研究者基本情報

• 博士（医学）, 北海道大学, 2019年03月

• https://researchmap.jp/m_ohara_hokkaido

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=202101004367760370
• https://orcid.org/0000-0002-4366-3184

• 40930649

• https://orcid.org/0000-0002-4366-3184

• 202101004367760370

• サルコペニア
• 肝線維化
• 肝硬変
• 肝炎対策

• ライフサイエンス, 消化器内科学

研究活動情報

• Tenofovir alafenamide prevents HBV reactivation in anticancer/immunosuppression: 24-month multicentre prospective study
  Goki Suda; Masatsugu Ohara; Masaru Baba; Yoshiya Yamamoto; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Hidetaka Hosono; Daisuke Yokoyama; Shoichi Kitano; Takatsugu Tanaka; Akimitsu Meno; Naohiro Yasuura; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Koji Ogawa; Osamu Maehara; Shunsuke Ohnishi; Takaaki Izumi; Ren Yamada; Takashi Meguro; Katsumi Terashita; Tomofumi Takagi; Jun Ito; Tomoe Kobayashi; Izumi Tsunematsu; Naoya Sakamoto
  Journal of Infection, 92, 4, 106715, 106715, 2026年04月, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVE: Our prior interim report remains the only prospective study evaluating tenofovir alafenamide (TAF) for HBV reactivation prevention, with prophylaxis assessed up to 12 months. Herein, we report the final 24-month follow-up results. METHODS: This multicentre prospective-study enrolled HBV carriers who received prophylactic TAF before antineoplastic or immunosuppressive therapy and patients with resolved HBV infection who developed reactivation and received TAF as reactivation-related hepatitis prophylaxis. We examined TAF effectiveness at 12 and 24 months. The primary endpoints were HBV reactivation and reactivation-related hepatitis. RESULTS: Of 191 enrolled patients, 150 and 127 were evaluable at 12 and 24 months, respectively. At 12 months, no HBV reactivation, HBV reactivation-related hepatitis, or therapy interruption occurred. Between months 12-24, four patients discontinued TAF. None of the remaining patients experienced HBV reactivation, HBV reactivation-related-hepatitis, or treatment interruption. Virologic relapse occurred in one of two patients with TAF discontinuation after anticancer/immunosuppressive therapy completion; TAF re-initiation enabled biochemical hepatitis prevention and viral suppression. Neither patient who switched to entecavir experienced reactivation. No patients on high-risk regimens developed reactivation, reactivation-related hepatitis, or treatment interruption. No patient discontinued therapy for TAF-related adverse events. CONCLUSIONS: Over 24 months, TAF demonstrated effectiveness in preventing HBV reactivation and reactivation-related hepatitis.
• Soluble Cluster of Differentiation 14 as a Prognostic Marker in Decompensated Cirrhosis With Water Retention
  Masato Nakai; Masatsugu Ohara; Daisuke Yokoyama; Shoichi Kitano; Takatsugu Tanaka; Naohiro Yasuura; Akimitsu Meno; Takashi Kitagataya; Takuya Sho; Goki Suda; Naoya Sakamoto
  Hepatology Research, 2026年04月
  研究論文（学術雑誌）
• Corticosteroid rescue of immune checkpoint inhibitor-induced hepatitis triggers HCV reactivation in HCV-related HCC.
  Goki Suda; Masatsugu Ohara; Masato Nakai; Takuya Sho; Naoya Sakamoto
  European journal of cancer (Oxford, England : 1990), 237, 116580, 116580, 2026年03月26日, ［国際誌］
  英語
• Effect of Skeletal Muscle Mass Loss on Outcomes of Patients With Intraductal Papillary Mucinous Neoplasm.
  Soichiro Oda; Kazumichi Kawakubo; Ryo Takagi; Katsuma Nakajima; Shoya Shiratori; Hiroki Yonemura; Shunichiro Nozawa; Ryo Sugiura; Masatsugu Ohara; Masaki Kuwatani; Naoya Sakamoto
  Pancreas, 2026年03月12日, ［国際誌］
  英語, 研究論文（学術雑誌）, OBJECTIVE: To investigate the association between skeletal muscle mass loss and long-term outcomes in patients with intraductal papillary mucinous neoplasm (IPMN). METHODS: This retrospective, single-center cohort study included 700 patients diagnosed with IPMN at Hokkaido University Hospital between April 2011 and April 2023. Skeletal muscle mass was assessed using the psoas muscle index (PMI) measured on a computed tomography scan at the initial visit. The primary outcome was the incidence of pancreatic cancer, and the secondary outcome was overall mortality. Cox proportional hazard models and competing risk analyses were employed to identify independent risk factors. RESULTS: During a median follow-up of 71 months, 27 patients developed pancreatic cancer with an annual incidence rate of 0.63% (95% CI: 0.55-1.86%). Patients with a low PMI had a significantly higher risk of pancreatic cancer than those with a high PMI (adjusted HR: 3.44, 95% CI: 1.62-7.32, P <0.01). Multivariate analysis identified a low PMI and a main pancreatic duct diameter ≥5 mm as independent risk factors for the development of pancreatic cancer. Among the 69 deaths, 61 were comorbidity-related and 8 were pancreatic cancer-related. Low PMI (adjusted HR: 2.57, 95% CI: 1.60-4.12, P <0.01) and a high age-adjusted Charlson Comorbidity Index (aCCI) (adjusted HR: 9.06, 95% CI: 4.63-17.72, P <0.01) were independently associated with all-cause mortality. Competing risk analysis revealed that skeletal muscle mass loss was significantly associated with the incidence of pancreatic cancer in patients with a low aCCI score but not in those with a high aCCI score. CONCLUSIONS: Skeletal muscle mass loss was an independent risk factor for all-cause mortality, and it might be associated with the risk factor for the incidence of pancreatic cancer, particularly IPMN-derived carcinoma in patients with IPMN. Patients with a low PMI and minimal comorbidities might be better to undergo long-term surveillance due to their increased risk of pancreatic cancer.
• Continuity of long-term follow-up in patients with chronic hepatitis C after sustained virologic response following direct-acting antiviral therapy: a nationwide real-world multicenter cohort study in Japan.
  Masatsugu Ohara; Ritsuzo Kozuka; Yoshihito Uchida; Chikara Iino; Ryo Sasaki; Hiroki Tojima; Kazuhito Kawata; Satoru Kakizaki; Yoshio Tokumoto; Mizuki Endo; Akira Asai; Jun Inoue; Kenji Nagata; Hirokazu Takahashi; Tetsuro Shimakami; Koji Ogawa; Masaru Enomoto; Tadashi Ikegami; Tatsuya Ide; Naoya Sakamoto; Masaaki Korenaga
  Journal of gastroenterology, 2026年01月27日, ［国内誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Long-term follow-up is essential after a sustained virologic response (SVR) to direct-acting antivirals (DAAs) in patients with chronic hepatitis C. However, real-world continuity of care and determinants of disengagement are poorly characterized at the national level. Here, we quantified the follow-up continuity within Japan's government-designated regional core centers and identified independent factors associated with transfer and self-discontinuation. METHODS: We conducted a retrospective multicenter cohort study of 3702 patients with chronic hepatitis C who achieved SVR at 16 regional core centers (2015-2018). Continuation was assessed using Kaplan-Meier analysis and competing-risk analysis, and Fine-Gray regression identified determinants of transfer and discontinuation. RESULTS: At 5 years, 56% of the patients were followed up, 24% were transferred, and 18% self-discontinued. Older age was significantly associated with transfer (subdistribution hazard ratio [sHR] 1.41, 95% CI 1.23-1.61), whereas hepatocellular carcinoma (HCC) and other malignancies favored continuous follow-up. Self-discontinuation was more frequent with hepatitis C virus (HCV) serotype 2 (sHR 1.36, 95% CI 1.18-1.57) and less common among patients with advanced disease or prior hospitalization. CONCLUSIONS: Within Japan's core-center network, long-term continuation after SVR is high but not universal. Follow-up was generally maintained for patients with severe comorbidities, while disengagement was more likely among those with lower perceived risk. Strengthening low-intensity, structured support for such patients may improve the continuity and equity of post-SVR care. These findings provide a foundation for optimizing post-SVR care pathways in national liver disease networks.
• Serum fibroblast growth factor 21 is a novel biomarker of cachexia in chronic liver disease.
  Takatsugu Tanaka; Goki Suda; Masatsugu Ohara; Osamu Maehara; Tomoka Yoda; Qingjie Fu; Zijian Yang; Naohiro Yasuura; Akimitsu Meno; Takashi Sasaki; Risako Kohya; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Shunsuke Ohnishi; Naoya Sakamoto
  Frontiers in nutrition, 13, 1730695, 1730695, 2026年, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Cachexia is associated with poor prognosis in chronic liver disease (CLD), yet robust predictors remain poorly defined. This study examined clinical factors and serum biomarkers associated with cachexia in patients with CLD. METHODS: We analyzed 356 of 526 patients with CLD who had complete cachexia assessment and available stored serum samples. In a discovery cohort (n = 240; Aug 2014-Jun 2023), serum fibroblast growth factor 21 (FGF21), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. Multivariable logistic regression and receiver operating characteristic analyses were used to identify independent predictors and optimal cutoff values. Findings were subsequently evaluated in an independent validation cohort (n = 116; Jul 2023-May 2025). RESULTS: Median age was 68 years (range 19-90), 65.8% of participants were male, and 24.6% had cachexia, which independently predicted worse overall survival (hazard ratio 1.64; 95% CI 1.03-2.62; p = 0.038). Patients with cachexia had higher serum FGF21 concentrations than those without cachexia (median, 292 vs. 177 pg./mL; p = 0.002), whereas IL-6 and TNF-α levels did not differ significantly between groups. FGF21 was the only biomarker independently associated with cachexia (odds ratio, 1.71; 95% CI, 1.10-2.66; p = 0.016). Advanced Child-Pugh class and platelet count were identified as additional independent clinical predictors. CONCLUSION: Serum FGF21 independently predicts cachexia in CLD and may facilitate earlier identification of at-risk patients, enabling timely intervention to improve clinical outcomes.
