研究者データベース

榊原 純(サカキバラ ジユン)
北海道大学病院 内科
講師

基本情報

所属

  • 北海道大学病院 内科

職名

  • 講師

学位

  • 医学博士(北海道大学)

ホームページURL

J-Global ID

研究分野

  • ライフサイエンス / 呼吸器内科学

研究活動情報

論文

  • Houman Goudarzi, Hirokazu Kimura, Hiroki Kimura, Hironi Makita, Munehiro Matsumoto, Nozomu Takei, Kaoruko Shimizu, Masaru Suzuki, Taku Watanabe, Eiki Kikuchi, Hiroshi Ohira, Ichizo Tsujino, Jun Sakakibara-Konishi, Naofumi Shinagawa, Noriharu Shijubo, Hirokazu Sato, Katsunori Shigehara, Kichizo Kaga, Yasuhiro Hida, Soichi Murakami, Yuma Ebihara, Akinobu Nakamura, Hideaki Miyoshi, Satoshi Hirano, Nobuyuki Hizawa, Tatsuya Atsumi, Shau-Ku Huang, Yoichi M Ito, Masaharu Nishimura, Satoshi Konno
    Respiratory research 23 1 174 - 174 2022年06月29日 
    INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.
  • クリゾチニブ既治療のROS1融合遺伝子陽性非小細胞肺癌に対するブリグチニブの第2相試験(Barossaコホート2)
    田中 洋史, 仁保 誠治, 駄賀 晴子, 榊原 純, 後藤 悌, 大橋 圭明, 豊澤 亮, 小谷 昌広, 高橋 利明, 服部 剛弘, 森瀬 昌宏, 池田 喬哉, 松本 慎吾, 葉 清隆, 野村 尚吾, 後藤 功一
    肺癌 61 6 597 - 597 (NPO)日本肺癌学会 2021年10月
  • Haruko Daga, Seiji Niho, Jun Sakakibara-Konishi, Hiroshi Tanaka, Yasushi Goto, Kadoaki Ohashi, Ryo Toyozawa, Masahiro Kodani, Toshiaki Takahashi, Yoshihiro Hattori, Masahiro Morise, Takaya Ikeda, Shingo Matsumoto, Kiyotaka Yoh, Shogo Nomura, Koichi Goto
    Journal of Clinical Oncology 39 15_suppl 9040 - 9040 2021年05月20日 
    9040 Background: Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket, study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2. Patients with ROS 1 positive solid tumors other than NSCLC were enrolled in the cohort 3. This time we report the cohort 2 results. Methods: Patients with advanced, previously treated with crizotinib, ROS1 positive NSCLC received brigatinib at a dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary end point was objective response rate (ORR; RECIST 1.1) by independent review. Key secondary endpoint was PFS, OS, and safety. The sample size was set at 19 patients, with a one-sided alpha of 0.05, beta of 0.2, and threshold and expected values for primary endpoint of 20% and 50%, respectively. Results: From July 2019 and Jan 2020, 19 patients were enrolled from 9 institutions. Baseline characteristics as follows: median age (range): 60 (31-75) years; women, n = 10 (53%); ECOG PS of 0 to 1, n = 18 (95%); never smoker, n = 11 (58%); tumor histopathological type: adenocarcinoma, n = 18 (95%). Five and 6 patients achieved PR and SD, respectively at data cutoff date of 30 Oct 2020. The ORR was 26.3% (90%CI, 11.0-47.6), and the disease control rate was 57.9% (95%CI, 33.5-79.7). The median duration of follow-up for PFS was 12.0 months. The median PFS was 7.3 months (95% CI, 1.3-9.3), and the 1-year PFS rate was 26.9% (95%CI, 9.2-48.6). Grade ≥3 TRAEs were CPK increased (21.1%), infection (5.3%), AST and/or ALT increased (5.3%), hypercalcemia (5.3%), anorexia (5.3%), hypoxia (5.3%), erythema (5.3%), hypertension (5.3%). Pneumonitis was observed in one patient (5.3%, Grade 2). No treatment-related death was observed. Conclusions: Brigatinib has modest activity for ROS1 positive NSCLC patients previously treated with crizotinib. The safety profile of brigatinib was consistent with previous studies. Enrollment of the cohort 1 for ROS1 inhibitor-naïve NSCLC patients is ongoing, and the data will be presented at a future congress. Clinical trial information: JapicCTI-194851.
  • Hironori Takagi, Songji Zhao, Satoshi Muto, Hiroshi Yokouchi, Hiroshi Nishihara, Toshiyuki Harada, Hikaru Yamaguchi, Hayato Mine, Masayuki Watanabe, Yuki Ozaki, Takuya Inoue, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Osugi, Mika Hoshino, Mitsunori Higuchi, Yutaka Shio, Ryuzo Kanno, Miho Aoki, Chengbo Tan, Saki Shimoyama, Shigeo Yamazaki, Hajime Kikuchi, Jun Sakakibara-Konishi, Satoshi Oizumi, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Osamu Honjo, Yoshinori Minami, Masaharu Nishimura, Hirotoshi Dosaka-Akita, Koji Nakamura, Akihiro Inano, Hiroshi Isobe, Hiroyuki Suzuki
    Lung cancer (Amsterdam, Netherlands) 153 134 - 142 2021年03月 
    OBJECTIVES: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.
  • 山本 岳, 朝比奈 肇, 伊藤 祥太郎, 古田 恵, 水柿 秀紀, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲
    肺癌 61 1 66 - 66 (NPO)日本肺癌学会 2021年02月
  • Kana Watanabe, Yukihiro Toi, Atsushi Nakamura, Ryosuke Chiba, Masachika Akiyama, Jun Sakakibara-Konishi, Hisashi Tanaka, Naruo Yoshimura, Eisaku Miyauchi, Taku Nakagawa, Ryotaro Igusa, Hiroyuki Minemura, Yoshiaki Mori, Keisuke Fujimoto, Haruo Matsushita, Fumiaki Takahashi, Tatsuro Fukuhara, Akira Inoue, Shunichi Sugawara, Makoto Maemondo
    Translational lung cancer research 10 2 712 - 722 2021年02月 
    Background: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC. Methods: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m2 on days 1-14 and 29-42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948). Results: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%). Conclusions: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.
  • Shotaro Ito, Hajime Asahina, Naoko Yamaguchi, Utano Tomaru, Tadashi Hasegawa, Yutaka Hatanaka, Kanako C Hatanaka, Hiroshi Taguchi, Taisuke Harada, Hiroshi Ohira, Daisuke Ikeda, Hidenori Mizugaki, Eiki Kikuchi, Junko Kikuchi, Jun Sakakibara-Konishi, Naofumi Shinagawa, Satoshi Konno
    Respiratory medicine case reports 32 101364 - 101364 2021年 
    SMARCA4-deficient thoracic sarcomatoid tumors were characterized by inactivating mutations of SMARCA4 and often found in the chest of young and middle-aged males with a smoking history. Recently, SMARCA4-deficient thoracic sarcomatoid tumors were reported to represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. The main complication of this tumor is compression of the respiratory tract and/or blood vessels. A 39-year-old man presented with a 2-month history of fever and dyspnea. Computed tomography revealed a mediastinal tumor invading the right and left pulmonary arteries. Because of severe right heart failure, we considered him ineligible for bronchoscopy. We scheduled palliative irradiation with 40 Gy/20 Fr to improve hemodynamics and perform endobronchial ultrasound transbronchial needle aspiration later. However, irradiation was ineffective, and his general condition deteriorated quickly and he died after a 7-week hospitalization. An autopsy revealed that the diagnosis was SMARCA4-deficient thoracic undifferentiated carcinoma. It has been reported that this tumor is insensitive to radiotherapy and there were some cases which responded to an immune checkpoint inhibitor. Therefore, when caring for patients with mediastinal tumors that invade and compress the trachea and large vessels, it is important to consider this tumor as a differential diagnosis and try to make a pathological diagnosis as soon as possible.
  • Shinsuke Otagiri, Takehiko Katsurada, Kana Yamanashi, Kensuke Sakurai, Michiko T Sato, Jun Sakakibara-Konishi, Naoya Sakamoto
    JGH open : an open access journal of gastroenterology and hepatology 4 6 1231 - 1232 2020年12月 
    We performed capsule endoscopy for a patient with immune checkpoint inhibitor-induced enteritis and found multiple erosions or small ulcers in the small intestine. No reports demonstrated the effectiveness of capsule endoscopy for immune checkpoint inhibitor-induced gastrointestinal adverse events, and our case suggests that capsule endoscopy may be useful to evaluate immune checkpoint inhibitor-induced enteritis.
  • 伊藤 祥太郎, 品川 尚文, 高島 雄太, 國崎 守, 古田 恵, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 加藤 徳雄, 田口 大志, 青山 英史, 今野 哲
    気管支学 42 6 576 - 576 (NPO)日本呼吸器内視鏡学会 2020年11月
  • 國崎 守, 品川 尚文, 山本 岳, 辻 康介, 伊藤 祥太郎, 佐藤 峰嘉, 高橋 宏典, 高島 雄太, 古田 恵, 庄司 哲明, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 今野 哲
    気管支学 42 6 575 - 576 (NPO)日本呼吸器内視鏡学会 2020年11月
  • 伊藤 祥太郎, 品川 尚文, 高島 雄太, 國崎 守, 古田 恵, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 加藤 徳雄, 田口 大志, 青山 英史, 今野 哲
    気管支学 42 6 576 - 576 (NPO)日本呼吸器内視鏡学会 2020年11月
  • 辻 康介, 水柿 秀紀, 伊藤 祥太郎, 猪狩 智生, 佐藤 峰嘉, 高橋 宏典, 國崎 守, 高島 雄太, 古田 恵, 庄司 哲明, 朝比奈 肇, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲
    肺癌 60 6 638 - 638 (NPO)日本肺癌学会 2020年10月
  • 山本 岳, 朝比奈 肇, 伊藤 祥太郎, 古田 恵, 水柿 秀紀, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲
    肺癌 60 6 564 - 564 (NPO)日本肺癌学会 2020年10月
  • 古田 恵, 水柿 秀紀, 伊藤 祥太郎, 辻 康介, 佐藤 峰嘉, 高橋 宏典, 國崎 守, 高島 雄太, 庄司 哲明, 朝比奈 肇, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲
    肺癌 60 6 631 - 631 (NPO)日本肺癌学会 2020年10月
  • 辻 康介, 水柿 秀紀, 伊藤 祥太郎, 猪狩 智生, 佐藤 峰嘉, 高橋 宏典, 國崎 守, 高島 雄太, 古田 恵, 庄司 哲明, 朝比奈 肇, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲
    肺癌 60 6 638 - 638 (NPO)日本肺癌学会 2020年10月
  • 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 
    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.
  • Takashi Seto, Hidetoshi Hayashi, Miyako Satouchi, Yasushi Goto, Seiji Niho, Naoyuki Nogami, Toyoaki Hida, Toshiaki Takahashi, Jun Sakakibara-Konishi, Masahiro Morise, Takashi Nagasawa, Mie Suzuki, Masayuki Ohkura, Kei Fukuhara, Holger Thurm, Gerson Peltz, Makoto Nishio
    Cancer science 111 10 3726 - 3738 2020年10月 
    Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC-ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged/ROS1-rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. The ORR and the IC-ORR for Japanese patients in EXP2-5 were 54.8% (95% confidence interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single-dose and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
  • 塩泡 亜衣, 榊原 純, 國崎 守, 古田 恵, 高島 雄太, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 品川 尚文, 今野 哲
    日本呼吸器学会誌 9 5 319 - 324 (一社)日本呼吸器学会 2020年09月 
    思春期・若年成人(adolescent and young adult:AYA)世代胸部悪性腫瘍患者36例を後方視的に検討した。肺癌/胸腺腫瘍/原発不明癌が31/4/1例、performance status(PS)0/1は33例、1例を除いて併存疾患はなかった。肺腺癌18例中EGFR遺伝子変異陽性は6例、ALK融合遺伝子陽性は4例だった。生存期間中央値(median survival time:MST)は全体で69.4ヵ月、肺癌で32.8ヵ月だった。PS良好で併存疾患が少なく遺伝子変異陽性が多いことがAYA世代患者の特徴であり、予後延長に寄与した可能性がある。(著者抄録)
  • Shin-Ichi Fukumoto, Satoshi Oizumi, Masao Harada, Noriaki Sukoh, Kosuke Nakano, Satoshi Fuke, Jun Sakakibara-Konishi, Kei Takamura, Kenichiro Ito, Yuka Fujita, Yutaka Nishigaki, Toshiyuki Harada, Kenji Akie, Ichiro Kinoshita, Toraji Amano, Hiroshi Isobe, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    Cancer chemotherapy and pharmacology 86 1 117 - 127 2020年07月 
    PURPOSE: This study evaluated the efficacy and safety of platinum plus gemcitabine (P/G) combinations as postoperative adjuvant chemotherapies for non-small cell lung cancer. METHODS: Patients with postoperative stage IB-IIIA non-small cell lung cancer were randomly assigned to receive either cisplatin plus gemcitabine (GP arm) or carboplatin plus gemcitabine (GC arm) every 3 weeks for four cycles. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints were safety, feasibility, overall survival (OS), and biomarker analyses. RESULTS: A total of 102 patients were randomized (stage IB, 22%; II, 36%; IIIA, 42%; histology: 74% adenocarcinoma). Of the 51 patients in each arm, 37 (73%) completed 4 cycles. During follow-up (median 5.8 years; range 0.1-9.7 years), estimated DFS and OS rates at 2 years were 59.6% and 86.3% with GP and 68.0% and 86.3% with GC, respectively. No significant difference in DFS was noted between arms (P = 0.163), although 3-, 4-, and 5-year DFS rates were higher with GC. Hematological toxic effects were comparable and non-hematological toxic effects were infrequent. DFS was significantly higher in the excision repair cross-complementation group 1 (ERCC1)-low group than in the ERCC1-high group for the GP arm (P = 0.045). CONCLUSION: Both P/G combination regimens were feasible and well-tolerated, and thus may represent valid options for postoperative adjuvant treatment of non-small cell lung cancer. Although no significant differences in DFS were evident between regimens, the present data favor the adoption of GC for further evaluation. CLINICAL TRIAL REGISTRATION: UMIN-CTR ( https://www.umin.ac.jp/ctr/ ) identifier: UMIN000000913.
  • 伊藤 祥太郎, 品川 尚文, 高島 雄太, 國崎 守, 古田 恵, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 加藤 徳雄, 田口 大志, 青山 英史, 今野 哲
    気管支学 42 Suppl. S277 - S277 (NPO)日本呼吸器内視鏡学会 2020年06月
  • 國崎 守, 品川 尚文, 辻 康介, 伊藤 祥太郎, 佐藤 峰嘉, 高橋 宏典, 高島 雄太, 古田 恵, 庄司 哲明, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 今野 哲
    気管支学 42 Suppl. S241 - S241 (NPO)日本呼吸器内視鏡学会 2020年06月
  • Mototsugu Shimokawa, Kaname Nosaki, Takashi Seto, Kadoaki Ohashi, Masahiro Morise, Hidehito Horinouchi, Jun Sakakibara, Haruyasu Murakami, Seiji Yano, Miyako Satouchi, Shingo Matsumoto, Koichi Goto, Kiyotaka Yoh
    Trials 21 1 298 - 298 2020年03月30日 
    BACKGROUND: MET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations. METHODS: Co-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients. DISCUSSION: The results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.
  • Tetsuaki Shoji, Eiki Kikuchi, Junko Kikuchi, Yuta Takashima, Megumi Furuta, Hirofumi Takahashi, Kosuke Tsuji, Makie Maeda, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno
    Cancer chemotherapy and pharmacology 2020年03月30日 [査読有り][通常論文]
     
