2022/03/20 更新

写真a

イチハラ エイキ
市原 英基
ICHIHARA Eiki
所属
岡山大学病院 講師
職名
講師
外部リンク

学位

  • 医学博士 ( 2010年3月   岡山大学 )

  • 医学博士 ( 2010年3月   岡山大学大学院医歯薬学総合研究科 )

研究キーワード

  • 薬剤tolerance

  • 薬剤耐性

  • COVID-19

  • 肺癌

  • 免疫チェックポイント阻害薬

  • 分子標的治療

研究分野

  • ライフサイエンス / 呼吸器内科学

学歴

  • 岡山大学   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences  

    2006年4月 - 2010年3月

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  • 岡山大学   Medical School   Faculty of Medicine

    1995年4月 - 2001年3月

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    国名: 日本国

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経歴

  • 岡山大学病院   呼吸器・アレルギー内科   講師

    2018年1月 - 現在

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  • 岡山大学病院   呼吸器・アレルギー内科   助教

    2017年4月 - 2017年12月

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  • 岡山大学   大学院医歯薬学総合研究科   助教

    2016年2月 - 2017年3月

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  • Vanderbilt Ingram Cancer Center   Postdoctoral Fellow

    2013年7月 - 2016年1月

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所属学協会

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委員歴

  • 日本臨床腫瘍学会   COVID-19関連教育事業WG 委員  

    2022年2月 - 現在   

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  • 日本肺癌学会 中国・四国支部   事務局  

    2021年7月 - 現在   

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  • 日本呼吸器学会   学術講演会プログラム委員会 委員  

    2021年4月 - 現在   

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  • 日本呼吸器学会   COVID-19 診療 expert opinion ワーキング委員会 委員  

    2020年12月 - 現在   

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  • 日本肺癌学会   評議員  

    2020年11月 - 現在   

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  • 日本肺癌学会   利益相反委員  

    2020年11月 - 現在   

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  • 日本臨床腫瘍学会   がん関連3学会合同連携委員会 新型コロナウイルス(COVID-19)対策ワーキンググループ委員(WG)  

    2020年4月 - 現在   

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  • 日本呼吸器学会   代議員  

    2019年8月 - 現在   

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  • 日本呼吸器学会   腫瘍学術部会 委員  

    2019年4月 - 現在   

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    団体区分:学協会

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  • 日本肺癌学会   臨床研究推進委員  

    2018年12月 - 現在   

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  • 日本肺癌学会   用語委員  

    2018年12月 - 2020年11月   

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  • 日本がん治療認定医機構   教育委員会協力員  

    2018年11月   

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  • 日本がん治療学会   G-CSF適正使用ガイドライン委員  

    2018年8月 - 現在   

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  • 日本呼吸器学会 中国四国支部   代議員  

    2017年 - 現在   

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  • 日本肺癌学会 中国・四国支部   評議員  

    2016年7月 - 現在   

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  • 日本呼吸器学会   間質性肺炎合併肺癌に関するステートメント編集委員  

    2016年3月 - 2019年11月   

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  • 日本臨床腫瘍学会   協議員  

    2013年8月 - 現在   

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  • 日本内科学会中国支部   評議員  

    2012年 - 現在   

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論文

  • Identification of targetable kinases in idiopathic pulmonary fibrosis. 国際誌

    Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

    Respiratory research   23 ( 1 )   20 - 20   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

    DOI: 10.1186/s12931-022-01940-y

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  • Significance of PD-L1 expression in the cytological samples of non-small cell lung cancer patients treated with immune checkpoint inhibitors. 国際誌

    Naofumi Hara, Eiki Ichihara, Daijiro Harada, Koji Inoue, Keiichi Fujiwara, Shinobu Hosokawa, Daizo Kishino, Kawai Haruyuki, Nobuaki Ochi, Naohiro Oda, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Journal of cancer research and clinical oncology   147 ( 12 )   3749 - 3755   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    OBJECTIVES: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated. PATIENTS AND METHODS: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples. RESULTS: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001). CONCLUSION: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs.

    DOI: 10.1007/s00432-021-03615-5

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  • A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer. 国際誌

    Hiroyuki Yasuda, Eiki Ichihara, Jun Sakakibara-Konishi, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katuyuki Kiura, Yuta Takashima, Seiji Yano, Junji Koyama, Takahiro Fukushima, Junko Hamamoto, Hideki Terai, Shinnosuke Ikemura, Ryo Takemura, Koichi Goto, Kenzo Soejima

    Lung cancer (Amsterdam, Netherlands)   162   140 - 146   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    OBJECTIVES: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. MATERIALS AND METHODS: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. RESULTS: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. CONCLUSIONS: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

    DOI: 10.1016/j.lungcan.2021.10.006

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  • Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B).

    Yukari Tsubata, Kana Watanabe, Ryota Saito, Atsushi Nakamura, Hiroshige Yoshioka, Mami Morita, Ryoichi Honda, Nobuhiro Kanaji, Satoshi Ohizumi, Daisuke Jingu, Taku Nakagawa, Kensuke Nakazawa, Atsuto Mouri, Susumu Takeuchi, Naoki Furuya, Yuki Akazawa, Kiyotaka Miura, Eiki Ichihara, Makoto Maemondo, Satoshi Morita, Kunihiko Kobayashi, Takeshi Isobe

    International journal of clinical oncology   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER JAPAN KK  

    BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

    DOI: 10.1007/s10147-021-02043-2

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  • Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease.

    Sachi Okawa, Kammei Rai, Nobuharu Fujii, Yuka Gion, Kiichiro Ninomiya, Yuka Kato, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Nobuaki Miyahara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   60 ( 17 )   2831 - 2837   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy.

    DOI: 10.2169/internalmedicine.6470-20

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  • SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naïve ALK-, ROS1-, or EGFR-altered Non-small Cell Lung Cancer. 国際誌

    Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Molecular cancer therapeutics   20 ( 9 )   1653 - 1662   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non-small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.

    DOI: 10.1158/1535-7163.MCT-20-0965

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  • Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression. 国際誌

    Kazuya Nishii, Kadoaki Ohashi, Hiromi Watanabe, Go Makimoto, Takamasa Nakasuka, Hisao Higo, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Oncology letters   22 ( 3 )   639 - 639   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.

    DOI: 10.3892/ol.2021.12900

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  • Pulmonary Aspergilloma and Allergic Bronchopulmonary Aspergillosis Following the 2018 Heavy Rain Event in Western Japan: A Case Report.

    Eri Ando, Takamasa Nakasuka, Toshio Kubo, Akihiko Taniguchi, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masaomi Yamane, Nobuaki Miyahara, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 16-year-old boy with asthma participated in recovery volunteer work following the 2018 heavy rains in Japan. One month later, he experienced chest pain and dyspnea. Chest computed tomography revealed a cavity with a fungal ball, and Aspergillus fumigatus was detected in his bronchoalveolar lavage fluid. He was treated with voriconazole, but new consolidations appeared rapidly. He also experienced allergic bronchopulmonary aspergillosis. After prednisolone prescription, the consolidations improved; however, his asthma worsened. He underwent partial lung resection to avoid allergens, and his symptoms improved. We must recognize cases of infection after a disaster, especially in patients with chronic respiratory diseases.

    DOI: 10.2169/internalmedicine.7124-21

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  • Survival of chemo-naïve patients with EGFR mutation-positive advanced non-small cell lung cancer after treatment with afatinib and bevacizumab: updates from the Okayama Lung Cancer Study Group Trial 1404. 国際誌

    Takashi Ninomiya, Naoyuki Nogami, Toshiyuki Kozuki, Daijiro Harada, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Shoichi Kuyama, Kenichiro Kudo, Akihiro Bessho, Makoto Sakugawa, Nobukazu Fujimoto, Keisuke Aoe, Daisuke Minami, Keisuke Sugimoto, Nobuaki Ochi, Nagio Takigawa, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   51 ( 8 )   1269 - 1276   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    BACKGROUND: In a phase I study, afatinib (30 mg/body daily) plus bevacizumab (15 mg/kg every 3 weeks) was well tolerated and showed favourable outcomes in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer. Herein, we report the 2-year progression-free survival, overall survival and safety profile of these patients. METHODS: Chemo-naïve patients with EGFR-mutant advanced non-small-cell lung cancer were enrolled. One group of patients received 40 mg afatinib daily and 15 mg/kg bevacizumab every 3 weeks (level 0) until disease progression or severe toxicity. Another group of patients received 30 mg afatinib daily and the same dose of bevacizumab (level 1). Dose-limiting toxicity was the primary endpoint, whereas long-term progression-free survival, overall survival and tolerability were secondary endpoints. Survival rates were estimated using the Kaplan-Meier method. RESULTS: The study included 19 patients (level 0: 5; level - 1: 14). Until the data cut-off date, seven patients continued the treatment, whereas 12 discontinued due to disease progression (n = 5) or toxicity (n = 7). The median PFS was 24.2 months, while the median overall survival was not reached. All patients developed adverse effects. Diarrhoea and skin rash were frequently observed as severe adverse events (grade 3). A secondary EGFR mutation (T790M) was detected in two patients after progression. CONCLUSIONS: Prolonged follow-up revealed that combination therapy with afatinib and bevacizumab might improve survival outcomes in EGFR-mutant advanced non-small-cell lung cancer patients and seems to be promising. TRIAL REGISTRATION: UMIN000015944.

    DOI: 10.1093/jjco/hyab084

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  • Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non-small-cell lung cancer: KEYNOTE-189 Japan Study. 国際誌

    Hidehito Horinouchi, Naoyuki Nogami, Hideo Saka, Makoto Nishio, Takaaki Tokito, Toshiaki Takahashi, Kazuo Kasahara, Yoshihiro Hattori, Eiki Ichihara, Noriaki Adachi, Kazuo Noguchi, Fabricio Souza, Takayasu Kurata

    Cancer science   112 ( 8 )   3255 - 3265   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator's choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co-primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7-38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9-29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07-1.15). The median (95% CI) PFS was 16.5 (8.8-21.1) compared with 7.1 (4.7-21.4) months (HR, .62; 95% CI, .27-1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.

    DOI: 10.1111/cas.14980

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  • A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R. 国際誌

    Go Makimoto, Kiichiro Ninomiya, Toshio Kubo, Ryota Sunami, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   51 ( 6 )   956 - 965   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.

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  • VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers. 国際誌

    Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Go Makimoto, Kiichiro Ninomiya, Kazuya Nishii, Hisao Higo, Chihiro Ando, Sachi Okawa, Takamasa Nakasuka, Hirohisa Kano, Naofumi Hara, Atsuko Hirabae, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Cancer science   112 ( 5 )   1853 - 1864   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.

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  • The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression. 国際誌

    Nobuaki Ochi, Eiki Ichihara, Nagio Takigawa, Daijiro Harada, Koji Inoue, Takuo Shibayama, Shinobu Hosokawa, Daizo Kishino, Shingo Harita, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    European journal of cancer (Oxford, England : 1990)   149   73 - 81   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    BACKGROUND: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear. METHODS: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model. RESULTS: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort. CONCLUSIONS: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.

