF ALPHA-1 ANTITRYPSIN AS A NON-INVASIVE BIOMARKER FOR NON-ALCOHOLIC STEATOHEPATITIS

  Takashi Kobayashi, Koji Ogawa, Jun-Ichi Furukawa, Hisatoshi Hanamatsu, Masato Nakai, Takuya Sho, Goki Suda, Kenichi Morikawa, Megumi Hato, Kenichi Higashino, Yasuro Shinohara, Naoya Sakamoto  HEPATOLOGY  70-  1079A  -1079A  2019/10  [Not refereed][Not invited]
  
• ENTECAVIR TREATMENT OF HEPATITIS B VIRUS-INFECTED PATIENTS WITH SEVERE RENAL IMPAIRMENT, INCLUDING THOSE ON HEMODIALYSIS

  Kazuharu Suzuki, Goki Suda, Taku Shigesawa, Akihisa Nakamura, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto  HEPATOLOGY  70-  314A  -314A  2019/10  [Not refereed][Not invited]
  
• C型肝炎患者の血清Angiopoietin-2値はDAAs治療後の肝線維化非改善例を予測する

  川岸 直樹, 須田 剛生, 中井 正人, 荘 拓也, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  60-  (Suppl.2)  A653  -A653  2019/10  [Not refereed][Not invited]
  
• カルニチンは肝硬変患者における筋肉量減少を抑制する

  大原 正嗣, 須田 剛生, 重沢 拓, 鈴木 和治, 中村 晃久, 川岸 直樹, 中井 正人, 荘 拓也, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  60-  (Suppl.2)  A677  -A677  2019/10  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブ投与症例からみた適格使用時期の検討

  荘 拓也, 須田 剛生, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  60-  (Suppl.2)  A705  -A705  2019/10  [Not refereed][Not invited]
  
• 【進化する肝細胞癌の薬物療法-2019 Update(Part 2)】切除・ablation後のアジュバント試験 ニボルマブによる根治治療後の再発抑制試験(CheckMate 9DX trial)

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝・胆・膵  79-  (3)  461  -465  2019/09  [Not refereed][Not invited]
  
• 増大傾向を認めた肝血管筋脂肪腫の一切除例

  北潟谷 隆, 山田 錬, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉, 折茂 達也, 神山 俊哉, 武冨 紹信, 杉野 弘和, 三橋 智子  日本消化器病学会北海道支部例会プログラム・抄録集  125回-  46  -46  2019/09  [Not refereed][Not invited]
  
• 急速な経過をたどった肉腫様肝癌の1例

  山田 錬, 北潟谷 隆, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉, 清水 亜衣, 三橋 智子  日本消化器病学会北海道支部例会プログラム・抄録集  125回-  59  -59  2019/09  [Not refereed][Not invited]
  
• 門亢症を伴う肝硬変に対する薬物療法の進歩〜腹水・脳症・血栓など〜 リファキシミン投与前後でのNPT改善効果、Bacterial translocationマーカーの検討

  中井 正人, 北潟谷 隆, 山田 錬, 重沢 拓, 鈴木 和治, 中村 晃久, 梅村 真知子, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  日本門脈圧亢進症学会雑誌  25-  (3)  70  -70  2019/09  [Not refereed][Not invited]
  
• 肝静脈-下大静脈ステント留置にて改善した4型Budd-Chiari症候群の一例

  鈴木 和治, 中井 正人, 阿保 大介, 北潟谷 隆, 山田 錬, 中村 晃久, 梅村 真知子, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 吉野 裕紀, 曽山 武士, 坂本 直哉  日本門脈圧亢進症学会雑誌  25-  (3)  154  -154  2019/09  [Not refereed][Not invited]
  
• 腎機能低下症例 透析症例での治療—DAAs treatment for HCV infected patients with severe renal dysfunction, including on hemodialysis—特集 C型肝炎の治療 : 最終章を迎えて

  須田 剛生, 木村 恵, 川岸 直樹, 重沢 拓, 鈴木 和治, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  5-  (6)  628  -632  2019/06
• ACCURACY OF AN ENDOCYTOSCOPY SYSTEM FOR DIFFERENTIATION OF ESOPHAGEAL LESIONS AND INTEROBSERVER AGREEMENT AMONG ENDOSCOPISTS AND AMONG PATHOLOGISTS

  Inoue Masaki, Yuichi Shimizu, Ikko Tanaka, Sayoko Kinowaki, Marin Ishikawa, Kana Matsuda, Momoko Tsuda, Masakazu Takahashi, Keiko Yamamoto, Shouko Ono, Manabu Nakagawa, Soichi Nakagawa, Yasuaki Mori, Kanako Hatanaka, Shin Ichihara, Akira Suzuki, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  89-  (6)  AB623  -AB623  2019/06
• FLUORESCENCE IMAGING OF EARLY ADENOCARCINOMA OF THE ESOPHAGOGASTRIC JUNCTION BY TOPICALLY SPRAYING PROBE TARGETING DIPEPTIDYLPEPTIDASE-IV

  Keiko Yamamoto, Shunsuke Ohnishi, Takeshi Mizushima, Junichi Kodaira, Masayoshi Ono, Yutaka Hatanaka, Kanako Hatanaka, Nobuyuki Ehira, Keisuke Shinada, Hiroaki Takahashi, Yugo Kuriki, Mako Kamiya, Yuichi Shimizu, Yasuteru Urano, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  89-  (6)  AB624  -AB624  2019/06
• リファキシミン投与によるNPT改善効果とカルニチン製剤との比較

  中井正人, 重沢拓, 鈴木和治, 中村晃久, 大原正嗣, 川岸直樹, 梅村真知子, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  60-  (Supplement 1)  A523  -A523  2019/04/20  [Not refereed][Not invited]
  
• リファキシミン投与によるNPT改善効果とカルニチン製剤との比較

  中井 正人, 重沢 拓, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 梅村 真知子, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  60-  (Suppl.1)  A523  -A523  2019/04  [Not refereed][Not invited]
  
• Is It Possible to Improve Liver Fibrosis by Antiviral Therapy Against Hepatitis B Virus?

  小川浩司, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  Progress in Medicine  39-  (4)  405  -408  2019/04  [Not refereed][Not invited]
  
• B型慢性肝炎の核酸アナログ治療におけるインターフェロンλ3の役割の検討

  森川賢一, 小川浩司, 坂本直哉  肝臓  60-  (Suppl.1)  A73  -A73  2019/04  [Not refereed][Not invited]
  
• B型肝炎の抗ウイルス療法:肝発癌の制御を目指した治療の最前線 B型慢性肝炎の核酸アナログ治療におけるインターフェロンλ3の役割の検討

  森川 賢一, 小川 浩司, 坂本 直哉  肝臓  60-  (Suppl.1)  A73  -A73  2019/04  [Not refereed][Not invited]
  
• 【B型肝炎治療におけるアンメットニーズ】肝線維化を戻すことは可能か

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  Progress in Medicine  39-  (4)  405  -408  2019/04  [Not refereed][Not invited]
  
• 肝性脳症治療の変遷 肝性脳症治療の最近の考え方 肝性脳症治療の流れと各薬剤の位置づけ

  小川浩司, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  肝胆膵  78-  (3)  379  -384  2019/03  [Not refereed][Not invited]
  
• 当院におけるE型急性肝不全4例の検討

  重沢 拓, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会北海道支部例会プログラム・抄録集  124回-  45  -45  2019/03  [Not refereed][Not invited]
  
• 肝細胞癌に対してレンバニチニブ導入後破壊性甲状腺炎を呈した一例

  久々湊 雅, 重沢 拓, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会北海道支部例会プログラム・抄録集  124回-  60  -60  2019/03  [Not refereed][Not invited]
  
• 肝硬変様の形態を呈した肝サルコイドーシスの一例

  中村 晃久, 重沢 拓, 鈴木 和治, 大原 正嗣, 川岸 直樹, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会北海道支部例会プログラム・抄録集  124回-  62  -62  2019/03  [Not refereed][Not invited]
  
• 肝疾患患者における筋肉量測定方法別の経時的変化

  大原 正嗣, 重沢 拓, 中村 晃久, 鈴木 和治, 梅村 真知子, 川岸 直樹, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会雑誌  116-  (臨増総会)  A372  -A372  2019/03  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブの4週/8週における治療効果と安全性の検討

  荘 拓也, 須田 剛生, 重沢 拓, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 梅村 真知子, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会雑誌  116-  (臨増総会)  A415  -A415  2019/03  [Not refereed][Not invited]
  
• 肝疾患患者における筋肉量測定方法別の経時的変化

  大原 正嗣, 重沢 拓, 中村 晃久, 鈴木 和治, 梅村 真知子, 川岸 直樹, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会雑誌  116-  (臨増総会)  A372  -A372  2019/03  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブの4週/8週における治療効果と安全性の検討

  荘 拓也, 須田 剛生, 重沢 拓, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 梅村 真知子, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉  日本消化器病学会雑誌  116-  (臨増総会)  A415  -A415  2019/03  [Not refereed][Not invited]
  
• A retrospective analysis of neoadjuvant chemotherapy followed by surgery or definitive chemoradiotherapy in patients with advanced esophageal squamous cell carcinoma.

  Hiroshi Nakatsumi, Yoshito Komatsu, Shintaro Nakano, Kentaro Sawada, Tetsuhito Muranaka, Yasuyuki Kawamoto, Satoshi Yuki, Yusuke Uchinami, Hiroshi Taguchi, Hiroki Shirato, Yuma Ebihara, Toshiaki Shichinohe, Satoshi Hirano, Naoya Sakamoto  JOURNAL OF CLINICAL ONCOLOGY  37-  (4)  2019/02
• Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in patients who are receiving antiplatelet and anticoagulant therapy

  Kazumichi Kawakubo, Hiroshi Kawakami, Naoya Sakamoto  Gastroenterological Endoscopy  61-  (12)  2575  -2581  2019  

  Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is associated with a high risk of bleeding. Patients who are taking an antithrombotic agent tend to carry a higher hemorrhagic risk, but inappropriate cessation of antithrombotic agents would lead to serious thrombotic events. Therefore, appropriate management of antithrombotic agents is necessary. In this review, we summarize clinical tips for EUS-FNA in patients who are taking antithrombotic agents (antiplatelet and/or anticoagulant therapy).
• FPGおよびIPG法による標的タンパク質におけるN-結合型糖鎖解析法の開発

  花松久寿, 小林隆史, 小川浩司, 羽藤愛美, 吉永知世, 森川賢一, 須田剛生, 荘拓也, 中井正人, 東野賢一, 沼田義人, 篠原康郎, 坂本直哉, 古川潤一  日本糖質学会年会要旨集  38th-  2019
• 食道がん研究の最前線 3 食道扁平上皮がんの早期診断

  清水勇一, 井上雅貴, 石川麻倫, 津田桃子, 山本桂子, 小野尚子, 坂本直哉  GI Forefront  15-  (1)  2019
• MM浸潤,静脈侵襲を伴った微小食道扁平上皮癌の1例

  石川麻倫, 清水勇一, 津田桃子, 山本桂子, 高橋正和, 中川学, 中川宗一, 田中一光, 井上雅貴, 木脇佐代子, 松田可奈, 小野尚子, 坂本直哉  北海道医学雑誌  94-  (2)  2019
• カプセル内視鏡を施行した経口抗凝固薬服用者のOGIB-ワルファリンとDOACの比較-

  井上雅貴, 小野尚子, 田中一光, 木脇佐代子, 石川麻倫, 松田可奈, 津田桃子, 高橋正和, 山本桂子, 中川学, 中川宗一, 清水勇一, 坂本直哉  Gastroenterological Endoscopy (Web)  61-  (Supplement1)  2019
• 膵嚢胞が胃潰瘍を発症したと考えられる一例

  木脇佐代子, 小野尚子, 井上雅貴, 田中一光, 石川麻倫, 大野正芳, 山本桂子, 清水勇一, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  125th-119th-  2019
• 食道癌ESD後に喉頭浮腫を来し緊急気管切開術を施行した1例

  井上雅貴, 清水勇一, 霜田佳彦, 田中一光, 木脇佐代子, 石川麻倫, 大野正芳, 山本桂子, 小野尚子, 対馬那由多, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  125th-119th-  2019
• 上咽頭癌を合併したEpstein-Barr virus関連胃癌の1例

  白鳥翔也, 山本桂子, 田中一光, 井上雅貴, 木脇佐代子, 松田可奈, 石川麻倫, 津田桃子, 小野尚子, 清水勇一, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  124th-118th-  2019
• 腺癌と神経内分泌腫瘍が混在した直腸腫瘍の1例

  津田桃子, 小野尚子, 田中一光, 井上雅貴, 木脇佐代子, 石川麻倫, 松田可奈, 高橋正和, 山本桂子, 森康明, 中川学, 中川宗一, 清水勇一, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  124th-118th-  2019
• メトトレキセート長期使用中に発症した小腸びまん性大細胞型B細胞性リンパ腫の1例

  石川麻倫, 小野尚子, 田中一光, 井上雅貴, 木脇佐代子, 松田可奈, 津田桃子, 山本桂子, 高橋正和, 中川学, 中川宗一, 清水勇一, 坂本直哉, 坂本直哉, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  124th-118th-  2019
• 十二指腸神経内分泌腫瘍に対する内視鏡治療後の後出血に対し,Over The Scope Clipで止血が得られた一例.

  木脇佐代子, 小野尚子, 小野雄司, 井上雅貴, 田中一光, 石川麻倫, 松田可奈, 津田桃子, 山本桂子, 清水勇一, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  124th-118th-  2019
• Epstein-Barr virus陽性リンパ上皮腫様大腸癌の1例

  木脇佐代子, 山本桂子, 井上雅貴, 田中一光, 松田可奈, 石川麻倫, 津田桃子, 小野尚子, 小野尚子, 清水勇一, 岡田宏美, 三橋智子, 松野吉宏, 坂本直哉  日本大腸肛門病学会雑誌(Web)  72-  (1)  2019
• 消化管に多発潰瘍を認めた造血幹細胞移植後EBウイルス関連リンパ増殖性疾患の1例

  松田可奈, 小野尚子, 井上雅貴, 田中一光, 木脇佐代子, 石川麻倫, 津田桃子, 山本桂子, 清水勇一, 坂本直哉  日本大腸肛門病学会雑誌(Web)  72-  (1)  2019
• 早期食道癌発癌因子としてのHuman Papilloma Virus感染およびアルコール代謝遺伝子多型に関する検討

  井上雅貴, 清水勇一, 田中一光, 木脇佐代子, 石川麻倫, 松田可奈, 津田桃子, 山本桂子, 小野尚子, 三橋智子, 坂本直哉  日本消化器病学会雑誌(Web)  116-  2019
• デュオドーパ経腸療法中にPEG-J(percutaneous endoscopic gastro-jejunostomy)逸脱により十二指腸潰瘍を形成した一例

  田中一光, 小野尚子, 井上雅貴, 木脇佐代子, 石川麻倫, 松田可奈, 津田桃子, 山本桂子, 清水勇一, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  124th-118th-  2019
• 内視鏡切除した過形成性腺窩上皮を有する有茎性胃底腺ポリープの1例

  石川麻倫, 小野尚子, 霜田佳彦, 田中一光, 井上雅貴, 木脇佐代子, 大野正芳, 高橋正和, 山本桂子, 森康明, 中川学, 中川宗一, 清水勇一, 坂本直哉  日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集  125th-119th-  2019
• 当院における消化管内視鏡検査の鎮静剤使用の現状と課題

  大野正芳, 霜田佳彦, 田中一光, 井上雅貴, 木脇佐代子, 石川麻倫, 山本桂子, 小野尚子, 中川学, 中川宗一, 清水勇一, 坂本直哉  Gastroenterological Endoscopy (Web)  61-  (Supplement2)  2019
• NORTH/HGCSG1003 Stage III結腸癌に対する術後補助化学療法FOLFOXの第II相研究 腫瘍内科医と外科医の比較

  村中 徹人, 小松 嘉人, 結城 敏志, 川本 泰之, 高橋 典彦, 七戸 俊明, 久須美 貴哉, 中村 文隆, 大森 一吉, 伊藤 陽一, 武冨 紹信, 平野 聡, 坂本 直哉  日本大腸肛門病学会雑誌  72-  (1)  48  -48  2019/01  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブの初期治療経験

  荘拓也, 須田剛生, 鈴木和治, 中村晃久, 大原正嗣, 川岸直樹, 梅村真知子, 中井正人, 森川賢一, 小川浩司, 坂本直哉  Liver Cancer Journal  10-  (Suppl.2)  55‐56  -56  2018/12/10  [Not refereed][Not invited]
  
• Clinicopathological significance of ADAM28 expression in colorectal cancer

  Takuya Hattori, Naoya Sakamoto, Koh Horie, Masayuki Shimoda, Akira Ishikawa, Ririno Honma, Daiki Taniyama, Takao Hinoi, Hiroyuki Egi, Hideki Ohdan, Yasunori Okada, Fearon Eric, Wataru Yasui  CANCER SCIENCE  109-  1346  -1346  2018/12
• 進行肝細胞癌に対するレンバチニブの初期治療経験

  荘 拓也, 須田 剛生, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 梅村 真知子, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉  The Liver Cancer Journal  10-  (Suppl.2)  55  -56  2018/12  [Not refereed][Not invited]
  
• B型慢性肝炎患者における核酸アナログ長期治療によるHBs抗原減少効果の検討

  梅村真知子, 森川賢一, 坂本直哉  肝臓  59-  (Supplement 3)  A782  2018/11/25  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するレンバチニブの早期治療効果と安全性の検討

  荘拓也, 須田剛生, 坂本直哉  肝臓  59-  (Supplement 3)  A929  2018/11/25  [Not refereed][Not invited]
  
• Sorafenib不応進行肝細胞癌におけるRegorafenibの初期使用経験

  中村晃久, 中井正人, 重沢拓, 鈴木和治, 大原正嗣, 川岸直樹, 梅村真知子, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  59-  (Supplement 3)  A931  2018/11/25  [Not refereed][Not invited]
  
• DAAs治療後の肝線維化・肝脂肪化改善・非改善と関連する因子の包括的検討

  須田剛生, 川岸直樹, 坂本直哉  肝臓  59-  (Supplement 3)  S852  2018/11/25  [Not refereed][Not invited]
  
• サルコペニア―今注目される肝胆膵疾患の新たな病態―サルコペニアと肝疾患:診断 肝疾患患者における筋肉量の測定とその問題点

  大原正嗣, 須田剛生, 小川浩司, 坂本直哉  肝胆膵  77-  (4)  763‐768  2018/10/28  [Not refereed][Not invited]
  
• 【あれから5年 抗血栓薬-とめない覚悟と勇気】抗血栓薬服用者におけるEUS-FNAおよびinterventional EUSの留意点

  川久保 和道, 桑谷 将城, 杉浦 諒, 加藤 新, 平田 幸司, 坂本 直哉  消化器内視鏡  30-  (10)  1474  -1479  2018/10  [Not refereed][Not invited]
   

  超音波内視鏡ガイド下穿刺吸引法(EUS-FNA)やinterventional EUSは、出血高危険度手技である。抗血栓薬服用中の患者においては、出血性偶発症の頻度が上昇する可能性があり、適切な休薬方法をとる必要がある。EUS-FNAの出血性偶発症の頻度は0.5%程度であり重篤なものも少ない。したがって、安易に抗血栓薬を休薬するのではなく、「止めない覚悟」で臨むことも必要である。超音波内視鏡(EUS)ガイド下胆道ドレナージ術は、出血性偶発症の頻度は4%程度で、重篤なものも少なくない。つまり、抗血栓薬はガイドラインに従って必要最低限の休薬を行う、「止める勇気」が必要である。EUSガイド下膵周囲液体貯留ドレナージ術、さらに内視鏡的ネクロセクトミーでの出血性偶発症の頻度は18%と非常に高いものである。抗血栓薬については、ガイドラインに従った休薬を行うことは当然であるが、「止めない覚悟」は必要でなく、適切な休薬方法をとるべきである。それぞれの手技において出血性偶発症の頻度を下げる明確な方法はなく、抗血栓薬服用中患者においては、細心の注意を払って施行するべきである。(著者抄録)
• 核酸アナログによるウイルス制御下での肝発癌の検討

  小川浩司, 重沢拓, 中村晃久, 鈴木和治, 川岸直樹, 大原正嗣, 梅村真知子, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  肝臓  59-  (Supplement 2)  A659  2018/09/20  [Not refereed][Not invited]
  
• 高発癌リスク群HIV/HCV重複感染例に対するHCV治療

  荘拓也, 須田剛生, 鈴木和治, 中村晃久, 大原正嗣, 川岸直樹, 梅村真知子, 中井正人, 森川賢一, 小川浩司, 坂本直哉  肝臓  59-  (Supplement 2)  A707  2018/09/20  [Not refereed][Not invited]
  
• C型肝疾患に対するDAA治療後の臨床パラメータの変化とDAA治療後肝発癌についての検討

  馬場英, 古家乾, 須田剛生, 森川賢一, 坂本直哉  肝臓  59-  (Supplement 2)  A671  2018/09/20  [Not refereed][Not invited]
  
• 肝硬変症に伴う高アンモニア血症に対するリファキシミンの効果,安全性の検討

  中井正人, 鈴木和治, 中村晃久, 大原正嗣, 川岸直樹, 梅村真知子, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  59-  (Supplement 2)  A721  2018/09/20  [Not refereed][Not invited]
  
• HCV肝炎治療高齢化時代における,HCV排除後LDL‐C上昇の動脈硬化リスクの検討

  川岸直樹, 須田剛生, 鈴木和治, 中村晃久, 大原正嗣, 梅村真知子, 中井正人, 荘拓也, 森川賢一, 小川浩司, 坂本直哉  肝臓  59-  (Supplement 2)  A665  2018/09/20  [Not refereed][Not invited]
  
• 急速に変貌する肝細胞癌の薬物療法2018 Update 免疫チェックポイント阻害剤と分子標的薬の併用療法 ソラフェニブvsアテゾリズマブ+ベバシズマブの第III相試験(IMbrave150試験)

  小川浩司, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  肝胆膵  77-  (2)  486‐490  2018/08/28  [Not refereed][Not invited]
  
• 【急速に変貌する肝細胞癌の薬物療法2018 Update】 免疫チェックポイント阻害剤同士のコンビネーション治療 ソラフェニブvsアテゾリズマブ+ベバシズマブの第III相試験(IMbrave150試験)

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝・胆・膵  77-  (2)  486  -490  2018/08  [Not refereed][Not invited]
  