• Cachexia in Cirrhosis Is Characterized by Sex-Specific Loss of Muscle Mass and Adipose Tissue.
  Takao Miwa; Goki Suda; Ryosuke Tateishi; Masatsugu Ohara; Yasuhiro Hagiwara; Shinji Unome; Kazuya Okushin; Mina Nakagawa; Naoya Sakamoto; Masahito Shimizu
  Hepatology research : the official journal of the Japan Society of Hepatology, 2025年12月29日, ［国際誌］
  英語
• Simplified monitoring of sofosbuvir/velpatasvir in Japanese patients with chronic hepatitis C based on a retrospective analysis of a prospective multicenter cohort.
  Goki Suda; Masaru Baba; Yoshiya Yamamoto; Sonoe Yoshida; Tetsuhito Muranaka; Takashi Meguro; Katsumi Terashita; Jun Ito; Tomoe Kobayashi; Takaaki Izumi; Tomofumi Takagi; Shunichi Hosoda; Ren Yamada; Qingjie Fu; Zijian Yang; Daisuke Yokoyama; Takatsugu Tanaka; Akimitsu Meno; Naohiro Yasuura; Takashi Kitagataya; Masatsugu Ohara; Naoki Kawagishi; Masato Nakai; Takuya Sho; Koji Ogawa; Naoya Sakamoto
  Scientific reports, 15, 1, 42628, 42628, 2025年11月28日, ［国際誌］
  英語, 研究論文（学術雑誌）, Simplified ("minimal monitoring") pathways can expand access to direct-acting antivirals (DAAs) by reducing visit burden. In Japan, where hepatitis C virus (HCV) patients are among the oldest worldwide, whether DAA regimens can be delivered safely and effectively with fewer visits remains unclear, and real-world outcomes with sofosbuvir/velpatasvir are scarce. We evaluated effectiveness, safety, and visit frequency in a multicenter cohort. Sixty patients with HCV-infection, with or without compensated liver cirrhosis, received 12 weeks of sofosbuvir/velpatasvir with follow-up to sustained virologic response at 12 weeks post-treatment (SVR12). The visit number was set with no schedule and analyzed post hoc (≤ 3 vs. ≥4 visits). There were 1-8 outpatient visits (median 3). SVR12 was 96.7% by intention-to-treat (ITT; 58/60; 95% CI, 88.6-99.6) and 100% per protocol (57/57; 95% CI, 90.0-100.0). Cure rates were comparable (ITT 95.8-97.2% for ≤ 3 vs. ≥4 visits; p = 1.00; PP 100% in both). Sofosbuvir/velpatasvir was well-tolerated: adverse events were recorded in 10%, none grade ≥ 3, no treatment-related serious events, and no toxicity-related discontinuations. Two patients were lost to follow-up; one who discontinued treatment achieved SVR12. This is the first Japanese real-world evaluation of DAA under simplified monitoring and supports low-burden pathways with high efficacy and safety.
• Employment Status of Patients With Liver Disease: A Nationwide Questionnaire Survey in Japan.
  Yoshio Tokumoto; Yoichi Hiasa; Yoshihito Uchida; Takashi Oono; Atsushi Yukimoto; Takao Watanabe; Ryo Sasaki; Sachiko Tatsuki; Hironori Tanaka; Takako Inoue; Mika Horino; Akira Hirose; Tadashi Ikegami; Jun Inoue; Hiroshi Isoda; Hirokazu Takahashi; Yoshihisa Arao; Isao Hidaka; Hiroki Tojima; Satoru Kakizaki; Tetsuro Shimakami; Masayuki Tatemichi; Tatehiro Kagawa; Koji Ogawa; Masatsugu Ohara; Ritsuzo Kozuka; Masaru Enomoto; Mizuki Endo; Yuichiro Eguchi; Kenji Nagata; Masaaki Korenaga
  Hepatology research : the official journal of the Japan Society of Hepatology, 56, 2, 214, 222, 2025年10月04日, ［国際誌］
  英語, 研究論文（学術雑誌）, AIM: Patients with chronic liver disease often experience significant physical, psychological, and financial burdens. These burdens result from repeated long-term hospital visits or admissions caused by progression to decompensated cirrhosis or hepatocellular carcinoma. Patients with viral liver disease may fear discrimination or social prejudice. This study aimed to clarify the employment status of patients with liver disease in Japan and provide basic data to promote support for balancing treatment and work responsibilities. METHODS: A cross-sectional questionnaire survey on employment was conducted among patients attending 22 hospitals across Japan. RESULTS: Of the 4022 respondents, 2183 were analyzed, including 1694 (77.6%) participants with liver disease. Patients with liver disease were predominantly male and in their 60 s. Disclosure of health information to the workplace was significantly lower among patients with viral liver disease (80.8%) than among those without liver disease or with nonviral liver disease. The intention to continue working after diagnosis was significantly higher among patients with malignancies than among those without. However, this intention did not significantly differ between liver disease and non-liver disease groups. The awareness rate of the support system for balancing treatment and work program was 27.1%, with no significant difference observed between the liver disease and malignancy groups. Awareness was significantly higher in large workplaces, where full-time occupational health physicians are mandated. CONCLUSION: Workers with viral liver disease may hesitate to disclose their condition owing to fear of discrimination or prejudice. Therefore, raising awareness of support systems that protect all workers with illnesses, while considering stigma and discrimination, is essential.
• Long non-coding RNA PWRN4 associated with post-SVR hepatocellular carcinoma: a genome-wide association study.
  Goki Suda; Masaya Sugiyama; Hayato Hikita; Akira Nishio; Tomohide Tatsumi; Tetsuo Takehara; Miyako Murakawa; Mina Nakagawa; Yasuhiro Asahina; Masashi Mizokami; Tatsuhiko Kakisaka; Yuzuru Sakamoto; Akinobu Taketomi; Koji Miyanishi; Yoshiyuki Ueno; Hiroaki Haga; Shinya Maekawa; Nobuyuki Enomoto; Masayuki Kurosaki; Motoyuki Kohjima; Makoto Nakamuta; Yasuhito Tanaka; Yoshiya Yamamoto; Masaru Baba; Hisatoshi Hanamatsu; Jun-Ichi Furukawa; Masatsugu Ohara; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Takuya Sho; Koji Ogawa; Naoya Sakamoto
  Biomarker research, 13, 1, 113, 113, 2025年09月24日, ［国際誌］
  英語, A subset of patients still develops hepatocellular carcinoma (HCC) even after eradication of the hepatitis-C virus (HCV) by anti-HCV treatment. We conducted a genome-wide association study (GWAS) to identify host genetic factors associated with HCC development following HCV eradication in Japan. In this GWAS (n = 517), the discovery cohort included 118 patients without HCC and 67 who developed HCC following HCV eradication with interferon-based therapy. A genome-wide scan for HCC-associated variants was conducted. An independent cohort of 274 patients without HCC and 58 patients with post-eradication HCC was used for replication. The effects of candidate gene variants were assessed clinically and through in vitro cellular assays. The GWAS identified significant variants associated with HCC development following HCV eradication, including rs4778350, located near the long non-coding RNA Prader-Willi non-protein coding RNA 4 (PWRN4) on chromosome 15. In the combined analysis, rs4778350 remained significantly associated with HCC, showing a high odds ratio of 5.86 (95% CI, 3.63-9.44). The frequency of the A allele in rs4778350 differs across ethnic populations. Multivariate analysis revealed that female sex, high platelet count, and higher serum albumin levels were associated with reduced HCC risk, while fibrosis stage F4 and the AA genotype of rs4778350 were linked to increased risk. The AA genotype of rs4778350 enhanced PWRN4 expression, promoting cell proliferation, migration, and invasion. These findings suggest a role for PWRN4 in hepatocarcinogenesis through its association with rs4778350 in patients achieving HCV eradication.
• Three-year overall survival in unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab.
  Masatsugu Ohara; Goki Suda; Risako Kohya; Yutaka Yasui; Kaoru Tsuchiya; Masayuki Kurosaki; Joji Tani; Shinya Maekawa; Nobuyuki Enomoto; Makoto Chuma; Manabu Morimoto; Shun Kaneko; Mina Nakagawa; Yasuhiro Asahina; Atsumasa Komori; Yuki Kugiyama; Masaru Baba; Akihisa Nakamura; Jun Ito; Ren Yamada; Shunichi Hosoda; Yoshiya Yamamoto; Sonoe Yoshida; Takuya Sho; Takashi Sasaki; Tomoka Yoda; Akimitsu Meno; Naohiro Yasuura; Qingjie Fu; Zijian Yang; Osamu Maehara; Shunsuke Ohnishi; Yoshimasa Tokuchi; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Koji Ogawa; Naoya Sakamoto