    PURPOSE: We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells. METHODS: Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines. RESULTS: All five CR cell lines highly expressed one or both of the immunoproteasome subunit genes, PSMB8 and PSMB9, while no clear trend was observed in the expression of constitutive proteasome subunits. The CR cells expressed significantly higher levels of PSMB8 and PSMB9 proteins, as well. The CR variants of the H1299 and SBC3 cell lines were more sensitive to immunoproteasome inhibitors, and had significantly more proteasomal proteolytic activity than their parental counterparts. CONCLUSIONS: The immunoproteasome may be an effective therapeutic target in a subset of CR lung cancers. Proteasomal proteolytic activity may be a predictive marker for the efficacy of immunoproteasome inhibitors in cisplatin-resistant SCLC and NSCLC.
  • Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Motofumi Suzuki, Hajime Kikuchi, Makie Maeda, Tetsuaki Shoji, Megumi Furuta, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi, Satoshi Konno
    International journal of cancer 146 4 1114 - 1124 2020年02月15日 [査読有り][通常論文]
     
    Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775-induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775-induced DNA double-strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET-inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
  • 佐々木 真知子, 水柿 秀紀, 榊原 純, 近藤 桂一, 深澤 雄一郎, 今野 哲
    日本呼吸器学会誌 9 1 71 - 75 (一社)日本呼吸器学会 2020年01月 
    症例は65歳女性。半年前より尿蛋白を指摘されネフローゼ症候群の精査目的に当院腎臓内科を受診した。左肺下葉に腫瘤影を指摘され当科を紹介され、肺扁平上皮癌cStage IVと診断した。ネフローゼ症候群の原因は肺癌に伴う膜性腎症と診断された。1次治療後に原発巣の増悪があり、2次治療としてニボルマブ(nivolumab)を開始し、1コースの5日目にGrade 2のクレアチニン増加を認めた。腎生検を施行され、病理組織診断は膜性腎症および尿細管間質性腎炎であった。その後、1.5〜4ヵ月ごとにニボルマブを投与し部分奏効を維持している。(著者抄録)
  • Jun Sakakibara-Konishi, Mineyoshi Sato, Michiko Takimoto Sato, Kohei Kasahara, Masahiro Onozawa, Hidenori Mizugaki, Eiki Kikuchi, Hajime Asahina, Naofumi Shinagawa, Satoshi Konno
    Respiratory medicine case reports 31 101170 - 101170 2020年 [査読有り][通常論文]
     
    Malignant pleural mesothelioma (MPM) is a rare and highly aggressive tumor. Nivolumab showed durable antitumor effect in patients with recurrent MPM and was approved for those patients in Japan in 2018. Immune related adverse event (irAE) is occurred in various organs and is suggestive to be related to better outcome of nivolumab. Frequency of hematological irAE is low and there are few reports about hematological irAE and association between irAE and outcome of nivolumab in patients with MPM. We present a case of recurrent MPM who responded to nivolumab treatment and experienced nivolumab-induced immune thrombocytopenia (ITP). Although high dose dexamethasone was administered and platelet count increased transiently, re-administration of dexamethasone was required to maintain normal count of platelet. The careful and intensive management of ITP treatment is necessary in cases who show no response or relapse to initial glucocorticoids treatment. This is the first report about nivolumab-induced ITP and association with response to nivolumab in MPM.
  • Shiro Watanabe, Tetsuya Inoue, Shozo Okamoto, Keiichi Magota, Ayumi Takayanagi, Jun Sakakibara-Konishi, Norio Katoh, Kenji Hirata, Osamu Manabe, Takuya Toyonaga, Yuji Kuge, Hiroki Shirato, Nagara Tamaki, Tohru Shiga
    EJNMMI research 9 1 104 - 104 2019年12月04日 [査読有り][通常論文]
     
    BACKGROUND: We investigated the prognostic predictive value of the combination of fluorodeoxyglucose (FDG)- and fluoromisonidazole (FMISO)-PET in patients with non-small cell lung carcinoma (NSCLC) treated with stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: We prospectively examined patients with pathologically proven NSCLC; all underwent FDG and FMISO PET/CT scans before SBRT. PET images were acquired using a whole-body time-of-flight PET-CT scanner with respiratory gating. We classified them into recurrent and non-recurrent groups based on their clinical follow-ups and compared the groups' tumor diameters and PET parameters (i.e., maximum of the standardized uptake value (SUVmax), metabolic tumor volume, tumor-to-muscle ratio, and tumor-to-blood ratio). We performed univariate analysis to evaluate the impact of the PET variables on the patients' progression-free survival (PFS). We divided the patients by thresholds of FDG SUVmax and FMISO SUVmax obtained from receiver operating characteristic analysis for assessment of recurrence rate and PFS. RESULTS: Thirty-two NSCLC patients (19 male and 13 females; median age, 83 years) were enrolled. All received SBRT. At the study endpoint, 23 patients (71.9%) were non-recurrent and nine patients (28.1%) had recurrent disease. Significant between-group differences were observed in tumor diameter and all the PET parameters, demonstrating that those were significant predictors of the recurrence in all patients. In the 22 patients with tumors > 2 cm, tumor diameter and FDG SUVmax were not significant predictors. Thirty-two patients were divided into three patterns from the thresholds of FDG SUVmax (6.81) and FMISO SUVmax (1.89); A, low FDG and low FMISO (n = 14); B, high FDG and low FMISO (n = 8); C, high FDG and high FMISO (n = 10). No pattern A patient experienced tumor recurrence, whereas two pattern B patients (25%) and seven pattern C patients (70%) exhibited recurrence. A Kaplan-Meier analysis of all patients revealed a significant difference in PFS between patterns A and B (p = 0.013) and between patterns A and C (p < 0.001). In the tumors > 2 cm patients, significant differences in PFS were demonstrated between pattern A and C patients (p = 0.002). CONCLUSION: The combination of FDG- and FMISO-PET can identify patients with a baseline risk of recurrence and indicate whether additional therapy might be performed to improve survival.
  • ロルラチニブ治療後にクリゾチニブ再投与が著効したALK融合遺伝子陽性肺腺癌の1例
    辻 康介, 榊原 純, 北井 秀典, 水柿 秀紀, 朝比奈 肇, 菊地 順子, 菊地 英毅, 品川 尚文, 今野 哲, 池澤 靖元, 畑中 豊, 佐々木 高明, 吉田 遼平, 千葉 伸一, 松本 慎吾, 後藤 功一
    肺癌 59 7 1200 - 1200 (NPO)日本肺癌学会 2019年12月
  • 辻 康介, 水柿 秀紀, 猪狩 智生, 佐藤 峰嘉, 國崎 守, 高島 雄太, 古田 恵, 朝比奈 肇, 菊地 順子, 菊地 英毅, 榊原 純, 品川 尚文, 今野 哲
    肺癌 59 6 776 - 776 (NPO)日本肺癌学会 2019年11月
  • 國崎 守, 品川 尚文, 辻 康介, 佐藤 理子, 猪狩 智生, 佐藤 峰嘉, 高橋 宏典, 高島 雄太, 古田 恵, 庄司 哲明, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 今野 哲, 松野 吉宏
    気管支学 41 6 678 - 678 (NPO)日本呼吸器内視鏡学会 2019年11月
  • 榊原 純, 善家 善貴, 葉 清隆, 駄賀 晴子, 細見 幸生, 野上 尚之, 岡本 勇, 松本 慎吾, 黒田 咲子, 若林 将史, 野村 省吾, 石井 源一郎, 坪井 正博, 後藤 功一
    肺癌 59 6 867 - 867 (NPO)日本肺癌学会 2019年11月
  • 辻 康介, 榊原 純, 北井 秀典, 猪狩 智生, 佐藤 峰嘉, 高橋 宏典, 國崎 守, 庄司 哲明, 高島 雄太, 古田 恵, 水柿 秀紀, 朝比奈 肇, 菊地 順子, 菊地 英毅, 品川 尚文, 樋田 泰浩, 加賀 基知三, 大井 優子, 中條 聖子, 畑中 佳奈子, 畑中 豊, 松野 吉宏, 今野 哲
    気管支学 41 6 678 - 678 (NPO)日本呼吸器内視鏡学会 2019年11月
  • Kato Terufumi, 池田 喬哉, 梅村 茂樹, 宇田川 響, 仲地 一郎, 宮本 信吾, 榊原 純, 菅原 俊一, 西野 和美, 大橋 圭明, 中尾 美香, 松本 慎吾, 後藤 功一
    肺癌 59 6 537 - 537 2019年11月
  • 宮内 栄作, 渡邉 香奈, 戸井 之裕, 中村 敦, 福原 達朗, 千葉 亮祐, 秋山 真親, 榊原 純, 田中 寿志, 吉村 成央, 中川 拓, 井草 龍太郎, 峯村 浩之, 守 義明, 藤本 圭介, 松下 晴雄, 高橋 史朗, 井上 彰, 菅原 俊一, 前門戸 任
    肺癌 59 6 672 - 672 (NPO)日本肺癌学会 2019年11月
  • Jun Sakakibara-Konishi, Hidenori Kitai, Yasuyuki Ikezawa, Yutaka Hatanaka, Takaaki Sasaki, Ryohei Yoshida, Shinichi Chiba, Shingo Matsumoto, Koichi Goto, Hidenori Mizugaki, Naofumi Shinagawa
    Clinical lung cancer 20 5 e555-e559  2019年09月 [査読有り][通常論文]
  • Tomoo Ikari, Jun Sakakibara-Konishi, Gaku Yamamoto, Hidenori Kitai, Hidenori Mizugaki, Hajime Asahina, Eiki Kikuchi, Naofumi Shinagawa
    Clinical lung cancer 20 4 e531-e533  2019年07月 [査読有り][通常論文]
  • Gaku Yamamoto, Jun Sakakibara-Konishi, Tomoo Ikari, Hidenori Kitai, Hidenori Mizugaki, Hajime Asahina, Eiki Kikuchi, Naofumi Shinagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 5 e97-e99  2019年05月 [査読有り][通常論文]
  • Megumi Furuta, Hajime Kikuchi, Tetsuaki Shoji, Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Jun Sakakibara-Konishi
    Cancer science 110 5 1599 - 1608 2019年05月 [査読有り][通常論文]
     
    Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell-fate decisions and is tumor-suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss-of-function and gain-of-function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.
  • Saito Y, Kobayashi M, Yamada T, Sakakibara-Konishi J, Shinagawa N, Kinoshita I, Dosaka-Akita H, Iseki K
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2019年04月 [査読有り][通常論文]
  • 当院におけるFFPE検体、細胞診検体を用いたROS1融合遺伝子の検査成功率の検証
    北井 秀典, 榊原 純, 高橋 宏典, 國崎 守, 庄司 哲明, 高島 雄太, 古田 恵, 水柿 秀紀, 朝比奈 肇, 菊地 英毅, 品川 尚文, 畑中 佳奈子, 畑中 豊, 松野 吉宏, 大井 優子
    肺癌 59 1 112 - 112 (NPO)日本肺癌学会 2019年02月 [査読有り][通常論文]
  • Furuta M, Sakakibara-Konishi J, Kikuchi H, Yokouchi H, Nishihara H, Minemura H, Harada M, Yamazaki S, Akie K, Fujita Y, Takamura K, Kojima T, Harada T, Minami Y, Watanabe N, Oizumi S, Suzuki H, Nishimura M, Dosaka-Akita H, Isobe H
    Oncologist 24 11 e1172-e1179  Oncologist 2019年 [査読無し][通常論文]
     
    © AlphaMed Press 2019 Background: Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods: We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results: Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was obse
  • Saito Y, Yamada T, Kobayashi M, Sakakibara-Konishi J, Shinagawa N, Kinoshita I, Dosaka-Akita H, Iseki K
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 139 12 1601 - 1608 2019年 [査読有り][通常論文]
  • 高島 雄太, 榊原 純, 畑中 豊, 畑中 佳奈子, 大原 克仁, 大泉 聡史, 樋田 泰浩, 加賀 基知三, 木下 一郎, 秋田 弘俊, 松野 吉宏, 品川 尚文
    肺癌 58 6 633 - 633 (NPO)日本肺癌学会 2018年10月 [査読有り][通常論文]
  • Tetsuya Inoue, Norio Katoh, Yoichi M Ito, Tomoki Kimura, Yasushi Nagata, Kengo Kuriyama, Hiroshi Onishi, Tadamasa Yoshitake, Yoshiyuki Shioyama, Yusuke Iizuka, Koji Inaba, Koji Konishi, Masaki Kokubo, Katsuyuki Karasawa, Takuyo Kozuka, Kensuke Tanaka, Jun Sakakibara-Konishi, Ichiro Kinoshita, Hiroki Shirato
    Lung Cancer 122 107 - 112 2018年08月01日 [査読有り][通常論文]
     
    Objectives: Even with advanced image guidance, biopsies occasionally fail to diagnose small lung lesions, which are highly suggestive of primary lung cancer by radiological examination. The aim of this study was to evaluate the outcome of stereotactic body radiotherapy (SBRT) to treat small lung lesions clinically diagnosed as primary lung cancer. Materials and methods: This is a prospective, multi-institutional observation study. Strict inclusion and exclusion criteria were determined in a nation-wide consensus meeting and used to include patients who were clinically diagnosed with primary lung cancer using precise imaging modalities, for whom further surgical intervention was not feasible, who refused watchful waiting, and who were highly tolerable of SBRT with informed consent. SBRT was performed with 48 Gy in 4 fractions at the tumor isocenter. Results: From August 2009 to August 2014, 62 patients from 11 institutions were enrolled. Their median age was 80 years. The tumors ranged in size from 9 to 30 mm in diameter (median, 18 mm). The median follow-up interval was 55 months. The 3-year overall survival rate was 83.3% (95% confidence interval (CI) 71.1–90.7%) for all the patients and 94.7% (95% CI 68.1–99.2%) for the patients younger than 75 years. Local failure, regional lymph node metastases and distant metastases occurred in 4 (6.4%), 3 (4.8%) and 11 (17.7%) patients, respectively. Grades 3 and 4 toxicities were observed in 8 (12.9%) patients and 1 (1.6%) patient, respectively. No grade 5 toxicities were observed. Conclusions: SBRT is safe and effective for patients with small lung lesions clinically diagnosed as primary lung cancer that satisfied the proposed strict indication criteria as previously reported. A prospective interventional study is required to ascertain if SBRT is an alternative strategy for these patients.
  • Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
    Clinical lung cancer 19 4 352 - 359 2018年07月 [査読有り][通常論文]
     
    BACKGROUND: Approximately 20% to 30% of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKIs. MATERIALS AND METHODS: The characteristics of 124 NSCLC patients with EGFR mutations who had received EGFR-TKIs were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8 and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically. RESULTS: Primary resistance was observed in 13.7% of the patients (17 of 124). A significant difference in smoking history was observed between patients with primary resistance and those with non-primary resistance. A lower density of total TILs and negative PD-L1 expression on immunohistochemical analysis correlated significantly with primary resistance, in contrast to that with non-primary resistance. Moreover, the negative PD-L1 expression with low TIL density, indicating immune ignorant phenotype of tumor microenvironment, was observed in those with primary resistance with a significant difference. CONCLUSION: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs.
  • Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Eiki Kikuchi, Junko Kikuchi, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    Oncotarget 9 50 29379 - 29391 2018年06月29日 [査読有り][通常論文]
     
    Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma. To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells and inhibited Notch signaling and epithelial-mesenchymal transition in vitro. Numb overexpression also inhibited subcutaneous adenocarcinoma tumor growth. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.
  • Tetsuaki Shoji, Hidenori Mizugaki, Yasuyuki Ikezawa, Megumi Furuta, Yuta Takashima, Hajime Kikuchi, Houman Goudarzi, Hajime Asahina, Junko Kikuchi, Eiki Kikuchi, Jun Sakakibara-Konishi, Naofumi Shinagawa, Ichizo Tsujino, Masaharu Nishimura
    Internal medicine (Tokyo, Japan) 57 12 1769 - 1772 2018年06月15日 [査読有り][通常論文]
     
    This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed. Chemotherapy was then administered to control the tumor which was thought to have been the main cause of VTE, which had been treated by UFH. After tumor shrinkage was achieved by chemotherapy, we were able to successfully switch from UFH to edoxaban. Controlling the tumor size and activity enabled the use of edoxaban as maintenance therapy for VTE.
  • Yasuyuki Ikezawa, Hajime Asahina, Satoshi Oizumi, Masahiro Watanabe, Kei Takamura, Yasutaka Kawai, Noriyuki Yamada, Toshiyuki Harada, Ichiro Kinoshita, Yuka Fujita, Eisaku Miyauchi, Takahiro Ogi, Toraji Amano, Megumi Furuta, Jun Sakakibara-Konishi, Hiroshi Nishihara, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 80 5 955 - 963 2017年11月 [査読有り][通常論文]
     
    A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC. This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1-21) or S-1 (80-120 mg/day, days 1-14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL). From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3-4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL. S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib. UMIN000005308.
  • Morikawa N, Inoue A, Sugawara S, Maemondo M, Harada T, Harada M, Fujita Y, Katoh T, Yokouchi H, Watanabe H, Usui K, Suzuki T, Sakakibara-Konishi J, Nagai H, Kanbe M, Nukiwa T
    Lung cancer (Amsterdam, Netherlands) 111 38 - 42 2017年09月 [査読有り][通常論文]
     
    Objective: Carboplatin-based regimens are the standard regimens for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, the efficacies of these regimens are unsatisfactory. We previously identified carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) as promising new carboplatin-based regimens. Accordingly, we conducted a randomized phase II study to identify the appropriate regimen for future phase III trials. Materials and methods: Chemotherapy-naive patients with ES-SCLC were randomly assigned to receive 4-6 cycles of carboplatin [area under the curve (AUC) 5.0, day 1] plus irinotecan (70 mg/m(2), days 1 and 8) every 3 weeks (CI arm) or carboplatin (AUC 4.0, day 1) plus amrubicin (35 mg/m(2), days 1-3) every 3 weeks (CA arm). The primary endpoint was the overall response rate (ORR). The secondary endpoints were the progression-free survival, (PFS), overall survival (OS) and toxicity. Results: Between December 2009 and March 2013, 71 patients were enrolled. One patient in each arm did not receive any protocol treatment due to rapid disease progression. The characteristics of the treated patients were as follows: median age, 70 years (range 51-84 years); proportion of males, 84%. The ORRs were 79% and 89% in the CI and CA arms, respectively. The median PFS values were 5.1 and 6.2 months in the CI and CA arms, respectively [CA; hazard ratio (HR) = 0.59, 95% confidence interval (CI): 0.35-0.98, P = 0.042]. The grade 3 or higher toxicity severities were neutropenia (CI, 53% and CA, 89%), anemia (CI, 26% and CA, 20%), thrombocytopenia (CI, 18% and CA, 14%), and febrile neutropenia (CI, 12% and CA, 29%). No treatment-related deaths were observed. Conclusion: CA was numerically more effective than CI, with acceptable toxicity, in chemo-naive ES-SCLC patients. CA could be selected for future phase III trials.
  • Yuka Suimon, Wataru Saito, Kiriko Hirooka, Atsuhiro Kanda, Hidenori Kitai, Jun Sakakibara-Konishi, Susumu Ishida
    American Journal of Ophthalmology Case Reports 5 137 - 140 2017年04月01日 [査読有り][通常論文]
     
    Purpose To report an anti-recoverin antibody-positive cancer-associated retinopathy (anti-recoverin CAR) patient with remarkable improvements of visual function and outer retinal morphology following spontaneous regression of cancer. Observations A 65-year-old woman with small cell lung carcinoma developed progressive, bilateral vision loss with diffuse loss of the ellipsoid zone at the macula on optical coherence tomography and marked reduced responses of a- and b-waves on electroretinography. Western blot analysis led to a diagnosis of anti-recoverin CAR. The visual function and outer retinal morphology gradually improved following spontaneous regression of the cancer and the initiation of systemic corticosteroid. Subsequent intermittent chemotherapy and continuation of corticosteroid maintained reduction of the cancer and prevented the recurrence of CAR, with preservation of improvements of the visual function and macular outer retinal morphology. Conclusions and importance These results suggest that requirement for obtaining good visual prognosis in CAR patients is to make the cancer regress prior to falling into photoreceptor apotosis.
  • Sakakibara-Konishi J, Ikezawa Y, Oizumi S, Kikuchi J, Kikuchi E, Mizugaki H, Kinoshita I, Dosaka-Akita H, Nishimura M
    International journal of clinical oncology 22 2 257 - 268 2017年04月 [査読有り][通常論文]
     