• 【急速に変貌する肝細胞癌の薬物療法2018 Update】 免疫チェックポイント阻害剤同士のコンビネーション治療 ソラフェニブvsアテゾリズマブ+ベバシズマブの第III相試験(IMbrave150試験)

  小川 浩司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝・胆・膵  77-  (2)  486  -490  2018/08  [Not refereed][Not invited]
  
• Acute on chronic―慢性病態の急性増悪―各論 慢性B型肝炎(非肝硬変例)の急性増悪,急性発症,reactivation

  須田剛生, 重沢拓, 鈴木和治, 川岸直樹, 百瀬美樹, 木村恵, 坂本直哉  肝胆膵  76-  (6)  1065‐1069  2018/06/28  [Not refereed][Not invited]
  
• 長期生存を目指した分子標的治療ほか 進行肝細胞癌に対するソラフェニブ治療不応例の検討

  中村晃久, 小川浩司, 鈴木和治, 大原正嗣, 川岸直樹, 出水孝章, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  Liver Cancer Journal  75‐76  2018/06/10  [Not refereed][Not invited]
  
• 進行肝細胞癌に対するソラフェニブ治療不応例の検討

  中村 晃久, 小川 浩司, 鈴木 和治, 大原 正嗣, 川岸 直樹, 出水 孝章, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  The Liver Cancer Journal  (Suppl.1)  75  -76  2018/06  [Not refereed][Not invited]
  
• NASH/NAFLDの新知見 画像診断 Transient elastography

  小川浩司, 中井正人, 荘拓也, 須田剛生, 森川賢一, 西田睦, 坂本直哉  肝胆膵  76-  (4)  662‐667  2018/04/28  [Not refereed][Not invited]
  
• フォンタン術後肝合併症の検討

  荘拓也, 森川賢一, 坂本直哉  肝臓  59-  (Supplement 1)  A181  2018/04/20  [Not refereed][Not invited]
  
• Palmitoylethanolamideの星細胞活性化抑制およびラット肝線維症モデルにおける抗線維化効果

  大原正嗣, 大西俊介, 須田剛生, 坂本直哉  肝臓  59-  (Supplement 1)  A528  2018/04/20  [Not refereed][Not invited]
  
• 肝硬変症の成因別実態

  小川浩司, 鈴木和治, 中村晃久, 川岸直樹, 大原正嗣, 梅村真知子, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  肝臓  59-  (Supplement 1)  A272  2018/04/20  [Not refereed][Not invited]
  
• Fibroscanで測定したC型肝炎治療前後の肝硬度,脂肪化(CAP)および血液生化学的検査の変化と治療後肝発癌についての検討

  馬場英, 古家乾, 須田剛生, 森川賢一, 坂本直哉  肝臓  59-  (Supplement 1)  A498  2018/04/20  [Not refereed][Not invited]
  
• HBV感染者に対する核酸アナログ投与の脂質代謝に及ぼす影響の検討

  鈴木和治, 須田剛生, 中村晃久, 大原正嗣, 川岸直樹, 出水孝章, 梅村真知子, 中井正人, 荘拓也, 森川賢一, 小川浩司, 坂本直哉  肝臓  59-  (Supplement 1)  A486  2018/04/20  [Not refereed][Not invited]
  
• DAAsによるHCV排除後の肝脂肪化・脂質代謝変化の包括的検討

  川岸直樹, 鈴木和治, 中村晃久, 大原正嗣, 梅村真知子, 出水孝章, 中井正人, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  59-  (Supplement 1)  A387  2018/04/20  [Not refereed][Not invited]
  
• 【腸管感染症-最新の話題を含めて】 最近注目される腸管感染症 サイトメガロウイルス腸炎

  松田 可奈, 小野 尚子, 石川 麻倫, 宮本 秀一, 安孫子 怜史, 津田 桃子, 山本 桂子, 工藤 俊彦, 清水 勇一, 松野 吉宏, 坂本 直哉  胃と腸  53-  (4)  446  -450  2018/04  [Not refereed][Not invited]
   

  ＜文献概要＞サイトメガロウイルス(CMV)感染症は易感染性宿主の日和見感染症として知られている.多くは造血幹細胞移植後,自己免疫性疾患や炎症性腸疾患などの免疫抑制状態や易感染状態を背景としてCMV再活性化がみられるが,慢性腎不全や侵襲的な手術後などにも発症しうる.CMV腸炎は消化器症状,内視鏡検査所見および生検による病理組織学的診断をもって診断される.内視鏡像としては打ち抜き様潰瘍が特徴的とされているが,多彩な潰瘍やびらん性病変を呈することが多い.一方で,発赤・浮腫などの非特異的な炎症所見も多く認められる.治療は抗ウイルス薬であるガンシクロビルが第一選択薬となる.
• 成因別の肝発がんリスクの臨床的評価法の確立と治療介入 肝弾性度と肝脂肪量を用いた肝発がんリスク評価と高発がん危険群の囲い込み

  森川 賢一, 荘 拓也, 坂本 直哉  肝臓  59-  (Suppl.1)  A102  -A102  2018/04  [Not refereed][Not invited]
  
• B型肝炎 HBs抗原陰性化を目指した治療戦略 B型慢性肝疾患に対するエンテカビル、テノホビルによるHBs抗原低下作用

  小川 浩司, 森川 賢一, 坂本 直哉  肝臓  59-  (Suppl.1)  A111  -A111  2018/04  [Not refereed][Not invited]
  
• 成因別の肝発がんリスクの臨床的評価法の確立と治療介入 肝弾性度と肝脂肪量を用いた肝発がんリスク評価と高発がん危険群の囲い込み

  森川 賢一, 荘 拓也, 坂本 直哉  肝臓  59-  (Suppl.1)  A102  -A102  2018/04  [Not refereed][Not invited]
  
• B型肝炎 HBs抗原陰性化を目指した治療戦略 B型慢性肝疾患に対するエンテカビル、テノホビルによるHBs抗原低下作用

  小川 浩司, 森川 賢一, 坂本 直哉  肝臓  59-  (Suppl.1)  A111  -A111  2018/04  [Not refereed][Not invited]
  
• うっ血性肝硬変の診療における諸問題〜肝臓内科医が避けられない移行期医療を含めて〜 フォンタン術後肝合併症の検討

  荘 拓也, 森川 賢一, 坂本 直哉  肝臓  59-  (Suppl.1)  A181  -A181  2018/04  [Not refereed][Not invited]
  
• 超音波検査を用いた肝予備能評価の検討

  杉浦 諒, 桑谷 将城, 西田 睦, 平田 幸司, 加藤 新, 川久保 和道, 坂本 直哉  超音波医学  45-  (Suppl.)  S688  -S688  2018/04  [Not refereed][Not invited]
  
• 胆管ステントの現況と将来 悪性胆道狭窄に対するメタリックステント留置時の乳頭括約筋切開術付加は、ERCP後膵炎の発症を抑制するか

  加藤 新, 桑谷 将城, 坂本 直哉  Gastroenterological Endoscopy  60-  (Suppl.1)  612  -612  2018/04  [Not refereed][Not invited]
  
• 超音波内視鏡ガイド下治療の現状と問題点 膵周囲液体貯留に対する超音波内視鏡下ドレナージの現状と問題点

  加藤 新, 桑谷 将城, 坂本 直哉  日本消化器病学会雑誌  115-  (臨増総会)  A69  -A69  2018/04  [Not refereed][Not invited]
  
• 肝門部領域胆管癌の胆管水平方向進展診断における経乳頭的鉗子生検の診断能

  杉浦 諒, 桑谷 将城, 平田 幸司, 加藤 新, 川久保 和道, 坂本 直哉  日本消化器病学会雑誌  115-  (臨増総会)  A301  -A301  2018/04  [Not refereed][Not invited]
  
• 低分化胃癌におけるSox10発現の臨床病理学的検討

  石川 麻倫, 西原 広史, 林 秀幸, 木村 太一, 石田 雄介, 王 磊, 津田 真寿美, 谷野 美智枝, 坂本 直哉, 田中 伸哉  日本消化器病学会雑誌  115-  (臨増総会)  A375  -A375  2018/03  [Not refereed][Not invited]
  
• HER2陽性切除不能進行胃癌に対してSOX+トラスツズマブ療法を施行後に根治切除可能となった3例(Three cases that became resectable after SOX/Tmab for HER2-positive unresectable gastric cancer)

  川本 泰之, 結城 敏志, 八木澤 允貴, 村中 徹人, 中積 宏之, 川村 秀樹, 神山 俊哉, 高桑 恵美, 三橋 智子, 武冨 紹信, 坂本 直哉, 小松 嘉人, 本間 重紀  日本胃癌学会総会記事  90回-  552  -552  2018/03  [Not refereed][Not invited]
  
• 咽頭癌CRT後遺残再発に対するサルベージEMR/ESD

  安孫子怜史, 清水勇一, 石川麻倫, 松田可奈, 宮本秀一, 津田桃子, 高橋正和, 山本桂子, 森康明, 中川学, 小野尚子, 中川宗一, 工藤俊彦, 坂本直哉  Gastroenterological Endoscopy (Web)  60-  (Supplement1)  2018
• Helicobacter pylori除菌後発見胃癌からみた効率的な内視鏡スクリーニング

  津田桃子, 小野尚子, 石川麻倫, 松田可奈, 宮本秀一, 安孫子怜史, 山下充孝, 高橋正和, 山本桂子, 中川学, 森康明, 中川宗一, 工藤俊彦, 清水勇一, 坂本直哉  Gastroenterological Endoscopy (Web)  60-  (Supplement1)  2018
• 内視鏡を用いた小腸絨毛萎縮診断の正診率についての検討

  松田可奈, 小野尚子, 石川麻倫, 宮本秀一, 安孫子怜史, 津田桃子, 山本桂子, 工藤俊彦, 清水勇一, 坂本直哉  Gastroenterological Endoscopy (Web)  60-  (Supplement2)  2018
• ADH1B/ALDH2遺伝子型と飲酒習慣による食道癌ER後の異時性扁平上皮癌発症リスクの検討

  安孫子怜史, 清水勇一, 石川麻倫, 松田可奈, 宮本秀一, 津田桃子, 山本桂子, 小野尚子, 工藤俊彦, 坂本直哉  日本食道学会学術集会抄録集(CD-ROM)  72nd-  2018
• 食道癌内視鏡的切除後の異時性多発癌に及ぼす節酒禁煙効果の検討

  安孫子怜史, 松田可奈, 津田桃子, 工藤俊彦, 坂本直哉, 清水勇一, 石川麻倫, 宮本秀一, 山本桂子, 小野尚子  北海道医学雑誌  93-  (2)  2018
• 食道癌内視鏡的切除後の異時性多発癌に及ぼす節酒禁煙効果の検討

  安孫子怜史, 安孫子怜史, 清水勇一, 石川麻倫, 松田可奈, 宮本秀一, 津田桃子, 山本桂子, 小野尚子, 工藤俊彦, 坂本直哉  日本消化器病学会雑誌(Web)  115-  2018
• Clinicopathological significance of RCAN-2 expression in gastric carcinoma

  Hattori Yui, Kazuhiro Sentani, Takuya Hattori, Takeharu Imai, Shunsuke Shinmei, Naoya Sakamoto, Naohide Oue, Hiroaki Niitsu, Takao Hinoi, Hideki Ohdan, Wataru Yasui  CANCER SCIENCE  109-  1086  -1086  2018/01
• 【変わりゆく早期胃癌のスペクトラム-H.pylori未感染・現感染・除菌後は違う!】 H.pylori除菌後、感染既往のある胃癌治療後のサーベイランス

  小野 尚子, 石川 麻倫, 松田 可奈, 安孫子 怜史, 津田 桃子, 宮本 秀一, 山本 桂子, 工藤 俊彦, 清水 勇一, 坂本 直哉  消化器内視鏡  30-  (1)  85  -91  2018/01  [Not refereed][Not invited]
   

  本邦の多施設共同ランダム化比較試験により「胃癌内視鏡治療後のH.pyloriの除菌治療は異時性胃癌の発生を1/3に減少させる」ことが示されてから、約10年が経過した。異時多発胃癌のリスクは個々の症例で異なるが、特にリスクが高いのは除菌前の高度萎縮、胃癌の既往と高齢男性である。除菌後胃癌の発生部位は、多発性病変を含めてL領域が中心であるが、高度萎縮粘膜では体部や大彎にも病変がみられている。胃癌既往者では既往のない患者に比べて、除菌後の胃癌発生リスクは明らかに高く、除菌後も長期にわたり胃癌を繰り返す症例がある。そのため、サーベイランスは除菌後も長期に継続する必要があり、除菌前の萎縮部位を意識し、画像強調内視鏡を併用して色調差に着目するのが効率的である。(著者抄録)
• プロトンポンプ阻害薬による胃粘膜変化の検討 ひび割れ粘膜と敷石様粘膜

  宮本 秀一, 加藤 元嗣, 津田 桃子, 松田 加奈, 村中 徹人, 安孫子 怜史, 大野 正芳, 水島 健, 大森 沙織, 山本 桂子, 間部 克裕, 小野 尚子, 工藤 俊彦, 清水 勇一, 坂本 直哉  Gastroenterological Endoscopy  60-  (1)  68  -77  2018/01  [Not refereed][Not invited]
   

  【目的】プロトンポンプ阻害薬(以下PPI:Proton pump inhibitor)により胃底腺の拡張や壁細胞の内腔突出といった病理学的変化が報告されている。また、PPI服用者における上部消化管内視鏡検査では、ひび割れ粘膜(以下GCM:Gastric cracked mucosa)や敷石様粘膜(以下GCSM:Gastric cobblestone-like mucosa)などの胃粘膜変化を体部領域に認めることが多いことが知られている。しかし、これらの胃粘膜変化とPPIの関連についての検討はこれまでに報告されておらず、本検討ではPPIと胃粘膜変化(GCM、GCSM)との関連を明らかにすることを目的とする。【方法】単施設、観察研究。対象は2014年8月から2014年11月までに北海道大学病院で上部消化管内視鏡検査を施行した連続症例。内視鏡施行医と画像確認医師2人の合計3人でPPI内服状況を伏せた状態でGCSM、GCMの有無を評価した。対象をPPI服用者(PPI group)とPPI非服用者(Control group)の2つのグループに分け、胃粘膜所見を比較検討した。【結果】除外症例を除き最終的に解析対象症例となったのは538症例(Control group:374人、男性/女性:204人/170人、平均年齢:65.2歳;PPI group:164人、男性/女性:89人/75人、平均年齢:67.1歳)であった。全解析症例の54人(10%)にひび割れ粘膜を認め、18人(3.3%)に敷石様粘膜を認めた。PPI groupでは、ひび割れ粘膜は40人(24.4%)、敷石様粘膜は15人(9.1%)に認め、Control groupと比較し有意差をもってひび割れ粘膜や敷石様粘膜を多く認めた。【結語】PPI服用者にひび割れ粘膜と敷石様粘膜を多く認め、PPIとの関連が示唆された。(著者抄録)
• 肝臓の栄養管理 肝硬変患者に対するカルニチン投与による筋肉量への影響

  大原 正嗣, 須田 剛生, 小川 浩司, 鈴木 和治, 中村 晃久, 川岸 直樹, 梅村 真知子, 出水 孝章, 中井 正人, 荘 拓也, 森川 賢一, 坂本 直哉  日本病態栄養学会誌  21-  (Suppl.)  S  -38  2018/01  [Not refereed][Not invited]
  
• 【ここまでできるIEE】 [胃・十二指腸] 精密診断 量的診断(staging) BLIを中心に

  小野 尚子, 石川 麻倫, 松田 可奈, 安孫子 怜史, 津田 桃子, 宮本 秀一, 山本 桂子, 工藤 俊彦, 清水 勇一, 坂本 直哉  消化器内視鏡  29-  (12)  2178  -2185  2017/12  [Not refereed][Not invited]
   

  拡大内視鏡検査は早期胃癌の範囲診断のうえで最も重要なツールである。レーザー光を使用した狭帯域光画像であるblue laser imagingの波長は、白色光も含まれた多波長であり、被写界深度が大きく、拡大内視鏡観察においても焦点が合わせやすい。近接弱拡大でも表面微細構造は明瞭に観察できることが多く、demarcation lineを同定しやすい。さらに中拡大〜強拡大観察では、微小血管構築と表面微細構造がともに明瞭に視認され、特に表面微細構造の描出に優れていることが特徴である。(著者抄録)
• Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C

  N. Kawagishi, G. Suda, M. Onozawa, M. Kimura, O. Maehara, M. Ohara, T. Izumi, M. Umemura, J. Ito, M. Nakai, T. Sho, M. Natsuizaka, K. Morikawa, K. Ogawa, N. Sakamoto  JOURNAL OF VIRAL HEPATITIS  24-  (12)  1098  -1106  2017/12  [Not refereed][Not invited]
   

  Hepatitis B virus (HBV) reactivation has been reported during antihepatitis C treatment in patients with hepatitis C virus (HCV) and HBV co-infection. We aimed to evaluate the frequency and risk factors of HBV reactivation during anti-HCV therapy and compared those between interferon (IFN)-free direct-acting antiviral (DAA) therapies and IFN-based therapies. Three hundred and twenty-two patients with HCV infection receiving anti-HCV therapy were retrospectively screened. The baseline HBV infection statuses of all eligible patients and the HBV-DNA level of all patients with current or previous HBV infection were examined at the end of treatment. In patients with baseline anti-HBs positivity, changes in anti-HBs titre were evaluated. Of 287 patients who met the inclusion criteria, 157 had current (n=4) or previous (n=153) HBV infection; 85 were treated with IFN-free DAA therapies and 72 were treated with IFN-based therapies. Six patients experienced HBV reactivation (n=2) or HBV reappearance (n=4) after IFN-free DAA therapies, while no patient developed HBV reactivation after IFN-based therapies. The risk factors of HBV reactivation or reappearance were DAA therapies and a reduction in anti-HBs titre to <12mIUmL(-1) by the end of treatment. The decline changes of anti-HBs titre were significantly higher in patients treated with DAA therapies. Although HBV reactivation hepatitis was not observed, three of four patients with HBV reactivation or reappearance after achieving HCV eradication had viremia 8weeks after completion of therapy. A significant proportion of patients develop HBV reactivation or reappearance without hepatitis after IFN-free DAA therapies. Low levels of anti-HBs and their decrease to <12mIUmL(-1) after treatment are significant risk factors for HBV reactivation or reappearance.
• 【膵疾患に対する内視鏡治療の新展開】 膵切除後膵液瘻に対する内視鏡治療

  桑谷 将城, 川久保 和道, 加藤 新, 杉浦 諒, 平田 幸司, 平野 聡, 坂本 直哉  消化器・肝臓内科  2-  (6)  625  -631  2017/12  [Not refereed][Not invited]
  
• 内視鏡的粘膜下層剥離術後に骨転移をきたした食道表在癌(SM1)の一例

  松田 宗一郎, 清水 勇一, 水島 健, 安孫子 怜史, 松田 可奈, 宮本 秀一, 津田 桃子, 坂本 直哉, 高橋 正和, 山本 桂子, 小野 尚子, 森 康明, 中川 学, 中川 宗一, 工藤 俊彦  北海道医学雑誌  92-  (2)  112  -113  2017/11  [Not refereed][Not invited]
  
• 内視鏡的粘膜下層剥離術後に骨転移をきたした食道表在癌(SM1)の一例

  松田 宗一郎, 清水 勇一, 水島 健, 安孫子 怜史, 松田 可奈, 宮本 秀一, 津田 桃子, 坂本 直哉, 高橋 正和, 山本 桂子, 小野 尚子, 森 康明, 中川 学, 中川 宗一, 工藤 俊彦  北海道医学雑誌  92-  (2)  112  -113  2017/11  [Not refereed][Not invited]
  
• 肝硬変患者における血中亜鉛の検討

  小川 浩司, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  58-  (Suppl.3)  A779  -A779  2017/11  [Not refereed][Not invited]
  
• 慢性肝疾患患者のそう痒症状に対するナルフラフィンの治療効果の検討

  鈴木 和治, 中井 正人, 中村 晃久, 大原 正嗣, 川岸 直樹, 出水 孝章, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.3)  A788  -A788  2017/11  [Not refereed][Not invited]
  
• C型肝炎のDAAs治療における脂質、糖代謝の変化の検討

  川岸 直樹, 鈴木 和治, 中村 晃久, 大原 正嗣, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.3)  A813  -A813  2017/11  [Not refereed][Not invited]
  
• 同種末梢血幹細胞移植8年後に発症した若年発症の食道扁平上皮癌の1例

  村中徹人, 小松嘉人, 原田一顕, 中積宏之, 川本泰之, 村中徹人, 原田一顕, 結城敏志, 山本桂子, 清水勇一, 坂本直哉, 海老原裕磨, 倉島庸, 七戸俊明, 三橋智子  北海道医学雑誌  92-  (2)  111‐112  2017/11/01  [Not refereed][Not invited]
  
• 肝硬変患者における血中亜鉛の検討

  小川 浩司, 鈴木 和治, 中村 晃久, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  58-  (Suppl.3)  A779  -A779  2017/11  [Not refereed][Not invited]
  
• 慢性肝疾患患者のそう痒症状に対するナルフラフィンの治療効果の検討

  鈴木 和治, 中井 正人, 中村 晃久, 大原 正嗣, 川岸 直樹, 出水 孝章, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.3)  A788  -A788  2017/11  [Not refereed][Not invited]
  
• C型肝炎のDAAs治療における脂質、糖代謝の変化の検討

  川岸 直樹, 鈴木 和治, 中村 晃久, 大原 正嗣, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.3)  A813  -A813  2017/11  [Not refereed][Not invited]
  
• Hepatocellular carcinoma development in Japanese patients with HCV genotype 1 infection who achieved sustained virologic response by ledipasvir/sofosbuvir and protease inhibitor with peginterferon plus ribavirin

  Masaaki Korenaga, Namiki Izumi, Osamu Yokosuka, Tetsuo Takehara, Naoya Sakamoto, Shuhei Nishiguchi, Fusao Ikeda, Mikio Yanase, Hidenori Toyoda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Tatsuya Ide, Nobuo Toda, Kazushige Nirei, Yoshiyuki Ueno, Yoichi Nishigaki, Kunio Nakane, Tatsuya Kanto, Masao Omata, Masashi Mizokami  HEPATOLOGY  66-  563A  -564A  2017/10  [Not refereed][Not invited]
  