  Hepatology international, 2025年08月28日, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality. Although the atezolizumab/bevacizumab regimen demonstrated impressive efficacy in the IMbrave150 clinical trial, long-term outcomes, particularly 3-year overall survival (OS), remain unestablished because of limited follow-up. Long-term outcomes have been reported for the tremelimumab/durvalumab combination, highlighting the need for comparable data on atezolizumab/bevacizumab. We aimed to elucidate the 3-year OS in patients with unresectable HCC (uHCC) treated with atezolizumab plus bevacizumab. METHODS: This retrospective multicenter study included patients with uHCC who received atezolizumab/bevacizumab. Among the 506 patients treated at the participating institutions, only those who initiated therapy between October 2020 and January 2022 were included. Comprehensive clinical, laboratory, and imaging data were collected, and the patients were followed up until March 2025. RESULTS: A total of 257 patients were analyzed, with a median follow-up of 48.23 months (range, 36.23-53.60 months). The 2- and 3-year OS rates were 39.2% and 25.3%, respectively. Among patients meeting the IMbrave150 criteria, the 3-year OS rate was 31.6%. Multivariate regression analysis identified baseline alpha-fetoprotein level > 116 ng/mL (odds ratio [OR] 0.41; 95% confidence interval [CI] 0.20-0.84; p = 0.015) and modified albumin-bilirubin grade 1-2a (OR 2.50; 95% CI 1.18-5.32; p = 0.017) as significant factors associated with 3-year OS. CONCLUSIONS: In a real-world setting, the 3-year OS for uHCC patients treated with atezolizumab/bevacizumab was 25.3%, rising to 31.6% among those meeting the IMbrave150 criteria. Survival outcomes underscore the clinical value of atezolizumab/bevacizumab in improving long-term prognosis and guiding first-line treatment decisions for patients with unresectable HCC.
• Novel glycan-related biomarker discovery by total glycomic and focused protein glycomic analyses.
  Hisatoshi Hanamatsu; Goki Suda; Masatsugu Ohara; Masaki Kurogochi; Naoya Sakamoto; Jun-Ichi Furukawa
  Journal of human genetics, 2025年08月06日, ［国際誌］
  英語, 研究論文（学術雑誌）, The cell surface is covered with a variety of glycan subtypes (sub-glycans) such as N-glycans, O-glycans, glycosphingolipid-glycans, and glycosaminoglycans, which are collectively called the glycocalyx. The expression patterns of sub-glycans change in response to various biological events during disease pathogenesis; however, the structures of all major sub-glycans and their relative concentrations in a cell have been hardly reported. Total glycomic analysis, which comprehensively measures all major sub-glycans, is a powerful tool to discover cellular and clinical biomarkers. In this review, we provide an overview of the analytical methods for sub-glycans and the total glycome in cultured cell lines, human serum, mouse brain tissue, and human osteoarthritis cartilage. This approach not only facilitates characterization of cells, but also has applications for hierarchical clustering analysis, glycan-related biomarker discovery, and investigation of the relationship between sub-glycans and gene expression levels using the total glycome. Moreover, we discuss our recent research focused on identifying potential biomarkers of nonalcoholic fatty liver disease. These glycomic technologies are expected to contribute to diagnostics and drug development for rare diseases in the future.
• Urinary Titin as a Non-Invasive Biomarker for Sarcopenia Sex Differences in Unresectable Digestive Malignancies: A Retrospective Cohort Study.
  Shiho Kaneko; Kazuaki Harada; Masatsugu Ohara; Shintaro Sawaguchi; Tatsuya Yokoyama; Koichi Ishida; Yasuyuki Kawamoto; Satoshi Yuki; Yoshito Komatsu; Naoya Sakamoto
  International journal of molecular sciences, 26, 14, 2025年07月15日, ［国際誌］
  英語, 研究論文（学術雑誌）, The prognosis of sarcopenia is poor in cancer patients. Recently, urinary titin, a biomarker of muscle damage, has been suggested as a potential marker for sarcopenia. However, its utility in patients with unresectable digestive malignancies remains unclear. In addition, sex differences have been reported in the association between sarcopenia and urinary titin levels. This study aimed to evaluate urinary titin as a diagnostic marker for unresectable digestive malignancies, focusing on sex differences. This retrospective study enrolled 96 patients (58 males, 38 females; median age 70), and urinary titin was evaluated as a diagnostic biomarker in relation to clinical factors (e.g., age, Eastern Cooperative Oncology Group performance status [ECOG PS], albumin [Alb]) and muscle indicators (e.g., psoas muscle index [PMI], handgrip strength). In male patients, urinary titin levels were significantly higher in the sarcopenia subgroup (5.78 vs. 2.79 pmol/mgCr, p = 0.008), and multivariate analyses identified urinary titin as an independent predictor of sarcopenia (odds ratio 13.4, p = 0.028). The receiver operating characteristic (ROC) analysis demonstrated fair diagnostic performance (area under the curve [AUC] 0.729), with an optimal cutoff value of 3.676 pmol/mgCr. Urinary titin may serve as a useful non-invasive diagnostic biomarker for sarcopenia in patients with unresectable digestive malignancies, particularly in males. These findings suggest that sex-specific approaches are required for sarcopenia assessment with urinary titin.
• Cachexia and Type 2 Diabetes Mellitus Are Independent Factors for Mortality in Patients With Cirrhosis
  Takao Miwa; Goki Suda; Ryosuke Tateishi; Tatsunori Hanai; Masatsugu Ohara; Yasuhiro Hagiwara; Shinji Unome; Kazuya Okushin; Mina Nakagawa; Naoya Sakamoto; Masahito Shimizu
  Hepatology Research, 2025年07月12日, ［国際誌］
  英語, 研究論文（学術雑誌）
• Pretreatment serum angiopoietin-2 predicts prognosis and liver functional reserve after successful HCV eradication with sofosbuvir and velpatasvir in patients with HCV-related decompensated cirrhosis.
  Naoki Kawagishi; Goki Suda; Yuki Tahata; Hayato Hikita; Takahiro Kodama; Satoshi Mochida; Nobuyuki Enomoto; Seiichi Mawatari; Hidekatsu Kuroda; Daiki Miki; Masayuki Kurosaki; Yoichi Hiasa; Norifumi Kawada; Taro Yamashita; Hiroshi Yatsuhashi; Hitoshi Yoshiji; Naoya Kato; Taro Takami; Hisamitsu Miyaaki; Kentaro Matsuura; Yasuhiro Asahina; Yoshito Itoh; Ryosuke Tateishi; Yasunari Nakamoto; Eiji Kakazu; Shuji Terai; Masahito Shimizu; Yoshiyuki Ueno; Norio Akuta; Masatsugu Ohara; Naoya Sakamoto; Tetsuo Takehara
  Journal of gastroenterology, 60, 9, 1145, 1156, 2025年06月20日, ［国内誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Direct-acting-antivirals (DAAs) achieve high sustained-virologic response (SVR) rates, even in patients with hepatitis C virus (HCV)-related decompensated liver cirrhosis (LC). However, predictors of post-treatment liver function improvement and survival remain unclear. This study evaluated pretreatment angiopoietin-2 (Ang2) levels as a predictor of prognosis and liver functional reserve after DAA treatment. METHODS: This multicenter retrospective study included 123 patients with HCV-related decompensated LC treated with sofosbuvir/velpatasvir. Serum Ang2 levels were quantified, and liver function was assessed using the Child-Pugh grading at baseline and 12 weeks after the end of treatment (SVR12). Factors associated with prognosis and post-SVR liver functional reserve (Child-Pugh grade C) were investigated. RESULTS: Multivariate Cox regression analysis revealed that, in addition to age and creatinine levels at SVR12, baseline Ang2 levels (hazard ratio [HR] = 1.151 per 1000 pg/mL, P = 0.033) and Child-Pugh grade C at SVR12 (HR = 11.765, P < 0.001), but not baseline Child-Pugh grade C, were significantly associated with the overall survival. Multivariate analysis revealed that baseline Ang2 levels and baseline Child-Pugh grade C were significantly and independently associated with Child-Pugh grade C at SVR12. The combination of elevated baseline Ang2 levels (≥ 8684 pg/mL; 1 point) and baseline Child-Pugh grade C (1 point) effectively stratified patients with a high likelihood of having Child-Pugh Grade C at SVR12. The incidence rates were as follows: 0 points, 2.1% (2/96); 1 point, 37.5% (9/24); and 2 points, 100% (2/2) (P < 0.001). CONCLUSIONS: Pretreatment Ang2 levels predict survival and liver functional reserve after SVR in HCV-related decompensated LC.
• Cirrhotic Cardiomyopathy: Prevalence and Clinical Impact on Liver Cirrhosis Outcomes.
  Takashi Kitagataya; Goki Suda; Takatsugu Tanaka; Shoichi Kitano; Naohiro Yasuura; Akimitsu Meno; Takashi Sasaki; Risako Kohya; Qingjie Fu; Shunichi Hosoda; Sonoe Yoshida; Osamu Maehara; Shunsuke Ohnishi; Masatsugu Ohara; Masato Nakai; Takuya Sho; Kosuke Nakamura; Suguru Ishizaka; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 2025年06月19日, ［国際誌］
  英語, 研究論文（学術雑誌）, AIM: Cirrhotic cardiomyopathy (CCM) is a significant complication of liver cirrhosis; however, its prevalence and impact in Asian populations remain unclear. The aim of this study was to assess the prevalence of CCM in Japanese patients with liver cirrhosis and to evaluate its impact on clinical outcomes. METHODS: In this retrospective study, 80 patients with liver cirrhosis confirmed using transient elastography (liver stiffness ≥ 12.5 kPa) were included. Study was performed at Hokkaido University Hospital between January 2014 and April 2024. CCM was diagnosed using the 2019 Cirrhotic Cardiomyopathy Consortium criteria. Subsequently, patient characteristics, survival, and the incidences of decompensation and cardiovascular events were analyzed. RESULTS: The prevalence of CCM was 46.3% (37/80), with 78.4% of patients with CCM showing isolated systolic dysfunction based on global longitudinal strain. Patients with CCM were significantly older, had lower serum ammonia and bilirubin levels, and had higher platelet counts. CCM was associated with a significantly higher incidence of decompensation events (hazard ratio 3.97, 95% confidence interval 1.64-9.61, p = 0.003) and was an independent risk factor for decompensation in the multivariate analysis (hazard ratio 3.24, 95% confidence interval 1.29-8.11, p = 0.012). Patients with and without CCM showed no significant differences in overall survival or cardiovascular events. CONCLUSIONS: CCM is prevalent among Japanese patients with liver cirrhosis and is associated with an increased risk of hepatic decompensation. These findings highlight the importance of cardiac evaluation in patients with cirrhosis and suggest that CCM should be considered in the management of liver cirrhosis to improve patient outcomes.