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  • Comparison of bronchoscopy and computed tomography-guided needle biopsy for re-biopsy in non-small cell lung cancer patients. 国際誌

    Hirohisa Kano, Toshio Kubo, Kiichiro Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Takao Hiraki, Susumu Kanazawa, Yoshinobu Maeda, Katsuyuki Kiura

    Respiratory investigation   59 ( 2 )   240 - 246   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    BACKGROUND: New therapeutic drugs have been developed for non-small cell lung cancer (NSCLC), and the prognosis of advanced NSCLC patients has improved. However, resistance to these drugs is a concern, and re-biopsy is necessary to determine the mechanism of drug resistance. There are many reports about the protocols for re-biopsy, including techniques such as bronchoscopy and computed tomography-guided needle biopsy (CTNB); however, there is no consensus on which method is optimal. Therefore, we retrospectively reviewed the bronchoscopy and CTNB re-biopsies conducted at our hospital. METHODS: We retrospectively analyzed 79 cases of re-biopsies with bronchoscopy or CTNB in patients with NSCLC from January 2014 to December 2016 at our institute. RESULTS: Forty-nine cases of bronchoscopy and 30 cases of CTNB were taken for re-biopsy. The diagnostic rates of bronchoscopy and CTNB were 83.7% and 100%, respectively (p = 0.023). The complication rates of bronchoscopy and CTNB were 18.4% and 36.7%, respectively (p = 0.11), with a statistically significant difference in the incidence of pneumothorax (0% vs. 23.3%, respectively; p < 0.01). Pneumothorax required drainage in 6.7% of all CTNB cases. There were no fatalities in either group. CONCLUSIONS: CTNB showed a higher diagnostic rate; however, it was associated with a higher rate of complications such as pneumothorax. Hence, the optimal modality must be determined individually for each patient.

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  • Impact of previous thoracsic radiation therapy on the efficacy of immune checkpoint inhibitors in advanced non-smasll-cell lung cancer. 国際誌

    Shinobu Hosokawa, Eiki Ichihara, Akihiro Bessho, Daijiro Harada, Koji Inoue, Takuo Shibayama, Daizo Kishino, Shingo Harita, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   51 ( 2 )   279 - 286   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    OBJECTIVES: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort. PATIENTS AND METHODS: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated. RESULTS: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008). CONCLUSION: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.

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  • Randomized study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in non-small cell lung cancer: The OLCSG1406 trial. 国際誌

    Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Asia-Pacific journal of clinical oncology   17 ( 1 )   101 - 108   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS: Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS: The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION: The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

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  • Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors. 国際誌

    Eiki Ichihara, Daijiro Harada, Koji Inoue, Takuo Shibayama, Shinobu Hosokawa, Daizo Kishino, Shingo Harita, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Cancer immunology, immunotherapy : CII   70 ( 1 )   101 - 106   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    OBJECTIVES: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC. PATIENTS AND METHODS: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed. RESULTS: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025). CONCLUSION: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.

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  • 肺癌診療アップデート:分子標的治療(最近の進歩と残された課題)

    市原 英基

    肺癌   61 ( 5 )   377 - 382   2021年

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本肺癌学会  

    <p>上皮成長因子受容体(EGFR)遺伝子変異陽性非小細胞肺癌(NSCLC)に対するEGFRチロシンキナーゼ阻害薬(TKI)の有効性が発見されて以来,NSCLCにおける個別化医療は急激に進歩をした.現在,6種類のドライバー遺伝子異常に対する阻害薬が承認されている.これらドライバー遺伝子異常に対する各阻害薬の奏効率はおよそ60~80%,無増悪生存期間は1~2年,時として30カ月を超え,NSCLCの治療を大きく変えた.一方で課題も残されている.検査対象となる遺伝子数が次々と増えている中,検体量や診断確定までの時間が有限である状況で,ドライバー遺伝子をいかにもれなく検出するのか,検査そのものの戦略確立が必要となってきている.また,近年免疫チェックポイント阻害薬では進行NSCLCの治癒の可能性も示唆されているが,分子標的治療ではいまだそのような可能性を示唆する効果は得られておらず,このことも課題に挙げられる.</p>

    DOI: 10.2482/haigan.61.377

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  • Immune checkpoint inhibitor efficacy and safety in older non-small cell lung cancer patients. 国際誌

    Toshio Kubo, Hiromi Watanabe, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Kammei Rai, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   50 ( 12 )   1447 - 1453   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    OBJECTIVES: Immune checkpoint inhibitors offer longer survival than chemotherapy in several clinical trials for advanced non-small cell lung cancer. In subset analyses of clinical trials, immune checkpoint inhibitors extended survival in patients aged ≥65 years, but the effects in patients aged ≥75 years are controversial. We performed multicenter, collaborative and retrospective analyses of immune checkpoint inhibitor efficacy and safety in non-small cell lung cancer patients aged ≥75 years. METHODS: We retrospectively studied 434 advanced non-small cell lung cancer patients who received immune checkpoint inhibitors from December 2015 to December 2017, and retrospectively applied the Geriatric (G) 8 screening tool with medical records. RESULTS: Of the 434 patients who received immune checkpoint inhibitors, 100 were aged ≥75 years. Five patients with performance status 3 were omitted from the final analysis. Immune checkpoint inhibitors were given as a first-line treatment to 20 patients. The objective response rates, median progression-free survival rates and median survival times were 35.0%, 6.1 months and 10.7 months for first-line treatment, and 20.0%, 2.9 months and 14.7 months for second- or later-line treatments, respectively. The median modified G8 score was 11.0. The median survival time was longer in the high modified G8 (≥12.0) group than in the low modified G8 (≤11.0) group (18.7 vs. 8.7 months; P = 0.02). Likewise, the median survival time was 15.5 months (performance status 0-1) vs. 3.2 months (performance status 2) (P < 0.01). The grade ≥ 2 immune-related adverse events incidence was 36.8%. CONCLUSIONS: In this study, immune checkpoint inhibitors were effective and tolerable for patients aged ≥75 years. The modified G8 screening tool and performance status were associated with the outcome of older non-small cell lung cancer patients treated with immune checkpoint inhibitors.

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  • 【COVID-19パンデミックとがん医療への影響】COVID-19における肺炎

    工藤 健一郎, 市原 英基

    癌と化学療法   47 ( 12 )   1657 - 1661   2020年12月

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    記述言語:日本語   出版者・発行元:(株)癌と化学療法社  

    がん患者ではCOVID-19に罹患した場合、重症化や死亡リスクが高い可能性があり、COVID-19へ罹患することは極力避けなくてはならない。急速な拡がりをみせるCOVID-19であるが、このような状況下でも可能な限り日々のがん診療は通常どおり継続していく必要がある。進行がん患者にとって抗がん剤などの薬物治療ががん治療の中心となる。がん薬物療法中に発症した肺炎は通常の細菌性肺炎だけではなく、ニューモシスチス肺炎、真菌感染症などその他の感染性肺炎や抗がん剤による薬剤性肺障害などを鑑別する必要がある。加えて現在のコロナ禍では、COVID-19肺炎も念頭に置かなくてはならない。COVID-19で頻度の高い症状として発熱・倦怠感などに加え、咳嗽や呼吸困難があげられる。COVID-19肺炎の画像所見は数多く報告されているが、画像検査のみでCOVID-19肺炎を診断するのは困難であり、がん薬物療法中の患者では特に薬剤性肺障害との鑑別に難渋する。画像所見に加えて患者の臨床症状、行動歴やその他の臨床検査などを総合的に判断し対応、適切な加療を行っていく必要がある。ここではCOVID-19肺炎にみられる臨床的特徴、画像所見を示しながらがん診療において注意すべき点について述べていく。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00296&link_issn=&doc_id=20201217400003&doc_link_id=%2Fab8gtkrc%2F2020%2F004712%2F003%2F1657-1661%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2020%2F004712%2F003%2F1657-1661%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations. 国際誌

    Hiroe Kayatani, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Kazuya Nishii, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Biochemical and biophysical research communications   532 ( 3 )   341 - 346   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

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  • Treatment Rationale and Design of a Phase III Study of Afatinib or Chemotherapy in Patients with Non-small-cell Lung Cancer Harboring Sensitizing Uncommon Epidermal Growth Factor Receptor Mutations (ACHILLES/TORG1834). 国際誌

    Satoru Miura, Takeharu Yamanaka, Terufumi Kato, Satoshi Ikeda, Hidehito Horinouchi, Eiki Ichihara, Masaki Kanazu, Yuichi Takiguchi, Kentaro Tanaka, Yasuhiro Goto, Masafumi Sata, Koichi Hagiwara, Hiroaki Okamoto, Hiroshi Tanaka

    Clinical lung cancer   21 ( 6 )   e592-e596 - E596   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CIG MEDIA GROUP, LP  

    We describe the treatment rationale and design of our randomized phase III study, the ACHILLES trial (Japan Registry of Clinical Trials: jRCTs031180175). The aim of this study is to investigate the superiority of afatinib over chemotherapy as first-line treatment in patients with advanced nonsquamous non-small-cell lung cancer with sensitizing uncommon or compound epidermal growth factor receptor (EGFR) mutations, with the exception of de novo T790M mutations and exon 20 insertions. Eligible patients will be randomized at a 1:2 ratio to receive either chemotherapy or afatinib until disease progression or unacceptable toxicity. Patients in the chemotherapy arm will receive pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin area under the curve (AUC) 5 or 6 every 3 weeks × 4 cycles, followed by pemetrexed 500 mg/m2 every 3 weeks. In the afatinib arm, investigators will choose the starting dose of afatinib (30 mg or 40 mg orally daily). The primary endpoint is progression-free survival. A total of 106 patients will be enrolled in this trial over a 30-month registration period with a 15-month follow-up. Enrollment began in March 2019. The results of this trial will establish the superiority of afatinib over chemotherapy in a cohort with a large variety of EGFR mutations.

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  • Rapid Disease Progression of Advanced Non-small Cell Lung Cancer Five Months after Cessation of Pembrolizumab.

    Atsuko Hirabae, Eiki Ichihara, Ryota Sunami, Moeko Ota, Yoshitaka Iwamoto, Yoshinobu Maeda, Katsuyuki Kiura

    Acta medica Okayama   74 ( 5 )   423 - 425   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We report a case of late-onset hyperprogressive disease after cessation of a PD-1 inhibitor. A male was diagnosed with metastatic lung adenocarcinoma with little progression for 2 months before treatment. He received pembrolizumab as a second-line treatment and was subsequently prescribed docetaxel for 3 months until a slight increase in pleural effusion. At the time of progression to docetaxel, he commenced prednisolone because of immune-system-related diarrhea. After that, his general condition rapidly worsened with severe fatigue and hypoxia. Computed tomography revealed a massive increase of pleural effusion and replacement of almost the entire liver with cancer over a period of 5 weeks.

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  • Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status. 国際誌

    Hirohisa Kano, Eiki Ichihara, Daijiro Harada, Koji Inoue, Hiroe Kayatani, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Kiichiro Ninomiya, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Cancer science   111 ( 10 )   3739 - 3746   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.

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  • Association between Histological Types and Enhancement of Dynamic CT for Primary Lung Cancer.

    Shogo Fukuma, Takayoshi Shinya, Junichi Soh, Ryuichiro Fukuhara, Nanako Ogawa, Fumiyo Higaki, Takehiro Tanaka, Eiki Ichihara, Takao Hiraki, Shinichi Toyooka, Susumu Kanazawa

    Acta medica Okayama   74 ( 2 )   129 - 135   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The aim of this study was to explore enhancement patterns of different types of primary lung cancers on 2-phase dynamic computed tomography (CT). This study included 217 primary lung cancer patients (141 adenocarcinomas [ADs], 48 squamous cell carcinomas [SCCs], 20 small cell lung carcinomas [SCLCs], and 8 others) who were examined using a 2-phase dynamic scan. Regions of interest were identified and mean enhancement values were calculated. After excluding the 20 SCLCs because these lesions had different clinical stages from the other cancer types, the mean attenuation values and subtractions between phases were compared between types of non-small cell lung carcinomas (NSCLCs) using the Kruskal-Wallis test. Late phase attenuation and attenuation of the late minus unenhanced phase (LMU) of SCCs were significantly higher than those of ADs (p<0.05). To differentiate SCC and AD in the late phase, a threshold of 80.21 Hounsfield units (HU) gave 52.9% accuracy. In LMU, a threshold of 52.16 HU gave 59.3% accuracy. Dynamic lung CT has the potential to aid in differentiating among NSCLC types.

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  • Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report. 国際誌

    Natsumi Matsuoka, Kenji Tsuji, Eiki Ichihara, Takayuki Hara, Kazuhiko Fukushima, Kishio Toma, Shinji Kitamura, Kenichi Inagaki, Hitoshi Sugiyama, Jun Wada

    BMC nephrology   21 ( 1 )   113 - 113   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMC  

    BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. CASE PRESENTATION: A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. CONCLUSION: All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed.