• 免疫チェックポイント阻害薬投与中に発症した大腸炎の2例

  長島 一哲, 桂田 武彦, 小田切 信介, 山梨 香菜, 木下 賢治, 村中 徹人, 秦 洋郎, 竹内 啓, 本間 理央, 合田 智宏, 三橋 智子, 小松 嘉人, 坂本 直哉  日本癌治療学会学術集会抄録集  55回-  O23  -2  2017/10  [Not refereed][Not invited]
  
• Imatinib不応・不耐GISTに対するsunitinibの有効性について 遺伝子変異別の検討

  中積 宏之, 小松 嘉人, 八木澤 允貴, 村中 徹人, 川本 泰之, 結城 敏志, 坂本 直哉  日本癌治療学会学術集会抄録集  55回-  P174  -3  2017/10  [Not refereed][Not invited]
  
• 腎不全・透析患者における抗HCV治療—Anti-HCV treatment for patients with severe renal dysfunction, including those on hemodialysis—第5土曜特集 ウイルス肝炎のすべて ; 血液伝播するウイルス肝炎 ; C型肝炎

  須田 剛生, 坂本 直哉  医学のあゆみ  262-  (14)  1420  -1425  2017/09/30
• ここまで変わったC型肝炎の治療 Unmet Needsへの挑戦 1.腎不全患者の治療

  須田剛生, 木村恵, 川岸直樹, 坂本直哉  最新医学  72-  (9)  1261‐1267  2017/09/10  [Not refereed][Not invited]
  
• 切除不能進行/再発結腸直腸癌症例に対するTAS‐102投与症例の後方視的検討:HGCSG1503―初回報告―

  結城敏志, 小松嘉人, 坂本直哉  肝臓  58-  (Supplement 2)  A560  2017/09/10  [Not refereed][Not invited]
  
• North Japan multicenter phase II study of FOLFOX as adjuvant chemotherapy for stage III colon cancer (NORTH/HGCSG1003): Analysis of tumor location

  A. Ishiguro, S. Yuki, Y. Kawamoto, H. Nakatsumi, N. Takahashi, T. Shichinohe, T. Kusumi, I. Iwanaga, T. Miyagishima, K. Hatanaka, K. Oomori, M. Nakamura, N. Senmaru, K. Iwai, M. Koike, N. Sakamoto, A. Taketomi, S. Hirano, Y. M. Ito, Y. Komatsu  ANNALS OF ONCOLOGY  28-  2017/09  [Not refereed][Not invited]
  
• 【Interventional EUSの最新情報-適応、手技、デバイス-】 胆管挿管困難例に対するEUS-guided rendezvous technique

  川久保 和道, 桑谷 将城, 加藤 新, 杉浦 諒, 平田 幸司, 坂本 直哉  消化器・肝臓内科  2-  (3)  274  -281  2017/09  [Not refereed][Not invited]
  
• ジェノタイプ2型C型肝炎・肝硬変に対するSofosbuvir(SOF)+Ribavirin(RBV)併用療法の治療効果と非著効例における薬剤耐性ウイルスの検討

  荘拓也, 須田剛生, 大原正嗣, 出水孝章, 川岸直樹, 中井正人, 森川賢一, 伊藤淳, 山本義也, 小野雄司, 永坂敦, 寺下勝巳, 小林智絵, 古家乾, 坂本直哉  肝臓  58-  (Suppl.2)  A575  -A575  2017/09  [Not refereed][Not invited]
  
• DAA治療非著効により獲得される耐性変異の検討

  伊藤淳, 大原正嗣, 川岸直樹, 出水孝章, 梅村真知子, 中井正人, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  58-  (Suppl.2)  A589  -A589  2017/09  [Not refereed][Not invited]
  
• 肝硬変患者における筋肉量測定方法の検討

  大原正嗣, 鈴木和治, 中村晃久, 川岸直樹, 出水孝章, 梅村真知子, 中井正人, 荘拓也, 須田剛生, 森川賢一, 小川浩司, 坂本直哉  肝臓  58-  (Suppl.2)  A633  -A633  2017/09  [Not refereed][Not invited]
  
• 核酸アナログ製剤によるHBs抗原の低下作用

  小川浩司, 中村晃久, 鈴木和治, 大原正嗣, 川岸直樹, 出水孝章, 梅村真知子, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  肝臓  58-  (Suppl.2)  A616  -A616  2017/09  [Not refereed][Not invited]
  
• NBNC肝癌の臨床的特徴

  小川浩司, 中村晃久, 鈴木和治, 大原正嗣, 川岸直樹, 出水孝章, 梅村真知子, 中井正人, 荘拓也, 須田剛生, 森川賢一, 坂本直哉  肝臓  58-  (Suppl.2)  A604  -A604  2017/09  [Not refereed][Not invited]
  
• Innovative therapeutic endoscopy 大腸ESD/EMRの課題と将来展望 ブタ大腸ESD後狭窄モデルに対する羊膜間葉系幹細胞由来培養上清の注腸投与による狭窄予防効果

  津田 桃子, 大西 俊介, 坂本 直哉  日本消化器病学会雑誌  114-  (臨増大会)  A557  -A557  2017/09  [Not refereed][Not invited]
  
• 粘膜下局注併用APCと標準的APCの生体ブタ組織に対する焼灼効果の検討

  安孫子 怜史, 清水 勇一, 大西 俊介, 水島 健, 加藤 麻倫, 松田 可奈, 宮本 秀一, 津田 桃子, 山本 桂子, 小野 尚子, 工藤 俊彦, 坂本 直哉  Gastroenterological Endoscopy  59-  (Suppl.2)  2223  -2223  2017/09  [Not refereed][Not invited]
  
• ジェノタイプ2型C型肝炎・肝硬変に対するSofosbuvir(SOF)+Ribavirin(RBV)併用療法の治療効果と非著効例における薬剤耐性ウイルスの検討

  荘 拓也, 須田 剛生, 大原 正嗣, 出水 孝章, 川岸 直樹, 中井 正人, 森川 賢一, 伊藤 淳, 山本 義也, 小野 雄司, 永坂 敦, 寺下 勝巳, 小林 智絵, 古家 乾, 坂本 直哉  肝臓  58-  (Suppl.2)  A575  -A575  2017/09  [Not refereed][Not invited]
  
• DAA治療非著効により獲得される耐性変異の検討

  伊藤 淳, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.2)  A589  -A589  2017/09  [Not refereed][Not invited]
  
• NBNC肝癌の臨床的特徴

  小川 浩司, 中村 晃久, 鈴木 和治, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  58-  (Suppl.2)  A604  -A604  2017/09  [Not refereed][Not invited]
  
• 核酸アナログ製剤によるHBs抗原の低下作用

  小川 浩司, 中村 晃久, 鈴木 和治, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  58-  (Suppl.2)  A616  -A616  2017/09  [Not refereed][Not invited]
  
• 肝硬変患者における筋肉量測定方法の検討

  大原 正嗣, 鈴木 和治, 中村 晃久, 川岸 直樹, 出水 孝章, 梅村 真知子, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.2)  A633  -A633  2017/09  [Not refereed][Not invited]
  
• PBL初学者に対する臨床実習におけるPBL導入の試み

  川久保 和道, 村上 壮一, 北市 雄士, 小野澤 真弘, 坊垣 暁之, 金野 陽輔, 折茂 達也, 藤岡 容一郎, 稲葉 直子, 本間 理央, 武冨 貴久子, 桂田 武彦, 森川 賢一, 工藤 俊彦, 中積 宏之, 小華和 柾志, 川畑 秀伸, 坂本 直哉, 大滝 純司  医学教育  48-  (Suppl.)  206  -206  2017/08  [Not refereed][Not invited]
  
• 北海道多施設共同研究における膵癌術前化学(放射線)療法中の胆道ドレナージの臨床成績 metal stent vs.plastic stent

  桑谷 将城, 中村 透, 林 毅, 木村 康利, 小野 道洋, 本谷 雅代, 山北 圭介, 後藤 拓磨, 高橋 邦幸, 真口 宏介, 平野 聡, 坂本 直哉  胆道  31-  (3)  567  -567  2017/08  [Not refereed][Not invited]
  
• Non-coding RNAs are promising targets for stem cell-based cancer therapy.

  Naoya Sakamoto, Ririno Honma, Yohei Sekino, Keisuke Goto, Kazuhiro Sentani, Akira Ishikawa, Naohide Oue, Wataru Yasui  Non-coding RNA research  2-  (2)  83  -87  2017/06  [Not refereed][Not invited]
   

  The term "non-coding RNA" (ncRNA) is generally used to indicate RNA that does not encode a protein and includes several classes of RNAs, such as microRNA and long non-coding RNA. Several lines of evidence suggest that ncRNAs appear to be involved in a hidden layer of biological procedures that control various levels of gene expression in physiology and development including stem cell biology. Stem cells have recently constituted a revolution in regenerative medicine by providing the possibility of generating suitable cell types for therapeutic use. Here, we review the recent progress that has been made in elaborating the interaction between ncRNAs and tissue/cancer stem cells, discuss related technical and biological challenges, and highlight plausible solutions to surmount these difficulties. This review particularly emphasises the involvement of ncRNAs in stem cell biology and in vivo modulation to treat and cure specific pathological disorders especially in cancer. We believe that a better understanding of the molecular machinery of ncRNAs as related to pluripotency, cellular reprogramming, and lineage-specific differentiation is essential for progress of cancer therapy.
• A retrospective cohort study of the relations between progress of chemotherapy and outcomes for metastatic pancreatic cancer

  Kawamoto Yasuyuki, Yuki Satoshi, Yagisawa Masataka, Muranaka Tetsuhito, Harada Kazuaki, Nakatsumi Hiroshi, Kawakubo Kazumichi, Kuwatani Masaki, Sakamoto Naoya, Komatsu Yoshito  ANNALS OF ONCOLOGY  28-  2017/06  [Not refereed][Not invited]
  
• 【胃潰瘍は変わったか-新しい胃潰瘍学の構築を目指して】 H.pylori除菌後の胃潰瘍

  小野 尚子, 加藤 元嗣, 松田 可奈, 安孫子 怜史, 津田 桃子, 宮本 秀一, 水島 健, 山本 桂子, 工藤 俊彦, 清水 勇一, 坂本 直哉  胃と腸  52-  (7)  885  -891  2017/06  [Not refereed][Not invited]
   

  Helicobacter pylori(H.pylori)除菌は明らかな消化性潰瘍再発予防効果を認めるものの,除菌成功後にもわずかながら潰瘍の発生,再発を認める.その原因はH.pylori再陽性化によるH.pylori潰瘍とH.pyloriに起因しない非H.pylori潰瘍の2つに分かれ,後者は薬剤性潰瘍とりわけアスピリンを含む非ステロイド性抗炎症薬(NSAIDs)潰瘍が大部分を占める.また,原因を特定できない特発性潰瘍もまれながら存在し,その再発率は高い.再発潰瘍への対応としては,酸分泌抑制薬の投与に加え,H.pyloriの再検査,服用薬の確認など潰瘍の誘因を調べることが大切である.(著者抄録)
• T1a-MM食道扁平上皮癌EMR/ESD症例の長期予後 5年以上経過例の検討

  安孫子 怜史, 清水 勇一, 水島 健, 松田 可奈, 宮本 秀一, 津田 桃子, 山本 桂子, 小野 尚子, 工藤 俊彦, 坂本 直哉  日本食道学会学術集会プログラム・抄録集  71回-  P20  -1  2017/06  [Not refereed][Not invited]
  
• 激変する肝疾患診療の現状 ウイルス性肝炎の診療 高齢者と腎障害を合併するC型慢性肝炎の治療

  須田剛生, 木村恵, 川岸直樹, 坂本直哉  月刊臨床と研究  94-  (5)  534‐538  2017/05/20  [Not refereed][Not invited]
  
• The Efficacy and Safety of a Novel Transpapillary Dilation Technique With a Diathermic Catheter for Severe Malignant Bile Duct Stricture

  Shin Kato, Masaki Kuwatani, Ryo Sugiura, Itsuki Sano, Kazumichi Kawakubo, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  85-  (5)  AB631  -AB632  2017/05  [Not refereed][Not invited]
  
• Mid- to Long-Term Outcomes After Therapeutic Ercp Using Balloon-Assisted Enteroscopy for Anastomotic Stenosis of Choledochojejunostomy or Pancreaticojejunostomy: A Multicenter Observation Study in Japan

  Itsuki Sano, Akio Katanuma, Masaki Kuwatani, Hiroshi Kawakami, Hironari Kato, Takao Itoi, Michihiro Ono, Atsushi Irisawa, Yoshinobu Okabe, Takuji Iwashita, Ichiro Yasuda, Shomei Ryozawa, Seiji Kaino, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  85-  (5)  AB228  -AB229  2017/05  [Not refereed][Not invited]
  
• Endoscopic Reintervention Following Multiple Metallic Stent Placement for Hilar Malignant Biliary Stricture

  Kazumichi Kawakubo, Masaki Kuwatani, Itsuki Sano, Ryo Sugiura, Shin Kato, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  85-  (5)  AB617  -AB617  2017/05  [Not refereed][Not invited]
  
• 進化するB型肝炎治療 未来を拓く新薬の開発状況

  須田剛生, 森川賢一, 木村恵, 坂本直哉  月刊消化器・肝臓内科  1-  (4)  435‐440  2017/04/28  [Not refereed][Not invited]
  
• C型肝炎の診断と治療 インターフェロン・フリー療法―ソホスブビル・レジパスビル併用療法およびソホスブビル・リバビリン併用療法―

  須田剛生, 木村恵, 川岸直樹, 坂本直哉  医学と薬学  74-  (5)  547‐551  2017/04/27  [Not refereed][Not invited]
  
• 【今IPMNをどう診るか】 サーベイランスをめぐる諸問題 IPMNの予後を決める因子は?

  川久保 和道, 多田 稔, 桑谷 将城, 佐野 逸紀, 杉浦 諒, 加藤 新, 坂本 直哉  肝・胆・膵  74-  (4)  597  -600  2017/04  [Not refereed][Not invited]
  
• サイトメガロウイルス腸炎の内視鏡像 腸管GVHD合併例と非合併例の比較

  松田 可奈, 小野 尚子, 宮本 秀一, 安孫子 怜史, 津田 桃子, 水島 健, 山本 桂子, 工藤 俊彦, 清水 勇一, 坂本 直哉  Gastroenterological Endoscopy  59-  (Suppl.1)  1024  -1024  2017/04  [Not refereed][Not invited]
  
• Helicobacter pylori除菌後の胃がん予防 Helicobacter pylori除菌後の胃癌の内視鏡的特徴 2)

  山本桂子, 加藤元嗣, 松田可奈, 津田桃子, 安孫子怜史, 宮本秀一, 水島健, 小野尚子, 工藤俊彦, 清水勇一, 松野吉宏, 坂本直哉  Helicobacter Research  21-  (2)  123‐129  2017/04/01  [Not refereed][Not invited]
  
• NASH診療の現状と問題点 非アルコール性脂肪性肝疾患診断における問題点

  小川 浩司, 荘 拓也, 坂本 直哉  肝臓  58-  (Suppl.1)  A106  -A106  2017/04  [Not refereed][Not invited]
  
• RFA/TACE前後のM2BPGiの変化とRFA後再発予測因子としてのM2BPGiの有用性

  中井 正人, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 伊藤 淳, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  58-  (Suppl.1)  A352  -A352  2017/04  [Not refereed][Not invited]
  
• エキスパートオピニオン:超高齢者の肝胆膵疾患診療 超高齢者における病態の特性,治療の適応,治療の実際:肝疾患 C型肝炎

  森川賢一, 荘拓也, 須田剛生, 坂本直哉  肝胆膵  74-  (3)  385‐390  2017/03/28  [Not refereed][Not invited]
  
• 【炎症性腸疾患-最近の診断・治療-】 炎症性腸疾患の検査・診断 画像検査(X線・CT・MRI・超音波検査)

  桂田 武彦, 西田 睦, 坂本 直哉  日本臨床  75-  (3)  387  -391  2017/03  [Not refereed][Not invited]
  
• DPP-IV活性により蛍光を発するプローブによる頭頸部扁平上皮表在がんの検出

  山本 桂子, 大西 俊介, 坂本 直哉  日本消化器病学会雑誌  114-  (臨増総会)  A253  -A253  2017/03  [Not refereed][Not invited]
  
• イマチニブ耐性GISTに対するスニチニブの有効性・安全性(Retrospective analysis of the efficacy and safety of sunitinib in patients with advanced GIST)

  中積 宏之, 小松 嘉人, 村中 徹人, 原田 一顕, 川本 泰之, 結城 敏志, 坂本 直哉  日本胃癌学会総会記事  89回-  259  -259  2017/03  [Not refereed][Not invited]
  
• 進行胃癌化学療法時の成分栄養剤併用の有効性に関する探索的臨床試験 HGCSG1202(Feasibility study to evaluate the efficacy of elemental diet with chemotherapy for AGC: HGCSG1202)

  結城 敏志, 小松 嘉人, 中積 宏之, 川本 泰之, 原田 一顕, 村中 徹人, 畑中 一映, 曽我部 進, 中村 路夫, 武藤 理, 奥田 博介, 佐藤 温, 江藤 和範, 坂本 直哉, 坂田 優  日本胃癌学会総会記事  89回-  345  -345  2017/03  [Not refereed][Not invited]
  
• 【エキスパートオピニオン:超高齢者の肝胆膵疾患診療】 超高齢者における病態の特性、治療の適応、治療の実際 肝疾患 C型肝炎

  森川 賢一, 荘 拓也, 須田 剛生, 坂本 直哉  肝・胆・膵  74-  (3)  385  -390  2017/03  [Not refereed][Not invited]
  
• C型肝炎の治療到達点と新たな課題 HIV/HCV重複感染の現状とIFN-based therapyおよびDAA therapyの治療効果

  荘 拓也, 小川 浩司, 坂本 直哉  日本消化器病学会雑誌  114-  (臨増総会)  A59  -A59  2017/03  [Not refereed][Not invited]
  
• 肝炎ウイルス陽性者アラートシステム導入後の改善効果

  小川 浩司, 川岸 直樹, 大原 正嗣, 出水 孝章, 梅村 真知子, 伊藤 淳, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  日本消化器病学会雑誌  114-  (臨増総会)  A340  -A340  2017/03  [Not refereed][Not invited]
  
• North Japan multicenter phase II study of oxaliplatin-containing regimen as adjuvant chemotherapy for stage III colon cancer (NORTH/HGCSG1003).

  Toshiaki Shichinohe, Satoshi Yuki, Norihiko Takahashi, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Takaya Kusumi, Atsushi Ishiguro, Susumu Sogabe, Ichiro Iwanaga, Kazuteru Hatanaka, Kazuyoshi Oomori, Michio Nakamura, Naoto Senmaru, Kazuhiro Iwai, Masahiko Koike, Naoya Sakamoto, Akinobu Taketomi, Satoshi Hirano, Yoichi M. Ito, Yoshito Komatsu  JOURNAL OF CLINICAL ONCOLOGY  35-  (4)  2017/02
• 当院における除菌後発見胃癌の臨床病理学的再評価

  山本 桂子, 安孫子 怜史, 宮本 秀一, 水島 健, 小野 尚子, 工藤 俊彦, 清水 勇一, 松田 可奈, 津田 桃子, 坂本 直哉  胃病態機能研究会誌  49-  17  -17  2017/02  [Not refereed][Not invited]
  
• C型肝炎治療の新時代 インターフェロンベース治療―その存在意義

  須田剛生, 木村恵, 坂本直哉  月刊消化器・肝臓内科  1-  (1)  66‐71  2017/01/28  [Not refereed][Not invited]
  
• 目覚ましく治療効果を発揮するC型肝炎治療 腎障害・透析患者におけるC型肝炎抗ウイルス治療

  須田剛生, 木村恵, 川岸直樹, 坂本直哉  Mebio  34-  (1)  52‐59  2017/01/10  [Not refereed][Not invited]
  
• 開かれた透析医療―Integrated Careの具現化 7 透析患者の肝炎治療―肝炎患者に対する肝臓専門医との連携

  須田剛生, 木村恵, 伊藤淳, 坂本直哉  臨床透析  33-  (1)  53‐60  -60  2017/01/10  [Not refereed][Not invited]
  
• インターフェロンベース治療 : その存在意義—Interferon-based therapy, what is the significance of existence—特集 C型肝炎治療の新時代

  須田 剛生, 木村 恵, 坂本 直哉  消化器・肝臓内科 = Gastroenterology & hepatology / 消化器・肝臓内科編集委員会 編  1-  (1)  66  -71  2017/01
• Hepatitis B virus infected cell slows down its cell cycle and proliferation by viral protein and replication

  K. Morikawa, T. Shimazaki, T. Izumi, M. Umemura, M. Nakai, G. Suda, N. Sakamoto  JOURNAL OF HEPATOLOGY  66-  (1)  S644  -S644  2017  [Not refereed][Not invited]
  
• Sustained virologic response by ledipasvir/sofosbuvir reduces the incidence of hepatocellular carcinoma in Japanese patients with HCV genotype 1 infection. - Comparison with Simeprevir with peginterferon plus ribavirin

  M. Korenaga, N. Izumi, O. Yokosuka, T. Takehara, N. Sakamoto, S. Nishiguchi, F. Ikeda, M. Yanase, H. Toyota, T. Genda, T. Umemura, H. Yatsuhashi, T. Ide, N. Toda, K. Nirei, Y. Ueno, Y. Nishigaki, M. Omata, M. Mizokami  JOURNAL OF HEPATOLOGY  66-  (1)  S23  -S23  2017  [Not refereed][Not invited]
  
• 【臨床応用を見据えた肝線維化研究の新展開】 治療 羊膜由来間葉系幹細胞投与による肝線維化治療

  大西 俊介, 久保 公利, 坂本 直哉  肝・胆・膵  74-  (1)  95  -98  2017/01  [Not refereed][Not invited]
  
• 切除不能膵癌に対する化学療法の進歩と治療成績の関係の検討(単施設の後方視的検討)

  川本泰之, 川本泰之, 結城敏志, 八木澤允貴, 八木澤允貴, 村中徹人, 村中徹人, 原田一顕, 原田一顕, 中積宏之, 中積宏之, 川久保和道, 桑谷将城, 小松嘉人, 坂本直哉  日本臨床腫瘍学会学術集会(CD-ROM)  15th-  ROMBUNNO.P1‐107  2017  [Not refereed][Not invited]
  
• Stage III結腸癌の術後補助化学療法としてのFOL‐FOX療法の第II相臨床試験:NORTH/HGCSG1003

  小池雅彦, 結城敏志, 七戸俊明, 高橋典彦, 八木澤允貴, 村中徹人, 川本泰之, 中積宏之, 伊藤陽一, 坂本直哉, 平野聡, 武冨紹信, 小松嘉人  大腸癌研究会プログラム・抄録集  87th-  88  2017  [Not refereed][Not invited]
  