• Cachexia is an independent predictor of mortality in patients with cirrhosis
  Takao Miwa; Goki Suda; Ryosuke Tateishi; Tatsunori Hanai; Masatsugu Ohara; Yasuhiro Hagiwara; Shinji Unome; Kazuya Okushin; Mina Nakagawa; Naoya Sakamoto; Masahito Shimizu
  Hepatology Research, 55, 6, 859, 867, 2025年06月, ［国際誌］
  英語, 研究論文（学術雑誌）, AIM: Cachexia is a systemic response syndrome characterized by disabling wasting during disease progression. This study aimed to elucidate factors associated with cachexia in patients with cirrhosis and to examine the impact of cachexia on patient survival. METHODS: This multicenter retrospective cohort study included patients with cirrhosis admitted to two distinct institutes in Japan. Cachexia was diagnosed according to the criteria proposed by the Asian Working Group for Cachexia. Factors associated with cachexia and the prognostic impact of cachexia were assessed using logistic regression and Cox proportional hazards regression, respectively. RESULTS: Of the 723 patients enrolled (median [interquartile range] age, 71 [64-77] years; 456 [63%] were male; and 390 [54%] had viral hepatitis), 200 (28%) met the criteria for cachexia diagnosis, with the prevalence increasing with Child-Pugh class from A (17%) to B (40%) and C (66%). Multivariable logistic regression analysis revealed that age and indices of liver function reserve, including Child-Pugh score, were associated with cachexia, whereas sex, etiology of cirrhosis, and complications with hepatocellular carcinoma (HCC) were not. During a median follow-up period of 3.2 years, 264 (37%) patients died. Multivariable Cox regression analyses showed that cachexia was independently associated with increased mortality (adjusted hazard ratio, 1.62; 95% confidence interval, 1.24-2.12), along with factors related to liver function, HCC, and alcohol-associated liver disease as the etiology. [Correction added on 22 May 2025, after first online publication: The adjusted hazard ratio and confidence interval in the Results section of Abstract have been changed from '1.59; 95% and 1.43-1.77' to '1.62; 95% and 1.24-2.12'.] CONCLUSIONS: Cachexia is associated with poor liver function in patients with cirrhosis and is an independent prognostic factor.
• Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC
  Risako Kohya; Goki Suda; Masatsugu Ohara; Shunichi Hosoda; Takuya Sho; Makoto Chuma; Atsumasa Komori; Yuki Kugiyama; Yutaka Yasui; Kaoru Tsuchiya; Masayuki Kurosaki; Joji Tani; Shun Kaneko; Mina Nakagawa; Yasuhiro Asahina; Shinya Maekawa; Nobuyuki Enomoto; Yoshiya Yamamoto; Masaru Baba; Ren Yamada; Takashi Sasaki; Tomoka Yoda; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Osamu Maehara; Shunsuke Ohnishi; Yoshimasa Tokuchi; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Mitsuteru Natsuizaka; Koji Ogawa; Naoya Sakamoto
  JHEP Reports, 7, 5, 101364, 101364, 2025年05月, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels. METHODS: In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels. RESULTS: The median overall survival (p <0.001) and progression-free survival (p = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 vs. 8.84 months; p = 0.027) and median overall survival (14.13 vs. 22.08 months; p <0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (p = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, p <0.001). CONCLUSIONS: Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab. IMPACT AND IMPLICATIONS: FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker and an indicator of treatment response in unresectable HCC treated with ICI-based therapy. These findings could be crucial for the implementation of personalised treatment strategies for unresectable HCC. However, identifying optimal therapeutic options for patients with unresectable HCC and high serum FGF21 levels remains an urgent and critical clinical issue.
• Current management and future perspectives of covert hepatic encephalopathy in Japan: a nationwide survey.
  Takao Miwa; Mio Tsuruoka; Hajime Ueda; Tamami Abe; Hiroki Inada; Yoshimi Yukawa-Muto; Masatsugu Ohara; Taeang Arai; Yasuyuki Tamai; Hiroshi Isoda; Tomoko Tadokoro; Tatsunori Hanai; Takanori Ito; Nobuharu Tamaki; Akira Sakamaki; Yoshihiko Aoki; Fujimasa Tada; Sachiyo Yoshio; Hirokazu Takahashi; Asahiro Morishita; Tsuyoshi Ishikawa; Jun Inoue; Goki Suda; Chikara Ogawa; Masanori Atsukawa; Atsushi Hiraoka; Hidekatsu Kuroda; Tadashi Namisaki; Takashi Honda; Takumi Kawaguchi; Yasuhito Tanaka; Shuji Terai; Tadashi Ikegami; Hitoshi Yoshiji; Motoh Iwasa; Masahito Shimizu
  Journal of gastroenterology, 2025年03月07日, ［国内誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Covert hepatic encephalopathy (CHE) leads to devastating outcomes in patients with cirrhosis. This study aims to elucidate the current management and future perspectives of CHE in Japan. METHODS: A questionnaire-based cross-sectional study was conducted among physicians involved in managing cirrhosis in Japan. The primary aim was to elucidate the real-world management of CHE, including testing and treatment. Factors influencing the implementation of CHE testing were analyzed using a logistic regression model. Limitations and future perspectives for improving the management of CHE were also evaluated. RESULTS: Of 511 physicians surveyed, 93.9% recognized CHE as a significant problem, and 86.9% agreed that it should be tested. Overall, 62.8% of physicians tested for CHE, whereas 37.2% did not. Multivariable analysis identified institutional factors and certifying board as significant determinants of CHE test implementation. The Stroop (68.2%) and neuropsychiatric tests (57.5%) were the most commonly used methods of identifying CHE. Among those who tested for CHE, 87.7% treated CHE; the most common treatments were lactulose (81.5%), rifaximin (76.3%), and branched-chain amino acids (70.4%). Among non-testers, the primary barrier was the time requirement for testing. Proposals to encourage CHE testing included the development of simple tests and integration of multidisciplinary teams. CONCLUSIONS: Most physicians involved in cirrhosis care in Japan recognize CHE as a significant problem that warrants testing. However, testing for CHE remains limited by institutional factors and physician specialties. Time requirements for CHE testing are the primary barrier, and simple tests and multidisciplinary teams are recommended to enhance CHE management.
• Elevated A2F bisect N-glycans of serum IgA reflect progression of liver fibrosis in patients with MASLD.
  Hisatoshi Hanamatsu; Goki Suda; Masatsugu Ohara; Koji Ogawa; Nobuharu Tamaki; Hayato Hikita; Hiroaki Haga; Shinya Maekawa; Masaya Sugiyama; Tatsuhiko Kakisaka; Masato Nakai; Takuya Sho; Nobuaki Miura; Masayuki Kurosaki; Yasuhiro Asahina; Akinobu Taketomi; Yoshiyuki Ueno; Tetsuo Takehara; Takashi Nishikaze; Jun-Ichi Furukawa; Naoya Sakamoto
  Journal of gastroenterology, 60, 4, 456, 468, 2025年01月24日, ［国内誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Advanced liver fibrosis in cases of metabolic dysfunction-associated steatotic liver disease (MASLD) leads to cirrhosis and hepatocellular carcinoma. The current gold standard for liver fibrosis is invasive liver biopsy. Therefore, a less invasive biomarker that accurately reflects the stage of liver fibrosis is highly desirable. METHODS: This study enrolled 269 patients with liver biopsy-proven MASLD. Patients were divided into three groups (F0/1 (n = 41/85), F2 (n = 47), and F3/4 (n = 72/24)) according to fibrosis stage. We performed serum N-glycomics and identified glycan biomarker for fibrosis stage. Moreover, we explored the carrier proteins and developed a sandwich ELISA to measure N-glycosylation changes of carrier protein. RESULTS: Comprehensive N-glycomic analysis revealed significant changes in the expression of A2F bisect and its precursors as fibrosis progressed. The sum of neutral N-glycans carrying bisecting GlcNAc and core Fuc (neutral sum) had a better diagnostic performance to evaluate advanced liver fibrosis (AUC = 0.804) than conventional parameters (FIB4 index, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), and serum level of Mac-2-binding protein glycol isomer (M2BPGi). The combination of the neutral sum and FIB4 index enhanced diagnostic performance (AUC = 0.840). IgM, IgA, and complement C3 were identified as carrier proteins with A2F bisect N-glycan. A sandwich ELISA based on N-glycans carrying bisecting GlcNAc and IgA showed similar diagnostic performance than the neutral sum. CONCLUSIONS: A2F bisect N-glycan and its precursors are promising candidate biomarkers for advanced fibrosis in MASLD patients. Analysis of these glycan alterations on IgA may have the potential to serve as a novel ELISA diagnostic tool for MASLD in routine clinical practice. CLINICAL TRIAL NUMBER: UMIN000030720.
• Subcutaneous adipose tissue radiodensity as a predictor of poor prognosis in advanced biliary tract cancer
  Ryo Sugiura; Yasuyuki Kawamoto; Masaki Kuwatani; Kazumichi Kawakubo; Kazuaki Harada; Masatsugu Ohara; Hiroki Yonemura; Shunichiro Nozawa; Naoya Sakamoto
  Journal of Hepato-Biliary-Pancreatic Sciences, 32, 3, 194, 202, Wiley, 2025年01月08日, ［国内誌］
  英語, 研究論文（学術雑誌）, Abstract
  