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  • Influence of age on the efficacy of immune checkpoint inhibitors in advanced cancers: a systematic review and meta-analysis. 国際誌

    Kiichiro Ninomiya, Isao Oze, Yuka Kato, Toshio Kubo, Eiki Ichihara, Kammei Rai, Kadoaki Ohashi, Toshiyuki Kozuki, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Katsuyuki Hotta

    Acta oncologica (Stockholm, Sweden)   59 ( 3 )   249 - 256   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    Background: Immune checkpoint inhibitors (ICIs) represent a paradigm shift in the development of cancer treatment. However, it remains to be clarified whether the benefits that they confer differ according to patient age. We conducted a systematic review and meta-analysis to assess age differences in the benefits of ICI treatment.Methods: We systematically searched the PubMed database for randomised controlled trials of ICIs, including PD-1, PD-L1 and CTLA-4 inhibitors across multiple cancer types, such as melanoma, lung cancer and gastric cancer. We extracted trials including hazard ratios (HRs) for death stratified by patient age (cut-off age, 65 years). The primary objective of this study was to assess the difference in ICI efficacy between younger and older patients. We calculated pooled HRs and 95% confidence intervals (CIs) for younger and older cancer patients, and assessed data heterogeneity.Results: We identified 3999 studies in our search. Of these, 24 eligible randomised trials, including a total of 8157 (57%) younger and 6104 (43%) older cancer patients, fulfilled the criteria for our study and were thus further analysed. The pooled HRs of the younger and older patients were 0.76 (95% CI: 0.69-0.84) and 0.80 (95% CI: 0.71-0.86), respectively; the difference in ICI efficacy between younger and older cancer patients was not significant (p = .82). Regarding the PD-1 and PD-L1 inhibitors, the survival benefit was similar in both age groups (HR: 0.74; p = .96), whereas for the CTLA-4 inhibitors, there tended to be less survival benefit for older versus younger patients (HR: 0.90 and 0.77, respectively; p = .26).Conclusions: The survival benefit conferred by ICI was not age-dependent, amongst patients aged 65 years or younger. However, age-dependent benefits may vary amongst different types of ICIs.

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  • Patients' preferences and perceptions of lung cancer treatment decision making: results from Okayama lung cancer study group trial 1406. 国際誌

    Go Makimoto, Katsuyuki Hotta, Isao Oze, Kiichiro Ninomiya, Masamoto Nakanishi, Naofumi Hara, Hirohisa Kano, Hiromi Watanabe, Yusuke Hata, Kazuya Nishii, Takamasa Nakasuka, Junko Itano, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Eiki Ichihara, Daisuke Minami, Akiko Sato, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Acta oncologica (Stockholm, Sweden)   59 ( 3 )   324 - 328   2020年3月

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS LTD  

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  • Managing Lung Cancer with Comorbid Interstitial Pneumonia.

    Eiki Ichihara, Nobuaki Miyahara, Yoshinobu Maeda, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   59 ( 2 )   163 - 167   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Systemic therapy for advanced non-small cell lung cancer (NSCLC) has dramatically changed in the latest 15 years. Molecular-targeted therapy has brought about an era of precision medicine, and immune checkpoint inhibitors have brought hope for a cure for advanced NSCLC. In the wake of this remarkable advancement, lung cancer with comorbid interstitial pneumonia (IP) has been completely left behind, as most clinical trials exclude patients with comorbid IP. IP, especially idiopathic pulmonary fibrosis (IPF), is often accompanied by lung cancer, and acute exacerbation can develop during various cancer therapies, including surgery, radiotherapy and pharmacotherapy. In this review, we focus on the clinical questions concerning pharmacotherapy in cases of advanced lung cancer with comorbid IP and discuss what we can do with the currently available data.

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  • The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer. 国際誌

    Eiki Ichihara, Daijiro Harada, Koji Inoue, Ken Sato, Shinobu Hosokawa, Daizo Kishino, Kazuhiko Watanabe, Nobuaki Ochi, Naohiro Oda, Naofumi Hara, Katsuyuki Hotta, Yoshinobu Maeda, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   139   140 - 145   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    OBJECTIVES: Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC. MATERIALS AND METHODS: The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment. RESULTS: A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021). CONCLUSION: BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.

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  • Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia. 国際誌

    Takashi Ogura, Nagio Takigawa, Keisuke Tomii, Kazuma Kishi, Yoshikazu Inoue, Eiki Ichihara, Sakae Homma, Kazuhisa Takahashi, Hiroaki Akamatsu, Satoshi Ikeda, Naohiko Inase, Tae Iwasawa, Yuichiro Ohe, Hiromitsu Ohta, Hiroshi Onishi, Isamu Okamoto, Kazumasa Ogawa, Kazuo Kasahara, Hiroki Karata, Takumi Kishimoto, Yuka Kitamura, Akihiko Gemma, Hirotsugu Kenmotsu, Hiroyuki Sakashita, Susumu Sakamoto, Katsutoshi Sekine, Yuichi Takiguchi, Yuji Tada, Shinichi Toyooka, Yuko Nakayama, Yasuhiko Nishioka, Koichi Hagiwara, Masaki Hanibuchi, Junya Fukuoka, Yuji Minegishi, Toyoshi Yanagihara, Nobuyuki Yamamoto, Hiromasa Yamamoto, Mina Gaga, Kwun M Fong, Charles A Powell, Katsuyuki Kiura

    Respiratory investigation   57 ( 6 )   512 - 533   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

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  • Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. 国際誌

    Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   14 ( 11 )   2009 - 2018   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

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  • Granulation Tissue-induced Pseudo-relapse During Nivolumab Treatment in Advanced Non-small Cell Lung Cancer

    Chihiro Ando, Eiki Ichihara, Hirohisa Kano, Yoshitaka Iwamoto, Atsuko Hirabae, Takamasa Nakasuka, Yoshinobu Maeda, Katsuyuki Kiura

    IN VIVO   33 ( 6 )   2113 - 2115   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Atypical tumor responses such as pseudo-progression or hyper-progression sometimes occur during immune check point inhibitor therapy. Distinct from both responses, we experienced a case of non-small cell lung cancer (NSCLC) with a pseudo-relapse, in which development of granulation mimicked cancer relapse during nivolumab therapy. A male with advanced NSCLC started nivolumab as a second-line therapy. After 15 cycles of nivolumab with a complete response, tumor markers started increasing and positron-emission computed tomography indicated a hot spot in the sigmoid colon. Laparoscopic segmental sigmoid colon resection revealed granulation tissue without any relapse of malignant cells. The results showed that even if radiographical tumor progression is found during immune therapy, histological confirmation should be considered.

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  • Programmed cell death-ligand 1 expression and efficacy of cisplatin-based chemotherapy in lung cancer: A sub-analysis of data from the two Okayama Lung Cancer Study Group prospective feasibility studies. 国際誌

    Kazuya Nishii, Katsuyuki Hotta, Kiichiro Ninomiya, Yuka Kato, Eiki Ichihara, Kadoaki Ohashi, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Respiratory investigation   57 ( 5 )   460 - 465   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    BACKGROUND: Cisplatin-based chemotherapy remains the mainstay treatment for advanced lung cancer; however, it remains controversial whether the efficacy of chemotherapy can be modulated by the immune-checkpoint status. In this study, we investigated the relationship between programmed cell death-ligand 1 (PD-L1) expression status and the efficacy of cisplatin-based chemotherapy by using individual patient data and pathological specimens obtained during our two previously performed prospective studies on the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy. METHODS: Among 91 patients who participated in the two aforementioned trials, those with assessable tumor specimens were included in this sub-analysis. PD-L1 expression levels were determined using immunohistochemical staining, while the Response Evaluation Criteria in Solid Tumors, version 1.1, were used for determining treatment efficacy. RESULTS: Thirty-two patients were investigated. PD-L1 expression was observed in 8 patients (25.0%; the PD-L1-positive group), with 2 exhibiting a PD-L1 expression of 50% or more. None of the patients in the PD-L1-positive group responded to treatment, while the overall response rate in the PD-L1-negative group was 20.8% (5 of 24; P = 0.296). Both the progression-free survival and overall survival rates were worse in the PD-L1-positive group than in the PD-L1-negative group (3.7 vs. 5.9 months [P = 0.018] and 5.8 vs. 37.3 months [P = 0.070], respectively). CONCLUSION: PD-L1 expression was negatively correlated with survival in patients receiving cisplatin-based chemotherapy.

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  • The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer. 国際誌

    Hiromi Watanabe, Toshio Kubo, Kiichiro Ninomiya, Kenichiro Kudo, Daisuke Minami, Etsuko Murakami, Nobuaki Ochi, Takashi Ninomiya, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Kadoaki Ohashi, Keiichi Fujiwara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   49 ( 8 )   762 - 765   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    INTRODUCTION: Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients. METHODS: We defined 'rechallenge' as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers. RESULTS: A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8-2.6] and 6.5 months [95% CI: 1.4-19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs. CONCLUSIONS: In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.

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  • Efficacy of afatinib treatment for lung adenocarcinoma harboring exon 18 delE709_T710insD mutation. 国際誌

    Yoshitaka Iwamoto, Eiki Ichihara, Naofumi Hara, Takamasa Nakasuka, Chihiro Ando, Takahiro Umeno, Atsuko Hirabae, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   49 ( 8 )   786 - 788   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient's clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.

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  • Primary Resistance to Alectinib Was Lost after Bevacizumab Combined Chemotherapy in ALK-Rearranged Lung Adenocarcinoma. 国際誌

    Takamasa Nakasuka, Eiki Ichihara, Go Makimoto, Yoshinobu Maeda, Katsuyuki Kiura

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   14 ( 8 )   e168-e169 - E169   2019年8月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Re-administration of osimertinib in osimertinib-acquired resistant non-small-cell lung cancer. 国際誌

    Eiki Ichihara, Katsuyuki Hotta, Kiichiro Ninomiya, Toshio Kubo, Kadoaki Ohashi, Kammei Rai, Hisaaki Tanaka, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   132   54 - 58   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    BACKGROUND: Osimertinib is a tyrosine kinase inhibitor (TKI) that is an essential agent for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). However, there is no established strategy for treatment following acquired resistance to this agent. One potential strategy for treating acquired resistance to EGFR TKIs is re-administration, which has been evaluated mainly using first- or second-generation EGFR TKIs. However, no clinical data are available with which to determine the significance of re-administration of osimertinib, a third-generation EGFR TKI. The aim of this study was to evaluate the efficacy of re-administering osimertinib to patients who had acquired resistance to this agent. PATIENTS AND METHODS: We reviewed the medical records of consecutive patients with advanced NSCLC harboring EGFR-activating mutations and secondary T790M, who had undergone osimertinib re-administration to treat acquired resistance. RESULTS: Seventeen patients were re-administered osimertinib after acquiring resistance to osimertinib. Of these, two received osimertinib to treat carcinomatous meningitis without any measurable lesion. Responses were evaluated in the remaining 15 patients. The objective response and disease control rates were 33% and 73%, respectively. Tumor shrinkage by osimertinib re-administration was associated with that due to initial osimertinib treatment (r = 0.585, 95% confidence interval [CI]: 0.104-0.844). In the remaining two patients without measurable lesions, one exhibited improved clinical symptoms following osimertinib re-administration. The median progression-free survival (PFS) time of all 17 patients was 4.1 months (95% CI: 1.9-6.7). The toxicity of re-administration was low, without interruption of the treatment due to adverse events (AEs). Most patients had grade 2 AEs or lower. CONCLUSIONS: Re-administration of osimertinib for EGFR-mutant NSCLC yielded modest activity with tolerable toxicity.