    Inhibition of Notch by gamma-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis. The Notch-expressing NSCLC cell lines H460, A549, H1793, and HCC2429 were used. The combined antitumor effect of GSI and ABT-737 was evaluated using the MTT proliferation assay in vitro and in xenograft mouse models. The expression of the Notch pathway and Bcl-2 family was analyzed using Western blotting analysis when cells were treated with a single drug treatment or a combination treatment. GSI XX or ABT-737 alone inhibited cell proliferation in a dose-dependent manner, and combination drug treatment showed a synergistic antitumor effect in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to the single drug treatment. Phospho-Bcl-2 was downregulated and Bax was upregulated by both the single and combination drug treatments. Bim was induced by a single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim. Based on our data, we propose that the combination treatment is a promising strategy for NSCLC therapy.
  • Yasuyuki Ikezawa, Jun Sakakibara-Konishi, Hidenori Mizugaki, Satoshi Oizumi, Masaharu Nishimura
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 22 1 59 - 69 2017年02月 [査読有り][通常論文]
     
    Background The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor gamma secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation. Based on reports of Notch expression being activated through the hypoxia inducible factor 1 (HIF-1) under hypoxic conditions, we hypothesized that HIF-1 would be involved in radiation-induced Notch activation in NSCLC. Methods Changes in HIF-1 and Notch expression in two Notch expressing NSCLC cells line after radiation treatment were examined using Western blotting. Notch expression was evaluated after the suppression of HIF-1a by small interfering RNA. The cytotoxic effect of YC-1, a HIF inhibitor, GSI and radiation was examined using the MTT assay in vitro and the xenograft model. Result We found radiation-induced expression of HIF-1a protein at 2-6 h after treatment and upregulated expression of Notch3 protein at 24 h after treatment under hypoxic conditions. Specific suppression of HIF-1 alpha expression downregulated the radiation-induced Notch3 activation, suggesting that the Notch pathway is activated though HIF-1a after radiation. An antitumor effect of YC-1 was evident under hypoxic conditions only when there was simultaneous radiation treatment. GSI and YC-1 had a synergistic antitumor effect in vitro, and the combination of GSI and YC-1 showed the greatest radiosensitivity in vivo. Conclusion Radiation-induced upregulation of the Notch pathway and HIF-1a protein may be potential therapeutic targets for more effective radiation therapy.
  • Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura
    ONCOTARGET 8 6 10348 - 10358 2017年02月 [査読有り][通常論文]
     
    Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.
  • Taichi Takashina, Ichiro Kinoshita, Junko Kikuchi, Yasushi Shimizu, Jun Sakakibara-Konishi, Satoshi Oizumi, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    CANCER SCIENCE 107 7 955 - 962 2016年07月 [査読有り][通常論文]
     
    Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non-small-cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3-deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co-treatment with 3-deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co-treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co-treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co-treatment strongly suppressed EGFR signaling, not only in EGFR-wild-type NSCLC cells, but also in EGFR-mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co-treatment suppressed the in vivo tumor growth of EGFR-mutant, EGFR-tyrosine kinase-resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC.
  • Tomoaki Naka, Yutaka Hatanaka, Katsuji Marukawa, Hiromi Okada, Kanako C. Hatanaka, Jun Sakakibara-Konishi, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Tomoko Mitsuhashi, Yoshihiro Matsuno
    DIAGNOSTIC PATHOLOGY 11 38  2016年04月 [査読有り][通常論文]
     
    Background: Although asbestos acts as a potent carcinogen in pleural mesothelial and pulmonary epithelial cells, it still remains unclear whether asbestos causes specific and characteristic gene alterations in these different kinds of target cells, because direct comparison in an identical patient is not feasible. We experienced a rare synchronous collision tumor composed of malignant pleural mesothelioma (MPM) and primary pulmonary adenocarcinoma (PAC) in a 77-year-old man with a history of long-term smoking and asbestos exposure, and compared the DNA copy number alteration (CNA) and somatic mutation in these two independent tumors. Methods: Formalin-fixed paraffin-embedded (FFPE) tissues of MPM and PAC lesions from the surgically resected specimen were used. Each of these MPM and PAC lesions exhibited a typical histology and immunophenotype. CNA analysis using SNP array was performed using the Illumina Human Omni Express-12_FFPE (Illumina, San Diego, CA, USA) with DNA extracts from each lesion. Somatic mutation analysis using next-generation sequencing was performed using the TruSeq Amplicon Cancer Panel (Illumina). Results: The CNA analysis demonstrated a marked difference in the frequency of gain and loss between MPM and PAC. In PAC, copy number (CN) gain was detected more frequently and widely than CN loss, whereas in MPM there was no such obvious difference. PAC did not harbor CNAs that have been identified in asbestos-associated lung cancer, but did harbor some of the CNAs associated with smoking. MPM exhibited CN loss at 9p21.2-3, which is the most common genetic alteration in mesothelioma. Conclusion: In this particular case, asbestos exposure may not have played a primary role in PAC carcinogenesis, but cigarette smoking may have contributed more to the occurrence of CN gains in PAC. This comparative genetic analysis of two different lesions with same amount of asbestos exposure and cigarette smoke exposure has provided information on differences in the cancer genome related to carcinogenesis.
  • Tomoaki Naka, Yutaka Hatanaka, Katsuji Marukawa, Hiromi Okada, Kanako C. Hatanaka, Jun Sakakibara-Konishi, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Tomoko Mitsuhashi, Yoshihiro Matsuno
    DIAGNOSTIC PATHOLOGY 11 38  2016年04月 [査読有り][通常論文]
     
    Background: Although asbestos acts as a potent carcinogen in pleural mesothelial and pulmonary epithelial cells, it still remains unclear whether asbestos causes specific and characteristic gene alterations in these different kinds of target cells, because direct comparison in an identical patient is not feasible. We experienced a rare synchronous collision tumor composed of malignant pleural mesothelioma (MPM) and primary pulmonary adenocarcinoma (PAC) in a 77-year-old man with a history of long-term smoking and asbestos exposure, and compared the DNA copy number alteration (CNA) and somatic mutation in these two independent tumors. Methods: Formalin-fixed paraffin-embedded (FFPE) tissues of MPM and PAC lesions from the surgically resected specimen were used. Each of these MPM and PAC lesions exhibited a typical histology and immunophenotype. CNA analysis using SNP array was performed using the Illumina Human Omni Express-12_FFPE (Illumina, San Diego, CA, USA) with DNA extracts from each lesion. Somatic mutation analysis using next-generation sequencing was performed using the TruSeq Amplicon Cancer Panel (Illumina). Results: The CNA analysis demonstrated a marked difference in the frequency of gain and loss between MPM and PAC. In PAC, copy number (CN) gain was detected more frequently and widely than CN loss, whereas in MPM there was no such obvious difference. PAC did not harbor CNAs that have been identified in asbestos-associated lung cancer, but did harbor some of the CNAs associated with smoking. MPM exhibited CN loss at 9p21.2-3, which is the most common genetic alteration in mesothelioma. Conclusion: In this particular case, asbestos exposure may not have played a primary role in PAC carcinogenesis, but cigarette smoking may have contributed more to the occurrence of CN gains in PAC. This comparative genetic analysis of two different lesions with same amount of asbestos exposure and cigarette smoke exposure has provided information on differences in the cancer genome related to carcinogenesis.
  • Hidenori Kitai, Jun Sakakibara-Konishi, Satoshi Oizumi, Yoshihiko Hirohashi, Wataru Saito, Atsuhiro Kanda, Noriyuki Sato, Masaharu Nishimura
    LUNG CANCER 87 1 73 - 76 2015年01月 [査読有り][通常論文]
     
    Spontaneous regression (SR) is defined as the complete or partial disappearance of disease without anticancer treatments. We report a case of SR of small cell lung cancer (SCLC) combined with cancer associated retinopathy (CAR). A 65-year-old woman was admitted to our hospital to examine abnormal shadows of the lung with visual loss. She was diagnosed with SCLC associated with CAR. Subsequent chest X-ray and CT scan showed partial regression of both primary tumor and lymph node metastasis without anticancer treatment. Recoverin antigen was present on the tumor cells and anti-recoverin antibody was observed in the patient's serum. Activation of recoverin-specific antitumor cytotoxic T lymphocyte (CTL) was observed in this patient. SCLC was considered to reduce spontaneously by the activation of recoverin-specific antitumor CTL. To the best of our knowledge, this is the first report of SR in SCLC combined with CAR. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Hidenori Mizugaki, Jun Sakakibara-Konishi, Junko Kikuchi, Jun Moriya, Kanako C. Hatanaka, Eiki Kikuchi, Ichiro Kinoshita, Satoshi Oizumi, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 19 2 254 - 259 2014年04月 [査読有り][通常論文]
     
    CD133 is a membrane glycoprotein containing five transmembrane loops. Previous reports suggest that a CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal characteristics has biological features of a cancer stem cell. In addition, the presence of CD133-positive cells was associated with a significantly poorer prognosis for some solid tumors, compared to those with CD133-negative cells. However, the clinicopathological significance of CD133 in non-small cell lung cancer (NSCLC) remains controversial. We conducted immunohistochemical assessment of 161 NSCLCs surgically resected at Hokkaido University Hospital between 1982 and 1994 to evaluate correlations between CD133 expression and various clinicopathological features. CD133 expression was significantly correlated with pathological stages (pStages) II, III, and IV for the various NSCLC types analyzed and was an independent factor for unfavorable prognosis in this population (hazard ratio = 3.157, P = 0.015). CD133 expression was correlated with pStage and was predictive of unfavorable prognosis in patients with pStages II, III, and IV NSCLC. These results suggest the possibility of using CD133 as a novel prognostic marker in these patients.
  • 当院における悪性胸膜中皮腫27例の検討
    菊池 創, 朝比奈 肇, 北井 秀典, 池澤 靖元, 高階 太一, 品川 尚文, 榊原 純, 大泉 聡史, 西村 正治, 樋田 泰浩, 加賀 基知三, 井上 哲也, 加藤 徳雄
    肺癌 53 7 918 - 918 (NPO)日本肺癌学会 2013年12月 [査読有り][通常論文]
  • Tetsuya Inoue, Norio Katoh, Rikiya Onimaru, Shinichi Shimizu, Kazuhiko Tsuchiya, Ryusuke Suzuki, Jun Sakakibara-Konishi, Naofumi Shinagawa, Satoshi Oizumi, Hiroki Shirato
    Radiation Oncology 8 1 69  2013年03月21日 [査読有り][通常論文]
     
    Background: To clarify the clinical outcomes of two dose schedule of stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) using a real-time tumor-tracking radiation therapy (RTRT) system in single institution.Methods: Using a superposition algorithm, we administered 48 Gy in 4 fractions at the isocenter in 2005-2006 and 40 Gy in 4 fractions to the 95% volume of PTV in 2007-2010 with a treatment period of 4 to 7 days. Target volume margins were fixed irrespective of the tumor amplitude.Results: In total, 109 patients (79 T1N0M0 and 30 T2N0M0). With a median follow-up period of 25 months (range, 4 to 72 months), the 5-year local control rate (LC) was 78% and the 5-year overall survival rate (OS) was 64%. Grade 2, 3, 4, and 5 radiation pneumonitis (RP) was experienced by 15 (13.8%), 3 (2.8%), 0, and 0 patients, respectively. The mean lung dose (MLD) and the volume of lung receiving 20 Gy (V20) were significantly higher in patients with RP Grade 2/3 than in those with RP Grade 0/1 (MLD p = 0.002, V20 p = 0.003). There was no correlation between larger maximum amplitude of marker movement and larger PTV (r = 0.137), MLD (r = 0.046), or V20 (r = 0.158).Conclusions: SBRT using the RTRT system achieved LC and OS comparable to other SBRT studies with very low incidence of RP, which was consistent with the small MLD and V20 irrespective of tumor amplitude. For stage I NSCLC, SBRT using RTRT was suggested to be reliable and effective, especially for patients with large amplitude of tumor movement. © 2013 Inoue et al.; licensee BioMed Central Ltd.
  • Junko Kikuchi, Taichi Takashina, Ichiro Kinoshita, Eiki Kikuchi, Yasushi Shimizu, Jun Sakakibara-Konishi, Satoshi Oizumi, Victor E. Marquez, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    LUNG CANCER 78 2 138 - 143 2012年11月 [査読有り][通常論文]
     
    EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of PRC2 (polycomb repressive complex 2), which mediates histone methyltransferase activity and functions as transcriptional repressor involved in gene silencing. EZH2 is involved in malignant transformation and biological aggressiveness of several human malignancies. We previously demonstrated that non-small cell lung cancers (NSCLCs) also overexpress EZH2 and that high expression of EZH2 correlates with poor prognosis. Growing evidence indicates that EZH2 may be an appropriate therapeutic target in malignancies, including NSCLCs. Recently, an S-adenosyl-L-homocysteine hydrolase inhibitor, 3-Deazaneplanocin A (DZNep), has been shown to deplete and inhibit EZH2. The aim of this study was to determine the effect of DZNep in NSCLC cells. Knockdown of EZH2 by small-interfering RNA (siRNA) resulted in decreased growth of four NSCLC cell lines. MTT assays demonstrated that DZNep treatment resulted in dose-dependent inhibition of proliferation in the NSCLC cell lines with a half maximal inhibitory concentration (IC50) ranging from 0.08 to 0.24 mu M. Immortalized but non-cancerous bronchial epithelial and fibroblast cell lines were less sensitive to DZNep than the NSCLC cell lines. Soft agarose assays demonstrated that anchorage-independent growth was also reduced in all three NSCLC cell lines that were evaluated using this assay. Flow cytometry analysis demonstrated that DZNep induced apoptosis and G1 cell cycle arrest in NSCLC cells, which was partially associated with cyclin A decrease and p27(Kip1) accumulation. DZNep depleted cellular levels of EZH2 and inhibited the associated histone H3 lysine 27 trimethylation. These results indicated that an epigenetic therapy that pharmacologically targets EZH2 via DZNep may constitute a novel approach to treatment of NSCLCs. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
  • Jun Sakakibara-Konishi, Satoshi Oizumi, Junko Kikuchi, Eiki Kikuchi, Hidenori Mizugaki, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    BMC CANCER 12 286  2012年07月 [査読有り][通常論文]
     
    Background: The BH3-only members of the Bcl-2 protein family have been proposed to play a key role in the control of apoptosis and in the initiation of the apoptotic pathways. In this study, we evaluated the expression of Bim, Noxa, and Puma in non-small cell lung cancer (NSCLC). Methods: A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Bim, Noxa, and Puma expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes were analyzed. Results: Immunohistochemical reactivity for Bim, Noxa, and Puma was detected in the cytoplasm of the tumor cells. Bim expression was associated with several clinicopathological factors, including sex (p < 0.001), smoking habit (p = 0.03), pathological histology (p = 0.001), pathological T stage (p = 0.03), pathological disease stage (p = 0.02), and differentiation of tumor (p < 0.001). Multivariate logistic regression analysis showed a significant correlation between low Bim expression and squamous cell carcinoma (p = 0.04), in addition to a correlation between high Bim expression and well differentiated tumors (p = 0.02). Analysis of cellular biological expression demonstrated a link between low Bim expression and high Ki67. While Noxa expression was also shown to be correlated with both smoking habit (p = 0.02) and the pathological histology (p = 0.03), there was no strong association observed between the expression and the clinical features when they were examined by a multivariate logistic regression analysis. No correlations were noted between Puma expression and any of the variables. Our analyses also indicated that the expression levels of the BH3-only proteins were not pertinent to the survival outcome. Conclusions: The current analyses demonstrated that Bim expression in the NSCLCs was associated with both squamous cell carcinoma histology and tumor proliferation.
  • Mizugaki H., Sakakibara-Konishi J., Ikezawa Y., Kikuchi J., Kikuchi E., Oizumi S., Dang T. P., Nishimura M.
    British Journal of Cancer 106 12 1953 - 1959 Cancer Research UK 2012年06月05日 
    BACKGROUND: Notch receptor has an important role in both development and cancer. We previously reported that inhibition of the Notch3 by γ-secretase inhibitor (GSI) induces apoptosis and suppresses tumour proliferation in non-small-cell lung cancer. Although radiation is reported to induce Notch activation, little is known about the relationship between radiation and Notch pathway. METHODS: We examined the effect of combining GSI and radiation at different dosing in three Notch expressing lung cancer cell lines. The cytotoxic effect of GSI and radiation was evaluated using MTT assay and clonogenic assay in vitro and xenograft models. Expressions of Notch pathway, mitogen-activated protein kinase (MAPK) pathway and Bcl-2 family proteins were investigated using western blot analysis. RESULTS: We discovered that the antitumour effect of combining GSI and radiation was dependent on treatment schedule. γ-Secretase inhibitor administration after radiation had the greatest growth inhibition of lung cancer in vitro and in vivo. We showed that the combination induced apoptosis of lung cancer cell lines through the regulation of MAPK and Bcl-2 family proteins. Furthermore, activation of Notch after radiation was ameliorated by GSI administration, suggesting that treatment with GSI prevents Notch-induced radiation resistance. CONCLUSION: Notch has an important role in lung cancer. Treatment with GSI after radiation can significantly enhance radiation-mediated tumour cytotoxicity.
  • Noriyuki Yamada, Satoshi Oizumi, Hajime Asahina, Naofumi Shinagawa, Eiki Kikuchi, Junko Kikuchi, Jun Sakakibara-Konishi, Tomoaki Tanaka, Kunihiko Kobayashi, Koichi Hagiwara, Masaharu Nishimura
    ONCOLOGY 82 6 341 - 346 2012年 [査読有り][通常論文]
     
    Objectives: Cytological examination of samples obtained by bronchoscopy is a useful method for establishing the diagnosis of non-small cell lung cancer (NSCLC). However, the utility of a highly sensitive method for the detection of epidermal growth factor receptor (EGFR) mutation in the cytological specimens has not been fully evaluated. Methods: We retrospectively examined the efficacy of the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method for detecting EGFR mutations in 122 bronchoscopic cytological specimens from NSCLC patients. Results: Overall, 41 specimens (33.6%) were positive for EGFR mutation. Twenty-nine (39.7%) of 73 specimens obtained by using endobronchial ultrasonography with a guide sheath, 7 (33.3%) of 21 specimens obtained under direct vision by using a conventional bronchoscope, 4 (36.4%) of 11 specimens obtained by using an ultrathin bronchoscope, and 1 (5.9%) of 17 specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration were positive for EGFR mutation. Furthermore, among 22 resected NSCLC cases, the EGFR mutation status obtained from bronchoscopic materials was consistent with the status obtained from surgical samples, with the exception of 1 case. Conclusion: The detection of EGFR mutation by subjecting bronchoscopic cytological specimens to a PNA-LNA PCR clamp assay proves useful. Copyright (C) 2012 S. Karger AG, Basel
  • Onimaru R, Katoh N, Inoue T, Shimizu S, Shinagawa N, Sakakibara-Konishi J, Oizumi S, Shirato H
    International Journal of Radiation Oncology Biology Physics 84 3 S575  2012年 [査読有り][通常論文]
  • Jun Sakakibara-Konishi, Satoshi Oizumi, Ichiro Kinoshita, Naofumi Shinagawa, Junko Kikuchi, Mototsugu Kato, Tetsuya Inoue, Norio Katoh, Rikiya Onimaru, Hiroki Shirato, Hirotoshi Dosaka-Akita, Masaharu Nishimura
    LUNG CANCER 74 2 248 - 252 2011年11月 [査読有り][通常論文]
     
    Introduction: Although paclitaxel with carboplatin and thoracic radiotherapy has improved survival for patients with locally advanced unresectable non-small cell lung cancer (NSCLC), the optimal dose of paclitaxel has not been well defined in Japan. This study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of paclitaxel in combination with carboplatin and concurrent real-time tumor-tracking thoracic radiation therapy (thoracic RTRT). Patients and methods: Previously untreated patients with histologically confirmed, locally advanced unresectable NSCLC were eligible. Before treatment, gold markers were inserted into the lung and the mediastinum of all patients. RTRT comprised a total of 66 Gy at 2 Gy/fraction, 5 days/week, for 7 weeks. Patients received paclitaxel at a starting dose of 40 mg/m(2) followed by carboplatin at a fixed area under the curve (AUC) of 2, as a weekly regimen with RTRT. The dose of paclitaxel was escalated by 5 mg/m(2) per level. Results: Eight patients with locally advanced unresectable NSCLC were enrolled and treated with two dose levels of paclitaxel (40 mg/m(2) and 45 mg/m(2)), carboplatin (AUC = 2) and RTRT. No dose limiting toxicities (DLTs) were observed at Level 1 (paclitaxel, 40 mg/m(2) and carboplatin, AUC = 2). At Level 2 (paclitaxel, 45 mg/m(2) and carboplatin, AUC = 2), two of five patients experienced DLTs, in the form of esophagitis and discontinuation of chemotherapy more than twice. The MTD and RD of paclitaxel were thus defined as 45 mg/m(2) and 40 mg/m(2), respectively. Conclusions: This phase I study was well tolerated and the RD of paclitaxel and carboplatin with RTRT is 40 mg/m(2) at AUC = 2, respectively. Further studies are warranted to evaluate the efficacy of this regimen. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Junko Kikuchi, Ichiro Kinoshita, Yasushi Shimizu, Eiki Kikuchi, Kayoko Takeda, Hiroyuki Aburatani, Satoshi Oizumi, Jun Konishi, Kichizo Kaga, Yoshihiro Matsuno, Michael J. Birrer, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    LUNG CANCER 72 2 229 - 237 2011年05月 [査読有り][通常論文]
     
    Background: Minichromosome maintenance (MCM) proteins 2-7 form a complex essential for the initiation of DNA replication. In the process to screen expression changes related to growth suppression of non-small cell lung cancer (NSCLC) cells by a cJun dominant-negative mutant, we found that reduced expression of MCM4 was correlated with this growth suppression. Method: We determined the relevance of MCM4 in proliferation of NSCLC by downregulating its expression with small-interfering RNA in three NSCLC cell lines. We then immunohistochemically analyzed MCM4 expression in 156 surgically resected NSCLCs to correlate clinicopathologic characteristics. Results: MCM4 downregulation reduced proliferation in two cell lines. MCM4 expression was higher in cancer cells than in adjacent normal bronchial epithelial cells (p < 0.001). High MCM4 expression was correlated with male gender, heavy smoking, poorer differentiation and non-adenocarcinoma histology (p < 0.001, respectively). High MCM4 expression was also correlated with proliferation markers, Ki-67 and cyclin E expression (p < 0.001, respectively). MCM4 expression was not associated with survival. Conclusion: MCM4 may play an essential role in the proliferation of some NSCLC cells. Taken together with higher expression in NSCLCs and its correlation with clinicopathologic characteristics such as non-adenocarcinoma histology. MCM4 may have potential as a therapeutic target in certain population with NSCLCs. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • 池澤 靖元, 品川 尚文, 高階 太一, 小倉 粋, 伊藤 健一郎, 竹内 裕, 水柿 秀紀, 山田 範幸, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 西村 正治, 須甲 憲明
    気管支学 33 1 58 - 58 特定非営利活動法人 日本呼吸器内視鏡学会 2011年
  • Sakakibara-Konishi J, Oizumi S, Kinoshita I, Shinagawa N, Kikuchi J, Kato M, Inoue T, Katoh N, Onimaru R, Shirato H, Dosaka-Akita H, Nishimura M
    Lung Cancer 74 2 248 - 52 2011年 [査読有り][通常論文]
  • Noriyuki Yamada, Satoshi Oizumi, Eiki Kikuchi, Naofumi Shinagawa, Jun Konishi-Sakakibara, Atsushi Ishimine, Keisuke Aoe, Kenichi Gemba, Takumi Kishimoto, Toshihiko Torigoe, Masaharu Nishimura
    CANCER IMMUNOLOGY IMMUNOTHERAPY 59 10 1543 - 1549 2010年10月 [査読有り][通常論文]
     
    Defects in human leukocyte antigen (HLA) class I expression may allow tumor cells to escape immune recognition. T cell infiltration is associated with a good prognosis in many cancers. However, the role of HLA class I expression and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM) has not been fully analyzed. In the present study, we investigated the immune profiles and conducted outcome analyses of MPM patients. HLA class I expression and TILs (CD4(+), CD8(+), and NK cells) were detected by immunohistochemistry in a series of 44 MPM cases. To detect HLA class I expression, specimens were stained with the anti-pan HLA class I monoclonal antibody EMR8-5. The expression of HLA class I was positive in all patients. There was no case that showed negative HLA class I expression. The density of CD4(+) and CD8(+) TILs were strongly correlated (R = 0.76, p < 0.001). A high density of CD8(+) TILs was a significantly better prognostic factor for the survival of patients with extrapleural pneumonectomy (p < 0.05). Multivariate analysis revealed that a high density of CD8(+) TILs is an independent prognostic factor for patients who underwent extrapleural pneumonectomy. The presence of intratumoral CD8(+) T cells was correlated with an improved clinical outcome, raising the possibility that CD8(+) T cells might play a pivotal role in the antitumor immune response against MPMs. Thus, the stimulation of CD8(+) lymphocytes might be an efficacious immunotherapy for MPM patients.
  • Junko Kikuchi, Ichiro Kinoshita, Yasushi Shimizu, Eiki Kikuchi, Jun Konishi, Satoshi Oizumi, Kichizo Kaga, Yoshihiro Matsuno, Masaharu Nishimura, Hirotoshi Dosaka-Akita
    CANCER 116 12 3015 - 3024 2010年06月 [査読有り][通常論文]
     