• pStage III結腸癌に対するFOLFOXの第II相試験[NORTH/HGCSG1003]原発部位による解析

  篠原敏樹, 結城敏志, 川本泰之, 川本泰之, 中積宏之, 中積宏之, 高橋典彦, 七戸俊明, 久須美貴哉, 中村文隆, 小林良充, 岩永一郎, 伊藤陽一, 坂本直哉, 武冨紹信, 平野聡, 小松嘉人, 小松嘉人  日本癌治療学会学術集会(Web)  55th-  ROMBUNNO.O29‐2 (WEB ONLY)  2017  [Not refereed][Not invited]
  
• 肝硬変を理解する―分子機構から実臨床に至るまで―治療 抗ウイルス治療(C型肝硬変)

  中井正人, 須田剛生, 坂本直哉  肝胆膵  73-  (6)  1093‐1099  2016/12/28  [Not refereed][Not invited]
  
• Genome-wide association study identifies a TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus

  Yasuhito Tanaka, Kentaro Matsuura, Hiromi Sawai, Kazuho Ikeo, Atsumasa Komori, Hitoshi Yoshiji, Naoya Sakamoto, Yasuhiro Asahina, Masayuki Kurosaki, Norifumi Kawada, Masao Honda, Katsushi Tokunaga  HEPATOLOGY  64-  (6)  1132A  -1133A  2016/12  [Not refereed][Not invited]
  
• A case of bile duct neuroendocrine tumor preoperatively diagnosed by endoscopic ultrasonography-guided fine-needle aspiration biopsy

  Shin Kato, Masaki Kuwatani, Ryo Sugiura, Itsuki Sano, Kazumichi Kawakubo, Naoya Sakamoto, Yoshitsugu Nakanishi, Satoshi Hirano, Takashi Ueno, Tomoko Mitsuhashi  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  31-  231  -231  2016/11  [Not refereed][Not invited]
  
• 【新規技術が創り出す肝疾患診療のスペクタクル】新規の技術はわれわれをどこに導くのか

  上野 義之, 坂本 直哉, 丸澤 宏之, 有井 滋樹  肝・胆・膵  73-  (5)  797  -810  2016/11  [Not refereed][Not invited]
  
• DCF療法で肺転移が消失し根治切除しえた食道がんの1切除例

  村中徹人, 小松嘉人, 中積宏之, 川本泰之, 澤田憲太郎, 結城敏志, 清水勇一, 坂本直哉, 海老原裕麿, 倉島庸, 七戸俊明, 藤澤孝志, 三橋智子  北海道医学雑誌  91-  (2)  93‐94  2016/11/01  [Not refereed][Not invited]
  
• 当院で内視鏡治療を施行したT1a‐MM食道扁平上皮癌の長期予後

  水島健, 清水勇一, 宮本秀一, 安孫子怜史, 津田桃子, 大野正芳, 村中徹人, 中積宏之, 坂本直哉, 高橋正和, 小野尚子, 中川学, 中川宗一, 小松嘉人  北海道医学雑誌  91-  (2)  91  2016/11/01  [Not refereed][Not invited]
  
• 切除不能進行・再発食道癌の二次化学療法におけるドセタキセル単剤およびパクリタキセル単剤療法の有効性・安全性の検討

  中積宏之, 小松嘉人, 村中徹人, 川本泰之, 澤田憲太郎, 結城敏志, 坂本直哉  北海道医学雑誌  91-  (2)  95  2016/11/01  [Not refereed][Not invited]
  
• 肝硬変患者に対するカルニチン製剤の有用性および初回投与量の検討

  小川浩司, 須田剛生, 坂本直哉  肝臓  57-  (Supplement 3)  A674  2016/10/25  [Not refereed][Not invited]
  
• DAAs療法非著効例に対する再治療成績の検討

  須田剛生, 古家乾, 坂本直哉  肝臓  57-  (Supplement 3)  A846  2016/10/25  [Not refereed][Not invited]
  
• Comprehensive understanding of associations between HLA class II genes and chronic hepatitis B infection in the Japanese population

  Nao Nishida, Jun Ohashi, Masaya Sugiyama, Hiromi Sawai, Keisuke Hino, Masao Honda, Shuichi Kaneko, Hiroshi Yatsuhashi, Osamu Yokosuka, Kazuhiko Koike, Masayuki Kurosaki, Namiki Izumi, Masaaki Korenaga, Jong-Hon Kang, Eiji Tanaka, Akinobu Taketomi, Yuichiro Eguchi, Naoya Sakamoto, Kazuhide Yamamoto, Akihiro Tamori, Isao Sakaida, Shuhei Hige, Yoshito Itoh, Satoshi Mochida, Eiji Mita, Yasuhiro Takikawa, Tatsuya Ide, Yoichi Hiasa, Minoru Nakamura, Hiroh Saji, Takehiko Sasazuki, Tatsuya Kanto, Katsushi Tokunaga, Masashi Mizokami  HEPATOLOGY  64-  311A  -311A  2016/10  [Not refereed][Not invited]
  
• 下咽頭上皮下浸潤癌EMR/ESD施行症例の病理組織学的検討

  安孫子 怜史, 清水 勇一, 水島 健, 松田 可奈, 宮本 秀一, 津田 桃子, 高橋 正和, 山本 桂子, 森 康明, 中川 学, 小野 尚子, 中川 宗一, 工藤 俊彦, 坂本 直哉  Gastroenterological Endoscopy  58-  (Suppl.2)  1990  -1990  2016/10  [Not refereed][Not invited]
  
• 生涯教育シリーズ XXI 消化器疾患診療の最前線 21.進行膵癌に対する薬物療法の現況

  結城敏志, 小松嘉人, 坂本直哉  北海道医報  (1177)  14‐16  2016/10/01  [Not refereed][Not invited]
  
• C型肝炎撲滅に向けた地域の取り組み 肝炎ウイルス陽性者アラートシステムによるC型肝炎受診率向上効果

  小川 浩司, 荘 拓也, 坂本 直哉  肝臓  57-  (Suppl.3)  A693  -A693  2016/10  [Not refereed][Not invited]
  
• 高齢者ジェノタイプ2型C型肝炎・肝硬変に対するSofosbuvir(SOF)+Ribavirin(RBV)併用療法の治療効果・安全性の検討

  荘 拓也, 須田 剛生, 大原 正嗣, 出水 孝章, 梅村 真知子, 川岸 直樹, 伊藤 淳, 中井 正人, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  57-  (Suppl.3)  A776  -A776  2016/10  [Not refereed][Not invited]
  
• 肝細胞癌合併ウイルス性肝硬変に対する肝移植後の抗ウイルス療法および再発の検討

  森川賢一, 小川浩司, 坂本直哉  日本消化器がん検診学会雑誌  54-  (Supplement)  910  -A454  2016/09/15  [Not refereed][Not invited]
  
• 肝細胞癌合併ウイルス性肝硬変に対する肝移植後の抗ウイルス療法および再発の検討

  森川 賢一, 小川 浩司, 坂本 直哉  肝臓  57-  (Suppl.2)  A454  -A454  2016/09  [Not refereed][Not invited]
  
• 【インターフェロン・フリーC型肝炎治療】 遺伝子型2型C型肝炎の抗ウイルス治療

  坂本 直哉, 須田 剛生, 小川 浩司, 森川 賢一  臨床消化器内科  31-  (11)  1475  -1479  2016/09  [Not refereed][Not invited]
   

  C型肝炎ゲノタイプ2型に対する抗ウイルス療法は従来PEGインターフェロン・リバビリン併用療法のみが行われてきたが,2015年にインターフェロンを使用しない,ソホスブビル・リバビリン併用12週療法が承認され,約96%のウイルス排除率を達成し,副作用が大幅に軽減されたことから治療対象が大きく広がった.今後は腎不全症例,ソホスブビル治療不成功例に対する治療の開発が課題となる.(著者抄録)
• 血清中に含まれる血液型特異的スフィンゴ糖脂質および遊離オリゴ糖鎖の同定

  横田 育子, 古川 潤一, 花松 久寿, 大西 俊介, 岡田 和恵, 湯山 耕平, 酒井 祥太, 伊東 信, 五十嵐 靖之, 坂本 直哉, 篠原 康郎  日本生化学会大会プログラム・講演要旨集  89回-  [1P  -056]  2016/09  [Not refereed][Not invited]
  
• 消化器領域における再生医療・幹細胞研究の現状 羊膜由来間葉系幹細胞を用いた消化器疾患の再生医療

  大西 俊介, 水島 健, 坂本 直哉  日本消化器病学会雑誌  113-  (臨増大会)  A480  -A480  2016/09  [Not refereed][Not invited]
  
• 核酸アナログ製剤によるHBs抗原の低下作用

  小川 浩司, 大原 正嗣, 川岸 直樹, 梅村 真知子, 出水 孝章, 伊藤 淳, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  57-  (Suppl.2)  A530  -A530  2016/09  [Not refereed][Not invited]
  
• ジェノタイプ2型C型肝炎・肝硬変に対するSofosbuvir(SOF)+Ribavirin(RBV)併用療法の治療効果の検討

  荘 拓也, 山本 義也, 永坂 敦, 古家 乾, 吉田 純一, 常松 泉, 伊藤 淳, 中井 正人, 須田 剛生, 森川 賢一, 坂本 直哉  日本消化器病学会雑誌  113-  (臨増大会)  A742  -A742  2016/09  [Not refereed][Not invited]
  
• FOLFOX or XELOX as adjuvant therapy after curative resection of metastatic or relapsed colorectal cancer

  Kentaro Sawada, Yoshito Komatsu, Satoshi Yuki, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Tetsuhito Muranaka, Atsusi Ishiguro, Kazuteru Hatanaka, Naohide Sasaki, Takuto Miyagishima, Naoya Sakamoto  ANNALS OF ONCOLOGY  27-  2016/07  [Not refereed][Not invited]
  
• Pancreatic Cancer With Infectious Pancreatic Pseudocyst Communicating to the Portal Vein

  Kimitoshi Kubo, Hiroshi Kawakami, Masaki Kuwatani, Tomoko Mitsuhashi, Kazumichi Kawakubo, Shuhei Kawahata, Yoshimasa Kubota, Naoya Sakamoto  PANCREAS  45-  (6)  925  -926  2016/07  [Not refereed][Not invited]
  
• Retrospective comparison of efficacy and safety of docetaxel and weekly-paclitaxel as 2nd-line chemotherapy for patients with unresectable or recurrent esophageal cancer

  H. Nakatsumi, Y. Komatsu, K. Sawada, T. Muranaka, Y. Kawamoto, S. Yuki, N. Sakamoto  ANNALS OF ONCOLOGY  27-  50  -50  2016/06  [Not refereed][Not invited]
  
• 異時性PBC‐AIH overlap症候群との鑑別に苦慮したAMA‐M2抗体陽性AIHの1例

  梅村真知子, 森川賢一, 森川賢一, 坂本直哉  たんじゅうさん  15-  (1)  16  -18  2016/06  [Not refereed][Not invited]
   

  70歳代女性。高血圧症、脂質異常症のため近医へ通院中であった。今回、定期検診時に肝胆道系酵素の上昇を指摘され、精査加療目的で著者らの施設へ紹介となった。初診時、自己抗体、AMA-M2抗体は陽性で、胆道系酵素優位の上昇と考えられた。当初、原発性胆汁性肝硬変(PBC)が疑われたが、その後、微熱、尿濃染、全身倦怠感が出現し、約1ヵ月後の再診時に急性肝炎を認めたため精査入院となった。入院時、高ビリルビン血症と肝胆道系酵素の上昇を認め、肝生検結果よりAMA-M2陽性自己免疫性肝炎(AIH)の診断に至った。治療としてUDCAに加え、PSLの投与を追加したところ、肝機能は改善傾向を示し、患者は第15病日目に軽快退院となった。
• 日本におけるB型肝炎キャリアの実態とその診療

  中井 正人, 小川 浩司, 坂本 直哉  消化器の臨床  19-  (3)  181  -186  2016/06  [Not refereed][Not invited]
   

  B型肝炎キャリア(=HBV持続感染者)は本邦に全人口の1%程度存在すると考えられる。HBVキャリアは垂直感染対策によって疫学的に減少傾向となっているが、いまだ感染者は多く存在し重要な感染症である。HBV持続感染者の自然史において、ALT正常の2種類のキャリア(無症候性キャリア、非活動性キャリア)が存在し、両者ともに通常は治療対象とならないが、長期経過にて肝炎を生じ、肝硬変や肝細胞癌発症のリスクとなるため、適切なフォローアップとタイミングでの治療介入の検討が必要である。(著者抄録)
• 進行肝細胞癌におけるSorafenib+5-FU併用療法の検討

  荘 拓也, 小川 浩司, 出水 孝章, 梅村 真知子, 伊藤 淳, 常松 聖司, 佐藤 史幸, 中井 正人, 須田 剛生, 森川 賢一, 坂本 直哉  The Liver Cancer Journal  8-  (1)  58  -59  2016/06  [Not refereed][Not invited]
  
• Gastric Endoscopic Submucosal Dissection Training for Novice Operators in Centers Without Expertise-Multicenter Prospective Study

  Shouko Ono, Kana Matsuda, Nobuyuki Ehira, Satoshi Abiko, Takeshi Mizushima, Keiko Yamamoto, Shinji Yoshii, Kazuhiro Takahashi, Mototsugu Kato, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  83-  (5)  AB265  -AB265  2016/05  [Not refereed][Not invited]
  
• Advantage and Disadvantage of Endoscopic Ultrasonography-Guided Fistula Creation As a Biliary Drainage Method

  Masaki Kuwatani, Hiroshi Kawakami, Kazumichi Kawakubo, Shuhei Kawahata, Kimitoshi Kubo, Yoshimasa Kubota, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  83-  (5)  AB355  -AB355  2016/05  [Not refereed][Not invited]
  
• Risk of Bleeding After Endoscopic Ultrasnography-Guided Fine Needle Aspiration for Patients With Antithrombotic Agents; a Prospective Multicenter Study

  Kazumichi Kawakubo, Kei Yane, Kazunori Eto, Hirotoshi Ishiwatari, Nobuyuki Ehira, Shin Haba, Ryusuke Matsumoto, Keisuke Shinada, Hiroaki Yamato, Taiki Kudo, Manabu Onodera, Toshinori Okuda, Yoko Taya, Shuhei Kawahata, Kimitoshi Kubo, Yoshimasa Kubota, Masaki Kuwatani, Hiroshi Kawakami, Akio Katanuma, Michihiro Ono, Tsuyoshi Hayashi, Minoru Uebayashi, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  83-  (5)  AB208  -AB208  2016/05  [Not refereed][Not invited]
  
• C型肝炎治療の新時代と将来への展望 Daclatasvir/Asunaprevir併用療法のC型肝炎合併透析患者に対する治療効果と安全性の検討

  須田 剛生, 工藤 峰生, 坂本 直哉  日本消化器病学会雑誌  113-  (臨増総会)  A31  -A31  2016/03  [Not refereed][Not invited]
  
• C型慢性肝疾患に対するダクラタスビル/アスナプレビル併用療法による肝線維化指標の改善効果

  小川 浩司, 出水 孝章, 梅村 真知子, 伊藤 淳, 佐藤 史幸, 常松 聖司, 中井 正人, 荘 卓也, 須田 剛生, 森川 賢一, 坂本 直哉  日本消化器病学会雑誌  113-  (臨増総会)  A312  -A312  2016/03  [Not refereed][Not invited]
  
• IBDモニタリングツールをいかに使いこなすか? 潰瘍性大腸炎における超音波検査有用性の検討

  木下 賢治, 桂田 武彦, 坂本 直哉  日本消化器病学会雑誌  113-  (臨増総会)  A80  -A80  2016/03  [Not refereed][Not invited]
  
• 消化管疾患における再生医療の最前線 羊膜由来間葉系幹細胞を用いた難治性腸炎に対する新規治療法の開発

  大野 正芳, 大西 俊介, 坂本 直哉  日本消化器病学会雑誌  113-  (臨増総会)  A117  -A117  2016/03  [Not refereed][Not invited]
  
• Phase II trial of bolus 5-FU/l-LV regimen as salvage line chemotherapy for oral fluorouracil resistant unresectable gastric cancer (HGCSG1502).

  Tetsuhito Muranaka, Satoshi Yuki, Kentaro Sawada, Yasuyuki Kawamoto, Hiroshi Nakatsumi, Masayoshi Dazai, Hideyuki Hayashi, Michio Nakamura, Atsushi Ishiguro, Susumu Sogabe, Yoshimitsu Kobayashi, Takuto Miyagishima, Ichiro Iwanaga, Miki Tateyama, Kazuteru Hatanaka, Takashi Kato, Naoya Sakamoto, Yuh Sakata, Yoshito Komatsu  JOURNAL OF CLINICAL ONCOLOGY  34-  (4)  2016/02  [Not refereed][Not invited]
  
• 注目の新薬 ソバルディ(ソフォスブビル)

  須田剛生, 常松聖司, 坂本直哉  診断と治療  104-  (2)  248‐250  2016/02/01  [Not refereed][Not invited]
  
• 肝臓における超音波組織弾性測定の機種間差の検討 Shear wave with Smart mapsとFibroScanとの比較

  若林 倭, 工藤 悠輔, 西田 睦, 堀江 達則, 岩井 孝仁, 表原 里実, 佐藤 恵美, 高杉 莉佳, 小川 浩司, 坂本 直哉  超音波医学  43-  (1)  131  -132  2016/01  [Not refereed][Not invited]
  
• 【H.pylori除菌後の諸問題】 H.pylori除菌がGERD発症にどのように影響するのか

  加藤 元嗣, 小野 尚子, 中川 学, 中川 宗一, 安孫子 怜史, 宮本 秀一, 水島 健, 津田 桃子, 大野 正芳, 大西 俊介, 清水 勇一, 坂本 直哉, 間部 克裕  The GI Forefront  11-  (2)  106  -109  2016/01  [Not refereed][Not invited]
   

  H.pylori感染は胃酸分泌との関わりからGERDの影響因子である。実際、H.pylori感染率とGERD有病率については相反する関係にあり、H.pylori感染がGERD発症に防御的に作用している可能性がある。一方、H.pylori除菌がGERDの発症を増加させるかについては、いくつかのメタ解析の結果から否定的である。むしろ、GERD症状はH.pylori除菌によって軽減する傾向がある。したがって、GERDの存在がH.pylori除菌の妨げとはならない。(著者抄録)
• 【慢性胃炎を見直す】 胃炎の内視鏡診断 通常光観察

  加藤 元嗣, 小野 尚子, 中川 学, 中川 宗一, 安孫子 怜史, 宮本 秀一, 水島 健, 津田 桃子, 大野 正芳, 大西 俊介, 清水 勇一, 坂本 直哉, 間部 克裕  胃と腸  51-  (1)  42  -51  2016/01  [Not refereed][Not invited]
   

  組織学的所見と内視鏡所見が一致しないために,慢性胃炎はこれまで組織学的に診断されてきた.しかし,最近の内視鏡機器の進歩により,組織学的胃炎と一致する内視鏡所見が次第に明らかになった.胃粘膜におけるH. pylori感染状態は,H. pylori未感染,H. pylori感染,H. pylori既感染・除菌後に分けることができる.新たな内視鏡による胃炎分類である京都分類では,19の胃炎所見を定義して,H. pylori感染状態との関連性を整理した.RAC,びまん性発赤,地図状発赤は,それぞれH. pylori未感染,H. pylori感染,H. pylori除菌後の特徴的な所見である.H. pylori感染状態によって,発生胃癌のリスクや特徴は異なるため,胃炎の診断は胃癌スクリーニングにおいても重要である.(著者抄録)
• 食道癌の二次化学療法におけるDocetaxelおよびPaclitaxelの有効性・安全性の検討

  中積宏之, 小松嘉人, 村中徹人, 原田一顕, 川本泰之, 結城敏志, 坂本直哉  日本癌治療学会学術集会(Web)  54th-  ROMBUNNO.WS72‐6 (WEB ONLY)  2016  [Not refereed][Not invited]
  
• 切除不能進行大腸癌に対するレゴラフェニブ療法の後方視的研究:HGCSG1401

  結城敏志, 小松嘉人, 川本泰之, 辻靖, 曽我部進, 吉田俊太郎, 畑中一映, 奥田博介, 佐々木尚英, 太宰昌佳, 太田智之, 本田琢也, 石黒敦, 坂田優, 坂本直哉  日本癌治療学会学術集会(Web)  54th-  ROMBUNNO.MS33‐3 (WEB ONLY)  2016  [Not refereed][Not invited]
  
• R0/1切除された転移性および再発結腸・直腸癌に対するOxaliplatinを含む術後補助化学療法の検討

  澤田憲太郎, 小松嘉人, 結城敏志, 中積宏之, 川本泰之, 村中徹人, 石黒敦, 畑中一映, 佐々木尚英, 宮城島拓人, 坂本直哉  日本臨床腫瘍学会学術集会(CD-ROM)  14th-  ROMBUNNO.P2‐049  2016  [Not refereed][Not invited]
  
• C型肝炎 臨床研究 DAA(Direct Acting Antivirals)療法の治療予測因子・薬剤耐性ウイルス

  須田剛生, 山崎和思, 坂本直哉  日本臨床  73-  189‐192  2015/12/20  [Not refereed][Not invited]
  
• 新規HCV治療薬を巡る状況

  須田剛生, 木村恵, 坂本直哉  週刊日本医事新報  (4780)  20  -24  2015/12/05  [Not refereed][Not invited]
  
• Safety analysis of FOLFOX as adjuvant chemotherapy for stage III colon cancer in phase II study (NORTH/HGCSG1003) - an analysis of surgeons vs oncologists

  A. Ishiguro, S. Yuki, Y. Kawamoto, F. Nakamura, N. Takahashi, T. Shichinohe, T. Kusumi, S. Sogabe, K. Hatanaka, K. Misawa, M. Nenohi, H. Hayashi, H. Fukushima, M. Takahashi, T. Amano, Y. M. Ito, N. Sakamoto, A. Taketomi, S. Hirano, Y. Komatsu  ANNALS OF ONCOLOGY  26-  50  -50  2015/12  [Not refereed][Not invited]
  
• Sofosbuvir in combination with ribavirin for 12weeks achieves 97% sustained virologic response in Japanese patients with chronic genotype 2 hepatitis C infection