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  • Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities. 国際誌

    Hisao Higo, Toshio Kubo, Satoko Makimoto, Go Makimoto, Hiroki Ihara, Yoshihisa Masaoka, Takashi Ninomiya, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Yoshinobu Maeda, Katsuyuki Kiura

    Japanese journal of clinical oncology   49 ( 5 )   458 - 464   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    INTRODUCTION: Although chemoradiotherapy for locally advanced lung cancer has the potential for cure, treatment is avoided in patients with interstitial lung disease because of the risk for severe radiation pneumonitis. Interstitial lung abnormalities (ILA) can be evaluated using high-resolution computed tomography (HRCT) to assess interstitial changes. In this study, we retrospectively examined the feasibility and efficacy of chemoradiotherapy for locally advanced lung cancer patients with ILA. METHODS: Patients who underwent chemoradiotherapy for locally advanced lung cancer at Okayama University Hospital between 2012 and 2015 were reviewed retrospectively. HRCT prior to treatment was evaluated by one pulmonologist and two radiologists using a sequential reading method. RESULTS: Of the 77 patients enrolled in this study, ILA was present in 25 (32.5%) and indeterminate ILA in 24 patients; 28 patients did not have ILA. Desaturation at rest (SpO2 < 95%) and honeycombing on HRCT were not observed in ILA patients. Only one patient with ILA had a low vital capacity (%VC < 80%). Severe radiation pneumonitis (≥Grade 2) occurred in 36.0% of the patients with ILA, but it was controllable; Grade 4 or 5 was not observed. Multivariate analysis showed that >25% of the lung volume receiving >20 Gy was risk factors of severe radiation pneumonitis, but ILA was not. The 2-year survival rates of patients with and without ILA were 56.8% and 74.1%, respectively, but the difference was not significant (P = 0.33). CONCLUSIONS: Chemoradiotherapy was feasible and effective in some patient population with ILA without desaturation, low VC and honeycombing on HRCT.

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  • Significance of re-biopsy of histological tumor samples in advanced non-small-cell lung cancer in clinical practice.

    Katsuyuki Hotta, Kiichiro Ninomiya, Eiki Ichihara, Katsuyuki Kiura

    International journal of clinical oncology   24 ( 1 )   41 - 45   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER JAPAN KK  

    The significance of evaluating oncogenes, including EGFR mutations, ALK abnormalities, and PD-L1 expression has become broadly recognized with recent advances in molecular biology. It is now extremely important to investigate tumor oncogene status in each patient at the initial diagnosis. By contrast, the significance of conducting a re-biopsy in the salvage setting has not been systematically reviewed. This review reports that the significance of a re-biopsy varies depending on the clinical situation.

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  • A phase II trial of EGFR-TKI readministration with afatinib in advanced non-small-cell lung cancer harboring a sensitive non-T790M EGFR mutation: Okayama Lung Cancer Study Group trial 1403. 国際誌

    Naohiro Oda, Kastuyuki Hotta, Kiichiro Ninomiya, Daisuke Minami, Eiki Ichihara, Toshi Murakami, Toshihide Yokoyama, Hirohisa Ichikawa, Kenichi Chikamori, Nagio Takigawa, Nobuaki Ochi, Shingo Harita, Yoshinobu Maeda, Katsuyuki Kiura

    Cancer chemotherapy and pharmacology   82 ( 6 )   1031 - 1038   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    PURPOSE: The aim of this study was to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration using afatinib in patients with non-small-cell lung cancer (NSCLC) with a sensitive non-T790M EGFR mutation who had received cytotoxic chemotherapy after acquiring resistance to EGFR-TKIs. METHODS: Eligible patients had EGFR-mutant tumors resistant to first- or second-generation EGFR-TKIs and an EGFR-TKI-free period with cytotoxic agents. Confirmation of absence of the T790M mutation was required before registration. Afatinib (40 mg/body) was administered daily. The primary endpoint was progression-free survival (PFS). We assumed estimated and threshold PFS times of 3.3 and 1 months, with an α of 0.05 and β of 0.1, respectively. RESULTS: Twelve patients were enrolled from December 2014 to May 2017. The objective response rate and disease control rate were 17% and 84%, respectively. The median PFS time was 4.2 months (95% confidence interval [CI] 2.0-5.8), which met the pre-defined primary endpoint. The median overall survival was 11.6 months (95% CI 9.2-not reached). Grade 3 or worse adverse events included diarrhea (25%), elevated creatinine levels (8%), and hypokalemia (8%), without any treatment-related deaths. CONCLUSION: EGFR-TKI readministration with afatinib for sensitive EGFR-mutant NSCLC without T790M after resistance to a first- or second-generation EGFR-TKI yielded modest activity with tolerable toxicity. It might be one of the treatment options in patients who do not possess T790M tumors, although further studies in this patient setting are warranted.

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  • Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. 国際誌

    Yuka Kato, Kiichiro Ninomiya, Kadoaki Ohashi, Shuta Tomida, Go Makimoto, Hiromi Watanabe, Kenichiro Kudo, Shingo Matsumoto, Shigeki Umemura, Koichi Goto, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

    Cancer science   109 ( 10 )   3149 - 3158   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

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  • Clinical significance of repeat rebiopsy in detecting the EGFR T790M secondary mutation in patients with non-small cell lung cancer. 国際誌

    Eiki Ichihara, Katsuyuki Hotta, Toshio Kubo, Tsukasa Higashionna, Kiichiro Ninomiya, Kadoaki Ohashi, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Oncotarget   9 ( 50 )   29525 - 29531   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Osimertinib is an essential drug to treat non-small-cell lung cancer (NSCLC) harboring the epidermal growth factor receptor (EGFR) T790M mutation, and rebiopsy is necessary to detect this mutation. However, the significance of repeat rebiopsy in NSCLC patients whose first rebiopsy was T790M-negative remains unclear. We used a retrospective cohort to clarify this issue. Methods: We reviewed the medical records of patients with NSCLC harboring EGFR mutations who underwent EGFR tyrosine kinase inhibitor (TKI) treatment at Okayama University Hospital between January 2015 and January 2017. Results: Of 102 patients with EGFR-mutant NSCLC, 55 underwent rebiopsy after acquired resistance to prior EGFR TKIs. Pre-existing activating EGFR mutations were found in all 55 rebiopsied samples. Of the 55 samples, 25 were T790M-positive (45%). Among the remaining 30 patients (T790M-negative on the first rebiopsy), 21 underwent additional rebiopsies following interval therapy. Of the 21 patients, 11 were T790M-positive on the second rebiopsy and 1 on the third. We also evaluated the efficacy of osimertinib in patients who needed a repeat rebiopsy to detect the T790M mutation. Osimertinib showed good activity with an objective response rate of 50%. Conclusions: Repeat rebiopsy increases the ability to detect a secondary mutation (T790M) in EGFR.

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  • Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.

    Go Makimoto, Eiki Ichihara, Katsuyuki Hotta, Kiichiro Ninomiya, Isao Oze, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Acta medica Okayama   72 ( 3 )   319 - 323   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.

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  • A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non-Small Cell Lung Cancer. 国際誌

    Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   13 ( 2 )   273 - 279   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Trastuzumab emtansine (T-DM1), an anti-erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years; male sex, 47%; performance status of 0 to 1, 80%; HER2 status IHC 3+, 33%; HER status IHC 2+/fluorescence in situ hybridization-positive, 20%; and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1-11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2-32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging; thus, additional molecular approaches are warranted.

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  • MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib. 国際誌

    Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Scientific reports   8 ( 1 )   1955 - 1955   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

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  • Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations. 国際誌

    Tomoki Tamura, Yuka Kato, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiroko Gotoda, Toshio Kubo, Eiki Ichihara, Takehiro Tanaka, Koichi Ichimura, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

    Biochemical and biophysical research communications   495 ( 1 )   360 - 367   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00-5.68; p < 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

    DOI: 10.1016/j.bbrc.2017.10.175

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  • Treatment Rationale and Design for J-SONIC: A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non-Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis. 国際誌

    Kohei Otsubo, Junji Kishimoto, Hirotsugu Kenmotsu, Yuji Minegishi, Eiki Ichihara, Akira Shiraki, Terufumi Kato, Shinji Atagi, Hidehito Horinouchi, Masahiko Ando, Yasuhiro Kondoh, Masahiko Kusumoto, Kazuya Ichikado, Nobuyuki Yamamoto, Yoichi Nakanishi, Isamu Okamoto

    Clinical lung cancer   19 ( 1 )   e5-e9 - E9   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CIG MEDIA GROUP, LP  

    We describe the treatment rationale and procedure for a randomized study (J-SONIC; University Hospital Medical Information Network Clinical Trials Registry identification no., UMIN000026799) of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without nintedanib for patients with advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy-naive patients with advanced NSCLC associated with IPF. Eligible patients (enrollment target, n = 170) will be randomized at a 1:1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily). The present trial is the first randomized controlled study for the treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone.

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  • Effects of (-)-epigallocatechin-3-gallate on EGFR- or Fusion Gene-driven Lung Cancer Cells.

    Yoshihiro Honda, Nagio Takigawa, Eiki Ichihara, Takashi Ninomiya, Toshio Kubo, Nobuaki Ochi, Masayuki Yasugi, Toshi Murakami, Hiromichi Yamane, Mitsune Tanimoto, Katsuyuki Kiura

    Acta medica Okayama   71 ( 6 )   505 - 512   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    (-)-Epigallocatechin-3-gallate (EGCG) has been shown to bind to several receptors including epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors and anaplastic lymphoma kinase (ALK) inhibitors are effective for non-small cell lung cancers harboring activating EGFR mutations and ALK or c-ros oncogene 1 (ROS1) fusion genes, respectively. We investigated the effects of EGCG on EGFR-or fusion gene-driven lung cancer cells such as PC-9, RPC-9, H1975, H2228 and HCC78. The five cell lines had similar sensitivity to EGCG. Phosphorylated (p) EGFR, pAkt and pErk in PC-9, RPC-9 and H1975 cells were suppressed by EGCG (50 or 100 mu M). EGCG also inhibited pALK in H2228, pROS1 in HCC78, and pErk and pAkt in both cell lines. All the xenograft tumors established using the 5 cell lines in EGCG-treated groups were significantly smaller than the tumors in the vehicle-treated groups. The numbers of tumor blood vessels of xenograft tissues in EGCG-treated mice were significantly lower than those in vehicle-treated mice. In conclusion, EGCG may be effective for EGFR-driven lung tumors irrespective of the presence of T790M, and for ALK or ROS1 fusion gene-driven lung tumors.

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  • Protective Effects of Bisoprolol against Acute Exacerbation in Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

    Akihiko Taniguchi, Nobuaki Miyahara, Naohiro Oda, Daisuke Morichika, Eiki Ichihara, Isao Oze, Yasushi Tanimoto, Hirohisa Ichikawa, Utako Fujii, Mitsune Tanimoto, Arihiko Kanehiro, Katsuyuki Kiura

    Acta medica Okayama   71 ( 5 )   453 - 457   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Although recent retrospective studies suggested that the use of β-blockers appears to help improve the mortality rate and decrease the rate of exacerbation in chronic obstructive pulmonary disease (COPD) patients with heart failure, the effects of β-blockers on COPD patients without heart failure have not been established. Based on previous reports, we have launched a multicenter, prospective, single-arm phase II study to evaluate the preventive effect of the cardioselective β-blocker bisoprolol in COPD exacerbation, in Japanese individuals with moderate-to-severe COPD who do not have heart failure but do have hypertension requiring the use of medication. The primary endpoint is the rate of mild-to-severe COPD exacerbation. The results of this study will clarify whether bisoprolol can prevent exacerbation in COPD patients without heart failure.

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  • A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202. 国際誌

    Shoichi Kuyama, Nobuaki Ochi, Akihiro Bessho, Katsuyuki Hotta, Genyo Ikeda, Daizo Kishino, Toshio Kubo, Daijiro Harada, Nobukazu Fujimoto, Masamoto Nakanishi, Takahiro Umeno, Toshiaki Okada, Kenichi Chikamori, Tomoko Yamagishi, Kadoaki Ohashi, Eiki Ichihara, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   112   188 - 194   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    INTRODUCTION: S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown. METHODS: The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40mg/m2, twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40mg/m2, twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated. RESULTS: Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134days (95% CI: 79-173) and 479days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P<0.01). CONCLUSION: This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option.