  Background
  
  High subcutaneous adipose tissue radiodensity (SATr), an indirect surrogate marker of adipose tissue quality, was associated with poor prognosis in various cancers. The present study aimed to assess the association of SATr with survival outcomes in patients with advanced biliary tract cancer (BTC).
  
  Methods
  
  This retrospective, single‐center study included patients with unresectable or recurrent BTC who underwent chemotherapy/chemoradiotherapy. Overall survival (OS) and progression‐free survival (PFS) were assessed using the log‐rank test and the Cox proportional hazards model according to the SATr status.
  
  Results
  
  The study cohort included 234 patients, including 38 and 196 patients with high and non‐high SATr, respectively. The median OS durations were 10.5 and 17.4 months (HR = 1.72, 95% CI: 1.19–2.49, p < .01) and the median PFS durations were 4.9 and 8.0 months (HR = 1.52, 95% CI: 1.05–2.20, p = .03) in patients with high and non‐high SATr, respectively. By multivariate analysis, high SATr, neutrophil/lymphocyte ratio >5, modified Glasgow prognostic score 1–2, and serum carcinoembryonic antigen >5.0 ng/mL were predictors for OS (HR, 1.66, 2.42, 2.00, and 1.56, respectively; p < .05). By multivariate analysis, metastatic disease status, high SATr, neutrophil/lymphocyte ratio >5, and modified Glasgow prognostic score 1–2 were independent risk factors for worse PFS (HR, 1.56, 1.56, 1.81, and 1.57, respectively; p < .05).
  
  Conclusions
  
  High SATr was associated with risk of tumor progression and poor prognosis in patients with advanced BTC treated by palliative chemotherapy/chemoradiotherapy.
• Letter: Positivity of High-Sensitivity HBsAg Test Was Significantly Associated With Poorer Prognosis in Patients With Non-HBV-Related HCC-Authors' Reply.
  Naohiro Yasuura; Goki Suda; Masatsugu Ohara; Naoya Sakamoto
  Alimentary pharmacology & therapeutics, 60, 11-12, 1647, 1649, 2024年12月, ［国際誌］
  英語
• Association of proteinuria with improved prognosis in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab, and the predictive role of serum vascular endothelial growth factor D levels: A multicenter retrospective study.
  Zijian Yang; Goki Suda; Takuya Sho; Osamu Maehara; Masatsugu Ohara; Tomoka Yoda; Qingjie Fu; Takashi Sasaki; Risako Kohya; Sonoe Yoshida; Shunichi Hosoda; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Mitsuteru Natsuizaka; Koji Ogawa; Shunsuke Ohnishi; Yoshiya Yamamoto; Masaru Baba; Ren Yamada; Tomoe Kobayashi; Minhu Chen; Naoya Sakamoto
  Hepatology research : the official journal of the Japan Society of Hepatology, 55, 3, 433, 443, 2024年11月25日, ［国際誌］
  英語, 研究論文（学術雑誌）, AIM: Atezolizumab/bevacizumab is a first-line therapy for unresectable hepatocellular carcinoma (HCC). Among several adverse events, grade ≥2 proteinuria is considered a significant adverse event that may cause bevacizumab interruption. Studies have shown that proteinuria might predict improved prognosis, although data are scarce and the association remains controversial, and the mechanisms and predictive factors remain unclear. We aimed to clarify these. METHODS: In this multicenter retrospective study, we screened patients with HCC treated with atezolizumab/bevacizumab. The prognostic impact of grade ≥2 proteinuria was examined in patients with proper clinical data and preserved serum for growth factor analysis. For biomarker analysis predicting proteinuria, baseline serum vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D levels were analyzed. RESULTS: This study included 75 patients, and 32 (42.7%) experienced grade ≥2 proteinuria. No significant differences were observed between those with or without proteinuria, except for aspartate transaminase and alanine transaminase levels. Time-dependent Cox proportional hazards analysis revealed that grade ≥2 proteinuria was significantly associated with better prognosis (hazard ratio 0.221; 95% confidence interval 0.082-0.592; p = 0.003). In biomarker analysis, low baseline serum VEGF-C and VEGF-D levels were significantly associated with proteinuria, and multivariate analysis demonstrated that baseline serum VEGF-D level was significantly associated with grade ≥2 proteinuria (hazard ratio 0.101; 95% confidence interval 0.029-0.357; p < 0.001). CONCLUSIONS: Grade ≥2 proteinuria in patients with unresectable HCC treated with atezolizumab/bevacizumab indicates a better prognosis, and baseline serum VEGF-D levels can help predict its occurrence. These findings can help in managing adverse events and prognosis in advanced HCC treated with atezolizumab/bevacizumab.
• Positivity of high-sensitivity HBsAg test, not previous HBV infection, indicates poor prognosis in patients with non-HBV-related HCC.
  Naohiro Yasuura; Goki Suda; Masatsugu Ohara; Akimitsu Meno; Takuya Sho; Risako Kohya; Takashi Sasaki; Tomoka Yoda; Sonoe Yoshida; Qingjie Fu; Zijian Yang; Shunichi Hosoda; Osamu Maehara; Shunsuke Ohnishi; Tomoya Saitou; Masaya Sugiyama; Takasuke Fukuhara; Masaru Baba; Takashi Kitagataya; Naoki Kawagishi; Masato Nakai; Mitsuteru Natsuizaka; Koji Ogawa; Akinobu Taketomi; Naoya Sakamoto
  Alimentary pharmacology & therapeutics, 60, 10, 1315, 1324, 2024年09月04日, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps. METHODS: We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC. RESULTS: A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC. CONCLUSIONS: In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis.
• Efficacy and Safety of Durvalumab/Tremelimumab in Unresectable Hepatocellular Carcinoma as Immune Checkpoint Inhibitor Rechallenge Following Atezolizumab/Bevacizumab Treatment.
  Takuya Sho; Goki Suda; Masatsugu Ohara; Risako Kohya; Takashi Sasaki; Sonoe Yoshida; Shunichi Hosoda; Koji Ogawa; Takashi Kitagataya; Osamu Maehara; Shunsuke Ohnishi; Naoki Kawagishi; Mitsuteru Natsuizaka; Masato Nakai; Masaru Baba; Yoshiya Yamamoto; Yoko Tsukuda; Takashi Meguro; Ren Yamada; Tomoe Kobayashi; Tomofumi Takagi; Naoya Sakamoto
  Targeted oncology, 19, 5, 769, 778, 2024年09月, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. OBJECTIVES: The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. PATIENTS AND METHODS: This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. CONCLUSION: Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.
• 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, 31, 8, 549, 558, Wiley, 2024年06月06日, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 134回・128回, 46, 46, 日本消化器病学会-北海道支部, 2024年03月
  日本語
• 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年07月, ［国内誌］
  英語, 研究論文（学術雑誌）, 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年06月20日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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, 53, 10, 960, 967, 2023年06月18日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年06月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年03月21日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 120, 臨増総会, A417, A417, (一財)日本消化器病学会, 2023年03月
  日本語
• 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年01月18日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年01月07日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年01月04日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年12月23日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, Springer Science and Business Media LLC, 2022年10月07日
  研究論文（学術雑誌）, 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, 63, Suppl.2, A592, A592, (一社)日本肝臓学会, 2022年09月
  日本語
• 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, 2022年08月15日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年07月27日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Burden of chronic hepatitis B and C infections in 2015 and future trends in Japan: A simulation study.
  Junko Tanaka; Akemi Kurisu; Masatsugu Ohara; Serge Ouoba; Masayuki Ohisa; Aya Sugiyama; Michelle L Wang; Lindsey Hiebert; Tatsuya Kanto; Tomoyuki Akita
  The Lancet regional health. Western Pacific, 22, 100428, 100428, 2022年05月, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Determining the number of chronic hepatitis B (HBV) and C virus (HCV) infections is essential to assess the progress towards the World Health Organization 2030 viral hepatitis elimination goals. Using data from the Japanese National Database (NDB), we calculated the number of chronic HBV and HCV infections in 2015 and predicted the trend until 2035. METHODS: NDB and first-time blood donors data were used to calculate the number of chronic HBV and HCV infections in 2015. A Markov simulation was applied to predict chronic infections until 2035 using transition probabilities calculated from NDB data. FINDINGS: The total number of chronic HBV and HCV infections in 2015 in Japan was 1,905,187-2,490,873 (HCV:877,841-1,302,179, HBV:1,027,346-1,188,694), of which 923,661-1,509,347 were undiagnosed or diagnosed but not linked to care ("not engaged in care"), and 981,526 were engaged in care. Chronic HBV and HCV infections are expected to be 923,313-1,304,598 in 2030, and 739,118-1,045,884 in 2035. Compared to 2015, by 2035, the number of persons with HCV not engaged in care will decline by 59·8 - 76·1% and 86·5% for patients in care. For HBV, a 47·3 - 49·3% decrease is expected for persons not engaged in care and a decline of 26·0% for patients engaged in care. INTERPRETATION: Although the burden of HBV and HCV is expected to decrease by 2035, challenges in controlling hepatitis remain. Improved and innovative screening strategies with linkage to care for HCV cases, and a functional cure for HBV are needed. FUNDING: Japan Ministry of Health, Labour and Welfare.