  Masao Omata, Shuhei Nishiguchi, Yoshiyuki Ueno, Hitoshi Mochizuki, Namiki Izumi, Fusao Ikeda, Hidenori Toyoda, Osamu Yokosuka, Kazushige Nirei, Takuya Genda, Akeji Umemura, Tetsuo Takehara, Naoya Sakamoto, Yoichi Nishigaki, Kunio Nakane, Nobuo Toda, Tatsuya Ide, Mikio Yanase, Keisuke Hino, Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote, Steven J. Knox, William T. Symonds, John G. Mchutchison, Hiroshi Yatsuhashi, Masashi Mizokami  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  30-  373  -373  2015/12  [Not refereed][Not invited]
  
• Treatment with the single-tablet regimen ledipasvir/sofosbuvir for 12weeks results in 100% sustained virologic response in Japanese patients with chronic genotype-1 hepatitis C virus infection

  Masashi Mizokami, Tetsuo Takehara, Osamu Yokosuka, Naoya Sakamoto, Masaaki Korenaga, Hitoshi Mochizuki, Kunio Nakane, Hirayuki Enomoto, Mikio Yanase, Hidenori Toyoda, Fusao Ikeda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Tatsuya Ide, Nobuo Toda, Kazushige Nirei, Yoshiyuki Ueno, Yoichi Nishigaki, Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote, Vivian Liu, Phillip S. Pang, Steven J. Knox, William T. Symonds, John G. Mchutchison, Namiki Izumi, Masao Omata  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  30-  372  -373  2015/12  [Not refereed][Not invited]
  
• Endoscopic nasobiliary drainage has lower incidence of complications than endoscopic biliary stenting for the management of hilar cholangiocarcinoma

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Shin Haba, Taiki Kudo, Yoko Abe, Shuhei Kawahata, Yoshimasa Kubota, Kimitoshi Kubo, Kazunori Eto, Nobuyuki Ehira, Hiroaki Yamato, Naoya Sakamoto  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  30-  235  -235  2015/12  [Not refereed][Not invited]
  
• 医療イノベーション創出ネットワークの現状と展望 新しいフェーズに入ったアカデミアのシーズ開発 シーズ発表・再生医療等製品 羊膜由来間葉系幹細胞を用いた肝硬変の治療法の開発 羊膜由来間葉系幹細胞の再生医療製品化と急性GVHDに対する治療応用 重症クローン病に対する同種卵膜間葉系幹細胞による新規治療法の開発

  坂本 直哉, 山原 研一, 大西 俊介  臨床評価  43-  (Suppl.XXXV)  221  -224  2015/12  [Not refereed][Not invited]
  
• 前治療無効例における慢性C型肝炎に対するシメプレビル治療効果予測因子の検討

  小林智絵, 須田剛生, 熊谷研一, 高木智史, 山本義也, 小野寺学, 宮城嶋拓人, 目黒高志, 工藤峰二, 常松泉, 永坂敦, 小川浩司, 坂本直哉  肝臓  56-  (Supplement 3)  A1015  2015/11/05  [Not refereed][Not invited]
  
• 肝移植後C型肝炎患者に対するダクラタスビル・アスナプレビル併用療法の検討

  小川 浩司, 梅村 真知子, 出水 孝章, 伊藤 淳, 佐藤 史幸, 常松 聖司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉, 嶋村 剛  肝臓  56-  (Suppl.3)  A981  -A981  2015/11  [Not refereed][Not invited]
  
• 肝細胞癌におけるKLF5による癌幹細胞制御機構

  佐藤 史幸, 夏井坂 光輝, 前原 経, 浅野 彩華, 久保田 良政, 出水 孝章, 梅村 真知子, 伊藤 淳, 常松 聖司, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 大西 俊介, 坂本 直哉  肝臓  56-  (Suppl.3)  A1002  -A1002  2015/11  [Not refereed][Not invited]
  
• 肝癌・非肝癌症例における肝弾性値の検討

  荘 拓也, 小川 浩司, 出水 孝章, 梅村 真知子, 伊藤 淳, 常松 聖司, 佐藤 史幸, 中井 正人, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  56-  (Suppl.3)  A1010  -A1010  2015/11  [Not refereed][Not invited]
  
• C型慢性肝炎治療のパラダイムシフト―治療から治癒へ―III.Genotype2型に対する新薬NS5Bポリメラーゼ阻害薬Sofosbuvir 薬剤耐性

  須田剛生, 木村恵, 坂本直哉  肝胆膵  71-  (4)  665  -668  2015/10/28  [Not refereed][Not invited]
  
• Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese

  Nao Nishida, Jun Ohashi, Masaya Sugiyama, Takayo Tsuchiura, Ken Yamamoto, Keisuke Hino, Masao Honda, Shuichi Kaneko, Hiroshi Yatsuhashi, Kazuhiko Koike, Osamu Yokosuka, Eiji Tanaka, Akinobu Taketomi, Masayuki Kurosaki, Namiki Izumi, Naoya Sakamoto, Yuichiro Eguchi, Takehiko Sasazuki, Katsushi Tokunaga, Masashi Mizokami, Tatsuya Kanto  HEPATOLOGY  62-  1004A  -1005A  2015/10  [Not refereed][Not invited]
  
• B型慢性肝疾患に対するエンテカビル投与待のHBs抗原,HBコア関連抗原の検討

  小川浩司, 須田剛生, 坂本直哉  肝臓  56-  (Supplement 2)  A761  2015/09/10  [Not refereed][Not invited]
  
• 単純性脂肪肝と非アルコール性脂肪性肝炎の臨床的検討

  寺下 勝巳, 小川 浩司, 伊藤 淳, 佐藤 史幸, 常松 聖司, 佃 曜子, 中井 正人, 荘 拓也, 須田 剛気, 森川 健一, 坂本 直哉  肝臓  56-  (Suppl.2)  A756  -A756  2015/09  [Not refereed][Not invited]
  
• B型慢性肝炎に対するテノホビル(TDF)の初期使用経験と短期効果の検討

  中井 正人, 伊藤 淳, 常松 聖司, 佐藤 史幸, 荘 拓也, 須田 剛生, 森川 賢一, 小川 浩司, 坂本 直哉  肝臓  56-  (Suppl.2)  A760  -A760  2015/09  [Not refereed][Not invited]
  
• 非消化器系診療科における院内肝炎ウイルス陽性者の動向調査

  小川 浩司, 伊藤 淳, 常松 聖司, 佐藤 史幸, 中井 正人, 荘 拓也, 須田 剛生, 森川 賢一, 坂本 直哉  肝臓  56-  (Suppl.2)  A788  -A788  2015/09  [Not refereed][Not invited]
  
• 小児の肝疾患 臨床・研究のup to date 当院におけるFontan術後の肝合併症の現状

  荘 拓也, 小川 浩司, 坂本 直哉  日本消化器病学会雑誌  112-  (臨増大会)  A637  -A637  2015/09  [Not refereed][Not invited]
  
• Endoscopic submucosal dissection for superficial esophageal carcinoma

  清水 勇一, 加藤 元嗣, 坂本 直哉  日本医師会雑誌  144-  (4)  703  -706  2015/07
• HCV感染症の治療と検査の進歩

  須田剛生, 坂本直哉  臨床病理  63-  (6)  762  -767  2015/06/25  [Not refereed][Not invited]
  
• Safety analysis of FOLFOX as adjuvant chemotherapy for stage III colon cancer in phase II study (NORTH/HGCSG1003) - an analysis of surgeons vs oncologists

  I. Iwanaga, S. Yuki, H. Fukushima, N. Takahashi, T. Shichinohe, T. Kusumi, F. Nakamura, S. Sogabe, K. Hatanaka, K. Oomori, K. Misawa, N. Senmaru, K. Iwai, T. Shinohara, M. Koike, K. Miyashita, T. Amano, Y. M. Ito, N. Sakamoto, A. Taketomi, S. Hirano, Y. Komatsu  ANNALS OF ONCOLOGY  26-  2015/06  [Not refereed][Not invited]
  
• Novel Gastric Gastric Mucosal Changes Induced by Use of Pproton Pump Inhibitor

  Shuichi Miyamoto, Mototsugu Kato, Shouko Ono, Katsuhiro Mabe, Yuichi Shimizu, Naoya Sakamoto  GASTROINTESTINAL ENDOSCOPY  81-  (5)  AB465  -AB465  2015/05  [Not refereed][Not invited]
  
• C型肝炎合併慢性腎不全透析患者に対するDaclatasvir/Asunaprevir併用療法の検討

  小川浩司, 須田剛生, 坂本直哉  肝臓  56-  (Supplement 1)  A76  2015/04/20  [Not refereed][Not invited]
  
• 市中病院におけるC型慢性肝炎に対するDAAs併用療法導入症例の患者背景および治療効果の検討

  山本義也, 山梨香菜, 松田可奈, 堀本啓大, 大和弘明, 山本桂子, 畑中一映, 成瀬宏仁, 須田剛生, 坂本直哉  肝臓  56-  (Supplement 1)  A497  2015/04/20  [Not refereed][Not invited]
  
• 100% SVR12 WITH LEDIPASVIR/SOFOSBUVIR +/- RIBAVIRIN FOR 12 WEEKS IN JAPANESE PATIENTS WITH CHRONIC GENOTYPE 1 HEPATITIS C VIRUS WHO PREVIOUSLY FAILED THERAPY WITH PROTEASE INHIBITOR plus PEGYLATED INTERFERON alpha plus RIBAVIRIN

  M. Omata, T. Takehara, O. Yokosuka, N. Sakamoto, M. Korenagai, H. Mochizuki, K. Nakane, H. Enomoto, M. Yanase, H. Toyoda, F. Ikeda, T. Genda, T. Umemura, H. Yatsuhashi, T. Ide, N. Toda, K. Nirei, Y. Ueno, Y. Nishigaki, S. De-Oertel, B. Gao, H. Dvory-Sobol, A. Ishizaki, M. Omote, P. S. Pang, S. J. Knox, W. T. Symonds, J. G. McHutchison, N. Izumi, M. Mizokami  JOURNAL OF HEPATOLOGY  62-  S626  -S627  2015/04  [Not refereed][Not invited]
  
• Mutational Analysis of Pancreatic Neuroendocrine Tumor Using Endoscopic Ultrasound-Guided Fine-Needle Aspiration and Next-Generation Deep Sequencing

  Yoshimasa Kubota, Hiroshi Kawakami, Mitsuteru Natsuizaka, Masaki Kuwatani, Kazumichi Kawakubo, Yoko Abe, Shuhei Kawahata, Kimitoshi Kubo, Naoya Sakamoto  GASTROENTEROLOGY  148-  (4)  S941  -S941  2015/04  [Not refereed][Not invited]
  
• Merits and Demerits of Steroid Therapy for IgG4-Related Sclerosing Cholangitis

  Masaki Kuwatani, Hiroshi Kawakami, Kazumichi Kawakubo, Shuhei Kawahata, Kimitoshi Kubo, Yoko Abe, Naoya Sakamoto  GASTROENTEROLOGY  148-  (4)  S292  -S293  2015/04  [Not refereed][Not invited]
  
• NS3、NS5AおよびNS5B阻害剤耐性変異とシメプレビル3剤併用療法における治療効果の検討

  伊藤 淳, 常松 聖司, 佐藤 史幸, 佃 曜子, 寺下 勝巳, 中井 正人, 荘 拓也, 須田 剛生, 夏井坂 光輝, 森川 賢一, 小川 浩司, 永坂 敦, 古家 乾, 宮城島 拓人, 坂本 直哉  肝臓  56-  (Suppl.1)  A247  -A247  2015/04  [Not refereed][Not invited]
  
• 当科におけるC型肝炎SVR後の肝発癌症例の検討 発癌率と危険因子

  中井 正人, 伊藤 淳, 常松 聖司, 佐藤 史幸, 佃 曜子, 寺下 勝巳, 荘 拓也, 須田 剛生, 森川 賢一, 夏井坂 光輝, 小川 浩司, 坂本 直哉  肝臓  56-  (Suppl.1)  A262  -A262  2015/04  [Not refereed][Not invited]
  
• 肝動注化学療法における早期治療効果予測因子に関する検討

  常松 聖司, 須田 剛生, 伊藤 淳, 佐藤 史幸, 寺下 勝巳, 佃 曜子, 中井 正人, 荘 拓也, 夏井坂 光輝, 小川 浩司, 坂本 直哉  肝臓  56-  (Suppl.1)  A285  -A285  2015/04  [Not refereed][Not invited]
  
• C型肝炎ウイルスの粒子形成・分泌機構の解明と関与する細胞性因子の解析

  森川 賢一, 島崎 とも江, 伊藤 淳, 常松 聖司, 佐藤 史幸, 寺下 勝巳, 佃 曜子, 中井 正人, 荘 拓也, 須田 剛生, 夏井坂 光輝, 小川 浩司, 坂本 直哉  肝臓  56-  (Suppl.1)  A318  -A318  2015/04  [Not refereed][Not invited]
  
• 各種肝疾患における肝弾性度の検討

  荘 拓也, 小川 浩司, 伊藤 淳, 常松 聖司, 佐藤 史幸, 佃 曜子, 寺下 勝巳, 中井 正人, 須田 剛生, 森川 賢一, 夏井坂 光輝, 坂本 直哉  肝臓  56-  (Suppl.1)  A360  -A360  2015/04  [Not refereed][Not invited]
  
• Incidental Pancreatic Cyst is a Significant Predictor of Mortality? What Determines Life Expectancy?

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto  RADIOLOGY  274-  (3)  939  -939  2015/03  [Not refereed][Not invited]
  
• ヒト初代B細胞におけるHCVcc感染

  中井 正人, 伊藤 淳, 常松 聖司, 佐藤 史幸, 佃 曜子, 寺下 勝巳, 荘 拓也, 須田 剛生, 夏井坂 光輝, 小川 浩司, フセイン・ハッサン・アリ, 松本 美佐子, 瀬谷 司, 坂本 直哉  日本消化器病学会雑誌  112-  (臨増総会)  A354  -A354  2015/03  [Not refereed][Not invited]
  
• Safety analysis of FOLFOX as adjuvant chemotherapy for stage III colon cancer in phase II study (NORTH/HGCSG1003): Detailed analysis of peripheral sensory neuropathy.

  Susumu Sogabe, Satoshi Yuki, Hiraku Fukushima, Norihiko Takahashi, Toshiaki Shichinohe, Takaya Kusumi, Fumitaka Nakamura, Ichiro Iwanaga, Kazuteru Hatanaka, Kencho Miyashita, Jun Konno, Kazuhito Uemura, Masaaki Nenohi, Masaya Kina, Naoya Sakamoto, Akinobu Taketomi, Satoshi Hirano, Toraji Amano, Yoichi M. Ito, Yoshito Komatsu  JOURNAL OF CLINICAL ONCOLOGY  33-  (3)  2015/01  [Not refereed][Not invited]
  
• 切除不能進行/再発胃癌における一次化学療法導入時のGlasgow Prognostic Score(GPS)の有用性の検討

  結城敏志, 小松嘉人, 村中徹人, 林秀幸, 中積宏之, 福島拓, 坂本直哉  日本胃癌学会総会記事  87th-  439  2015  [Not refereed][Not invited]
  
• 当院における切除不能進行大腸癌に対するRegorafenib療法の安全性と有効性の検討

  川本泰之, 小松嘉人, 結城敏志, 中積宏之, 福島拓, 林秀幸, 村中徹人, 澤田憲太郎, 本間理央, 中野政子, 三宅亜矢, 石岡明子, 坂本直哉  日本癌治療学会学術集会(Web)  53rd-  P121‐3 (WEB ONLY)  2015  [Not refereed][Not invited]
  
• 当院における切除不能進行大腸癌に対するTAS‐102療法の安全性と有効性の検討

  結城敏志, 小松嘉人, 川本泰之, 中積宏之, 福島拓, 林秀幸, 村中徹人, 澤田憲太郎, 本間理央, 中野政子, 三宅亜矢, 石岡明子, 坂本直哉  日本癌治療学会学術集会(Web)  53rd-  P122‐6 (WEB ONLY)  2015  [Not refereed][Not invited]
  
• エラストを臨床に活かす 当科におけるフィブロスキャン活用の現状

  荘 拓也, 小川 浩司, 伊藤 淳, 佃 曜子, 寺下 勝巳, 中井 正人, 坂本 直哉, 工藤 悠輔, 西田 睦  超音波医学  42-  (1)  83  -83  2015/01  [Not refereed][Not invited]
  
• 進行食道癌と術前診断した,表面にHigh grade intraepithelial neoplasiaを伴う顆粒細胞腫の1例

  村中徹人, 林秀幸, 中積宏之, 福島拓, 小松嘉人, 結城敏志, 清水勇一, 坂本直哉, 七戸俊明  北海道外科雑誌  59-  (2)  202  -203  2014/12/20  [Not refereed][Not invited]
  
• C型肝炎は,完治できる時代へ

  須田剛生, 坂本直哉  臨床病理  62-  57  2014/10/31  [Not refereed][Not invited]
  
• 当院におけるフォンタン術後患者の肝合併症の現状

  荘 拓也, 小川 浩司, 伊藤 淳, 佐藤 史幸, 常松 聖司, 佃 曜子, 寺下 勝巳, 中井 正人, 須田 剛生, 夏井坂 光輝, 坂本 直哉, 泉 岳, 武田 充人, 有賀 正  肝臓  55-  (Suppl.3)  A855  -A855  2014/10  [Not refereed][Not invited]
  
• ENDOSCOPIC DIAGNOSIS OF H. PYLORI INFECTION USING LASEREO WITH A NOVEL IMAGE ENHANCEMENT

  M. Kato, S. Ono, K. Mabe, N. Sakamoto, M. Asaka  HELICOBACTER  19-  125  -125  2014/09  [Not refereed][Not invited]
  
• RECOVERY OF SERUM PEPSINOGEN AFTER ERADICATION OF HELICOBACTER PYLORI IN SUBJECTS WITH PEPTIC ULCER: 10-YEAR FOLLOW-UP STUDY

  S. Ono, K. Mabe, M. Kato, N. Sakamoto  HELICOBACTER  19-  108  -108  2014/09  [Not refereed][Not invited]
  
• EGFR阻害剤を用いた食道扁平上皮癌幹細胞を標的とした新規治療法の開発(EGFR inhibitors suppress EMT and diminish cancer stem-like cells in esophageal squamous cell carcinoma)

  佐藤 史幸, 夏井坂 光輝, 大橋 真也, 賀川 真吾, 桑谷 将城, 河上 洋, 大西 俊介, 小松 嘉人, 加藤 元嗣, 坂本 直哉  日本癌学会総会記事  73回-  J  -1034  2014/09  [Not refereed][Not invited]
  
• L-カルニチンのC型肝炎ウイルス増殖抑制効果に関する研究

  佃 曜子, 伊藤 淳, 常松 聖司, 佐藤 史幸, 寺下 勝巳, 中井 正人, 堀本 啓大, 荘 拓也, 須田 剛生, 夏井坂 光輝, 小川 浩司, 中馬 誠, 坂本 直哉  日本消化器病学会雑誌  111-  (臨増大会)  A916  -A916  2014/09  [Not refereed][Not invited]
  
• 非代償性肝硬変に伴う胸腹水および肝腎症候群に対するトルバプタン使用例の検討

  中井 正人, 伊藤 淳, 佃 曜子, 寺下 勝巳, 荘 拓也, 須田 剛生, 夏井坂 光輝, 小川 浩司, 坂本 直哉  肝臓  55-  (Suppl.2)  A670  -A670  2014/09  [Not refereed][Not invited]
  
• 当科における肝移植後C型肝炎再発例の治療成績の検討

  後藤了一, 山下健一郎, 腰塚靖之, 高橋徹, 青柳武史, 太田稔, 夏井坂光輝, 小川浩司, 鈴木友己, 神山俊哉, 坂本直哉, 武冨紹信, 嶋村剛  日本移植学会総会プログラム抄録集  50th-  259  2014/08  [Not refereed][Not invited]
  
• 大腸がん治療の新戦略 肝転移切除後の補助化学療法は何を選択すべきか?

  結城敏志, 小松嘉人, 坂本直哉  月刊腫瘍内科  14-  (1)  32  -39  2014/07/28  [Not refereed][Not invited]
  
• CTNNB1 Mutational Analysis of Solid-Pseudopapillary Neoplasms of the Pancreas Using Endoscopic Ultrasound-Guided Fine-Needle Aspiration and Next-Generation Deep Sequencing

  Yoshimasa Kubota, Hiroshi Kawakami, Mitsuteru Natsuizaka, Kazumichi Kawakubo, Katsuji Marukawa, Taiki Kudo, Yoko Abe, Kimitoshi Kubo, Masaki Kuwatani, Yutaka Hatanaka, Tomoko Mitsuhashi, Yoshihiro Matsuno, Naoya Sakamoto  GASTROENTEROLOGY  146-  (5)  S871  -S871  2014/05  [Not refereed][Not invited]
  
• 内視鏡治療と抗血栓薬 3.抗血小板薬服用時の内視鏡検査/生検とガイドライン―現状と課題―

  加藤元嗣, 小野尚子, 間部克裕, 大野正芳, 松本美櫻, 大森沙織, 高橋正和, 吉田武史, 清水勇一, 坂本直哉, 中川学, 中川宗一  モダンフィジシャン  34-  (5)  610  -614  2014/05/01  [Not refereed][Not invited]
  
• 当科におけるHCV/HIV重複感染症の現状と抗HCV療法

  荘 拓也, 中馬 誠, 常松 聖司, 佐藤 史幸, 佃 曜子, 寺下 勝巳, 中井 正人, 堀本 啓大, 須田 剛生, 夏井坂 光輝, 藤本 勝也, 遠藤 知之, 豊嶋 崇徳, 坂本 直哉  肝臓  55-  (Suppl.1)  A213  -A213  2014/04  [Not refereed][Not invited]
  
• L-カルニチンのC型肝炎ウイルス増殖抑制効果に関する研究

  佃 曜子, 伊藤 淳, 佐藤 史幸, 常松 聖司, 寺下 勝巳, 中井 正人, 堀本 啓大, 荘 拓也, 須田 剛生, 夏井坂 光輝, 中馬 誠, 坂本 直哉  肝臓  55-  (Suppl.1)  A240  -A240  2014/04  [Not refereed][Not invited]
  
• Is Intraductal Papillary Mucinous Neoplasm of the Pancreas Just a Precursor or Identical With Pancreatic Ductal Adenocarcinoma?