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  • Congestive Heart Failure During Osimertinib Treatment for Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC).

    Hiromi Watanabe, Eiki Ichihara, Hirohisa Kano, Kiichiro Ninomiya, Mitsune Tanimoto, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   56 ( 16 )   2195 - 2197   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    We herein report a case of congestive heart failure which developed during osimertinib treatment. A 78-year-old woman presented with mild exertional dyspnea three weeks after starting osimertinib for the treatment of epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer. She was diagnosed with congestive heart failure caused by the osimertinib. In contrast to trastuzumab, a human epidermal growth factor receptor 2 (HER2) monoclonal antibody that often causes cardiac dysfunction, the causal relationship between osimertinib and cardiotoxicity has so far received little attention and thus remains unclear. However, it inhibits HER2 in addition to mutant EGFR, thereby potentially causing cardiotoxicity.

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  • Clinical characteristics of Japanese candidates for lung transplant for interstitial lung disease and risk factors for early death while on the waiting list. 国際誌

    Hisao Higo, Takeshi Kurosaki, Eiki Ichihara, Toshio Kubo, Kentaroh Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Nobuaki Miyahara, Katsuyuki Kiura, Shinichiro Miyoshi, Takahiro Oto

    Respiratory investigation   55 ( 4 )   264 - 269   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    BACKGROUND: Lung transplants have produced very favorable outcomes for patients with interstitial lung disease (ILD) in Japan. However, because of the severe donor lung shortage, patients must wait approximately 2.5 years before they can undergo transplantation and many candidates die before allocation. We reveal the clinical characteristics of Japanese patients with ILD who are candidates for lung transplants and the risk factors for early death while on the waiting list. METHODS: We retrospectively reviewed the clinical data of patients registered in the Japan Organ Transplant Network from Okayama University Hospital who are candidates for cadaveric lung transplants for ILD between 1999 and 2015. RESULTS: Fifty-three patients with ILD were included (24 patients with idiopathic pulmonary fibrosis and 29 others). They had severe pulmonary dysfunction and low exercise tolerability. The median waiting time for transplantation was 462 days, and 22 patients died before allocation. Patients who died before 462 days without undergoing transplantation had more severe dyspnea, shorter 6-minute walk distance (6MWD), and lower performance status than those who waited ≥462 days. CONCLUSIONS: Japanese candidates for cadaveric lung transplants for ILD have severe pulmonary dysfunction. Severe dyspnea, short 6MWD, and low performance status are risk factors for early death while on the waiting list.

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  • SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer. 国際誌

    Eiki Ichihara, David Westover, Catherine B Meador, Yingjun Yan, Joshua A Bauer, Pengcheng Lu, Fei Ye, Amanda Kulick, Elisa de Stanchina, Robert McEwen, Marc Ladanyi, Darren Cross, William Pao, Christine M Lovly

    Cancer research   77 ( 11 )   2990 - 3000   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib-resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer. Cancer Res; 77(11); 2990-3000. ©2017 AACR.

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  • Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo. 国際誌

    Kenichiro Kudo, Kadoaki Ohashi, Go Makimoto, Hisao Higo, Yuka Kato, Hiroe Kayatani, Yasuko Kurata, Yoichiro Takami, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Tadashi Yoshino, Mitsune Tanimoto, Katsuyuki Kiura

    Molecular oncology   11 ( 6 )   670 - 681   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR-mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFRT790M mutations in clinical trials. The effect of bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, combined with EGFR-TKIs has also been investigated. We hypothesized that the dose of afatinib and cetuximab could be reduced by combination with bevacizumab and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975-harboring EGFRL858R+T790M and RPC-9-harboring EGFR19DEL+T790M , we tested the efficacy of the triplet therapy with a modified dose of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC-9 cells versus tumors treated with single or double therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31-positive vascular endothelial cells and increased cleaved caspase-3-positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFRT790M mutations. Therefore, clinical trials of this combination therapy are warranted.

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  • Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study. 国際誌

    Daisuke Minami, Nagio Takigawa, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   47 ( 5 )   434 - 437   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Objective: Although endobronchial intubation during a bronchoscopic examination is useful for invasive procedures, it is not routine practice in Japan. The present study evaluated discomfort due to endobronchial intubation using fentanyl and midazolam sedation during bronchoscopy. Methods: Thirty-nine patients were enrolled prospectively from November 2014 to September 2015 at Okayama University Hospital. Fentanyl (20 µg) was administered to the patients just before endobronchial intubation, and fentanyl (10 µg) and midazolam (1 mg) were added as needed during the procedure. A questionnaire survey was administered 2 h after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: excellent (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also asked. Predefined parameters (blood pressure, heart rate, oxygen saturation and complications) were recorded. Results: The enrolled patients included 22 males and 17 females; their median age was 70 (range: 28-88) years. The patients received a mean dose of 47.9 µg of fentanyl (range: 30-90 µg) and 2.79 mg of midazolam (range: 1-7 mg). In total, 28 patients (71.7%) agreed to undergo a second bronchoscopic examination; the mean levels of discomfort and for the re-examination were 2.07 points each. About 41% of the patients remembered the bronchoscopic examination. No severe complications were reported. Conclusion: Endobronchial intubation using fentanyl and midazolam sedation during an invasive bronchoscopic procedure might be recommended. Clinical Trial Registration: UMIN000015578 in the UMIN Clinical Trials Registry.

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  • Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403. 国際誌

    Naohiro Oda, Eiki Ichihara, Katsuyuki Hotta, Kiichiro Ninomiya, Takashi Ninomiya, Toshio Kubo, Daisuke Minami, Toshi Murakami, Toshihide Yokoyama, Daijiro Harada, Shoichi Kuyama, Hirohisa Ichikawa, Koji Inoue, Daizo Kishino, Masaaki Inoue, Nagio Takigawa, Takuo Shibayama, Shingo Harita, Mitsune Tanimoto, Katsuyuki Kiura

    Clinical lung cancer   18 ( 2 )   241 - 244   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CIG MEDIA GROUP, LP  

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.

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  • Three-Arm Randomized Trial of Sodium Alginate for Preventing Radiation-Induced Esophagitis in Locally Advanced Non-Small Cell Lung Cancer Receiving Concurrent Chemoradiotherapy: The OLCSG1401 Study Protocol. 国際誌

    Kiichiro Ninomiya, Eiki Ichihara, Katsuyuki Hotta, Naoyuki Sone, Toshi Murakami, Daijiro Harada, Isao Oze, Toshio Kubo, Hisaaki Tanaka, Shoichi Kuyama, Daizo Kishino, Akihiro Bessho, Shingo Harita, Kuniaki Katsui, Mitsune Tanimoto, Katsuyuki Kiura

    Clinical lung cancer   18 ( 2 )   245 - 249   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CIG MEDIA GROUP, LP  

    Concurrent chemoradiotherapy (CRT) is the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, this intensive therapy often causes severe esophagitis, which could deteriorate a patient's quality of life (QOL), leading to poor treatment compliance. Sodium alginate, approved in Japan for gastritis, is sufficiently highly viscous to remain in the esophageal mucosa, providing a protective effect in the esophagus. To investigate whether this compound has a preventive effect against severe esophagitis in patients receiving concurrent CRT, we plan a 3-arm randomized trial of sodium alginate with 2 different schedules versus water. The primary endpoint is set as the proportion of patients with grade ≥ 3 esophagitis using the Common Terminology Criteria for Adverse Events, version 4.0. With stratification by institute, performance status, and percentage of the esophageal volume receiving >35 Gy, the patients will be randomly assigned to 1 of the following groups: sodium alginate initiated concomitantly with CRT (group A), sodium alginate initiated soon after the development of extremely mild esophagitis during CRT (group B), or water administered throughout CRT (group C). Assuming that the proportion of grade ≥ 3 esophagitis would be 8% in groups A and B and 27% in group C, the required sample size would be 200 patients, with 70% power and 5% α. The secondary endpoints include QOL, the frequency of additional prescriptions of analgesics, treatment response, and survival. The results of the present study will clarify whether sodium alginate can prevent esophagitis in patients with LA-NSCLC undergoing CRT.

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  • Protocol Design for the Bench to Bed Trial in Alectinib-Refractory Non-Small-Cell Lung Cancer Patients Harboring the EML4-ALK Fusion Gene (ALRIGHT/OLCSG1405). 国際誌

    Hideko Isozaki, Katsuyuki Hotta, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Toshio Kubo, Takashi Ninomiya, Kiichiro Ninomiya, Naohiro Oda, Hiroshige Yoshioka, Hirohisa Ichikawa, Masaaki Inoue, Ichiro Takata, Takuo Shibayama, Shoichi Kuyama, Keisuke Sugimoto, Daijiro Harada, Shingo Harita, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

    Clinical lung cancer   17 ( 6 )   602 - 605   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CIG MEDIA GROUP, LP  

    Based on our preclinical study results, which showed that the activation of the hepatocyte growth factor/MET pathway is a potential mechanism of acquired resistance to alectinib, we launched the ALRIGHT (OLCSG1405 [alectinib-refractory non-small-cell lung cancer patients harboring the EML4-ALK fusion gene]), a phase II trial of the anaplastic lymphoma kinase (ALK)/MET inhibitor crizotinib in patients with non-small-cell lung cancer refractory to alectinib and harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. Patients with ALK-rearranged tumors who have developed disease progression during alectinib treatment will receive crizotinib monotherapy until disease progression or the occurrence of unacceptable toxicity. The primary endpoint is set as the objective response rate, assuming that a response in 50% of eligible patients will indicate potential usefulness and that 15% would be the lower limit of interest (1-sided α of 0.05, β of 0.20). The estimated accrual number of patients is 9. The secondary endpoints include progression-free survival, overall survival, adverse events, and patient-reported outcomes. We will also take tissue samples before crizotinib monotherapy to conduct an exploratory analysis of ALK and hepatocyte growth factor/MET expression levels and gene alterations (eg, mutations, amplifications, and translocations). We will obtain information regarding whether crizotinib, which targets not only ALK, but also MET, can truly produce efficacy with acceptable safety profiles in ALK+ non-small-cell lung cancer even in the alectinib-refractory setting.

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  • Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience. 国際誌

    Naohiro Oda, Katsuyuki Hotta, Hiroshige Yoshioka, Kenichiro Kudo, Eiki Ichihara, Yuka Kato, Kiichiro Ninomiya, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Nagio Takigawa, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer chemotherapy and pharmacology   78 ( 5 )   941 - 947   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    BACKGROUND: Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown. METHODS: We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-naïve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI) ≥ 25 kg/m2 and assessed its potential relationship with ≥grade 2 hepatic dysfunction. RESULTS: The patient demographics were as follows: 114 women; median age 72 years (range 42-95 years); BMI ≥ 25 kg/m2, n = 32; performance status 0-1, n = 136; stage IIIB/IV, n = 141; and major EGFR mutations, n = 171. Hepatic dysfunction ≥grade 2 during the gefitinib therapy was observed in 44 (24.0 %) patients, 22 (50.0 %) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56 days (range 6-1,352 days). Overweight patients were more likely to develop hepatic dysfunction ≥grade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95 % confidence interval 1.01-4.95; p = 0.046). CONCLUSION: These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.

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  • Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation.

    Masahiro Osawa, Kadoaki Ohashi, Toshio Kubo, Eiki Ichihara, Saburo Takata, Nagio Takigawa, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

    Acta medica Okayama   70 ( 4 )   243 - 53   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, p< 0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation.