• 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年03月30日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年03月29日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年01月04日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Nationwide awareness-raising program for viral hepatitis in Japan: the "Shitte kan-en" project.
  Yasue Takeuchi; Masatsugu Ohara; Tatsuya Kanto
  Global health & medicine, 3, 5, 301, 307, 2021年10月31日, ［国内誌］
  英語, 研究論文（学術雑誌）, Chronic viral hepatitis is one of the most widespread infectious diseases in Japan. In the 2009 financial year, the Japanese government enacted the Basic Act on Hepatitis Measures, followed by the Basic Guidelines for Promotion of Control Measures for Hepatitis 2 years later. The guidelines emphasize the importance of provision and dissemination of accurate information on viral hepatitis and public awareness-raising. A subsidy program on hepatitis was therefore launched by the Ministry of Health, Labour and Welfare in 2011, called "Shitte kan-en" (in English, "Let's learn about hepatitis"), and involves popular Japanese actors and singers. The project started awareness-raising activities in the 2013 financial year, as the "National Campaign Project for Hepatitis Measures". It aims to communicate concise and accurate information about hepatitis and the necessity of testing for viral hepatitis. It also encourages citizens to take a positive approach to early detection and treatment. To date, the main initiatives of the project are as follows: i) celebrity visits to prefectural governors to draw attention to the condition, ii) educational events in cooperation with hepatologists in regional core hospitals, iii) support for partner companies' hepatitis awareness activities in workplaces, and iv) support for the activities of program promoters. Targeting approaches to particular groups is likely to be key to success for general awareness-raising. Evaluation of the effectiveness of this multifaceted approach is warranted to reduce the undiagnosed population and improve the link between testing and care for viral hepatitis in Japan.
• 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年09月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 16616, 16616, 2021年08月16日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年07月20日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年07月14日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年05月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年04月28日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年02月11日, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年02月, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年12月, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年10月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年10月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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, 2020年10月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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年08月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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, Wiley, 2020年07月
  研究論文（学術雑誌）
• 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年06月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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年06月, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2020年02月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Tri-antennary tri-sialylated mono-fucosylated glycan of alpha-1 antitrypsin as a non-invasive biomarker for non-alcoholic steatohepatitis: a novel glycobiomarker for non-alcoholic steatohepatitis.
  Koji Ogawa; Takashi Kobayashi; Jun-Ichi Furukawa; Hisatoshi Hanamatsu; Akihisa Nakamura; Kazuharu Suzuki; Naoki Kawagishi; Masatsugu Ohara; Machiko Umemura; Masato Nakai; Takuya Sho; Goki Suda; Kenichi Morikawa; Masaru Baba; Ken Furuya; Katsumi Terashita; Tomoe Kobayashi; Manabu Onodera; Takahiro Horimoto; Keisuke Shinada; Seiji Tsunematsu; Izumi Tsunematsu; Takashi Meguro; Tomoko Mitsuhashi; Megumi Hato; Kenichi Higashino; Yasuro Shinohara; Naoya Sakamoto
  Scientific reports, 10, 1, 321, 321, 2020年01月15日, ［国際誌］
  英語, 研究論文（学術雑誌）, Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may lead to liver cirrhosis or hepatocellular carcinoma. Here, we examined the diagnostic utility of tri-antennary tri-sialylated mono-fucosylated glycan of alpha-1 antitrypsin (AAT-A3F), a non-invasive glycobiomarker identified in a previous study of NASH diagnosis. This study included 131 biopsy-proven Japanese patients with NAFLD. We evaluated the utility of AAT-A3F in NASH diagnosis, and conducted genetic analysis to analyse the mechanism of AAT-A3F elevation in NASH. Serum AAT-A3F concentrations were significantly higher in NASH patients than in NAFL patients, and in patients with fibrosis, lobular inflammation, and ballooning. Hepatic FUT6 gene expression was significantly higher in NASH than in NAFL. IL-6 expression levels were significantly higher in NASH than in NAFL and showed a positive correlation with FUT6 expression levels. The serum-AAT-A3F levels strongly correlated with hepatic FUT6 expression levels. AAT-A3F levels increased with fibrosis, pathological inflammation, and ballooning in patients with NAFLD and may be useful for non-invasive diagnosis of NASH from the early stages of fibrosis.
• 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年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2019年11月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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, 2019年11月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2019年10月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2019年07月, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2019年04月01日, ［国内誌］
  英語, 研究論文（学術雑誌）, 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).
• 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, 2019年03月15日, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, (一財)日本消化器病学会, 2019年03月
  日本語
• 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, (一財)日本消化器病学会, 2019年03月
  日本語
• 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, 2019年01月, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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.
  Nakai Masato; Suda Goki; Ogawa Koji; Suzuki Kazuharu; Nakamura Akihisa; Ohara Masatsugu; Kawagishi Naoki; Umemura Machiko; Sho Takuya; Morikawa Kenichi; Sakamoto Naoya
  HEPATOLOGY, 68, 843A, 844A, 2018年10月, ［査読有り］
• 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年08月, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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).
• 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, 2018年06月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2018年02月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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, 2018年02月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• Palmitoylethanolamide Ameliorates Carbon Tetrachloride-Induced Liver Fibrosis in Rats.
  Masatsugu Ohara; Shunsuke Ohnishi; Hidetaka Hosono; Koji Yamamoto; Qingjie Fu; Osamu Maehara; Goki Suda; Naoya Sakamoto
  Frontiers in pharmacology, 9, 709, 709, 2018年, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
  Ryo Sugiura; Shunsuke Ohnishi; Masatsugu Ohara; Marin Ishikawa; Shuichi Miyamoto; Reizo Onishi; Koji Yamamoto; Kazumichi Kawakubo; Masaki Kuwatani; Naoya Sakamoto
  American journal of translational research, 10, 7, 2102, 2114, 2018年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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 μL 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-α, 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.
• 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年, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
  Masatsugu Ohara; Shunsuke Ohnishi; Hidetaka Hosono; Koji Yamamoto; Kohei Yuyama; Hideki Nakamura; Qingjie Fu; Osamu Maehara; Goki Suda; Naoya Sakamoto
  Stem cells international, 2018, 3212643, 3212643, 2018年, ［査読有り］, ［筆頭著者］, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2017年10月, ［国内誌］
  英語, 研究論文（学術雑誌）, 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.
• 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, 2017年09月, ［国際誌］
  英語, 研究論文（学術雑誌）, 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.