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Naoya Sakamoto  AMERICAN JOURNAL OF GASTROENTEROLOGY  109-  (3)  446  -447  2014/03  [Not refereed][Not invited]
  
• L-カルニチンのC型肝炎ウイルス増殖抑制効果に関する研究

  佃 曜子, 須田 剛生, 佐藤 史幸, 常松 聖司, 寺下 勝巳, 中井 正人, 堀本 啓大, 荘 拓也, 夏井坂 光輝, 中馬 誠, 坂本 直哉  日本消化器病学会雑誌  111-  (臨増総会)  A306  -A306  2014/03  [Not refereed][Not invited]
  
• ヘリコバクター・ピロリ感染胃炎を診る,治す 3 H.pylori胃炎除菌による胃内環境への影響(1)除菌による内視鏡所見の変化

  加藤元嗣, 小野尚子, 間部克裕, 吉田武史, 清水勇一, 坂本直哉, 中川学, 中川宗一  臨床消化器内科  29-  (3)  329  -336  2014/02/20  [Not refereed][Not invited]
  
• Helicobacter Pylori除菌後フォローアップをどのようにおこなうか―除菌後胃癌の予防を含めて―Helicobacter Pylori除菌後胃癌の頻度―背景疾患の影響は?―

  間部克裕, 加藤元嗣, 津田桃子, 大野正芳, 大森沙織, 松本美櫻, 高橋正和, 吉田武史, 小野尚子, 中川学, 中川宗一, 清水勇一, 坂本直哉  Helicobacter Res  18-  (1)  34  -38  2014/02/01  [Not refereed][Not invited]
  
• 胃癌の治療戦略 外科治療・内視鏡治療 早期胃癌の内視鏡治療

  小野尚子, 加藤元嗣, 清水勇一, 坂本直哉, 浅香正博  日本臨床  72-  370  -373  2014/01/20  [Not refereed][Not invited]
  
• 胃癌の予防 H.pylori除菌

  加藤元嗣, 小野尚子, 間部克裕, 清水勇一, 坂本直哉  日本臨床  72-  673  -680  2014/01/20  [Not refereed][Not invited]
  
• 胃癌の治療戦略 化学療法 分子標的薬治療 切除不能進行・再発胃癌に対する分子標的治療薬併用の有用性と問題点

  結城敏志, 小松嘉人, 佐々木尚英, 福島拓, 坂本直哉  日本臨床  72-  485  -490  2014/01/20  [Not refereed][Not invited]
  
• 救急医のための消化器緊急内視鏡 消化器系緊急内視鏡の適応・前処置・術前術後管理

  高橋正和, 加藤元嗣, 大野正芳, 津田桃子, 大森沙織, 松本美櫻, 吉田武史, 森康明, 中川学, 小野尚子, 中川宗一, 間部克裕, 清水勇一, 坂本直哉  救急医学  38-  (1)  3  -8  2014/01/10  [Not refereed][Not invited]
  
• Expression of IFN lambda 4 in liver and PBMC is closely associated with higher basal expression of ISGs and impaired induction of IL28B by interferon treatment in chronic hepatitis C non-responder patients

  Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Naoya Sakamoto, Sayuri Nitta, Fukiko Kawai-Kitahata, Miki Taniguchi, Takako Watanabe, Yasuhiro Itsui, Sei Kakinuma, Mamoru Watanabe  HEPATOLOGY  60-  1065A  -1065A  2014  [Not refereed][Not invited]
  
• 100% SVR4 in Japanese Patients with Chronic Genotype 1 Hepatitis C Virus Infection Receiving Ledipasvir/Sofosbuvir Fixed Dose Combination for 12 Weeks: Results from a Multicenter Phase 3 Study

  Masashi Mizokami, Tetsuo Takehara, Osamu Yokosuka, Naoya Sakamoto, Masaaki Korenaga, Hitoshi Mochizuki, Kunio Nakane, Hirayuki Enomoto, Mikio Yanase, Hidenori Toyoda, Fusao Ikeda, Takuya Genda, Takeji Umemura, Hiroshi Yatsuhashi, Tatsuya Ide, Nobuo Toda, Kazushige Nirei, Yoshiyuki Ueno, Yoichi Nishigaki, Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote, Phillip S. Pang, Steven J. Knox, William T. Symonds, John G. McHutchison, Namiki Izumi, Masao Omata  HEPATOLOGY  60-  1130A  -1130A  2014  [Not refereed][Not invited]
  
• 97% Sustained Virologic Response in Japanese Patients with Chronic Genotype 2 Hepatitis C Virus Infection Receiving Sofosbuvir in Combination with Ribavirin for 12 Weeks: Results from a Phase 3 Multicenter Study

  Masao Omata, Shuhei Nishiguchi, Yoshiyuki Ueno, Hitoshi Mochizuki, Namiki Izumi, Fusao Ikeda, Hidenori Toyoda, Osamu Yokosuka, Kazushige Nirei, Takuya Genda, Takeji Umemura, Tetsuo Takehara, Naoya Sakamoto, Yoichi Nishigaki, Kunio Nakane, Nobuo Toda, Tatsuya Ide, Mikio Yanase, Keisuke Hino, Juan Betular, Bing Gao, Akinobu Ishizaki, Masa Omote, Diana M. Brainard, Steven J. Knox, William T. Symonds, John G. McHutchison, Hiroshi Yatsuhashi, Masashi Mizokami  HEPATOLOGY  60-  671A  -671A  2014  [Not refereed][Not invited]
  
• Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions

  Goki Suda, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Naoya Sakamoto  HEPATOLOGY  60-  703A  -704A  2014  [Not refereed][Not invited]
  
• Evaluation of usefulness of Royal Marsden Hospital prognostic index in second-line chemotherapy of advanced gastric cancer.

  Takahide Sasaki, Yoshito Komatsu, Satoshi Yuki, Kazuaki Harada, Yoshimitsu Kobayashi, Hiraku Fukushima, Naoya Sakamoto  JOURNAL OF CLINICAL ONCOLOGY  32-  (3)  2014/01  [Not refereed][Not invited]
  
• 進行胃癌の二次化学療法におけるRoyal Marsden Hospital prognostic indexの有用性の検討

  原田一顕, 結城敏志, 小林良充, 佐々木尚英, 福島拓, 小松嘉人, 坂本直哉  日本胃癌学会総会記事  86th-  282  2014  [Not refereed][Not invited]
  
• 当院における切除不能進行・再発大腸癌に対するSOX+BVの使用経験

  福島拓, 結城敏志, 原田一顕, 小林良充, 佐々木尚英, 坂本直哉, 小松嘉人  日本癌治療学会学術集会(CD-ROM)  52nd-  ROMBUNNO.P52-9  2014  [Not refereed][Not invited]
  
• 三次治療以降のKRAS野生型Cetuximab投与例でのGlasgow Prognostic Score(GPS)の有用性

  結城敏志, 小松嘉人, 原田一顕, 福島拓, 佐々木尚英, 小林良充, 辻靖, 成瀬宏仁, 奥田博介, 藤川幸司, 細川歩, 山本文泰, 工藤峰生, 坂田優, 坂本直哉  日本癌治療学会学術集会(CD-ROM)  52nd-  ROMBUNNO.O14-2  2014  [Not refereed][Not invited]
  
• 胃炎除菌時代の内視鏡診断 知っておくべき保険診療で行うピロリ診断と治療

  加藤元嗣, 小野尚子, 間部克裕, 大野正芳, 松本美櫻, 大森沙織, 高橋正和, 吉田武史, 清水勇一, 坂本直哉, 中川学, 中川宗一  消化器内視鏡  25-  (12)  1938  -1944  2013/12/25  [Not refereed][Not invited]
  
• フッ化ピリミジン系+プラチナ系抗癌剤に不応となった切除不能進行・再発食道癌に対するドセタキセルの有効性,安全性の検討:retrospective staudy

  佐々木尚英, 小林良充, 原田一顕, 福島拓, 小松嘉人, 結城敏志, 坂本直哉  北海道外科雑誌  58-  (2)  109  -110  2013/12/20  [Not refereed][Not invited]
  
• ESD後,頸部リンパ節再発を来した0‐IIa+IIb型下咽頭癌の1例

  高橋正和, 清水勇一, 吉田武史, 大野正芳, 大森沙織, 松本美櫻, 坂本直哉, 小野尚子, 間部克裕, 加藤元嗣  耳鼻咽喉科展望  56-  (6)  399  2013/12/15  [Not refereed][Not invited]
  
• Helicobacter pylori感染症の間違いのない診断と治療をもう一度学ぶ Helicobacter pylori除菌治療後の経過観察

  加藤元嗣, 小野尚子, 間部克裕, 大野正芳, 松本美櫻, 大森沙織, 高橋正和, 吉田武史, 清水勇一, 坂本直哉, 中川学, 中川宗一  Helicobacter Res  17-  (6)  551  -555  2013/12/01  [Not refereed][Not invited]
  
• 進行肝癌の集学的治療 進行肝細胞癌に対する分子標的治療、肝動注療法の位置づけ

  荘 拓也, 中馬 誠, 坂本 直哉  肝臓  54-  (Suppl.3)  A673  -A673  2013/11  [Not refereed][Not invited]
  
• Establishment of Interferon resistant genotype 2b/JFH-1 chimeric Hepatitis C virus cell culture system

  Goki Suda, Yoko Tsukuda, Mitsuteru Natsuizaka, Makoto Chuma, Naoya Sakamoto  HEPATOLOGY  58-  942A  -942A  2013/10  [Not refereed][Not invited]
  
• 食道扁平上皮癌におけるTGF-βおよびNotch1による癌幹細胞維持機構(TGF-β changes a switch of Notch1-mediated signaling to maintain tumor-initiating cells in esophageal SCC(ESCC))

  夏井坂 光輝, 大橋 真也, 長沼 誠二, 大西 俊介, 桑谷 将城, 河上 洋, 中馬 誠, 小松 嘉人, 加藤 元嗣, 坂本 直哉  日本癌学会総会記事  72回-  137  -137  2013/10  [Not refereed][Not invited]
  
• 胃内視鏡検診における胃癌偽陰性の検討

  清水 佐和子, 吉井 新二, 綿野 敬子, 羽場 真, 川本 泰之, 横山 朗子, 赤倉 伸亮, 間部 克裕, 加藤 元嗣, 坂本 直哉  Gastroenterological Endoscopy  55-  (Suppl.2)  2798  -2798  2013/09  [Not refereed][Not invited]
  
• 免疫学的便潜血陰性大腸腫瘍の検討

  吉井 新二, 綿野 敬子, 清水 佐和子, 羽場 真, 川本 泰之, 横山 朗子, 赤倉 伸亮, 間部 克裕, 加藤 元嗣, 坂本 直哉  Gastroenterological Endoscopy  55-  (Suppl.2)  2845  -2845  2013/09  [Not refereed][Not invited]
  
• H.pylori除菌後長期経過による内視鏡像の変化 H.pylori除菌後10年以上の長期観察例における萎縮粘膜の回復過程についての検討

  大森沙織, 加藤元嗣, 大野正芳, 高橋正和, 鈴木美櫻, 吉田武史, 森康明, 中川学, 小野尚子, 中川宗一, 間部克裕, 清水勇一, 坂本直哉  月刊消化器内科  57-  (2)  125  -130  2013/08/28  [Not refereed][Not invited]
  
• 早期咽喉頭腫瘍におけるEndocytoscopy(超拡大内視鏡)画像診断能の検討

  清水勇一, 高橋正和, 吉田武史, 小野尚子, 間部克裕, 加藤元嗣, 坂本直哉  耳鼻咽喉科展望  56-  (4)  214  2013/08/15  [Not refereed][Not invited]
  
• 粘膜内癌を合併したSSA/Pに腸管スピロヘータが確認された1例

  大森沙織, 間部克裕, 大野正芳, 鈴木美櫻, 高橋正和, 小野尚子, 清水勇一, 加藤元嗣, 畑中佳奈子, 坂本直哉  日本内科学会雑誌  102-  (8)  2046  -2049  2013/08/10  [Not refereed][Not invited]
  
• H.pylori除菌療法と胃癌撲滅へのロードマップ―【H.pylori除菌療法と胃癌予防:課題の克服に向けて】H.pylori除菌療法による胃癌予防―その効果と実際

  加藤元嗣, 小野尚子, 森康明, 中川学, 中川宗一, 間部克裕, 大野正芳, 石垣沙織, 鈴木美櫻, 高橋正和, 吉田武史, 清水勇一, 坂本直哉  消化器の臨床  16-  (4)  367  -371  2013/08/10  [Not refereed][Not invited]
  
• Helicobacter pylori update V.H.pylori感染症関連疾患と除菌治療の意義 早期胃癌の内視鏡治療後胃

  加藤元嗣, 小野尚子, 間部克裕, 坂本直哉, 浅香正博  日本臨床  71-  (8)  1429  -1435  2013/08/01  [Not refereed][Not invited]
  
• 原発不明癌頸部リンパ節転移として精査加療中に上部消化管内視鏡にて発見された中咽頭癌の1例

  高橋正和, 清水勇一, 大野正芳, 石垣沙織, 鈴木美櫻, 坂本直哉, 小野尚子, 間部克裕, 加藤元嗣  耳鼻咽喉科展望  56-  (3)  148  2013/06/15  [Not refereed][Not invited]
  
• ESDの実際(29)中下咽頭癌に対するESDの基本と工夫

  清水勇一, 高橋正和, 吉田武史, 小野尚子, 間部克裕, 加藤元嗣, 坂本直哉  消化器の臨床  16-  (3)  311  -315  2013/06/10  [Not refereed][Not invited]
  
• 慢性胃炎へのHelicobacter pylori除菌療法 保険適用拡大 胃癌を撲滅する計画はどのように変わっていくのか?

  加藤元嗣, 小野尚子, 間部克裕, 森康明, 中川学, 中川宗一, 工藤俊彦, 大野正芳, 石垣沙織, 鈴木美櫻, 高橋正和, 吉田武史, 清水勇一, 坂本直哉, 浅香正博  Helicobacter Res  17-  (3)  216  -211  2013/06/01  [Not refereed][Not invited]
  
• Wire-guided cannulationによる胆管挿管における早期double guidewire法の有用性についての多施設共同無作為化比較試験

  笹平 直樹, 伊佐山 浩通, 河上 洋, 伊藤 由紀子, 松原 三郎, 石渡 裕俊, 上林 実, 内野 里枝, 八木岡 浩, 外川 修, 有住 俊彦, 坂本 直哉, 加藤 淳二, 小池 和彦, EDUCATION Study Group  Gastroenterological Endoscopy  55-  (Suppl.1)  1036  -1036  2013/04  [Not refereed][Not invited]
  
• HCV Core領域アミノ酸70/91変異株を用いた反応機序の解析

  藤田 めぐみ, 加藤 孝宣, 村山 麻子, 山田 典栄, 脇田 隆字, 朝比奈 靖浩, 坂本 直哉  肝臓  54-  (Suppl.1)  A232  -A232  2013/04  [Not refereed][Not invited]
  
• 見える!使える!ここまでできるようになった最新消化器超音波 消化管の機能性疾患の診断

  加藤元嗣, 坂本直哉, 西田睦, 工藤俊彦  Mebio  30-  (3)  100  -107  2013/03/10  [Not refereed][Not invited]
  
• 胃癌撲滅を考慮したH.pylori感染性胃炎の対応

  加藤元嗣, 小野尚子, 間部克裕, 清水勇一, 坂本直哉  Clinician  60-  (617)  344  -351  2013/03/01  [Not refereed][Not invited]
  
• 切除不能進行/再発胃癌に対するS‐1+Cisplatin分割療法の第II相臨床試験:HGCSG0702―安全性の解析報告―

  結城敏志, 小松嘉人, 坂本直哉  日本消化器病学会雑誌  110-  A48  2013/02/20  [Not refereed][Not invited]
  
• 【摂食制御と消化管】 六君子湯による摂食不振・悪液質の改善

  武田 宏司, 中川 宏治, 西村 三恵, 大久保 直登, 細野 秀崇, 浅香 正博, 武藤 修一, 大西 俊介, 坂本 直哉  G.I.Research  21-  (1)  48  -58  2013/02  [Not refereed][Not invited]
   

  六君子湯は心窩部不快感や胃もたれ感、食欲不振などに対して広く使用されている漢方薬である。六君子湯はグレリンの分泌を亢進させ、さまざまな病態における食欲不振を改善する。シスプラチンは5-HT2B受容体および5-HT2C受容体を活性化してアシルグレリンを低下させ、食欲不振を引き起こすが、六君子湯は5-HT2B/5-HT2C受容体を阻害することにより、アシルグレリン分泌を回復させる。高齢動物では高濃度のレプチンにより視床下部弓状核ニューロペプチドY(NPY)/アグーチ関連ペプチド(AgRP)ニューロンでグレリンシグナルがブロックされているが、六君子湯はPDE3を阻害してグレリン抵抗性を解除し、食欲を回復させる。癌悪液質モデルでは、5-HT2C受容体の関与やグレリン抵抗性の存在が示唆されているが、六君子湯は5-HT2C受容体を阻害し、グレリン受容体の感受性を改善することにより食欲不振を改善させる。(著者抄録)
• 消化器領域における幹細胞研究の進歩 食道がん幹細胞におけるTGF-β/Notchシグナルを標的とした新規治療法の創出

  夏井坂 光輝, 大西 俊介, 坂本 直哉  日本消化器病学会雑誌  110-  (臨増総会)  A82  -A82  2013/02  [Not refereed][Not invited]
  
• Spontaneous intraductal stent migration after endoscopic ultrasound-guided choledochogastrostomy

  K. Kawakubo, H. Kawakami, M. Kuwatani, S. Haba, T. Kudo, Y. Abe, N. Sakamoto  Endoscopy  45-  (2)  E89  -E90  2013  [Not refereed][Not invited]
  
• 積極的な化学療法により3度にわたりDICから離脱しえた胃癌骨髄癌腫症の1例

  中野真太郎, 小松嘉人, 原田一顕, 小林良充, 佐々木尚英, 福島拓, 結城敏志, 坂本直哉  日本癌治療学会学術集会(CD-ROM)  51st-  ROMBUNNO.P80-13  2013  [Not refereed][Not invited]
  
• A safety and utility of single-session EUS and ERCP for the evaluation of pancreatobiliary diseases

  Kazumichi Kawakubo, Hiroshi Kawakami, Masaki Kuwatani, Yoko Abe, Taiki Kudo, Shin Haba, Naoya Sakamoto  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  27-  77  -77  2012/12  [Not refereed][Not invited]
  
• Helicobacter pylori感染率と酸関連疾患スペクトラムの変動 Helicobacter pylori陰性胃癌

  加藤元嗣, 小野尚子, 森康明, 中川学, 間部克裕, 工藤俊彦, 中川宗一, 大野正芳, 石垣沙織, 鈴木美櫻, 高橋正和, 清水勇一, 坂本直哉, 青木利佳, 安田貢  Helicobacter Res  16-  (6)  528  -532  2012/12/01  [Not refereed][Not invited]
  
• 食道・中下咽頭表在癌の診断と治療 食道癌内視鏡的切除症例に対する頭頸部癌サーベイランス

  清水勇一, 高橋正和, 吉田武史, 小野尚子, 間部克裕, 加藤元嗣, 坂本直哉  月刊消化器内科  55-  (4)  449-452  2012/10/28  [Not refereed][Not invited]
  
• The Characteristics of Gastric Cancer Detected after Helicobacter pylori Eradication, form a Clinical View Point

  KATO MOTOTSUGU, ONO SHOKO, MORI YASUAKI, NAKAGAWA MANABU, MABE KATSUHIRO, KUDO TAKAHIKO, NAKAGAWA SOICHI, ONO MASAYOSHI, ISHIGAKI SAORI, SUZUKI MIO, TAKAHASHI MASAKAZU, SHIMIZU YUICHI, SAKAMOTO NAOYA, YAMAMOTO KEIKO  胃と腸  47-  (11)  1640-1648  2012/10/25  [Not refereed][Not invited]
  
• ピロリ胃炎から胃癌を診る 除菌治療で胃癌が予防できるのか

  加藤元嗣, 小野尚子, 間部克裕, 大野正芳, 鈴木美櫻, 石垣沙織, 高橋正和, 清水勇一, 坂本直哉  消化器内視鏡  24-  (10)  1636-1641  2012/10/25  [Not refereed][Not invited]
  
• Impaired IL28B gene induction and poor IL28B promoter activity influenced by the IL28B minor allele are closely associated with a null response to interferon in chronic hepatitis C patients

  Yasuhiro Asahina, Miyako Murakawa, Naoya Sakamoto, Sei Kakinuma, Mina Nakagawa, Seishin Azuma, Yuki Nishimura-Sakurai, Sayuri Nitta, Akiko Kusano-Kitazume, Mamoru Watanabe  HEPATOLOGY  56-  697A  -698A  2012/10  [Not refereed][Not invited]
  
• Antiviral effetcts and action mechanisms of novel N-(morpholine-4-carbonyloxy) amidine compounds against hepatitis C virus

  Akiko Kusano-Kitazume, Naoya Sakamoto, Yukiko Okuno, Kenichi Mori, Mina Nakagawa, Sei Kakinuma, Sayuri Nitta, Miyako Murakawa, Seishin Azuma, Yuki Nishimura-Sakurai, Akihiro Matsumoto, Masatoshi Hagiwara, Yasuhiro Asahina, Mamoru Watanabe  HEPATOLOGY  56-  716A  -716A  2012/10  [Not refereed][Not invited]
  
• Antiviral effect of novel interferon-inducible proteins, GBP-1 and IFI-27, against hepatitis C virus replication

  Yasuhiro Itsui, Naoya Sakamoto, Goki Suda, Tsunehito Yauchi, Mamoru Watanabe  HEPATOLOGY  56-  713A  -713A  2012/10  [Not refereed][Not invited]
  
• 胃癌の予防と治療 III.胃癌の予防 H.pylori除菌療法の胃癌予防効果

  間部克裕, 加藤元嗣, 小野尚子, 浅香正博, 坂本直哉  日本臨床  70-  (10)  1726-1730  2012/10/01  [Not refereed][Not invited]
  
• 切除不能進行結腸直腸癌に対するセツキシマブ使用症例のレトロスペクティブ調査(HGCSG0901)―効果予測因子別の解析

  結城敏志, 小松嘉人, 坂本直哉  日本消化器病学会雑誌  109-  A697  2012/09/15  [Not refereed][Not invited]
  
• 消化吸収の側面からみた炎症性腸疾患の病態と栄養療法 成分栄養療法による抗TNF-α抗体療法効果減弱の抑制についての検討

  桂田 武彦, 平山 剛, 坂本 直哉  日本消化器病学会雑誌  109-  (臨増大会)  A485  -A485  2012/09  [Not refereed][Not invited]
  