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  • EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. 国際誌

    Kartik Konduri, Jean-Nicolas Gallant, Young Kwang Chae, Francis J Giles, Barbara J Gitlitz, Kyle Gowen, Eiki Ichihara, Taofeek K Owonikoko, Vijay Peddareddigari, Suresh S Ramalingam, Satyanarayan K Reddy, Beth Eaby-Sandy, Tiziana Vavalà, Andrew Whiteley, Heidi Chen, Yingjun Yan, Jonathan H Sheehan, Jens Meiler, Deborah Morosini, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, Siraj M Ali, Christine M Lovly

    Cancer discovery   6 ( 6 )   601 - 11   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    UNLABELLED: Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. SIGNIFICANCE: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.

    DOI: 10.1158/2159-8290.CD-16-0075

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  • Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases. 国際誌

    Hideko Isozaki, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Nobuaki Ochi, Masayuki Yasugi, Takashi Ninomiya, Hiromichi Yamane, Katsuyuki Hotta, Katsuya Sakai, Kunio Matsumoto, Shinobu Hosokawa, Akihiro Bessho, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer research   76 ( 6 )   1506 - 16   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.

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  • Short-term low-volume hydration in cisplatin-based chemotherapy for patients with lung cancer: the second prospective feasibility study in the Okayama Lung Cancer Study Group Trial 1201.

    Kiichiro Ninomiya, Katsuyuki Hotta, Akiko Hisamoto-Sato, Eiki Ichihara, Hiroko Gotoda, Daisuke Morichika, Tomoki Tamura, Hiroe Kayatani, Daisuke Minami, Toshio Kubo, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    International journal of clinical oncology   21 ( 1 )   81 - 7   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER JAPAN KK  

    OBJECTIVE: We previously reported the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy (Jpn J Clin Oncol 2013). We sought to determine the clinical usefulness of a more convenient hydration method, evaluating the safety and efficacy of shorter-term and lower-volume hydration. METHOD: Chemonaïve patients with advanced lung cancer who were ≤ 75 years and reserved an adequate renal function for cisplatin use (≥ 60 mg/m(2)) were eligible. An intravenously administered hydration of 1700 ml in ~3.5 h with 1500 ml of orally administered hydration was investigated. The primary endpoint was the proportion of patients without grade 2 or worse renal toxicity in the first cycle. RESULTS: A total of 45 patients were registered, all of whom were evaluable for renal toxicity. The median baseline creatinine score was 0.70 mg/dl, and the median cisplatin dose on day 1 was 75 mg/m(2). In the first cycle, one patient (2 %) developed grade 2 creatinine toxicity, and thus, the proportion of patients with less than grade 2 was 98 % (the lower limit of 95 % confidence interval; 93 %), which met the primary endpoint. Five patients (11 %) had grade 1 or greater nephrotoxicity, three of whom successfully recovered. The objective response rate was 24 % and median progression-free survival 5.8 months. CONCLUSION: This prospective study demonstrated the safety and efficacy of shorter-term lower-volume hydration.

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  • Short-term low-volume hydration in cisplatin-based chemotherapy: a feasibility study in lung cancer (OLCSG1201)

    Kiichiro Ninomiya, Katsuyuki Hotta, Hiroko Gotoda, Daisuke Morichika, Eiki Ichihara, Akiko Sato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    ANNALS OF ONCOLOGY   26   80 - 80   2015年11月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

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  • RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. 国際誌

    Gorjan Hrustanovic, Victor Olivas, Evangelos Pazarentzos, Asmin Tulpule, Saurabh Asthana, Collin M Blakely, Ross A Okimoto, Luping Lin, Dana S Neel, Amit Sabnis, Jennifer Flanagan, Elton Chan, Marileila Varella-Garcia, Dara L Aisner, Aria Vaishnavi, Sai-Hong I Ou, Eric A Collisson, Eiki Ichihara, Philip C Mack, Christine M Lovly, Niki Karachaliou, Rafael Rosell, Jonathan W Riess, Robert C Doebele, Trever G Bivona

    Nature medicine   21 ( 9 )   1038 - 47   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.

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  • Impact of body surface area on survival in EGFR-mutant non-small cell lung cancer patients treated with gefitinib monotherapy: observational study of the Okayama Lung Cancer Study Group 0703. 国際誌

    Kenichiro Kudo, Katsuyuki Hotta, Eiki Ichihara, Hiroshige Yoshioka, Kei Kunimasa, Kazuya Tsubouchi, Masahiro Iwasaku, Yuka Kato, Isao Oze, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer chemotherapy and pharmacology   76 ( 2 )   251 - 6   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    BACKGROUND: The approved dose of gefitinib is fixed, without adjustment for physical size. We demonstrated previously that its efficacy was affected by body surface area (BSA) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). To validate these observations, we assessed the association between BSA and the efficacy of gefitinib using a different patient cohort. METHODS: Prospective cohort data from 115 NSCLC patients with EGFR-mutant tumours, who received gefitinib monotherapy between 2007 and 2012, were analysed. RESULTS: Gefitinib was less effective in individuals with a high BSA (≥1.5 m(2)) in EGFR-mutant NSCLC compared with those with a low BSA (<1.5 m(2)). The median progression-free survival (PFS) in the high- and low-BSA groups was 4.2 and 8.5 months, respectively, although there was no difference in survival among the whole NSCLC cohort. Multivariate analysis also showed a significant effect of BSA on PFS (hazard ratio 1.72; 95 % confidence interval 1.08-2.74; p = 0.021). Sensitivity analysis revealed that the use of the BSA cut-off level around 1.50 m(2) was robust for detecting subpopulations that would benefit less from gefitinib monotherapy. CONCLUSION: We found in the prospective cohort data that BSA could affect the efficacy of gefitinib monotherapy in patients with EGFR-mutant NSCLC, suggesting that BSA-based dose setting of gefitinib monotherapy might be further investigated, despite the fact that no molecular-targeted agent described to date undergoes dose adjustment according to BSA.

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  • Shades of T790M: Intratumor Heterogeneity in EGFR-Mutant Lung Cancer. 国際誌

    Eiki Ichihara, Christine M Lovly

    Cancer discovery   5 ( 7 )   694 - 6   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    In the setting of recent exciting clinical results and numerous ongoing trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant-specific EGFR inhibitor rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small-cell transformation are all clinically relevant mechanisms of drug resistance. The authors provide a new paradigm for using quantitative assessment of the EGFR T790M:activation mutation allele frequency ratio to prognosticate responses to rociletinib and also demonstrate that plasma-based assessments of circulating tumor DNA can be used to monitor drug response and the emergence of drug resistance.

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  • Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models. 国際誌

    Catherine A Eberlein, Daniel Stetson, Aleksandra A Markovets, Katherine J Al-Kadhimi, Zhongwu Lai, Paul R Fisher, Catherine B Meador, Paula Spitzler, Eiki Ichihara, Sarah J Ross, Miika J Ahdesmaki, Ambar Ahmed, Laura E Ratcliffe, Elizabeth L Christey O'Brien, Claire H Barnes, Henry Brown, Paul D Smith, Jonathan R Dry, Garry Beran, Kenneth S Thress, Brian Dougherty, William Pao, Darren A E Cross

    Cancer research   75 ( 12 )   2489 - 500   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.

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  • Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. 国際誌

    Eiki Ichihara, Katsuyuki Hotta, Naoyuki Nogami, Shoichi Kuyama, Daizo Kishino, Masanori Fujii, Toshiyuki Kozuki, Masahiro Tabata, Daijiro Harada, Kenichi Chikamori, Keisuke Aoe, Hiroshi Ueoka, Shinobu Hosokawa, Akihiro Bessho, Akiko Hisamoto-Sato, Toshio Kubo, Isao Oze, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   10 ( 3 )   486 - 91   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    PURPOSE: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. METHODS: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. RESULTS: Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths. CONCLUSION: Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.

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  • A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. 国際誌

    Hideko Isozaki, Masayuki Yasugi, Nagio Takigawa, Katsuyuki Hotta, Eiki Ichihara, Akihiko Taniguchi, Shinichi Toyooka, Shinsuke Hashida, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   44 ( 10 )   963 - 8   2014年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    OBJECTIVE: The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK. METHODS: A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months. RESULTS: Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice. CONCLUSIONS: We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

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  • AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. 国際誌

    Darren A E Cross, Susan E Ashton, Serban Ghiorghiu, Cath Eberlein, Caroline A Nebhan, Paula J Spitzler, Jonathon P Orme, M Raymond V Finlay, Richard A Ward, Martine J Mellor, Gareth Hughes, Amar Rahi, Vivien N Jacobs, Monica Red Brewer, Eiki Ichihara, Jing Sun, Hailing Jin, Peter Ballard, Katherine Al-Kadhimi, Rachel Rowlinson, Teresa Klinowska, Graham H P Richmond, Mireille Cantarini, Dong-Wan Kim, Malcolm R Ranson, William Pao

    Cancer discovery   4 ( 9 )   1046 - 61   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    UNLABELLED: First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.

    DOI: 10.1158/2159-8290.CD-14-0337

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  • Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. 国際誌

    Masayuki Yasugi, Nagio Takigawa, Nobuaki Ochi, Kadoaki Ohashi, Daijiro Harada, Takashi Ninomiya, Toshi Murakami, Yoshihiro Honda, Eiki Ichihara, Mitsune Tanimoto, Katsuyuki Kiura

    Experimental cell research   326 ( 2 )   201 - 9   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER INC  

    Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9 ± 0.9 and 9.4 ± 3.2 (t-test, p<0.001), respectively. pS6 was suppressed during eve r olimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.

    DOI: 10.1016/j.yexcr.2014.04.012

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  • Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience. 国際誌

    Yuka Kato, Katsuyuki Hotta, Nagio Takigawa, Naoyuki Nogami, Toshiyuki Kozuki, Akiko Sato, Eiki Ichihara, Kenichiro Kudo, Isao Oze, Masahiro Tabata, Tetsu Shinkai, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer chemotherapy and pharmacology   73 ( 5 )   943 - 50   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    PURPOSE: Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients. METHODS: This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed. RESULTS: In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005). CONCLUSION: In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.

    DOI: 10.1007/s00280-014-2425-9

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  • Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. 国際誌

    Nobuaki Ochi, Nagio Takigawa, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Experimental cell research   322 ( 1 )   168 - 77   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER INC  

    To study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance.

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  • Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. 国際誌

    Toshi Murakami, Nagio Takigawa, Takashi Ninomiya, Nobuaki Ochi, Masaaki Yasugi, Yoshihiro Honda, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   83 ( 1 )   30 - 6   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    OBJECTIVE: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. MATERIALS AND METHODS: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MTT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. RESULTS: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model. Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1mm) in the AZD1480-treated group and control group were 0.37±0.18 and 2.25±0.53 (p<0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p<0.0001). CONCLUSION: AZD1480 may be effective against lung tumors driven by an activating EGFR mutation.

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  • Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. 国際誌

    Hiromi Hayakawa, Eiki Ichihara, Kadoaki Ohashi, Takashi Ninomiya, Masayuki Yasugi, Saburo Takata, Katsuya Sakai, Kunio Matsumoto, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer science   104 ( 11 )   1440 - 6   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Non-small-cell lung cancers with epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs); however, unlike cytotoxic agents, it is generally accepted that minimal doses of drugs inhibiting target molecules are sufficient when molecular-targeted agents, including EGFR-TKIs, are used. Thus, any utility of higher doses remains unclear. We compared low-dose (15 mg/kg) gefitinib therapy with high-dose (50 mg/kg) therapy using an EGFR-mutated lung cancer xenograft model. Both gefitinib doses induced tumor shrinkage, but tumors regrew in the low-dose group within 1 month, whereas tumors in the high-dose group did not. Neither the T790M mutation nor MET amplification was apparent in regrown tumors. We also compared outcomes after two doses of gefitinib (5 and 25 mg/kg) in a transgenic EGFR-mutated lung cancer mouse model. In line with the results obtained using the xenograft model, both gefitinib doses completely inhibited tumor growth, but tumors treated with the lower dose of gefitinib developed earlier drug resistance. In conclusion, a low gefitinib dose caused tumors to become drug-resistant prior to acquisition of the T790M mutation or MET amplification in EGFR-mutated models of lung cancer. This suggests that it is important to optimize the EGFR-TKI dose for treatment of EGFR mutation-associated lung cancer. Gefitinib may need to be given at a dose greater than the minimum required for inhibition of target molecules.