    BACKGROUND: The polycomb group genes Bmi1 polycomb ring finger oncogene (Bmi1) and enhancer of zeste homolog 2 (EZH2) function as transcriptional repressors involved in gene silencing and in the malignant transformation and biologic aggressiveness of several human carcinomas. In the current study, the authors evaluated Bmi1 and EZH2 protein expression in specimens of human nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted an immunohistochemical assessment of 157 surgically resected NSCLCs to evaluate the correlation between Bmi1 and EZH2 expression and various features, including clinical, clinicopathologic, and biologic characteristics. RESULTS: Normal bronchial epithelia revealed abundant expression of Bmi1 and sporadic expression of EZH2. Patients who had high EZH2 expression in tumor cells had a poorer prognosis than patients who had low EZH2 expression in tumor cells all pathologic stages of NSCLC (P=.001) and in pathologic stage I NSCLC (P=.006). Multivariate analysis revealed that high EZH2 expression was a independent, unfavorable prognostic factor in patients with pathologic stage I disease (P=.048). High EZH2 expression was correlated significantly with nonadenocarcinoma histology (P=.001), moderate and poor differentiation (P=.001), advanced pathologic tumor classification (P=.02), and high Ki-67 and cyclin E labeling indices (P<.001). Bmi1 expression, in contrast, was not a significant prognostic factor and was not correlated with any clinicopathologic factors other than early pathologic tumor classification. CONCLUSIONS: Bmi1 and EZH2 had characteristic and distinctive expression in NSCLCs. High EZH2 expression was correlated with tumor aggressiveness and may provide a novel prognostic marker for NSCLCs. Cancer 2010;116:3015-24. (C) 2010 American Cancer Society.
  • J. Konishi, F. Yi, X. Chen, H. Vo, D. P. Carbone, T. P. Dang
    ONCOGENE 29 4 589 - 596 2010年01月 [査読有り][通常論文]
     
    Notch signaling is a highly conserved pathway important for normal embryonic development and cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the epidermal growth factor receptor (EGFR) pathway was also inhibited, suggesting significant cross-talk between the two pathways. How Notch3 and epidermal growth factor receptor-mitogen-activated protein kinase (EGFR-MAPK) pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein, via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using c-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were observed to be enhanced compared with either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR-ras-MAPK signaling. Thus, our data support the hypothesis that Notch3 not only has a crucial role in lung cancer through regulating apoptosis, but also cooperates with the EGFR-MAPK pathway in modulating Bim. Oncogene (2010) 29, 589-596; doi: 10.1038/onc.2009.366; published online 2 November 2009
  • Satoshi Konno, Satoshi Oizumi, Naofumi Shinagawa, Eiki Kikuchi, Jun Konishi, Kenichiro Ito, Nobuyuki Hizawa, Akihiro Takiyama, Shinya Tanaka, Masaharu Nishimura
    INTERNAL MEDICINE 49 8 771 - 775 2010年 [査読有り][通常論文]
     
    Primary mediastinal liposarcoma was observed in a 73-year-old man. Because of tight adhesions to adjacent tissues, neither complete resection nor surgical debulking of the tumor was possible. A T-tube was inserted into the patient's trachea for severe dyspnea, and he was treated with radiotherapy and an oral peroxisome proliferator-activated receptor-gamma agonist. The patient died 6 years after the initial diagnosis. Autopsy revealed liposarcoma composed of 3 subtypes in the primary tumor: well-differentiated, dedifferentiated, and round cell components. Round cell and dedifferentiated liposarcomas were predominantly observed in the metastatic nodules.
  • 竹内 裕, 菊地 英毅, 品川 尚文, 池澤 靖元, 高階 太一, 小倉 粋, 伊藤 健一郎, 水柿 秀紀, 山田 範幸, 朝比奈 肇, 菊地 順子, 小西 純, 大泉 聡史, 松野 吉宏, 西村 正治
    気管支学 32 S155  特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 池澤 靖元, 品川 尚文, 高階 太一, 小倉 粋, 伊藤 健一郎, 竹内 裕, 水柿 秀紀, 山田 範幸, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 須甲 憲明, 西村 正治
    気管支学 32 S173  特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 高階 太一, 品川 尚文, 池澤 靖元, 小倉 粋, 伊藤 健一郎, 竹内 裕, 水柿 秀紀, 山田 範幸, 朝比奈 肇, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 西村 正治
    気管支学 32 S173  特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 竹内 裕, 品川 尚文, 小倉 粋, 河井 康孝, 伊藤 健一郎, 水柿 秀紀, 山田 範幸, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 西村 正治, 井上 哲也, 加藤 徳雄, 鬼丸 力也, 白土 博樹
    気管支学 32 1 80 - 80 特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 品川 尚文, 小倉 粋, 河井 康孝, 伊藤 健一郎, 竹内 裕, 水柿 秀紀, 山田 範幸, 菊地 順子, 菊地 英毅, 小西 純, 大泉 聡史, 西村 正治, 大岡 智学, 松居 喜郎
    気管支学 32 1 82 - 82 特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 小倉 粋, 品川 尚文, 河井 康孝, 伊藤 健一郎, 竹内 裕, 水柿 秀紀, 山田 範幸, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 西村 正治
    気管支学 32 1 80 - 81 特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 肝転移にて再発し、肝動脈化学塞栓療法が奏功した肺カルチノイドの1例
    竹内 裕, 菊地 英毅, 竹中 芳子, 河井 康孝, 小西 純, 大泉 聡史, 西村 正治, 中馬 誠, 中西 満, 作原 祐介, 阿保 大介
    肺癌 49 7 1056 - 1056 (NPO)日本肺癌学会 2009年12月
  • Satoshi Oizumi, Koichi Yamazaki, Hiroshi Yokouchi, Jun Konishi, Fumihiro Hommura, Tetsuya Kojima, Hiroshi Isobe, Masaharu Nishimura
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 14 2 125 - 129 2009年04月 [査読有り][通常論文]
     
    Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC. The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0-1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions. Treatment consisted of five dose levels, with amrubicin 35-45 mg/m(2) administered as a 5-min intravenous infusion on days 1-3 and vinorelbine 15-25 mg/m(2) given as a 1-h intravenous infusion on days 1 and 8, every 3 weeks. All patients had received carboplatin and paclitaxel as first-line therapy. Dose-limiting toxicity (DLT) was seen in two of six patients (febrile neutropenia and deep vein thrombosis ) at level 1, allowing us to conduct level 2. At level 2, all three patients experienced DLT (leucopenia a parts per thousand yen4 days in one patient; febrile neutropenia in three patients; and infection in two patients), and this level was determined as the MTD. Subsequently, level 1 (amrubicin 35 mg/m(2) and vinorelbine 15 mg/m(2)) was defined as the RD. Responses in the nine patients included a partial response in one patient and stable disease in four patients. As second-line therapy, the RD of the combination of amrubicin and vinorelbine is 35 mg/m(2) and 15 mg/m(2), respectively. Further study should proceed to clarify the efficacy of this regimen.
  • 山田 範幸, 大泉 聡史, 朝比奈 肇, 菊地 英毅, 菊地 順子, 小西 純, 品川 尚文, 小林 国彦, 宮澤 仁志, 田中 知明, 萩原 弘一, 西村 正治
    気管支学 31 S117  特定非営利活動法人 日本呼吸器内視鏡学会 2009年
  • 竹内 裕, 品川 尚文, 小倉 粋, 河井 康孝, 伊藤 健一郎, 水柿 秀紀, 山田 範幸, 菊地 英毅, 菊地 順子, 小西 純, 井上 哲也, 加藤 徳雄, 鬼丸 力也, 白土 博樹, 大泉 聡史, 西村 正治
    気管支学 31 S118  特定非営利活動法人 日本呼吸器内視鏡学会 2009年
  • 小倉 粋, 品川 尚文, 河井 康孝, 伊藤 健一郎, 竹内 裕, 水柿 秀紀, 山田 範幸, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 西村 正治
    気管支学 31 S95  特定非営利活動法人 日本呼吸器内視鏡学会 2009年
  • 品川 尚文, 大泉 聡史, 山田 範幸, 水柿 秀紀, 伊藤 健一郎, 竹内 裕, 菊地 英毅, 菊地 順子, 小西 純, 西村 正治
    気管支学 31 1 40 - 41 特定非営利活動法人 日本呼吸器内視鏡学会 2009年
  • 水柿 秀紀, 品川 尚文, 今野 哲, 伊藤 健一郎, 竹内 裕, 山田 範幸, 朝比奈 肇, 菊地 英毅, 菊地 順子, 小西 純, 大泉 聡史, 西村 正治
    気管支学 31 1 42 - 42 特定非営利活動法人 日本呼吸器内視鏡学会 2009年
  • Masaru Suzuki, Hajime Asahina, Jun Konishi, Koichi Yamazaki, Masaharu Nishimura
    INTERNAL MEDICINE 47 6 533 - 536 2008年 [査読有り][通常論文]
     
    Gefitinib, the epidermal growth factor receptor tyrosine kinase inhibitor, is effective for patients with non-small cell lung cancer. However, a serious adverse effect, interstitial lung disease ILD), has been reported. The re-administration of gefitinib might be considered when there is no other choice of treatment and a therapeutic effect can be expected; however, there is no published data on the safety of restarting gefitinib after its discontinuation in cases suspected of having gefitinib-induced ILD. We report a case with recurrent gefitinib-induced ILD, which suggests that re-administration of gefitinib should be considered cautiously in patients who have previously developed gefitinib-induced ILD.
  • Jun Konishi, Keiko S. Kawaguchi, Huan Vo, Nobuhiro Haruki, Adriana Gonzalez, David P. Carbone, Thao P. Dang
    CANCER RESEARCH 67 17 8051 - 8057 2007年09月 [査読有り][通常論文]
     
    Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms. Genes that are important for normal differentiation play a role in cancer when their normal functions became dysregulated. Notch signaling has been shown to promote and maintain survival of many types of cancers, and we previously have shown that Notch3 plays an important role in lung cancer. In this study, we showed that a high percentage of lung cancer lines expressed Jagged1, Notch receptors, and their transcriptional target genes (HES1, Hey1), suggesting that the Notch pathway plays an important role in lung cancer biology. Thus, inhibition of Notch receptor activation represents a compelling treatment strategy. Notch activation requires proteolytic cleavage of the receptor by gamma-secretase protein complex. In this study, we determined the ability of MRK-003, a gamma-secretase inhibitor, to inhibit Notch3 signaling, growth, and apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models. We also found that MRK-003 inhibited Notch3 signaling, reduced tumor cell proliferation, inhibited serum independence, and induced apoptosis. This drug had no effect when Notch3 expression was knocked down using small interfering RNA (siRNA), suggesting that the observed effects were mediated by specific action on this receptor. In conclusion, these results support the hypothesis that inhibition of Notch activation using gamma-secretase inhibitor represents a potential new approach for the targeted therapy of lung cancer.
  • Hiroshi Yokouchi, Koichi Yamazaki, Ichiro Kinoshita, Jun Konishi, Hajime Asahina, Noriaki Sukoh, Masao Harada, Kenji Akie, Shigeaki Ogura, Takashi Ishida, Mitsuru Munakata, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    BMC CANCER 7 51  2007年03月 [査読有り][通常論文]
     