• New method for induced fit docking (GENIUS) and its applicationto virtual screening of novel HCV NS3-4A protease inhibitors

  Daisuke Takaya, Atsuya Yamashita, Kazue Kamijo, Junko Gomi, Masahiko Ito, Shinya Maekawa, Nobuyuki Enomoto, Naoya Sakamoto, Yoshiaki Watanabe, Ryoichi Arai, Hideaki Umeyama, Teruki Honma, Takehisa Matsumoto, Shigeyuki Yokoyama  ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY  244-  2012/08  [Not refereed][Not invited]
  
• Transcriptome analysis of esophageal squamous cell carcinoma by SAGE identifies a new biomarker, NRD1

  Naohiro Uraoka, Naoya Sakamoto, Naohide Oue, Kazuhiro Sentani, Katsuhiro Anami, Tsuyoshi Noguchi, Kazuhiro Yoshida, Wataru Yasui  CANCER RESEARCH  72-  2012/04  [Not refereed][Not invited]
  
• THE SEARCH FOR SECRETED PROTEIN IN PROSTATE CANCER BY THE ESCHERICHIA COLI AMPICILLIN SECRETION TRAP: EXPRESSION OF NBL1 IS HIGHLY RESTRICTED IN PROSTATE AND RELATED IN PROGRESSION

  Tetsutaro Hayashi, Shinya Ohara, Jun Teishima, Kazuhiro Sentani, Naohide Oue, Naoya Sakamoto, Wataru Yasui, Akio Matsubara  JOURNAL OF UROLOGY  187-  (4)  E200  -E200  2012/04  [Not refereed][Not invited]
  
• 確定診断困難な多発小腸潰瘍の1例

  森尾 純子, 荒木 昭博, 岡田 英理子, 鈴木 伸治, 土屋 輝一郎, 藤井 俊光, 長沼 誠, 長堀 正和, 江頭 徹哉, 齊藤 詠子, 福島 啓太, 河合 富貴子, 藤木 純子, 櫻井 幸, 根本 泰, 中川 美奈, 岡本 隆一, 東 正新, 柿沼 晴, 永石 宇司, 中村 哲也, 坂本 直哉, 渡辺 守, 河内 洋, 江石 義信  栄養-評価と治療  29-  (1)  76  -77  2012/02
• Medial Regeneration Using a Biodegradable Felt as a Scaffold Preserves Integrity and Compliance of a Canine Dissected Aorta

  Mitsuru Sato, Osamu Adachi, Masatoshi Akiyama, Kiichiro Kumagai, Naotaka Motoyoshi, Shunsuke Kawamoto, Naoya Sakamoto, Masaaki Sato, Yasuhiko Tabata, Yoshikatsu Saiki  CIRCULATION  124-  (21)  2011/11  [Not refereed][Not invited]
  
• IL-6-MEDIATED INTERSUBGENOTYPIC VARIATION OF INTERFERON SENSITIVITY IN HEPATITIS C VIRUS GENOTYPE 2A/2B CHIMERIC CLONES

  Goki Suda, Naoya Sakamoto, Yasuhiro Itsui, Mina Nakagawa, Yusuke Funaoka, Sayuri Nitta, Takako Watanabe, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe  HEPATOLOGY  54-  1318A  -1318A  2011/10  [Not refereed][Not invited]
  
• LOSS OF WNT5A PROMOTES BILIARY DIFFERENTIATION OF MURINE HEPATIC STEM/PROGENITOR CELLS

  Kei Kiyohashi, Sei Kakinuma, Akihide Kamiya, Naoya Sakamoto, Hiromitsu Nakauchi, Mamoru Watanabe  HEPATOLOGY  54-  447A  -447A  2011/10  [Not refereed][Not invited]
  
• PREDICTION MODEL OF RIBAVIRIN-INDUCED ANEMIA INCORPORATING ITPA GENOTYPE COULD IDENTIFY CHRONIC HEPATITIS C PATIENTS AT HIGH RISK OF RELAPSE AMONG VIROLOGICAL RESPONDERS TO PEGYLATED-INTERFERON AND RIBAVIRIN

  Masayuki Kurosaki, Jun Itakura, Yutaka Yasui, Kaoru Tsuchiya, Hiroyuki Nakanishi, Yuka Takahashi, Yasuhiro Asahina, Yasuhito Tanaka, Masashi Mizokami, Naoya Sakamoto, Nobuyuki Enomoto, Namiki Izumi  HEPATOLOGY  54-  823A  -823A  2011/10  [Not refereed][Not invited]
  
• ANTIVIRAL EFFECT OF A NOVEL INTERFERON-INDUCIBLE PROTEIN, IFI-27, AGAINST HEPATITIS C VIRUS REPLICATION

  Yasuhiro Itsui, Naoya Sakamoto, Gouki Suda, Mina Nakagawa, Sei Kakinuma, Seishin Azuma, Tsunehito Yauchi, Mamoru Watanabe  HEPATOLOGY  54-  1338A  -1338A  2011/10  [Not refereed][Not invited]
  
• ITPA GENE VARIANT PROTECTS AGAINST TREATMENT-INDUCED ANEMIA AND IMPROVES VIRAL CLEARANCE BY PEGYLATED INTERFERON-ALFA AND RIBAVIRIN THERAPY IN CHRONIC HEPATITIS C PATIENTS

  Naoya Sakamoto, Yasuhito Tanaka, Mina Nakagawa, Hiroshi Yatsuhashi, Shuhei Nishiguchi, Nobuyuki Enomoto, Seishin Azuma, Yuki Nishimura-Sakurai, Sei Kakinuma, Nao Nishida, Katsushi Tokunaga, Masashi Mizokami, Mamoru Watanabe  HEPATOLOGY  54-  841A  -842A  2011/10  [Not refereed][Not invited]
  
• A HIGH-CONTENT SCREENING ASSAY USING INFECTIOUS FLUORESCENCE-TAGGED HEPATITIS C VIRUS REVEALS CANDIDATES FOR SMALL MOLECULE INHIBITORS OF VIRAL ENTRY

  Akiko Kusano-Kitazume, Naoya Sakamoto, Yukiko Okuno, Machi Yamamoto, Yuko Sekine-Osajima, Mina Nakagawa, Sei Kakinuma, Kei Kiyohashi, Sayuri Nitta, Miyako Murakawa, Masatoshi Hagiwara, Mamoru Watanabe  HEPATOLOGY  54-  549A  -549A  2011/10  [Not refereed][Not invited]
  
• MUTATIONS IN THE INTERFERON SENSITIVITY DETERMINING REGION OF HCV, AGE AND TOTAL RIBAVIRIN DOSE IS AN INDEPENDENT PREDICTOR OF RELAPSE AMONG EARLY VIROLOGICAL RESPONDERS TO PEGINTERFERON PLUS RIBAVIRIN THERAPY

  Masayuki Kurosaki, Naoya Sakamoto, Kentarou Matsuura, Sei Kakinuma, Mina Nakagawa, Yasuhiro Asahina, Nobuyuki Enomoto, Namiki Izumi  HEPATOLOGY  54-  830A  -831A  2011/10  [Not refereed][Not invited]
  
• IL28B AND ITPA GENE VARIANTS CORRELATE WITH TREATMENT EFFICACY IN PEGYLATED-INTERFERON PLUS RIBAVIRIN THERAPY FOR CHRONIC HEPATITIS C

  Kentaro Matsuura, Yasuhito Tanaka, Nao Nishida, Masaya Sugiyama, Tsunamasa Watanabe, Fuminaka Sugauchi, Masayuki Kurosaki, Namiki Izumi, Naoya Sakamoto, Nobuyuki Enomoto, Hiroshi Yatsuhashi, Shuhei Nishiguchi, Keisuke Hino, Shuichi Kaneko, Shunsuke Nojiri, Takashi Joh, Katsushi Tokunaga, Masashi Mizokami  HEPATOLOGY  54-  830A  -830A  2011/10  [Not refereed][Not invited]
  
• MMP-2 AND MMP-14 DERIVED FROM DONOR CELLS ENHANCE THERAPEUTIC EFFICACY OF LIVER CELL TRANSPLANTATION IN MICE

  Sei Kakinuma, Akihide Kamiya, Naoya Sakamoto, Hiromitsu Nakauchi, Mamoru Watanabe  HEPATOLOGY  54-  683A  -683A  2011/10  [Not refereed][Not invited]
  
• HCVコア70/91変異株培養系を用いたIFN抵抗性の解析

  船岡祐介, 坂本直哉, 須田剛生, 中川美奈, 柿沼晴, 新田沙由梨, 北詰晶子, 幾世橋佳, 村川美也子, 井津井康浩, 東正新, 渡辺守  肝臓  52-  (Supplement 2)  A586  2011/09/10  [Not refereed][Not invited]
  
• Genotype1b感染培養系株を用いたCore70/91,NS5A変異株の感染動態の解析

  船岡祐介, 須田剛生, 坂本直哉, 中川美奈, 柿沼晴, 渡辺貴子, 新田沙由梨, 北詰晶子, 幾世橋佳, 村川美也子, 東正新, 槇昇, 森健一, 田中榮司, 渡辺守  肝臓  52-  (Supplement 1)  A233  2011/04/25  [Not refereed][Not invited]
  
• HCVコア70/91変異株培養系を用いた感染動態・インターフェロン感受性の解析

  船岡祐介, 坂本直哉, 中川美奈, 柿沼晴, 須田剛生, 渡辺貴子, 新田沙由梨, 北詰晶子, 幾世橋佳, 村川美也子, 東正新, 渡辺守  肝臓  52-  (Supplement 1)  A231  2011/04/25  [Not refereed][Not invited]
  
• Genotype2b/JFH1キメラウイルス長期培養系を用いたIFN抵抗性株の解析

  須田剛生, 坂本直哉, 中川美奈, 井津井康浩, 幾世橋桂, 新田沙由梨, 北詰晶子, 柿沼晴, 東正新, 今村道雄, 茶山一彰, 渡辺守  肝臓  52-  (Supplement 1)  A144  2011/04/25  [Not refereed][Not invited]
  
• IDENTIFICATION OF TRANSMEMBRANE PROTEIN IN PROSTATE CANCER BY THE ESCHERICHIA COLI AMPICILLIN SECRETION TRAP: EXPRESSION OF CDON IS INVOLVED IN TUMOR CELL GROWTH AND INVASION

  Tetsutaro Hayashi, Shinya Ohara, Jun Teishima, Koichi Shoji, Katsuhiro Anami, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Akio Matsubara  JOURNAL OF UROLOGY  185-  (4)  E114  -E114  2011/04  [Not refereed][Not invited]
  
• Transcriptional regulation of REG4, a novel diagnostic marker of gastrointestinal cancer, by CDX2

  Yutaka Naito, Naohide Oue, Kazuhiro Sentani, Naoya Sakamoto, Katsuhiro Anami, Tetsutaro Hayashi, Naohiro Uraoka, Htoo Zarni Oo, Yuta Wakamatsu, Wataru Yasui  CANCER RESEARCH  71-  2011/04  [Not refereed][Not invited]
  
• DSC2 IS A NEW IMMUNOHISTOCHEMICAL MARKER INDICATIVE OF SQUAMOUS CELL CARCINOMA COMPONENT IN URINARY BLADDER CANCER AND A VALUABLE PROGNOSTIC FACTOR

  Tetsutaro Hayashi, Shinya Ohara, Jun Teishima, Koichi Shoji, Katsuhiro Anami, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Akio Matsubara  JOURNAL OF UROLOGY  185-  (4)  E498  -E499  2011/04  [Not refereed][Not invited]
  
• THE ITPA GENOTYPE CORRELATES WITH HEMOLYTIC ANEMIA AND OUTCOME AFTER TREATMENT WITH PEGYLATED-INTERFERON AND RIBAVIRIN IN GENOTYPE 1B CHRONIC HEPATITIS C

  M. Kurosaki, K. Tanaka, Y. Suzuki, Y. Hoshioka, N. Tamaki, T. Kato, Y. Yasui, T. Hosokawa, K. Ueda, K. Tsuchiya, T. Kuzuya, H. Nakanishi, J. Itakura, Y. Takahashi, Y. Asahina, M. Mizokami, Y. Tanaka, N. Sakamoto, N. Enomoto, N. Izumi  JOURNAL OF HEPATOLOGY  54-  S179  -S179  2011/03  [Not refereed][Not invited]
  
• ITPA GENE VARIANT PROTECTS AGAINST TREATMENT-INDUCED ANEMIA AND IMPROVES VIRAL CLEARANCE BY PEGYLATED INTERFERON-ALFA AND RIBAVIRIN THERAPY IN CHRONIC HEPATITIS C PATIENTS

  N. Sakamoto, Y. Tanaka, M. Nakagawa, H. Yatsuhashi, S. Nishiguchi, N. Enomoto, S. Azuma, Y. Nishimura-Sakurai, S. Kakinuma, N. Nishida, K. Tokunaga, M. Mizokami, M. Watanabe  JOURNAL OF HEPATOLOGY  54-  S191  -S192  2011/03  [Not refereed][Not invited]
  
• Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection with pegylated-interferon-alpha 2b plus ribavirin (vol 16, pg 1081, 2011)

  Mayumi Ueyama, Mina Nakagawa, Naoya Sakamoto, Izumi Onozuka, Yusuke Funaoka, Takako Watanabe, Sayuri Nitta, Kei Kiyohashi, Akiko Kitazume, Miyako Murakawa, Yuki Nishimura-Sakurai, Yuko Sekine-Osajima, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Mamoru Watanabe  ANTIVIRAL THERAPY  16-  (7)  1137  -1138  2011  [Not refereed][Not invited]
  
• PREDICTION OF RESPONSE TO PEGYLATED-INTERFERON FOR CHRONIC HEPATITIS C: IMPACT OF SNPS NEAR THE IL28B GENE AND MUTATIONS IN THE ISDR OF HCV REVEALED BY DATA MINING ANALYSIS

  Masayuki Kurosaki, Yasuhito Tanaka, Nao Nishida, Naoya Sakamoto, Nobuyuki Enomoto, Masao Honda, Kentaro Matsuura, Yasuhiro Asahina, Katsushi Tokunaga, Namiki Izumi, Masashi Mizokami  HEPATOLOGY  52-  (4)  774A  -774A  2010/10  [Not refereed][Not invited]
  
• VIRAL MUTATIONS THAT PREDICT TREATMENT FAILURE AND LIVER CANCER CONTROL EXPRESSION OF THE NEWLY-DISCOVERED HCV MINICORE PROTEINS

  Francis J. Eng, Yusuke Funaoka, Martina Kopp, Maria Teresa Catanese, Suresh M. Desai, Mamoru Watanabe, Naoya Sakamoto, Charles M. Rice, Andrea D. Branch  HEPATOLOGY  52-  (4)  817A  -817A  2010/10  [Not refereed][Not invited]
  
• IL-28B SNPS AND HCV GENETIC PROFILES, NS5A-ISDR AND CORE MUTATIONS ARE SIGNIFICANT PREDICTORS OF PEG-INTERFERON PLUS RIBAVIRIN TREATMENT OUTCOMES

  Naoya Sakamoto, Mina Nakagawa, Sei Kakinuma, Yasuhito Tanaka, Masashi Mizokami, Mamoru Watanabe  HEPATOLOGY  52-  (4)  786A  -786A  2010/10  [Not refereed][Not invited]
  
• ITPA GENE VARIANTS PROTECT AGAINST ANEMIA INDUCED BY PEGYLATED INTERFERON-ALFA AND RIBAVIRIN THERAPY FOR JAPANESE PATIENTS WITH CHRONIC HEPATITIS C

  Yasuhito Tanaka, Naoya Sakamoto, Nobuyuki Enomoto, Shuhei Nishiguchi, Hiroshi Yatsuhashi, Masayuki Kurosaki, Kentaro Matsuura, Fuat Kurbanov, Kiyoaki Ito, Namiki Izumi, Katsushi Tokunaga, Masashi Mizokami  HEPATOLOGY  52-  (4)  768A  -768A  2010/10  [Not refereed][Not invited]
  
• ANTIVIRAL DIRECT EFFECTS OF INTERFERON-INDUCIBLE PROTEINS ON HEPATITIS C VIRUS

  Yasuhiro Itsui, Naoya Sakamoto, Mina Nakagawa, Yuko Sekine-Osajima, Yuki Nishimura-Sakurai, Seishin Azuma, Sei Kakinuma, Tsunehito Yauchi, Mamoru Watanabe  HEPATOLOGY  52-  (4)  821A  -821A  2010/10  [Not refereed][Not invited]
  
• C型慢性肝炎のインターフェロン治療効果とIL28B遺伝子多型の解析

  中川美奈, 坂本直哉, 筬島裕子, 植山真由美, 北詰晶子, 新田沙由梨, 幾世橋佳, 船岡祐介, 渡辺貴子, 小野塚泉, 三島果子, 山本満千, 唐鎌優子, 須田剛生, 櫻井幸, 井津井康浩, 柿沼晴, 田中靖人, 溝上雅史, 渡辺守  肝臓  51-  (Supplement 2)  A539  2010/09/10  [Not refereed][Not invited]
  
• HCVコア70/91変異株培養系を用いた感染動態・インターフェロン感受性の解析

  船岡祐介, 坂本直哉, 須田剛生, 中川美奈, 幾世橋佳, 新田沙由梨, 北詰晶子, 柿沼晴, 東正新, 渡辺守  肝臓  51-  (Supplement 2)  A533  2010/09/10  [Not refereed][Not invited]
  
• 蛍光タグ付加HCV培養系を用いたウイルスライフサイクルの解析

  山本 満千, 坂本 直哉, 中川 美奈, 柿沼 晴, 東 正新, 加藤 孝宣, 脇田 隆字, 渡辺 守  肝臓  51-  (Suppl.2)  A530  -A530  2010/09  [Not refereed][Not invited]
  
• HCVコア変異株培養系を用いたinterferon抵抗性の分子機構の解析

  船岡祐介, 坂本直哉, 須田剛生, 中川美奈, 井津井康浩, 三島果子, 幾世橋佳, 新田沙由梨, 北詰晶子, 柿沼晴, 東正新, 渡辺守  肝臓  51-  (Supplement 1)  A245  2010/04/30  [Not refereed][Not invited]
  
• Genotype 2b急性肝炎由来HCV感染クローンを用いたInterferon抵抗性発現機構の解析

  須田剛生, 今村道雄, 坂本直哉, 中川美奈, 三島果子, 船岡祐介, 井津井康浩, 東正新, 柿沼晴, 茶山一彰, 渡辺守  肝臓  51-  (Supplement 1)  A244  2010/04/30  [Not refereed][Not invited]
  
• C型慢性肝炎のインターフェロン治療効果とIL28B遺伝子多型の解析

  中川美奈, 坂本直哉, 筬島裕子, 植山真由美, 北詰晶子, 新田沙由梨, 幾世橋佳, 船岡祐介, 渡辺貴子, 小野塚泉, 三島果子, 山本満千, 唐鎌優子, 須田剛生, 櫻井幸, 藤田めぐみ, 井津井康浩, 東正新, 柿沼晴, 田中靖人, 溝上雅史, 渡辺守  肝臓  51-  (Supplement 1)  A228  2010/04/30  [Not refereed][Not invited]
  
• C型慢性肝炎のPEGインターフェロン治療効果と治療後発癌に関する検討

  植山真由美, 中川美奈, 北詰晶子, 新田沙由梨, 幾世橋佳, 船岡祐介, 渡辺貴子, 小野塚泉, 三島果子, 山本満千, 唐鎌優子, 須田剛生, 櫻井幸, 藤田めぐみ, 筬島裕子, 井津井康浩, 東正新, 柿沼晴, 坂本直哉, 渡辺守  肝臓  51-  (Supplement 1)  A242  2010/04/30  [Not refereed][Not invited]
  
• Serial analysis of gene expression (SAGE) of esophageal squamous cell carcinoma: ADAMTS-16 is up-regulated in esophageal squamous carcinoma

  Naoya Sakamoto, Naohide Oue, Tsuyoshi Noguchi, Kazuhiro Sentani, Katsuhiro Anami, Yuichi Sanada, Kazuhiro Yoshida, Wataru Yasui  CANCER RESEARCH  70-  2010/04  [Not refereed][Not invited]
  
• Desmocollin 2 (DSC2), identified by CAST method, is associated with intestinal phenotype of gastric cancer

  Katsuhiro Anami, Naohide Oue, Naoya Sakamoto, Tetsutaro Hayashi, Shinya Ohara, Kazuhiro Sentani, Tsuyoshi Noguchi, Wataru Yasui  CANCER RESEARCH  70-  2010/04  [Not refereed][Not invited]
  
• Desmocollin 2 (DSC2), identified by CAST method, is associated with intestinal phenotype of gastric cancer

  Katsuhiro Anami, Naohide Oue, Naoya Sakamoto, Tetsutaro Hayashi, Shinya Ohara, Kazuhiro Sentani, Tsuyoshi Noguchi, Wataru Yasui  CANCER RESEARCH  70-  2010/04  [Not refereed][Not invited]
  
• 蛍光タグ付加HCV培養系を用いたウイルスライフサイクルの解析

  山本 満千, 坂本 直哉, 中川 美奈, 柿沼 晴, 東 正新, 加藤 孝宣, 脇田 隆字, 渡辺 守  肝臓  51-  (Suppl.1)  A248  -A248  2010/04  [Not refereed][Not invited]
  
• RFA治療におけるreal‐time3D超音波の有用性

  東正新, 坂本直哉, 櫻井幸, 北詰晶子, 幾世橋佳, 新田沙百梨, 船岡祐介, 唐鎌優子, 三島果子, 山本満千, 植山真由美, 須田剛生, 藤田めぐみ, 渡辺貴子, 筬島裕子, 中川美奈, 渡辺守  日本消化器病学会雑誌  107-  A230  2010/03/15  [Not refereed][Not invited]
  
• GENOME-WIDE ASSOCIATION STUDY IDENTIFIES IL28B ASSOCIATED WITH RESPONSE TO PEGYLATED INTERFERON-ALFA AND RIBAVIRIN THERAPY FOR JAPANESE PATIENTS WITH CHRONIC HEPATITIS C

  Y. Tanaka, N. Nishida, M. Sugiyama, M. Kurosaki, K. Matsuura, N. Sakamoto, M. Honda, F. Sugauchi, N. Izumi, K. Tokunaga, M. Mizokami  JOURNAL OF HEPATOLOGY  52-  S455  -S456  2010  [Not refereed][Not invited]
  