    DOI: 10.1111/cas.12284

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  • Reappraisal of short-term low-volume hydration in cisplatin-based chemotherapy: results of a prospective feasibility study in advanced lung cancer in the Okayama Lung Cancer Study Group Trial 1002. 国際誌

    Katsuyuki Hotta, Nagio Takigawa, Akiko Hisamoto-Sato, Eiki Ichihara, Kenichiro Kudo, Koji Uchida, Kayo Yanase-Nakamura, Hisaaki Tanaka, Yuka Kato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   43 ( 11 )   1115 - 23   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    OBJECTIVE: Cisplatin can induce severe renal toxicity. However, the degree and pattern of hydration that is most efficient at preventing it have scarcely been formally evaluated. We here performed a prospective feasibility study of cisplatin-based chemotherapy with short-term low-volume hydration in advanced lung cancer. METHODS: Chemo-naïve patients with advanced lung cancer and reserving renal function who were suitable for cisplatin use (≥60 mg/m(2) on Day 1) were eligible for this study. Two-and-a-half-liter hydration within ∼4.5 h was investigated. The primary end point was the proportion of patients who underwent cisplatin-based chemotherapy without any Grade 2 or more renal toxicity in the first cycle. RESULTS: A total of 46 patients were registered, all of whom were evaluable for renal toxicity. The median baseline creatinine score was 0.70 mg/dl and the median cisplatin dose on Day 1 was 80 mg/m(2). In the first cycle, none of the patients developed Grade 2 or more creatinine toxicity, which met the primary endpoint. Four patients (9%) had Grade 1 toxicity, with a median worst creatinine score of 1.19 mg/dl, but it disappeared rapidly. Creatinine toxicity was influenced by several clinical factors, including the performance status. Ten patients (22%) needed extra hydration during the first cycle, mainly due to gastrointestinal toxicity. However, all 10 were able to undergo further cycles of treatment. Thirty-two (86%) of the 37 patients who were assumed to be able to undergo further treatment at our institute received it in an outpatient setting. CONCLUSIONS: This study demonstrated prospectively the feasibility of short-term low-volume hydration.

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  • Usefulness of endobronchial ultrasound-guided transbronchial needle aspiration in distinguishing sarcoidosis from recurrent cancer in patients with lymphadenopathy after surgery. 国際誌

    Daisuke Minami, Nagio Takigawa, Hiromi Hayakawa, Makoto Mizuta, Kenichiro Kudo, Kozi Uchida, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   43 ( 11 )   1110 - 4   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration is a new minimally invasive test for investigating mediastinal and hilar lymphadenopathy. It is sometimes difficult to distinguish between a recurrent malignant lymph node and lymphadenopathy due to sarcoidosis in patients who develop lymphadenopathy after surgery for a malignant tumor. METHODS: Between December 2009 and October 2012, we performed endobronchial ultrasound-guided transbronchial needle aspiration in 13 selected patients with a suspected recurrence in the mediastinum and/or hilum of the lung after surgical resection of a malignant tumor. We examined their medical records to obtain information on the diagnosis, the sizes of lymph nodes, the number of needle passes and other complications. RESULTS: Definitive diagnoses were made using endobronchial ultrasound-guided transbronchial needle aspiration in 10 patients (three lung adenocarcinomas, one prostate carcinoma, one renal cell carcinoma, one neuroendocrine tumor and four sarcoidosis). Pathological specimens showing non-caseating granulomas led to the diagnosis of sarcoidosis in four patients; their previous malignancies had been papillary adenocarcinoma of the thyroid, carcinoma of the gingiva, thymoma and bladder cancer, but no recurrences were observed. The median of the longest diameter in 15 lymph nodes was 22 mm (range 13-35), and the median number of needle passes was two times (range 1-5) without severe complications. CONCLUSIONS: Endobronchial ultrasound-guided transbronchial needle aspiration might be useful in differentiating between benign lymphadenopathy, including sarcoidosis, and cancer recurrence in patients with mediastinal or hilar lymphadenopathy after surgical resection of a malignant tumor.

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  • Impact of physical size on gefitinib efficacy in patients with non-small cell lung cancer harboring EGFR mutations. 国際誌

    Eiki Ichihara, Katsuyuki Hotta, Nagio Takigawa, Kenichiro Kudo, Yuka Kato, Yoshihiro Honda, Hiromi Hayakawa, Daisuke Minami, Akiko Sato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   81 ( 3 )   435 - 439   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Gefitinib is an essential drug for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations. The approved dosage is 250 mg/body/day without adjustment for physical size such as body surface area (BSA), and the impact of physical size on the efficacy of gefitinib has not been evaluated. Here, we sought to clarify this issue using a retrospective cohort. We reviewed the medical records of patients with consecutive advanced NSCLC harboring EGFR mutations who underwent gefitinib monotherapy at Okayama University Hospital. In total, 101 patients were included in this study, and the median BSA in this cohort was 1.5 m(2). The median progression-free survival (PFS) of the patients with higher BSA (≥1.5 m(2)) was significantly worse than that of those with lower BSA (< 1.5 m(2)) (10.4 vs. 18.0 months; p = 0.019, log-rank test). Multivariate analysis also showed a significant impact of BSA on PFS (hazards ratio, 2.34; 95% confidence interval, 1.78-2.89; p = 0.002). By contrast, no significant association between BSA and PFS was observed in those undergoing cytotoxic chemotherapy (4.0 vs. 5.1 months; p = 0.989, log-rank test), suggesting that BSA is a predictive, rather than a prognostic, marker for gefitinib therapy in EGFR-mutated NSCLC. In conclusion, BSA affected PFS in patients with EGFR-mutated NSCLC who underwent gefitinib monotherapy, suggesting the need for appraisal of BSA-based dose adjustment, even for this molecular target-based therapy.

    DOI: 10.1016/j.lungcan.2013.05.021

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  • Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. 国際誌

    Ken Saito, Nagio Takigawa, Naoko Ohtani, Hidekazu Iioka, Yuki Tomita, Ryuzo Ueda, Junya Fukuoka, Kazuhiko Kuwahara, Eiki Ichihara, Katsuyuki Kiura, Eisaku Kondo

    Molecular cancer therapeutics   12 ( 8 )   1616 - 28   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinib-resistant mutations in EGFR, which is a critical issue for current therapeutics. We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14(ARF) expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14(ARF) triggered the most augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14(ARF) (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14(ARF) 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers.

    DOI: 10.1158/1535-7163.MCT-12-1239

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  • Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. 国際誌

    Kazuhiko Shien, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Masaru Jida, Kelsie L Thu, Shinsuke Hashida, Yuho Maki, Eiki Ichihara, Hiroaki Asano, Kazunori Tsukuda, Nagio Takigawa, Katsuyuki Kiura, Adi F Gazdar, Wan L Lam, Shinichiro Miyoshi

    Cancer research   73 ( 10 )   3051 - 61   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment.

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  • Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. 国際誌

    Takashi Ninomiya, Nagio Takigawa, Eiki Ichihara, Nobuaki Ochi, Toshi Murakami, Yoshihiro Honda, Toshio Kubo, Daisuke Minami, Kenichiro Kudo, Mitsune Tanimoto, Katsuyuki Kiura

    Molecular cancer therapeutics   12 ( 5 )   589 - 97   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation.

    DOI: 10.1158/1535-7163.MCT-12-0885

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  • Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency. 国際誌

    Hiromasa Takeda, Nagio Takigawa, Kadoaki Ohashi, Daisuke Minami, Itaru Kataoka, Eiki Ichihara, Nobuaki Ochi, Mitsune Tanimoto, Katsuyuki Kiura

    Experimental cell research   319 ( 4 )   417 - 23   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER INC  

    The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact PTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack PTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined.

    DOI: 10.1016/j.yexcr.2012.12.018

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  • Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells. 国際誌

    Daisuke Minami, Nagio Takigawa, Hiromasa Takeda, Minoru Takata, Nobuaki Ochi, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura

    Molecular cancer research : MCR   11 ( 2 )   140 - 8   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650(PTEN+)) and knocked down PTEN expression in the PC-9 cells (PC-9(PTEN-)) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9(PTEN-) cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650(PTEN+) and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair.

    DOI: 10.1158/1541-7786.MCR-12-0401

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  • Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer. 国際誌

    Katsuyuki Hotta, Etsuji Suzuki, Massimo Di Maio, Paolo Chiodini, Yoshiro Fujiwara, Nagio Takigawa, Eiki Ichihara, Martin Reck, Christian Manegold, Lothar Pilz, Akiko Hisamoto-Sato, Masahiro Tabata, Mitsune Tanimoto, Frances A Shepherd, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   79 ( 1 )   20 - 6   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    BACKGROUND: We examined how crossover therapy might affect the association between progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: We extracted PFS- and OS-hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function with the coefficient of determination (R-squared) to assess the correlation between PFS and OS. RESULTS: Thirty-four trials with 35 pairs for the investigational and reference arms were identified (24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R-squared = 0.14), suggesting PFS-HR could account only for 14% of variation in OS-HR. The median proportion of crossover therapy per trial was 20%. If patients seldom crossed over (none or <1%), the association between PFS- and OS-HRs was strong (R-squared = 0.69). When the proportion of crossover was ≥1%, however, R-squared declined considerably (≥1% to <20% crossover, R-squared = 0.27; ≥20% to <40%, R-squared = 0.06; and ≥40%, R-squared = 0.27). CONCLUSIONS: A PFS advantage seldom is associated with an OS advantage any longer. Our analysis suggests this is due to a high level of crossover now that an increasing number of active agents are available for NSCLC.

    DOI: 10.1016/j.lungcan.2012.10.007

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  • Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy. 国際誌

    Toshio Kubo, Nagio Takigawa, Masahiro Osawa, Daijiro Harada, Takashi Ninomiya, Nobuaki Ochi, Eiki Ichihara, Hiromichi Yamane, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer science   104 ( 1 )   78 - 84   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Tumors are presumed to contain a small population of cancer stem cells (CSCs) that initiate tumor growth and promote tumor spreading. Multidrug resistance in CSCs is thought to allow the tumor to evade conventional therapy. This study focused on expression of CD133 and CD87 because CD133 is a putative marker of CSCs in some cancers including lung, and CD87 is associated with a stem-cell-like property in small-cell lung cancer (SCLC). Six SCLC cell lines were used. The expression levels of CD133 and CD87 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry. CD133+/- and CD87+/- cells were isolated by flow cytometry. The drug sensitivities were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Non-obese diabetic/severe combined immunodeficiency mice were used for the tumor formation assay. SBC-7 cells showed the highest expression levels of both CD133 and CD87 among the cell lines. CD133-/CD87-, CD133+/CD87-, and CD133-/CD87+ cells were isolated from SBC-7 cells; however, CD133+/CD87+ cells could not be obtained. Both CD133+/CD87- and CD133-/CD87+ subpopulations showed a higher resistance to etoposide and paclitaxel and greater re-populating ability than the CD133-/CD87- subpopulation. CD133+/CD87- cells contained more G0 quiescent cells than CD133-/CD87- cells. By contrast, CD133-/CD87- cells showed the highest tumorigenic potential. In conclusion, both CD133 and CD87 proved to be inadequate markers for CSCs; however, they might be beneficial for predicting resistance to chemotherapy.

    DOI: 10.1111/cas.12045

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  • A definite case of (L)-carbocisteine-induced pneumonia with CATCH22 syndrome.