• 眼科医に対する肝炎ウイルス検査に関するアンケート調査(第2報)
  大原 正嗣; 井出 達也; 井上 淳; 戸島 洋貴; 柿崎 暁; 戸所 大輔; 日高 勲; 高橋 宏和; 西村 知久; 坂本 直哉; 是永 匡紹, 肝臓, 66, 9, 407, 410, 2025年09月
  (一社)日本肝臓学会, 日本語
• 慢性肝疾患におけるTPORAの有効性の検討 脾臓体積に注目して
  中井 正人; 横山 大輔; 田中 崇倫; 北野 翔一; 保浦 直弘; 目野 晃光; 北潟谷 隆; 大原 正嗣; 荘 拓也; 須田 剛生; 坂本 直哉, 日本門脈圧亢進症学会雑誌, 31, 3, 161, 161, 2025年08月
  (一社)日本門脈圧亢進症学会, 日本語
• 高齢者における肝がんの治療 75歳以上の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・安全性と肝予備能変化
  荘 拓也; 須田 剛生; 北野 翔一; 田中 崇倫; 保浦 直弘; 目野 晃光; 北潟谷 隆; 大原 正嗣; 中井 正人; 坂本 直哉, 日本高齢消化器病学会誌, 28, 1, 55, 55, 2025年07月
  (NPO)日本高齢消化器病学会, 日本語
• 肝硬変・サルコペニアの栄養評価と栄養療法・運動療法 L-カルニチン製剤が肝硬変患者の筋肉量に与える影響の前向き観察研究
  大原 正嗣; 須田 剛生; 坂本 直哉, 肝臓, 66, Suppl.1, A188, A188, 2025年04月
  (一社)日本肝臓学会, 日本語
• 肝炎撲滅の鍵 医療と行政の連携
  大原 正嗣, 日本消化器病学会北海道支部専門医セミナー, 28回, np2, np2, 2025年03月
  日本消化器病学会-北海道支部, 日本語
• 肝線維化・肝発癌における基礎と臨床の融合 慢性B型肝炎症例におけるCAMP-BとPAGE-Bによる発癌リスク評価の検討
  大原 正嗣; 須田 剛生; 保浦 直弘; 目野 晃光; 甲谷 理紗子; 佐々木 貴志; 北潟谷 隆; 中井 正人; 荘 拓也; 坂本 直哉, 日本消化器病学会雑誌, 122, 臨増総会, A212, A212, 2025年03月
  (一財)日本消化器病学会, 日本語
• 肝疾患診療連携拠点病院における肝炎医療コーディネーターの現状（第3報）
  瀬戸山 博子; 榎本 大; 佐藤 光明; 佐々木 嶺; 磯田 広史; 徳本 良雄; 池上 正; 大原 正嗣; 井上 貴子; 井出 達也; 内田 義人; 加川 建弘; 立木 佐知子; 酒井 規裕; 永原 天和; 戸島 洋貴; 井上 淳; 島上 哲朗; 飯野 勢; 橋本 まさみ; 川田 一仁; 末次 淳; 澤田 康司; 朝井 章; 難波 志穂子; 遠藤 美月; 米田 正人; 是永 匡紹, 肝臓, 66, 2, 54, 57, 2025年02月01日
  The present study assessed the roles and activities of hepatitis medical care coordinators (HMCCs) in regional core center hospitals through three surveys conducted in 2019, 2021, and 2023, revealing a working rate of 80%, with an increase observed in deployment to nonspecialist departments. The third survey including 27 hospitals revealed that 73.1% of the 1485 trained HMCCs were active, with a retention rate of 90% and an increasing rate of HMCC deployment to nonspecialist departments. New HMCC activities beyond those included in the Ministry of Health, Labor, and Welfare guidelines were also reported, such as educational efforts and the prevention of hepatitis B virus reactivation. These results highlight the importance of expanding the HMCC roles to increase motivation and efficacy and suggest that formalizing new activities in official notifications would support these goals., 一般社団法人 日本肝臓学会, 日本語
• 特集 肝疾患の早期発見･早期治療の要となる肝機能検査 肝炎ウイルスマーカー
  須田 剛生; 大原 正嗣; 北潟谷 隆, 医学のあゆみ, 292, 3, 234, 236, 2025年01月18日
  医歯薬出版, 日本語
• 肝胆膵診療のラストマイル I.疾患克服を視野に入れた領域 わが国におけるC型肝炎克服に向けた今後の展望
  是永匡紹; 是永匡紹; 井上淳; 大原正嗣; 小塚立蔵; 井上貴子; 西村知久; 戸所大輔; 立道昌幸, 肝胆膵, 91, 2, 137, 143, 2025年
  (株)アークメディア, 日本語
• 慢性B型肝炎症例におけるCAMP-BとPAGE-Bによる発癌リスク評価の検討
  大原正嗣; 須田剛生; 保浦直弘; 目野晃光; 甲谷理紗子; 佐々木貴志; 北潟谷隆; 中井正人; 荘拓也; 坂本直哉, 日本消化器病学会雑誌(Web), 122, 2025年
• 新たな疾患定義で広がる脂肪性肝疾患診療 V.治療 肝線維化を伴うMASLDに対するresmetiromの第III相ランダム化比較試験,国内外の動向
  大原正嗣; 須田剛生; 坂本直哉, 肝胆膵, 90, 3, 357, 362, 2025年
  (株)アークメディア, 日本語
• 切除不能肝細胞癌に対するレンバチニブ治療後のFGF21の変化と食欲不振の関連性について
  甲谷 理紗子; 須田 剛生; 大原 正嗣; 佐々木 貴志; 吉田 苑永; 細田 峻一; 北潟谷 隆; 中井 正人; 荘 拓也; 小川 浩司; 坂本 直哉, 日本消化器病学会雑誌, 121, 臨増大会, A802, A802, 2024年10月
  (一財)日本消化器病学会, 日本語
• ウイルス性肝疾患の診断と治療(De novo HBVの予防,肝炎啓発事業も含めて)—Diagnosis and treatment of chronic hepatitis virus infection—特集 慢性肝臓病の克服を目指して
  須田 剛生; 大原 正嗣; 坂本 直哉, 日本内科学会雑誌, 113, 1, 16, 23, 2024年01月10日
  世界では慢性ウイルス性肝炎に関連した死亡者数が毎年100万人以上にのぼり，世界的な公衆衛生上の問題となる．世界保健機関は，2030年までにウイルス性肝炎eliminationの戦略をたて，年間の死亡率を65％削減，新規感染を90％減少させることを目標とし活動を行っている．一方で慢性ウイルス性肝炎の主な原因ウイルスとなる，C型肝炎ウイルス（HCV），B型肝炎ウイルス（HBV）に対しては，革命的な薬剤の開発により排除または制御が可能となりつつある．本稿では，現在のウイルス性慢性肝炎に対する治療の進歩，残る問題点について概略する．, 東京 : 日本内科学会, 日本語
• 進行肝細胞癌に対するデュルバルマブ+トレメリムマブ併用療法の早期治療効果と安全性
  荘拓也; 須田剛生; 北潟谷隆; 大原正嗣; 中井正人; 小川浩司; 山田錬; 佃曜子; 小林智絵; 川岸直樹; 馬場英; 高木智史; 目黒高志; 山本義也; 坂本直哉, 日本肝がん分子標的治療研究会プログラム・抄録集, 29th, 2024年
• 進行肝細胞癌に対するデュルバルマブ+トレメリムマブ併用療法の治療効果と安全性の検討
  荘拓也; 須田剛生; 甲谷理紗子; 佐々木貴志; 北潟谷隆; 大原正嗣; 細田峻一; 山田錬; 佃曜子; 小林智絵; 川岸直樹; 小川浩司; 馬場英; 高木智史; 目黒高志; 吉田苑永; 山本義也; 坂本直哉, 日本肝がん分子標的治療研究会プログラム・抄録集, 30th, 2024年
• 肝炎ウイルス検査受検率の向上及び受診へ円滑につなげる方策の確立に資する研究 北海道における非専門医対策
  大原正嗣; 小川浩司, 肝炎ウイルス検査受検率の向上及び受診へ円滑につなげる方策の確立に資する研究 令和5年度 総括・分担研究報告書(Web), 2024年
• 肝炎ウイルス検査受検率の向上及び受診へ円滑につなげる方策の確立に資する研究 北海道における肝炎ウイルス検査状況とフォローアップ状況
  小川浩司; 大原正嗣, 肝炎ウイルス検査受検率の向上及び受診へ円滑につなげる方策の確立に資する研究 令和5年度 総括・分担研究報告書(Web), 2024年
• LEN-TACE療法の治療効果判定における造影USの役割
  荘拓也; 北潟谷隆; 大原正嗣; 中井正人; 須田剛生; 坂本直哉, 超音波医学 Supplement, 51, 2024年
• 門脈圧亢進症合併HCV症例のSVR後の肝予備能,非代償化の検討
  中井正人; 大原正嗣; 北潟谷隆; 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(Web), 121, 2024年
• 進行肝細胞癌に対するデュルバルマブ+トレメリムマブ併用療法の早期治療効果と安全性
  荘拓也; 須田剛生; 目野晃光; 保浦直弘; 甲谷理紗子; 佐々木貴志; 吉田苑永; 細田峻一; 北潟谷隆; 大原正嗣; 中井正人; 小川浩司; 山田錬; 佃曜子; 小林智絵; 川岸直樹; 馬場英; 高木智史; 目黒高志; 得地祐匡; 山本義也; 坂本直哉, 肝胆膵, 89, 3, 2024年
• 多職種で肝胆膵疾患の知識の拡散と浸透をはかる-今ある肝疾患コーディネーターはこの先どこに向かうのか-II.肝炎医療コーディネーターの配置と活躍の現状と課題 北海道における肝炎医療コーディネーター-医療過疎地域における肝炎医療コーディネーターの活躍への期待-
  小川浩司; 大原正嗣; 長谷川智子; 櫻井菜々子; 坂本直哉, 肝胆膵, 88, 2, 2024年
• 私の治療 C型肝炎
  大原正嗣; 須田剛生; 坂本直哉, 週刊日本医事新報, 5220, 2024年
• 高齢肝疾患患者における筋肉量評価法の検討
  大原正嗣; 須田剛生; 目野晃光; 保浦直弘; 甲谷理紗子; 佐々木貴志; 細田峻一; 吉田苑永; 北潟谷隆; 中井正人; 荘拓也; 小川浩司; 坂本直哉, 肝臓, 65, Supplement 1, 2024年
• A病院で実施した多職種カンファレンスの効果~院内の肝炎医療コーディネーターの協働~
  長谷川智子; 小川浩司; 小川浩司; 大原正嗣; 大原正嗣; 三宅亜矢; 櫻井菜々子; 坂本直哉, 肝臓, 65, Supplement 1, 2024年
• 慢性肝疾患患者の低栄養アセスメントを行うべき患者を適切に絞り込むスクリーニング方法の検討
  中井正人; 目野晃光; 保浦直弘; 甲谷理紗子; 佐々木貴志; 吉田苑永; 細田峻一; 北潟谷隆; 大原正嗣; 荘拓也; 須田剛生; 小川浩司; 坂本直哉, 肝臓, 65, Supplement 1, 2024年
• 進行肝細胞癌に対するデュルバルマブ+トレメリムマブ併用療法の初期治療成績
  荘拓也; 須田剛生; 吉田苑永; 細田峻一; 北潟谷隆; 大原正嗣; 中井正人; 小川浩司; 山田錬; 佃曜子; 小林智絵; 川岸直樹; 馬場英; 高木智史; 目黒高志; 山本義也; 坂本直哉, 肝臓, 65, Supplement 1, 2024年
• 北海道における肝炎ウイルス陽性者対策の課題
  大原正嗣; 小川浩司; 保浦直弘; 目野晃光; 甲谷理紗子; 佐々木貴志; 北潟谷隆; 中井正人; 荘拓也; 須田剛生; 坂本直哉, 肝臓, 65, Supplement 2, A687, A687, 2024年
  (一社)日本肝臓学会, 日本語
• 切除不能肝細胞癌に対するレンバチニブ治療後のFGF21の変化と食欲不振の関連性について
  甲谷理紗子; 須田剛生; 大原正嗣; 佐々木貴志; 吉田苑永; 細田峻一; 北潟谷隆; 中井正人; 荘拓也; 小川浩司; 坂本直哉, 日本消化器病学会雑誌(Web), 121, 2024年
• DAAsによるC型肝炎ウイルス排除の肝脂肪化変化に与える影響の検討
  須田剛生; 大原正嗣; 坂本直哉, 肝臓, 65, Supplement 3, 2024年
• 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中に自己免疫性脳炎を発症した1例
  北野翔一; 荘拓也; 保浦直弘; 目野晃光; 甲谷理紗子; 佐々木貴志; 北潟谷隆; 大原正嗣; 中井正人; 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, 135th-129th, 2024年
• 門脈圧亢進症症例における低栄養と適切なスクリーニング方法の検討
  中井正人; 北野翔一; 田中崇倫; 目野晃光; 保浦直弘; 甲谷理紗子; 佐々木貴志; 北潟谷隆; 大原正嗣; 荘拓也; 須田剛生; 坂本直哉, 日本門脈圧亢進症学会雑誌, 30, 3 (CD-ROM), 107, 107, 2024年
  (一社)日本門脈圧亢進症学会, 日本語
• 切除不能進行肝細胞癌におけるICI-Rechallenge療法の治療効果と安全性の検討
  荘拓也; 須田剛生; 甲谷理紗子; 佐々木貴志; 北潟谷隆; 大原正嗣; 中井正人; 山田錬; 佃曜子; 小林智絵; 川岸直樹; 小川浩司; 高木智史; 目黒高志; 馬場英; 山本義也; 坂本直哉, 日本肝がん分子標的治療研究会プログラム・抄録集, 31st, 2024年
• 今推しの肝胆膵研究手法と疾患モデル I.肝胆膵研究を推進する新しい研究手法 糖鎖解析による新規バイオマーカー探索
  古川潤一; 古川潤一; 花松久寿; 須田剛生; 大原正嗣; 坂本直哉, 肝胆膵, 89, 2, 2024年
• 【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, 88, 1, 7, 13, 2024年01月
  (株)アークメディア, 日本語
• 【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, 87, 4, 439, 446, 2023年10月
  (株)アークメディア, 日本語
• 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, 87, 4, 508, 509, 2023年10月
  (株)アークメディア, 日本語
• 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, 64, Suppl.3, A808, A808, 2023年10月
  (一社)日本肝臓学会, 日本語
• 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, 120, 臨増大会, A813, A813, 2023年10月
  (一財)日本消化器病学会, 日本語
• 【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, 87, 4, 439, 446, 2023年10月
  (株)アークメディア, 日本語
• 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, 87, 4, 508, 509, 2023年10月
  (株)アークメディア, 日本語
• 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, 133回・127回, 40, 40, 2023年09月
  日本消化器病学会-北海道支部, 日本語
• 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, 133回・127回, 40, 40, 2023年09月