• GENETIC POLYMORPHISM IN IL28B PREDICTS NULL VIROLOGICAL RESPONSE TO PEGYLATED-INTERFERON PLUS RIBAVIRIN THERAPY FOR CHRONIC HEPATITIS C

  M. Kurosaki, Y. Tanaka, N. Nishida, M. Sugiyama, K. Matsuura, Y. Asahina, F. Sugauchi, N. Sakamoto, M. Nakagawa, M. Watanabe, A. Sakai, M. Honda, S. Kaneko, K. Ito, N. Masaki, K. Tokunaga, N. Izumi, M. Mizokami  JOURNAL OF HEPATOLOGY  52-  S451  -S452  2010  [Not refereed][Not invited]
  
• PREDICTIVE MODEL OF RESPONSE TO PEGINTERFERON IN CHRONIC HEPATITIS C: IMPACT OF MUTATIONS IN ISDR AND CORE REGION REVEALED BY CLASSIFICATION AND REGRESSION TREE ANALYSIS

  M. Kurosaki, N. Sakamoto, M. Iwasaki, M. Sakamoto, Y. Suzuki, N. Hiramatsu, F. Sugauchi, A. Tamori, N. Izumi  JOURNAL OF HEPATOLOGY  52-  S113  -S113  2010  [Not refereed][Not invited]
  
• IN-VITRO AND IN-VIVO CHARACTERIZATION OF A NEW GENOTYPE 2B HCV CLONE AND 2B/JFH1 INTERGENOTYPIC CHIMERA AND ANALYSES OF THE FACTOR THAT REGULATE INTERFERON SENSITIVITY

  Gouki Suda, Naoya Sakamoto, Yasuhiro Itsui, Mina Nakagawa, Megumi Tasaka-Fujita, Yuki Nishimura-Sakurai, Kako Mishima, Yuko Onuki, Machi Yamamoto, Seishin Azuma, Sei Kakinuma, Michio Imamura, Kazuaki Chayama, Mamoru Watanabe  HEPATOLOGY  50-  (4)  952A  -953A  2009/10  [Not refereed][Not invited]
  
• IN-VITRO REPLICATION AND INTERFERON SENSITIVITY OF CORE AA 70 AND 91 MUTANT HCV CELL CULTURE

  Yusuke Funaoka, Naoya Sakamoto, Gouki Suda, Yasuhiro Itsui, Mina Nakagawa, Kako Mishima, Yuko Onuki, Machi Yamamoto, Seishin Azumo, Sei Kakinuma, Mamoru Watanabe  HEPATOLOGY  50-  (4)  953A  -953A  2009/10  [Not refereed][Not invited]
  
• 細胞障害性HCV‐JFH1subcloneの単離と機能解析

  三島果子, 坂本直哉, 筬島裕子, 中川美奈, 藤田めぐみ, 櫻井幸, 須田剛生, 唐鎌優子, 山本満千, 渡辺貴子, 植山真由美, 船岡祐介, 幾世橋佳, 新田沙由梨, 北詰晶子, 井津井康浩, 柿沼晴, 陳正新, 脇田隆字, 渡辺守  肝臓  50-  (Supplement 2)  A514  2009/09/10  [Not refereed][Not invited]
  
• Genotype2のC型慢性肝炎に対する最善の治療法の検討

  渡辺貴子, 中川美奈, 北詰晶子, 植山真由美, 船岡祐介, 唐鎌優子, 山本満千, 三島果子, 須田剛生, 藤田めぐみ, 櫻井幸, 筬島裕子, 井津井康浩, 柿沼晴, 陳正新, 坂本直哉, 渡辺守  肝臓  50-  (Supplement 2)  A526  2009/09/10  [Not refereed][Not invited]
  
• Genotype2b急性肝炎由来HCVクローンを用いたウイルス増殖,薬剤感受性の検討

  須田剛生, 坂本直哉, 中川美奈, 田坂めぐみ, 櫻井幸, 小貫優子, 山本満千, 三島果子, 渡辺貴子, 植山真由美, 船岡祐介, 井津井康浩, 陳正新, 今村道雄, 茶山一彰, 渡辺守  肝臓  50-  (Supplement 2)  A513  2009/09/10  [Not refereed][Not invited]
  
• 高齢者C型慢性肝炎に対する治療法の検討

  北詰晶子, 中川美奈, 幾世橋佳, 新田沙由梨, 植山真由美, 船岡祐介, 渡辺貴子, 唐鎌優子, 須田剛生, 三島果子, 山本満千, 櫻井幸, 藤田めぐみ, 筬島裕子, 井津井康浩, 柿沼晴, 陳正新, 坂本直哉, 渡辺守  肝臓  50-  (Supplement 2)  A525  2009/09/10  [Not refereed][Not invited]
  
• Induction of intestinal phenotype in gastric cancer by EGFR signaling

  Naoya Sakamoto, Naohide Oue, Kazuhiro Sentani, Reiko Ito, Wataru Yasui  CANCER RESEARCH  69-  2009/05  [Not refereed][Not invited]
  
• Long-Lived Colitogenic CD4(+) Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis

  Yasuhiro Nemoto, Kaori Kameyama, Takanori Kanai, Tamako Shinohara, Naoya Sakamoto, Teruji Totsuka, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Satoshi Matsumoto, Mamoru Watanabe  GASTROENTEROLOGY  136-  (5)  A240  -A240  2009/05  [Not refereed][Not invited]
  
• Olfactomedin 4 in combination with Reg IV have utility in the early detection of gastric cancer

  Naohide Oue, Kazuhiro Sentani, Naoya Sakamoto, Tsuyoshi Noguchi, Reiko Ito, Wataru Yasui  CANCER RESEARCH  69-  2009/05  [Not refereed][Not invited]
  
• IL-2 Is Essential for the Persistence of Colitis in Addition to IL-7-Dependent Maintenance of Colitogenic CD4(+) Memory T Cells

  Kaori Kameyama, Yasuhiro Nemoto, Takanori Kanai, Tamako Shinohara, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Teruji Totsuka, Mamoru Watanabe  GASTROENTEROLOGY  136-  (5)  A256  -A256  2009/05  [Not refereed][Not invited]
  
• Genotype2b急性肝炎由来HCVクローンの構築と増殖,粒子形成能の解析

  須田剛生, 坂本直哉, 中川美奈, 田坂めぐみ, 櫻井幸, 小貫優子, 山本満千, 三島果子, 渡辺貴子, 植山真由美, 船岡祐介, 井津井康浩, 陳正新, 今村道雄, 茶山一彰, 渡辺守  肝臓  50-  (Supplement 1)  A66  2009/04/30  [Not refereed][Not invited]
  
• Prospects for future therapy of HCV infection

  Naoya Sakamoto, George Y. Wu  Future Virology  4-  (5)  453  -462  2009  [Not refereed][Not invited]
   

  Worldwide, HCV infection is a major cause of chronic liver disease and hepatocellular carcinoma and is often refractory to current antiviral treatments. The most effective therapy, pegylated interferon plus ribavirin, unfortunately eliminates virus only in approximately half of patients treated and is frequently poorly tolerated. The recent development of in vitro and in vivo HCV infection and replication models has resulted in breakthroughs in basic research toward the development of new antiviral agents. Currently, many therapeutic agents with different mechanisms of action are under development, and several are in late-phase clinical trials. Some of these drugs have shown promise when used in combination with the standard peginterferon and ribavirin, and others could constitute tablet-based combination therapies without standard therapy. This article reviews the current status of drug development, ongoing clinical trials and future perspectives in the field of HCV therapeutics. © 2009 Future Medicine Ltd.
• ESTABLISHMENT AND GENETIC ANALYSES OF CYTOPATHOGENIC HCV-JFH1 MUTANTS BY PLAQUE-FORMING ASSAY

  Kako Mishima, Naoya Sakamoto, Yuko Sekine-Osajima, Mina Nakagawa, Yasuhiro Itsui, Megumi Tasaka, Yuki Nishimura-Sakurai, Gouki Suda, Yuko Onuki, Machi Yamamoto, Takaji Wakita, Mamoru Watanabe  HEPATOLOGY  48-  (4)  332A  -332A  2008/10  [Not refereed][Not invited]
  
• PRETREATMENT ASSESSMENT OF PEG-INTERFERON PLUS RIBAVIRIN ANTI-HCV THERAPY USING VIRAL GENETIC PROFILES, NS5A-ISDR AND CORE MUTATIONS

  Naoya Sakamoto, Mina Nakagawa, Cheng-Hsin Chen, Yasuhiro Itsui, Megumi Tasaka, Nobuyuki Enomoto, Mamoru Watanabe  HEPATOLOGY  48-  (4)  864A  -864A  2008/10  [Not refereed][Not invited]
  
• 細胞を用いた治療の臨床応用をめざして ドナー肝由来活性化リンパ球移入による肝移植後C型肝炎ウイルス増殖抑制

  大平 真裕, 大段 秀樹, 石山 宏平, 志々田 将幸, 伊禮 俊充, 番匠谷 将孝, 梶谷 桂子, 田代 裕尊, 板本 敏行, 坂本 直哉, 平賀 伸彦, 今村 道雄, 茶山 一彰, 浅原 利正  日本外科学会雑誌  109-  (臨増2)  139  -139  2008/04  [Not refereed][Not invited]
  
• 当科における高齢肝細胞癌患者に対するラジオ波熱凝固療法の治療成績

  陳正新, 坂本直哉, 井津井康浩, 小貫優子, 三島果子, 山本満千, 櫻井幸, 須田剛生, 田坂めぐみ, 筬島裕子, 中川美奈, 渡辺守  日本消化器病学会雑誌  105-  A216  2008/03/20  [Not refereed][Not invited]
  
• HCV nonstructural protein 4B suppresses RIG-I/Cardif induced interferon responses

  Megumi Tasaka, Naoya Sakamoto, Yoshie Itakura, Mina Nakagawa, Yasuhiro Itsui, Yuko Sekine-Osajima, Yuki Nishimura-Sakurai, Cheng-Hsin Chen, Mamoru Watanabe  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  22-  A224  -A224  2007/10  [Not refereed][Not invited]
  
• Clinical and virological factors that predict outcomes of interferon plus ribavirin combination therapy for HCV infection

  Naoya Sakamoto, Mina Nakagawa, Mamoru Watanabe  JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY  22-  A113  -A113  2007/10  [Not refereed][Not invited]
  
• Plaque-forming assays for hepatitis C virus and isolation of HCV-JFH1 mutants with enhanced cytopathogenicity and replication capacity

  Naoya Sakamoto, Yuko Sekine-Osojima, Koko Mishima, Mina Nakagawa, Megumi Tasaka, Yuki Nishimura-Sakurai, Yosuhiro Itsui, Takaji Wakita, Mamoru Watanabe  HEPATOLOGY  46-  (4)  457A  -457A  2007/10  [Not refereed][Not invited]
  
• Identification of modulators of HCV replication using a high- throughput screen

  Lee F. Peng, Sun-Suk Kim, Wenyu Lin, Naoya Sakamoto, Noboyuki Kato, Masanori Ikeda, Stuart Schreiber, Richard T. Baines  HEPATOLOGY  46-  (4)  852A  -852A  2007/10  [Not refereed][Not invited]
  
• Inhibition of RIG-I/Cardif-induced interferon responses by N terminus of HCVNS4B protein

  Megumi Tasaka, Naoya Sakamoto, Yoshie Itakura, Mina Nakagawa, Yasuhiro Itsui, Yuko Sekine-Osajima, Yuki Nishimura-Sakurai, Cheng-Hsin Chen, Mamoru Watanabe  HEPATOLOGY  46-  (4)  694A  -694A  2007/10  [Not refereed][Not invited]
  
• 高齢者C型慢性肝炎に対するインターフェロン療法の安全性と有効性

  中川美奈, 坂本直哉, 陳正新, 井津井康浩, 筬島裕子, 田坂めぐみ, 櫻井幸, 小貫優子, 須田剛生, 渡辺秀樹, 榎本信幸, 渡辺守  肝臓  48-  (Supplement 1)  A83  2007/04/25  [Not refereed][Not invited]
  
• HCV nonstructural proteins responsible for impairing RIG-I/Cardif-induced interferon responses

  Megumi Tasaka, Naoya Sakamoto, Yoshie Itakura, Mina Nakagawa, Yasuhiro Itsui, Yuko Sekine-Osajima, Yuki Nishimura-Sakurai, -Hsin Chen Chen, Mamoru Watanabe  HEPATOLOGY  44-  (4)  343A  -343A  2006/10  [Not refereed][Not invited]
  
• Comprehensive analysis of HCV-associated host genes and cell-cycle regulation using fluorescence-based HCV replicon system

  Yuki Sakurai, Naoya Sakamoto, Mina Nakagawa, Yuko Sekine-Osajima, Megumi Tasaka, Yasuhiro Itsui, Cheng-Hsin Chen, Mamoru Watanabe  HEPATOLOGY  44-  (4)  346A  -347A  2006/10  [Not refereed][Not invited]
  
• An efficient cell-based high-throughput method for screening small molecules to identify regulators of hepatitis C virus (HCV) replication

  Sun Suk Kim, Lee F. Peng, Wenyu Lin, Won Hyeok Choe, Kyung-Ah Kim, Naoya Sakamoto, Stuart L. Schreiber, Raymond T. Chung  HEPATOLOGY  44-  (4)  532A  -532A  2006/10  [Not refereed][Not invited]
  
• Two flavonoids extracts from a harb, glycyrrhizae radix, inhibit in-vitro hepatitis C virus replication

  Y Sekine, N Sakamoto, M Nakagawa, Y Itsui, M Tasaka, CH Chen, M Watanabe  HEPATOLOGY  42-  (4)  702A  -702A  2005/10  [Not refereed][Not invited]
  
• Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins

  N Sakamoto, M Nakagawa, Y Tanabe, Y Itsui, N Enomoto, M Watanabe  HEPATOLOGY  42-  (4)  703A  -703A  2005/10  [Not refereed][Not invited]
  
• Impaired intracellular double strand RNA-induced interferon responses by hepatitis C virus replication in various cell lines

  M Tasaka, N Sakamoto, Y Sekine, CH Chen, M Watanabe, Y Takeda, M Nakagawa, Y Itsui  HEPATOLOGY  42-  (4)  558A  -559A  2005/10  [Not refereed][Not invited]
  
• Enhancement of mitochondrial gene expression in the liver of primary biliary cirrhosis

  CH Chen, KN Nagayama, N Sakamoto, Y Sekine, Y Takeda, Y Itsui, T Koyama, M Nakagawa, Y Tanabe, S Kakinuma, M Watanabe  GASTROENTEROLOGY  128-  (4)  A772  -A772  2005/04  [Not refereed][Not invited]
  
• Differential activities of interferon-alpha subtypes against intracellular hepatitis C virus replication

  T Koyama, N Sakamoto, Y Tanabe, M Nakagawa, Y Itsui, Y Takeda, S Kakinuma, Y Sekine, Y Yanai, M Kunmoto, M Watanabe  GASTROENTEROLOGY  128-  (4)  A719  -A719  2005/04  [Not refereed][Not invited]
  
• Expressional screening of novel interferon-stimulated genes for antiviral activity against hepatitis C virus replication

  Y Itsui, N Sakamoto, Y Tanabe, M Nakagawa, T Koyama, N Kanazawa, S Kakinuma, Y Takeda, Y Sekine, CH Chen, M Watanabe  GASTROENTEROLOGY  128-  (4)  A712  -A712  2005/04  [Not refereed][Not invited]
  
• Analysis of interferon sensitivity for HCV replicons with different ISDR structures

  S Maekawa, N Sakamoto, N Enomoto, M Kurosaki, CH Chen, Y Tanabe, T Yamashiro, N Kanazawa, T Koyama, Y Itsui, M Watanabe  GASTROENTEROLOGY  126-  (4)  A687  -A687  2004/04  [Not refereed][Not invited]
  
• Specific inhibition of hepatitis C virus replication by cyclosporin A

  N Sakamoto, M Nakagawa, Y Tanabe, N Kanazawa, S Maekawa, T Koyama, Y Takeda, N Enomoto, M Watanabe  GASTROENTEROLOGY  126-  (4)  A764  -A764  2004/04  [Not refereed][Not invited]
  
• Mutations of hepatitis C virus NS5B region and the response to interferon plus ribavirin combination treatment

  K Hamano, N Sakamoto, N Enomoto, N Izumi, Y Asahina, M Kurosaki, E Ueda, Y Tanabe, S Maekawa, M Watanabe  GASTROENTEROLOGY  126-  (4)  A721  -A721  2004/04  [Not refereed][Not invited]
  
• Regulation of intracellular hepatitis C virus replication by interferon regulatory factor-1.

  N Kanazawa, M Kurosaki, N Sakamoto, N Enomoto, T Yamashiro, Y Tanabe, S Maekawa, M Nakagawa, CH Chen, M Watanabe  HEPATOLOGY  38-  (4)  455A  -455A  2003/10  [Not refereed][Not invited]
  
• Analysis of permissive cell lines for HCV replicon.

  CH Chen, N Enomoto, S Maekawa, Y Tanabe, N Kanazawa, M Nakagawa, T Yamashiro, N Sakamoto, M Kurosaki, M Watanabe  HEPATOLOGY  38-  (4)  472A  -472A  2003/10  [Not refereed][Not invited]
  
• Negative regulation of intracellular hepatitis C virus replication by interferon regulatory factor-3.

  T Yamashiro, M Kurosaki, N Sakamoto, N Enomoto, N Kanazawa, Y Tanabe, S Maekawa, M Nakagawa, CH Chen, M Watanabe  HEPATOLOGY  38-  (4)  363A  -363A  2003/10  [Not refereed][Not invited]
  
• Direct inhibition of intracellular hepatitis C virus replication by ribavirin and its synergistic action used in combination with interferon-alpha.

  Y Tanabe, N Sakamoto, N Enomoto, M Kurosaki, E Ueda, S Maekawa, T Yamashiro, M Nakagawa, CH Chen, N Kanazawa, M Watanabe  HEPATOLOGY  38-  (4)  637A  -637A  2003/10  [Not refereed][Not invited]
  
• Inhibition of intracellular hepatitis C virus replication by adenovirus delivery of vector-derived small interfering RNA.

  N Sakamoto, Y Tanabe, N Enomoto, S Maekawa, M Kurosaki, M Nakagawa, T Yamashiro, CH Chen, N Kanazawa, T Yokota, M Watanabe  HEPATOLOGY  38-  (4)  222A  -222A  2003/10  [Not refereed][Not invited]
  
• Introduction of NS5A mutations enables subgenomic HCV-replicon derived from chimpanzee-infectious HC-J4 isolate to replicate efficiently in Huh-7 cells.

  S Maekawa, N Enomoto, N Sakamoto, M Kurosaki, E Ueda, T Kohashi, H Watanabe, CH Chen, T Yamashiro, Y Tanabe, N Kanazawa, M Nakagawa, M Watanabe  HEPATOLOGY  38-  (4)  459A  -459A  2003/10  [Not refereed][Not invited]
  
• Establishment of a new hepatitis C virus-1b replicon

  S Maekawa, N Enomoto, N Sakamoto, M Watanabe  GASTROENTEROLOGY  122-  (4)  A678  -A678  2002/04  [Not refereed][Not invited]
  
• HCVNS5A protein inhibits apoptosis of Huh-7 cell induced by TNF-alpha

  Y Miyasaka, N Enomoto, M Kurosaki, N Sakamoto, M Watanabe  GASTROENTEROLOGY  122-  (4)  A679  -A679  2002/04  [Not refereed][Not invited]
  
• Selective elimination of IL-7 receptor(+) mucosal lymphocytes ameliorated established chronic colitis

  M Watanabe, M Yamazaki, T Kanai, E Okada, N Sakamoto, M Tanabe, T Takeuchi, T Yajima, T Hibi  GASTROENTEROLOGY  120-  (5)  A694  -A694  2001/04  [Not refereed][Not invited]
  
• Amino acid sequence of putative dsRNA-dependent protein kinase-eukaryotic initiation factor 2A phosphorylation homology domain of hepatitis C virus and interferon sensitivity.

  H Watanabe, K Nagayama, N Enomoto, M Kurosaki, Y Miyasaka, SH Yu, N Sakamoto, T Ikeda, N Izumi, C Sato  GASTROENTEROLOGY  118-  (4)  A939  -A939  2000/04  [Not refereed][Not invited]
  
• Repression of HCV-IRES-dependent protein translation by the activation of PKR with dsRNA.

  N Kanazawa, N Enomoto, M Kurosaki, N Sakamoto, N Izumi, C Sato  GASTROENTEROLOGY  118-  (4)  A938  -A938  2000/04  [Not refereed][Not invited]
  
• An intrahepatic mRNA expression profile of interferon-inducible antiviral genes in chronic hepatitis C: Relative importance of a dsRNA-dependent protein kinase system.

  SH Yu, K Nagayama, N Enomoto, HL Kurosaki, Y Miyasaka, N Sakamoto, C Sato  GASTROENTEROLOGY  118-  (4)  A938  -A938  2000/04  [Not refereed][Not invited]
  
• Overexpression of interferon Gamma-inducible protein 10 in the liver of autoimmune hepatitis.

  K Nagayama, N Enomoto, Y Miyasaka, M Kurosaki, CH Chen, H Takenawa, N Sakamoto, N Izumi, C Sato  GASTROENTEROLOGY  118-  (4)  A897  -A897  2000/04  [Not refereed][Not invited]
  
• Polymorphism analysis of the CD81 putative viral receptor in relation to various phases of hepatitis C virus infection.

  J Itakura, K Nagayama, N Enomoto, N Sakamoto, CH Chen, Y Miyasaka, SH Yu, M Kurosaki, J Tazawa, N Izumi, C Sato  GASTROENTEROLOGY  118-  (4)  A945  -A945  2000/04  [Not refereed][Not invited]
  
• Enhanced intracellular replication of hepatitis C virus genome in hepatoma cells by endogenous expression of the viral non-structural proteins.

  N Sakamoto, N Enomoto, M Kurosaki, F Marumo, GY Wu, C Sato  GASTROENTEROLOGY  116-  (4)  A1270  -A1270  1999/04  [Not refereed][Not invited]
  
• The nonstructural 5A protein of hepatitis C virus inhibits cellular responses to interferon in cultured cell lines.

  M Kurosaki, N Enomoto, N Sakamoto, S Maekawa, K Nagayama, Y Miyasaka, N Izumi, C Sato  HEPATOLOGY  28-  (4)  272A  -272A  1998/10  [Not refereed][Not invited]