    Background: Gefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments. Method: We retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response. Results: The best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments. Conclusion: Patients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.
  • Yokouchi H, Chamoto K, Wakita D, Yamazaki K, Shirato H, Takeshima T, Dosaka-Akita H, Nishimura M, Yue Z, Kitamura H, Nishimura T
    Clinical & experimental metastasis 24 533 - 540 7 2007年 [査読有り][通常論文]
  • Megumi Nakadate, Koichi Yamazaki, Jun Konishi, Ichiro Kinoshita, Noriaki Sukoh, Masao Harada, Kenji Akie, Shigeaki Ogura, Takashi Ishida, Mitsuru Munakata, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
    ANTICANCER RESEARCH 26 5B 3767 - 3772 2006年09月 [査読有り][通常論文]
     
    Background: The optimal schedule of taxane administration has been an area of active interest in several clinical trials. Patients and Methods: To evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy, a phase H study was conducted for chemo-naive, advanced non-small cell lung cancer (NSCLC) patients. Patients received paclitaxel 100 mg/m(2) on days 1, 8 and 15, and carboplatin with the target dose of area under the curve of 6 on day I every 28 days. Results: Forty patients were enrolled. Overall response rate and survival at one year by intent-to-treat analyses was 35% and 57.5%, respectively. The median survival time was 12.2 months. Twenty-two patients (56%) had grade 3 or greater neutropenia. Grade 3 sensory and motor neuropathy were seen in one patient (3%). Conclusion: Carboplatin and weekly paclitaxel combination chemotherapy is an active and feasible regimen for patients with advanced NSCLC.
  • J Konishi, K Yamazaki, Kinoshita, I, H Isobe, S Ogura, S Sekine, T Ishida, R Takashima, M Nakadate, S Nishikawa, T Hattori, H Asahina, M Imura, E Kikuchi, J Kikuchi, N Shinagawa, H Yokouchi, M Munakata, H Dosaka-Akita, M Nishimura
    ANTICANCER RESEARCH 25 1B 435 - 441 2005年01月 [査読有り][通常論文]
     
    Background: Gefitinib is an oral agent that inhibits the tyrosine kinase of epidermal growth factor receptor (EGFR), which had antitumor activity in patients with previously treated non-small cell lung cancer (NSCLC). We analyzed the efficacy, toxicity and overall survival time of gefitinib treatment in patients with NSCLC. Patients and Methods: One hundred and twenty-two patients with NSCLC, who received gefitinib between 2002 and 2004 in our institutes, were evaluated retrospectively. Results: The objective response rate was 24.6%. The variables identified as significant in univariate analysis included gender and smoking habit. The median overall survival time was 14.4 months. Significant variables associated with improved survival included good performance status (PS), female, adenocarcinoma and never smoked status, while never smoked status and good PS were independent prognostic factors in multivariate analysis. Four patients (3.3%) developed interstitial pneumonitis associated with gefitinib. Conclusion: Gefitinib showed favorable antitumor activity in females, never smokers and adenocarcinoma.
  • 朝比奈 肇, 山崎 浩一, 高島 理央, 中舘 恵, 西川 就, 猪村 帝, 菊地 英毅, 菊地 順子, 品川 尚文, 小西 純, 横内 浩, 西村 正治, 小野寺 祐也, 浅野 文祐
    気管支学 27 3 170 - 170 特定非営利活動法人 日本呼吸器内視鏡学会 2005年
  • 菊地 英毅, 山崎 浩一, 朝比奈 肇, 猪村 帝, 菊地 順子, 小西 純, 品川 尚文, 横内 浩, 小野寺 裕也, 西村 正治
    気管支学 27 1 43 - 49 特定非営利活動法人 日本呼吸器内視鏡学会 2005年 
    背景. 以前我々は直径30mm以下の肺末梢病変に対し1.4mm径超音波プローブ(XUM-S20-17R, オリンパス)を用いたEBUS-GSガイド下経気管支生検を施行し, 24病変中19病変(79%)がエコー下に確認可能であり, 14病変(58%)で細胞病理学的確定診断に至ったことを報告した. しかし, キュレット型誘導子の操作性が悪い, 検体量が不十分な症例があるなどの問題点があった. 目的. 問題点を改善するために誘導子に改良を加え, また症例によっては1.7mm径超音波プローブ(UM-S20-20R, オリンパス)を用いたEBUS-GSを施行することとし, 肺末梢病変の経気管支生検に対するEBUS-GSの有用性を再検討した. 対象. 2003年7月から2004年5月までに当科にてEBUS-GSガイド下経気管支生検を施行した肺末梢病変患者, 連続55名58病変(平均径は24.0±11.5mm). 結果. 50例(86.2%)で病変の描出が可能であり, 41例(70.7%)で細胞病理学的確定診断がなされた. またエコーで描出できた病変に限ると悪性病変37例のうち35例(94.6%)が確定診断可能であり, 良性病変13例のうち6例(46.2%)で確定診断に至った. 1.4mm径EBUS-GSでは改良型キュレット型誘導子は気管支を選択する際の操作性も良好で, 超音波プローブの誘導に有用であった. 1.7mm径プローブを用いたEBUS-GSは1.4mm径プローブを用いたEBUS-GSに比べて病理組織学的診断に至る割合が高く, 特に良性病変で有用であると考えられた. 結論. 肺末梢病変診断に際し, 改良型キュレットを用いたEBUS-GSガイド下経気管支生検は有用であると考えられた. また, 症例にあわせて1.4mm径と1.7mm径の超音波プローブを使い分けることも重要と考えられた.
  • 品川 尚文, 山崎 浩一, 高島 理央, 中舘 恵, 西川 就, 朝比奈 肇, 菊地 英毅, 菊地 順子, 小西 純, 横内 浩, 福元 伸一, 西村 正治, 小野寺 裕也, 浅野 文祐
    気管支学 27 3 206 - 206 特定非営利活動法人 日本呼吸器内視鏡学会 2005年
  • Yoshida T, Harada T, Fuke S, Konishi J, Yamazaki K, Kaji M, Morikawa T, Ota S, Itoh T, Dosaka-Akita H, Nishimura M
    Respiratory care 49 12 1522 - 1524 12 2004年12月 [査読有り][通常論文]
     
    We report a case of lung adenocarcinoma in which cystic lesions enlarged and multiloculated over 2 years. Histological examination of the resected specimen found proliferation of nonmucinous adenocarcinoma cells along the alveolar walls, revealing bronchioloalveolar cell carcinoma type extension. In cystic lesions, particularly those not associated with inflammation, lung adenocarcinoma, particularly bronchioloalveolar cell carcinoma type, should be a diagnostic consideration. .
  • J Konishi, K Yamazaki, H Yokouchi, N Shinagawa, K Iwabuchi, M Nishimura
    HUMAN IMMUNOLOGY 65 11 1377 - 1388 2004年11月 [査読有り][通常論文]
     
    The activation of human Valpha24(+)-Vbeta11(+) natural killer T cells (NKT) cells (Valpha24 NKT cells) induces effective antitumor responses with secondary immune effects through activation of conventional T cells and natural killer cells. In this study, we attempted to analyze the characteristics of human NKT cells in lung cancer patients. Valpha24 NKT cells stimulated with alpha-GalCer from healthy volunteers exhibited direct cytotoxic activity against two (RERF-LC-OK and PC-3) of seven human lung cancer cell lines studied. Cytotoxicity by Valpha24 NKT cells against human lung cancer cells was dependent on the perforin pathway and independent of Fas/FasL pathway. Intracellular adhesion molecule (ICAM)-1 expression on tumor cells was clearly associated with the cytotoxicity of Va24 NKT cells. On the other hand, the proportion of Va24 NKT cells in the patients with lung cancer was lower than that in the healthy volunteers. Furthermore, the proliferative response of Valpha24 NKT cells to alpha-GalCer was significantly lower in the peripheral blood mononuclear cells in the patients with lung cancer. Addition of granulocyte colony-stimulating factor moderately restored the low proliferative response of Valpha24 NKT cells in the patients with lung cancer, however the percentage by which the response was restored in these patients was still lower than the natural response in healthy volunteers. These results suggest that Valpha24 NKT cells may play a pivotal role or the antitumor response in lung cancer. (C) American Society for Histocompatibility and Immunogenetics, 2004. Published by Elsevier Inc.
  • J Kikuchi, K Yamazaki, Kinoshita, I, H Asahina, M Imura, E Kikuchi, J Konishi, N Shinagawa, H Oki, H Dosaka-Akita, M Nishimura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 34 9 505 - 509 2004年09月 [査読有り][通常論文]
     
    Objective: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. Methods: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. Results: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. Conclusion: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.
  • J Konishi, K Yamazaki, M Azuma, Kinoshita, I, H Dosaka-Akita, M Nishimura
    CLINICAL CANCER RESEARCH 10 15 5094 - 5100 2004年08月 [査読有り][通常論文]
     
    Purpose: B7-H1/PD-L1 (B7-H1) and B7-DC/PD-L2 (B7-DC) are ligands for the receptor PD-1, which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of B7-H1 and B7-DC in tumor specimens of non-small cell lung cancer and their relationships with clinicopathological variables and postoperative survival. Furthermore, we examined the correlation between B7-H1 expression on tumor cells and the number of tumor-infiltrating lymphocytes (TILs) or PD-1 expression on TILs. Experimental Design: The expression of B7-H1 and B7-DC in 52 surgically resected specimens of non-small cell lung cancer was evaluated immunohistochemically. Results: Expression of B7-H1 and B7-DC was focally observed in all non-small cell lung cancer tumor specimens. No relationship was found between the expression of B7-H1 or B7-DC and clinicopathological variables or postoperative survival. However, in the same sections evaluated, significantly fewer TILs were identified in B7-H1-positive tumor regions than in B7-H1-negative tumor regions in a subset of five patients (P = 0.01). Moreover, the percentage of TILs expressing PD-1 was significantly lower in B7-H1-positive tumor regions than in B7-H1-negative tumor regions (P = 0.02). Conclusions: The expression of B7-H1 on tumor cells in local areas reciprocally correlated with the number of TILs, and this may contribute to negative regulation in antitumor immune responses in non-small cell lung cancer.
  • J Konishi, K Yamazaki, K Chikai, K Nagashima, K Sakai, Kinoshita, I, H Dosaka-Akita, M Nishimura
    INTERNAL MEDICINE 43 7 602 - 606 2004年07月 [査読有り][通常論文]
     
    We report a case of a 71-year-old man who presented with cerebellar dysfunction. He was diagnosed as having squamous cell carcinoma of the lung (T2N3M0, Stage HI,). No anti-onconeural antibodies were found in his serum. Cerebral spinal fluid (CSF) examination showed mild mononuclear pleocytosis alone. Magnetic resonance imaging (MRI) of the brain and spinal cord revealed no abnormalities. At autopsy, there was complete disappearance of Purkinje cells with reactive astrocytosis. These findings are compatible with paraneoplastic cerebellar degeneration (PCD). To our knowledge, no case of PCD has been reported previously in patients with squamous cell carcinoma of the lung.
  • 山崎 浩一, 品川 尚文, 小野寺 祐也, 朝比奈 肇, 猪村 帝, 菊地 英毅, 菊地 順子, 小西 純, 浅野 文祐, 西村 正治
    気管支学 26 8 689 - 693 特定非営利活動法人 日本呼吸器内視鏡学会 2004年 
    肺末梢小型病変に到達する気管支をバーチャル気管支鏡によりシミュレーションする方法が報告され, 我々もCT透視下経気管支生検の際にバーチャル気管支鏡により肺末梢小型病変に到達する気管支のシミュレーションを行い, その有用性を発表してきた. さらに, 経気管支生検施行中にrealtimeで肺末梢小型病変に到達する気管支をナビゲーションする新しいシステム, 気管支内視鏡挿入支援システムを開発中である. バーチャル気管支鏡による気管支のナビゲーションは, CT透視下のみならずガイドシース併用気管支内腔超音波断層法(EBUS-GS)を併用した経気管支生検の際にも, 診断率の向上と検査時間, X線透視時間が短縮されることが期待される. また, 術前バリウムマーキングにバーチャル気管支鏡によるナビゲーションと極細径気管支鏡を用いる方法は, 病変近傍に正確にマーキングする極めて有用な方法と考えられる. 今回, 本法の利点, 問題点および今後の展望について報告する.
  • 山崎 浩一, 品川 尚文, 朝比奈 肇, 猪村 帝, 菊地 英毅, 菊地 順子, 小西 純, 西村 正治, 小野寺 祐也, 浅野 文祐
    気管支学 26 3 211 - 211 特定非営利活動法人 日本呼吸器内視鏡学会 2004年
  • T Kojima, K Yamazaki, Y Tamura, S Ogura, K Tani, J Konishi, N Shinagawa, Kinoshita, I, N Hizawa, E Yamaguchi, H Dosaka-Akita, M Nishimura
    HUMAN GENE THERAPY 14 8 715 - 728 2003年05月 [査読有り][通常論文]
     