  日本消化器病学会-北海道支部, 日本語
• 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, 64, Suppl.2, A558, A558, 2023年09月
  (一社)日本肝臓学会, 日本語
• 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, 64, Suppl.2, A644, A644, 2023年09月
  (一社)日本肝臓学会, 日本語
• 【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, 81, 増刊7 ウイルス性肝炎学2023, 203, 208, 2023年07月
  (株)日本臨床社, 日本語
• 【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, 38, 7, 807, 811, 2023年06月
  (株)日本メディカルセンター, 日本語
• 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, 64, 6, 289, 291, 2023年06月
  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。, (一社)日本肝臓学会, 日本語
• 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, 64, Suppl.1, A231, A231, 2023年04月
  (一社)日本肝臓学会, 日本語
• 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, 64, Suppl.1, A281, A281, 2023年04月
  (一社)日本肝臓学会, 日本語
• 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, 132回・126回, 42, 42, 2023年03月
  日本消化器病学会-北海道支部, 日本語
• 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, 132回・126回, 46, 46, 2023年03月
  日本消化器病学会-北海道支部, 日本語
• 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(Web), 120, 2023年
• 新たな手法を用いた肝炎ウイルス検査受検率・陽性者受診率の向上に資する研究 自治体肝炎ウイルス検査陽性者対策 北海道における肝炎ウイルス陽性者に対するフォローアップ状況
  小川浩司; 大原正嗣, 新たな手法を用いた肝炎ウイルス検査受検率・陽性者受診率の向上に資する研究 令和4年度 総括・分担研究報告書(Web), 2023年
• 新たな手法を用いた肝炎ウイルス検査受検率・陽性者受診率の向上に資する研究 非専門医連携対策 北海道における非専門医対策
  大原正嗣; 小川浩司, 新たな手法を用いた肝炎ウイルス検査受検率・陽性者受診率の向上に資する研究 令和4年度 総括・分担研究報告書(Web), 2023年
• 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, 63, Suppl.3, A691, A691, 2022年10月
  (一社)日本肝臓学会, 日本語
• 吐下血で発症した胆嚢十二指腸瘻の一例
  涌井 理之; 多谷 容子; 北野 翔一; 金子 志帆; 金光 雄哉; 佐々木 塁; 曽根 孝之; 大原 正嗣; 伊藤 淳; 中積 宏之; 馬場 麗; 清水 勇一, 国立病院総合医学会講演抄録集, 76回, 1783, 1783, 2022年10月
  国立病院総合医学会, 日本語
• 【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, 85, 3, 393, 398, 2022年09月
  (株)アークメディア, 日本語
• 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, 131回・125回, 1, 39, 39, 2022年09月
  日本消化器病学会-北海道支部, 日本語
• 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, 131回・125回, 40, 40, 2022年09月
  日本消化器病学会-北海道支部, 日本語
• 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年08月
  科学評論社, 日本語
• 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年08月
  科学評論社, 日本語
• 肝胆膵疾患とサルコペニア I.概論 日本人におけるpsoas muscle massのcut-off値
  大原正嗣; 須田剛生; 坂本直哉, 肝胆膵, 85, 2, 2022年
• B型肝炎診療の進歩 B型肝炎治療オーバービュー
  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, 月刊消化器・肝臓内科, 12, 2, 2022年
• Ehlers Danlos Syndromeに起因した腹腔内気腫を繰り返した1例
  西谷 高広; 中積 宏之; 加藤 茜; 曽根 孝之; 大原 正嗣; 伊藤 淳; 多谷 容子; 馬場 麗; 清水 勇一; 宮下 憲暢; 松島 理明; 柴田 有花, 国立病院総合医学会講演抄録集, 75回, 1263, 1263, 2021年10月
  国立病院総合医学会, 日本語
• 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, 62, Supplement 1, 2021年, ［筆頭著者］
• 日本人におけるpsoas muscle mass index最適cut-off値の検討と肝疾患患者における検討
  須田剛生; 大原正嗣; 坂本直哉, 日本消化器病学会雑誌(Web), 118, 2021年
• 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, 61, Supplement 1, 2020年
• 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年03月
  (一財)日本消化器病学会, 日本語
• 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年03月
  (一財)日本消化器病学会, 日本語
• 羊膜間葉系幹細胞由来細胞外小胞の慢性肝障害モデルに対する抗炎症・抗線維化効果
  大原正嗣; 大西俊介; 山本幸司; 付慶傑; 前原経; 須田剛生; 坂本直哉, 日本再生医療学会総会(Web), 18th, 2019年, ［筆頭著者］
• カルニチンの肝硬変患者におけるサルコペニア抑制効果
  須田剛生; 大原正嗣; 坂本直哉, 日本門脈圧亢進症学会雑誌, 25, 3, 2019年
• 肝胆膵の線維化up-to-date 肝臓の線維化-基礎研究-間葉系幹細胞による肝線維化治療
  大原正嗣; 大西俊介; 坂本直哉, 肝胆膵, 79, 5, 2019年, ［筆頭著者］
• 病初期HEV感染におけるIFN-lambda3の臨床的意義
  姜貞憲; 村田一素; 村田一素; 松居剛志; 狩野吉康; 山本義也; 新智文; 大原正嗣; 上林実; 高橋和明; 新井雅裕; 三代俊治; 杉山真也; 溝上雅史; 岡本宏明, 肝臓, 60, Supplement 1, 2019年
• 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, 2019年
• 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・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年
• 肝細胞癌に対してレンバ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・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年
• 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・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年
• 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, Supplement 2, 2019年
• 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, Supplement 2, 2019年
• 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(Web), 116, 2019年
• 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(Web), 116, 2019年
• 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, 2018年, ［筆頭著者］
• 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, 2018年
• 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, 2018年
• 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, 2018年
• 肝硬変患者におけるサルコペニア診断の検討
  大原正嗣; 小川浩司; 坂本直哉, 肝臓, 59, Supplement 1, 2018年, ［筆頭著者］
• 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, 2018年
• 羊膜間葉系幹細胞由来細胞外小胞の慢性肝障害モデルに対する抗炎症・抗線維化効果
  大原正嗣; 大西俊介; 坂本直哉, 肝臓, 59, Supplement 2, 2018年
• 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, 2018年
• 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, 2018年
• 肝硬変患者におけるサルコペニア診断の検討
  大原正嗣; 小川浩司; 坂本直哉, 日本消化器病学会雑誌(Web), 115, 2018年
• 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, 2018年
• 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, 2018年
• 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, 2018年
• 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, 2018年
• 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, 2018年
• 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(Web), 21, Supplement, 2018年
• 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年12月
  英語
• Prevalence and risk factors of hepatitis B virus reactivation in interferon-free direct-acting antiviral 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. Natsuizka; K. Morikawa; K. Ogawa; N. Sakamoto, JOURNAL OF HEPATOLOGY, 66, 1, S725, S726, 2017年
  英語, 研究発表ペーパー・要旨（国際会議）
• 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, 114, 5, 2017年
• 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, Supplement 2, 2017年
• 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, Supplement 2, 2017年
• 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, Supplement 2, 2017年
• 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, Supplement 2, 2017年
• 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, Supplement 3, 2017年
• 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, Supplement 2, 2017年
• 慢性肝疾患患者の掻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, Supplement 3, 2017年
• 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, Supplement 3, 2017年
• 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, Supplement 1, 2017年
• 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, 2017年
• 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, Supplement 3, 2016年
• 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, Supplement 2, 2016年
• 当科の膵関連疾患に対するInterventional EUSの現状
  江平宣起; 瀧新悠之介; 大原正嗣; 澤田憲太郎; 川岸直樹; 岩永一郎; 上林実, 膵臓, 30, 3, 2015年
• 当科のInterventional EUSの現状
  江平宣起; 上林実; 岩永一郎; 川岸直樹; 澤田憲太郎; 大原正嗣; 瀧新悠之介, Gastroenterological Endoscopy, 57, Supplement 2, 2015年
• mFOLFOX6療法における末梢神経障害発症に寒冷気候は影響を及ぼさない
  岩永一郎; 江平宣起; 瀧新悠之介; 大原正嗣; 杉浦諒; 宮本秀一; 水島健; 上林実, 日本癌治療学会学術集会(CD-ROM), 52nd, 2014年

• 日本臨床腫瘍学会
• 日本肝臓学会
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• 日本消化器病学会
• 日本内科学会

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  2025年04月01日 - 2028年03月31日
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• 肝筋連関を介したサルコペニア及び肝線維化改善に係る因子の同定
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