    Granulocyte-macrophage colony-stimulating factor (GM-CSF)-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine models, but the antitumor effects on established tumors have been minimal. Conversely, the major role of the heat shock protein gp96, localized in the endoplasmic reticulum ( ER), is to act as a molecular chaperone to assist the folding of nascent polypeptide chains in the ER. gp96 derived from tumor cells elicits specific protective immunity against parental tumors, presumably through the transport of tumor-specific peptides to antigen-presenting cells and the maturation of dendritic cells ( DCs). However, the therapeutic effects of tumor-derived gp96 on established tumors have not been promising. The present study analyzes the therapeutic effects of GM-CSF gene-transduced Lewis lung cancer (LLC/GM) cells combined with LLC-derived gp96 on established wild-type LLC tumors in immunocompetent C57BL/6 mice. Therapy with either irradiated LLC/GM cells or LLC-derived gp96 barely affected established LLC tumor growth. The antitumor effect was significantly enhanced when 1 mug of LLC-derived gp96 was administered together with 1 3 106 irradiated LLC/GM cells (p < 0.05). The antitumor effects of irradiated LLC/GM cells and LLC-derived gp96 required mainly CD8(+) T cells. Spleen cells obtained from mice vaccinated with irradiated LLC/GM cells and LLC-derived gp96 showed specific CD8 cytotoxic activities against LLC cells (specific lysis rate of approximately 28%). This antibody response was not associated with a synergic effect of the combination therapy. Moreover, draining lymph nodes from mice immunized with irradiated LLC/GM cells and LLC-derived gp96 contained more migrating mature CD11c(+) cells ( higher levels of CD86 and major histocompatibility complex [MHC] class II molecules) compared with those from any other immunization protocols. These results suggest that the combination of irradiated LLC/GM cells and tumor-derived gp96 has potential as a new immunogene therapeutic strategy against lung cancer.
  • J Konishi, K Yamazaki, E Tsukamoto, N Tamaki, Y Onodera, T Otake, T Morikawa, Kinoshita, I, H Dosaka-Akita, M Nishimura
    RESPIRATION 70 5 500 - 506 2003年 [査読有り][通常論文]
     
    Background: Accurate staging of mediastinal and hilar lymph nodes is a critical factor determining operability in patients with non-small cell lung cancer (NSCLC). Positron emission tomography with 2-[F-18]fluoro-2-deoxy-D-glucose as a tracer (FDG-PET) has recently been reported to be more effective in detecting tumor involvement in mediastinal and hilar lymph nodes than computed tomography (CT). Objective: In this study, we analyzed the accuracy of FDG-PET in mediastinal and hilar lymph node staging in patients with NSCLC and the factors associated with false-positive or false-negative FDG-PET findings in mediastinal and hilar lymph node staging. Methods: Fifty-four patients with NSCLC who underwent preoperative analysis including chest CT and whole-body FDG-PET were evaluated retrospectively. Using FDG-PET, lesions were considered to be positive if a definite, localized area of higher uptake, excluding physiologic uptake, than in surrounding normal tissue was present. On CT findings, lymph nodes were considered to be positive if they were 110 mm in short-axis diameter, except subcarinal lymph nodes (#7), which were considered to be positive if they were >15 mm in short-axis diameter. All patients underwent surgical resection of primary tumors and mediastinal and hilar lymph nodes between 1999 and 2001 in our institute. Resected lymph nodes were histologically examined for the existence of tumor cells. Results: A total of 306 lymph nodes were resected and used for analysis. The sensitivity, specificity, positive predictive value and negative predictive value of FDG-PET were 73, 98, 70 and 98%, while those of CT were 55, 96, 55 and 96%, respectively. When preoperative nodal staging was compared with post-operative histopathological staging, 44 patients (81%) were correctly staged, 7 (13%) were overstaged and 3 (6%) were understaged by FDG-PET, while 39 patients (72%) were correctly staged, 8 (15%) were overstaged and 7 (13%) were understaged by CT. All 7 overstaged patients by FDG-PET had other pulmonary complications, including interstitial pneumonitis (n = 2), previous pulmonary tuberculosis (n = 3), silicosis (n = 1) and emphysema ( n = 1), although they were not in the active stage. In 3 understaged patients by FDG-PET, lymph nodes were also undetectable by CT. Conclusion: FDG-PET is superior to CT in mediastinal and hilar lymph node staging of patients with NSCLC. However, care should be taken in lymph node staging for patients who have other pulmonary complications, including interstitial pneumonitis, previous pulmonary tuberculosis and silicosis. Copyright (C) 2003 S. Karger AG, Basel.
  • 品川 尚文, 山崎 浩一, 菊地 英毅, 大室 順子, 小西 純, 白間 信行, 原田 敏之, 木下 一郎, 西村 正治, 秋田 弘悛, 小野寺 祐也, 宮坂 和男
    気管支学 25 4 310 - 310 特定非営利活動法人 日本呼吸器内視鏡学会 2003年
  • K Onoe, K Iwabuchi, C Iwabuchi, S Tone, J Konishi, Y Kawakami, M Nishimura, K Onoe
    IMMUNOBIOLOGY 206 4 377 - 391 2002年10月 [査読有り][通常論文]
     
    In vitro treatment of thymocytes and splenocytes with rabbit complement (C') alone induced significant reductions in the proportion of NK-T cells in murine system. The reduction appeared to be prominent in the thymic NK-T cells compared to that in splenic NK-T cells. No reductions were detected in other populations, such as T, B and NK cells. Thus, NK-T cells lineage-specifically showed the enhanced C' sensitivity. However, NK-T cells in T cell receptor (TCR) transgenic mice of RAG(-/-) background that lack B cells and antibodies. exhibited no C' sensitivity. On the other hand those from the same TCR transgenic mice of RAG intact background that have a normal population of B cells and antibodies showed the C' sensitivity similar to that in normal mice These findings suggest that the enhanced C' sensitivity observed in the NK-T cell population is associated with the NK-T specific autoantibodies. Indeed, we found that a subset of NK-T cells in the thymus bound mouse immunoglobulins. Similar observations were obtained with several strains of lupus model mice, some of which show a decrease of NK-T cells with aging. Possible roles of the enhanced C' sensitivity of NK-T cells in pathophysiological conditions in various mouse strains including lupus models are discussed.
  • J Konishi, K Iwabuchi, C Iwabuchi, M Ato, J Nagata, K Onoe, K Nakagawa, M Kasai, K Ogasawara, K Kawakami, K Onoe
    CELLULAR IMMUNOLOGY 206 1 26 - 35 2000年11月 [査読有り][通常論文]
     
    We have previously shown that the generation of an NK1.1(+)TCR alpha beta (+) (NK-T) cell population is severely impaired in an alymphoplasia mutant (aly/aly) mouse strain and the defect resides in the thymic environment. In the present study, to elucidate the thymic stromal component(s) that affects the development of NK-T cells, radiation bone marrow chimeras were established with the aly/aly mouse as a donor and either the beta2 microglobulin knockout (beta 2m-/-) or the CD1d1-/- mouse that also lacks the NK-T cell population as a recipient. A normal population of NK-T cells with a typical NK-T phenotype and functions was detected in both the thymus and the spleen of these chimeras. These findings indicated that a radiation-resistant CD1(-) component of the thymus supported generation of functional NK-T cells from aly/aly precursors. Furthermore, transfer of an intact medullary thymic epithelial cell line into aly/aly thymus significantly induced the generation of NK-T cells in the thymus. These findings suggest that CD1 molecules of bone marrow-derived cells and the medullary epithelial cells acted in concert in the generation of the NK-T cell population and that a function(s) of the medullary thymic epithelial cells other than direct presentation of CD1 molecules to the NK-T precursors is indispensable for the development of NK-T cells. (C) 2000 Academic Press.
  • N TAMAKI, H OHTANI, K YAMASHITA, Y MAGATA, Y YONEKURA, R NOHARA, H KAMBARA, C KAWAI, K HIRATA, T BAN, J KONISHI
    JOURNAL OF NUCLEAR MEDICINE 32 4 673 - 678 1991年04月 [査読有り][通常論文]
     
    Reinjection of thallium-201 after recording the 3-hr delayed scan often demonstrates improvement in areas of persistent abnormalities. To determine the metabolic activity of these areas, the changes seen on stress/redistribution/reinjection thallium SPECT were compared with PET using fluorine-18-fluorodeoxyglucose (FDG) in 18 patients with coronary artery disease. Of 48 segments showing no redistribution on the delayed scan, the reinjection scan identified new fill-in in 20 segments (42%), all of which demonstrated FDG uptake. In contrast, only 7 of the 28 segments (25%) showing no fill-in after reinjection were PET viable (p < 0.01). Eleven patients had coronary bypass graft surgery after the radionuclide study. The majority of the segments showing redistribution (87%) and new fill-in after reinjection (65%) improved in wall motion, whereas only eight segments (25%) without new fill-in improved after surgery. Of those without new fill-in, two segments showing PET ischemia improved in wall motion, whereas the remaining six segments showing PET scar did not improve after surgery. Thus, the segments showing new fill-in after reinjection are PET viable myocardium. However, reinjection thallium imaging still underestimates the extent of tissue viability compared to PET imaging.
  • N TAMAKI, Y YONEKURA, K YAMASHITA, H SAJI, Y MAGATA, M SENDA, Y KONISHI, K HIRATA, T BAN, J KONISHI
    AMERICAN JOURNAL OF CARDIOLOGY 64 14 860 - 865 1989年10月 [査読有り][通常論文]
  • N TAMAKI, Y YONEKURA, K YAMASHITA, M SENDA, H SAJI, Y KONISHI, K HIRATA, T BAN, J KONISHI
    JOURNAL OF NUCLEAR MEDICINE 30 8 1302 - 1310 1989年08月 [査読有り][通常論文]
  • H. Ohtani, N. Tamaki, K. Yamashita, Y. Yonekura, Y. Magata, H. Saji, I. H. Mohiuddin, R. Nohara, H. Kambara, C. Kawai, K. Hirata, T. Ban, J. Konishi
    Kakuigaku 26 11 1389 - 1398 1989年 [査読有り][通常論文]
     
    Stress Tl-201 tomography (SPECT) is widely used for evaluating myocardial viability. To assess its value, redistribution (RD) on SPECT was compared with metabolic imaging using FDG. Thirty patients with coronary artery disease underwent stress-3 hour Tl-201 SPECT and PET using N-13 ammonia and FDG. RD was classified into 4 grading, including complete RD (CR), incomplete RD (IR), persistent defect (PD) and additional minimal RD (MR) defined as no definite RD on visual analysis but faint RD with Bull's eye quantitative analysis (QNT). All but one segment with CR or IR were viable regions (normal or ischemic regions) by PET. Of 74 segments without RD on visual analysis, 31 segments (42%) had RD by QNT (MR). All of them were viable regions by PET. Thus, QNT identified 31 segments (63%) of the metabolically viable segments which the visual Tl-201 analysis did not show RD and classified as myocardial scar. However, even such QNT cannot detect ischemic myocardium in 18 segments (42%) containing metabolic activity on PET. These data indicate that QNT of RD on Tl-201 SPECT is considered as a valuable means for assessing myocardial ischemia.
  • N. Tamaki, Y. Yonekura, S. Nishizawa, T. Fujita, J. Konishi, K. Torizuka
    Kakuigaku 25 6 579 - 588 1988年 [査読有り][通常論文]

その他活動・業績

共同研究・競争的資金等の研究課題

教育活動情報

主要な担当授業

  • 基本医学研究
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル
  • 基本医学総論
    開講年度 : 2021年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル
  • 医学総論
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル
  • 基盤医学研究
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル
  • 臨床医学研究
    開講年度 : 2021年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 炎症性肺疾患、免疫性肺疾患、腫瘍性肺疾患、感染性肺疾患、肺循環系疾患、がんプロフェッショナル


Copyright © MEDIA FUSION Co.,Ltd. All rights reserved.