    Kenichiro Kudo, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Nobuaki Miyahara, Yasushi Tanimoto, Sadaharu Akagi, Katsuya Kato, Mitsune Tanimoto, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   52 ( 1 )   97 - 100   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    A 32-year-old male with CATCH22 syndrome presented with a high fever and productive cough after taking drugs for acute bronchitis, including (L)-carbocisteine. Chest radiography revealed ground-glass opacities in the bilateral lung fields. He had a history of similar pneumonia. Under the assumption of drug-induced pneumonia, or bacterial or viral pneumonia, all drugs including (L)-carbocisteine were discontinued, and antibiotics were started. A drug-induced lymphocyte stimulation test was positive only for (L)-carbocisteine. The only drug in common between this and the previous episode of pneumonia was (L)-carbocisteine. We thus concluded that this was a definite case of (L)-carbocisteine-induced pneumonia in a patient with CATCH22 syndrome.

    DOI: 10.2169/internalmedicine.52.7882

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  • Influence of the timing of tumor regression after the initiation of chemoradiotherapy on prognosis in patients with limited-disease small-cell lung cancer achieving objective response. 国際誌

    Masanori Fujii, Katsuyuki Hotta, Nagio Takigawa, Akiko Hisamoto, Eiki Ichihara, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   78 ( 1 )   107 - 11   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    PURPOSE: Chemoradiotherapy (CHRT) yields a favorable antitumor activity in patients with limited-stage small-cell lung cancer (LD-SCLC) with a response rate of around 80%. Even in such responders, the majority recur, indicating the importance of identifying a subset of patients with a poor outcome earlier through the treatment. We investigated whether the timing of obtaining tumor regression with the CHRT could affect the prognosis in LD-SCLC patients who finally achieved the objective response through the treatment. PATIENTS AND METHODS: We retrospectively reviewed medical charts of 70 LD-SCLC patients who obtained complete response (CR) or partial response (PR) with the 3 or 4 cycles of first-line CHRT between 1988 and 2006. RESULTS: In the whole 70 patients with CR/PR, the median survival time and median progression free survival (PFS) were 39.6 and 12.3months, respectively. Fifty-two (74.3%) of the 70 patients entered CR/PR after the first cycle of CHRT, and their 2-year survival rates were significantly longer than that in the remaining 18 patients without entering CR/PR yet at the end of first cycle (72.3% and 7.1%, respectively, p<0.001). Cox regression analysis showed that the early response to the treatment was a significant prognostic factors (hazard ratio=0.098; 95% confidence interval=0.036-0.269). Regarding PFS, similar findings were observed. CONCLUSIONS: Patients without entering CR/PR yet after the first course had a poorer outcome even though the objective response was finally confirmed through the treatment. Development of more effective treatments for these high-risk patients is warranted to improve their poor prognosis.

    DOI: 10.1016/j.lungcan.2012.07.001

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  • JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. 国際誌

    Daijiro Harada, Nagio Takigawa, Nobuaki Ochi, Takashi Ninomiya, Masayuki Yasugi, Toshio Kubo, Hiromasa Takeda, Eiki Ichihara, Kadoaki Ohashi, Saburo Takata, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer science   103 ( 10 )   1795 - 802   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.

    DOI: 10.1111/j.1349-7006.2012.02363.x

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  • Phase II study of irinotecan and amrubicin in patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 0402. 国際誌

    Naoyuki Nogami, Katsuyuki Hotta, Yoshihiko Segawa, Nagio Takigawa, Shinobu Hosokawa, Isao Oze, Masanori Fujii, Eiki Ichihara, Takuo Shibayama, Atsuhiko Tada, Noboru Hamada, Masatoshi Uno, Akihiko Tamaoki, Shoichi Kuyama, Genyo Ikeda, Masahiro Osawa, Saburo Takata, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Acta oncologica (Stockholm, Sweden)   51 ( 6 )   768 - 73   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    BACKGROUND: The survival advantage achieved by existing anti-cancer agents as second-line therapy for relapsed non-small cell lung cancer (NSCLC) is modest and further improvement of treatment outcome is desired. Combination chemotherapy with irinotecan and amrubicin for advanced NSCLC has not been fully evaluated. METHODS: The primary endpoint of this phase II clinical trial was objective response. Patients with NSCLC who had been treated previously with one or two chemotherapy agents were enrolled. Irinotecan and amrubicin were both administered on Days 1 and 8 of a 21-day cycle, at doses of 100 mg/m(2) and 40 mg/m(2), respectively. RESULTS: Between 2004 and 2006, 31 patients received a total of 101 courses; the median number of courses administered was three (range, one to six). Objective response was obtained in nine of the 31 patients (29.0% response rate; 95% confidence interval (CI), 12.1-46.0%). With a median follow-up time of 43.9 months, median survival time and the median progression-free survival time were 14.2 and 4.0 months, respectively. Myelosuppression was the most frequently observed adverse event, with grade 3/4 neutropenia in 51% of patients. Febrile neutropenia developed after nine courses (9%) and resulted in one treatment-related death. Cardiac toxicity and diarrhea, possibly specific for both agents, were infrequent and manageable. CONCLUSION: Combination chemotherapy with irinotecan and amrubicin is effective in patients with NSCLC but showed moderate toxicities in second- or third-line settings.

    DOI: 10.3109/0284186X.2011.648342

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  • [Case report: Two cases of adult Langerhans cell histiocytosis treated with systemic chemotherapy].

    Kenichiro Kudo, Eiki Ichihara, Akiko Hisamoto, Katsuyuki Hotta, Koichi Ichimura, Yasushi Tanimoto, Masahiro Tabata, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   101 ( 5 )   1386 - 8   2012年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Treatment-related death in patients with small-cell lung cancer in phase III trials over the last two decades. 国際誌

    Nobuaki Ochi, Katsuyuki Hotta, Nagio Takigawa, Isao Oze, Yoshiro Fujiwara, Eiki Ichihara, Akiko Hisamoto, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    PloS one   7 ( 8 )   e42798   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    INTRODUCTION: Treatment-related death (TRD) remains a serious problem in small-cell lung cancer (SCLC), despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time. METHODS: We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis. RESULTS: In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139). However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033). CONCLUSIONS: The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.

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  • Favorable response of heavily treated Wilms' tumor to paclitaxel and carboplatin. 国際誌

    Saeko Ozaki, Nagio Takigawa, Eiki Ichihara, Katsuyuki Hotta, Isao Oze, Etsuko Kurimoto, Soichiro Fushimi, Tetsuya Ogino, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Onkologie   35 ( 5 )   283 - 6   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:KARGER  

    BACKGROUND: Heavily treated Wilms' tumor responding to the combination of paclitaxel and carboplatin has not yet been reported. CASE REPORT: A 17-year-old man presented with hematuria. He received a diagnosis of Wilms' tumor with multiple lung metastases and was treated with preoperative chemotherapy including vincristine, dactinomycin, and doxorubicin, a right nephrectomy, and adjuvant chemotherapy, followed by pulmonary metastasectomy. During the next 8 years, he suffered from 4 relapses and has been treated with multiple anticancer agents including high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Finally, the disease progressed due to peritoneal and pleural metastases. With opioid administration for left shoulder pain due to pleural metastasis, he received combination chemotherapy with carboplatin (area under the curve = 4) and paclitaxel (175 mg/m(2)) on day 1. After 2 cycles, he achieved a partial response with mild toxicity. He received 7 cycles of the chemotherapy and the time to progression was 200 days. CONCLUSION: In a refractory case after intensive treatments, we succeeded to control the disease for a while.

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  • Targeting angiogenesis in cancer therapy.

    Eiki Ichihara, Katsuyuki Kiura, Mitsune Tanimoto

    Acta medica Okayama   65 ( 6 )   353 - 62   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Angiogenesis is an essential process in tumor growth. The concept of angiogenesis, when proposed by Folksman in 1971, had a great impact on cancer research and therapy, as the survival and proliferation of cancer depend on angiogenesis, which could be a target of cancer therapy. In subsequent decades, numerous antiangiogenic agents were developed, and some of them have been applied clinically. However, angiogenesis includes a complex and multistep process that has not been sufficiently elucidated. In this review, we focus on signaling pathways related with tumor angiogenesis and several antiangiogenic agents approved by the United States Food and Drug Administration or under investigation.

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  • Establishment of pemetrexed-resistant non-small cell lung cancer cell lines. 国際誌

    Dan Zhang, Nobuaki Ochi, Nagio Takigawa, Yasushi Tanimoto, Yanyan Chen, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer letters   309 ( 2 )   228 - 35   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Pemetrexed (PEM), a multitargeted antifolate with manageable toxicity, is active against non-squamous non-small cell lung cancer; however, most patients eventually acquire resistance to PEM. To elucidate the resistant mechanism, we established PEM-resistant lung adenocarcinoma cell lines. Two parental cell lines, PC-9 and A549, were treated with step-wise increasing concentrations of PEM. Growth inhibition was determined by the 3-[4,5-dimethyl-thizol-2-yl]-2,5-diphenyltetrazolium bromide assay. Expression of the genes encoding thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) was analyzed by quantitative real-time reverse transcriptase polymerase chain reaction. The four PC-9 sublines were more resistant than the PC-9 cell line to PEM (2.2-, 2.9-, 8.4-, and 14.3-fold, respectively). The four A549 sublines also showed more resistance to PEM (7.8-, 9.6-, 42.3-, and 42.4-fold, respectively) than the parent cell line. All resistant sublines showed cross-resistance to cisplatin, but not to docetaxel, vinorelbine, 5-fluorouracil, or the active metabolite of irinotecan, SN-38. All PEM-resistant sublines expressed more TS than the parental cells, by polymerase chain reaction and Western blotting. DHFR was significantly increased in the four PEM-resistant A549 sublines. GARFT did not correlate with resistance to PEM. In summary, PEM-resistant cells remained sensitive to docetaxel, vinorelbine, 5-fluorouracil, and irinotecan. TS expression appeared to be associated with resistance to PEM.

    DOI: 10.1016/j.canlet.2011.06.006

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  • Liposomal delivery of MicroRNA-7-expressing plasmid overcomes epidermal growth factor receptor tyrosine kinase inhibitor-resistance in lung cancer cells. 国際誌

    Kammei Rai, Nagio Takigawa, Sachio Ito, Hiromi Kashihara, Eiki Ichihara, Tatsuji Yasuda, Kenji Shimizu, Mitsune Tanimoto, Katsuyuki Kiura

    Molecular cancer therapeutics   10 ( 9 )   1720 - 7   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR-7), targeting multiple sites in the 3'-untranslated region of EGFR mRNA. Two EGFR-TKI-sensitive cell lines (PC-9 and H3255) and two EGFR-TKI-resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7-expressing plasmid. After transfection of the miR-7-expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR-7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC-9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7-expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7-expressing plasmids against EGFR oncogene-addicted lung cancers including T790M resistance by liposomal delivery.

    DOI: 10.1158/1535-7163.MCT-11-0220

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  • Role of survival post-progression in phase III trials of systemic chemotherapy in advanced non-small-cell lung cancer: a systematic review. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Yoshiro Fujiwara, Nagio Takigawa, Akiko Hisamoto, Eiki Ichihara, Masahiro Tabata, Mitsune Tanimoto

    PloS one   6 ( 11 )   e26646   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    BACKGROUND: In advanced non-small-cell lung cancer (NSCLC), with the increasing number of active compounds available in salvage settings, survival after progression to first-line chemotherapy seems to have improved. A literature survey was conducted to examine whether survival post-progression (SPP) has improved over the years and to what degree SPP correlates with overall survival (OS). METHODS AND FINDINGS: Median progression-free survival (MPFS) time and median survival time (MST) were extracted in phase III trials of first-line chemotherapy for advanced NSCLC. SPP was pragmatically defined as the time interval of MST minus MPFS. The relationship between MPFS and MST was modeled in a linear function. We used the coefficient of determination (r(2)) to assess the correlation between them. Seventy trials with 145 chemotherapy arms were identified. Overall, median SPP was 4.7 months, and a steady improvement in SPP was observed over the 20 years (9.414-day increase per year; p<0.001) in parallel to the increase in MST (11.253-day increase per year; p<0.001); MPFS improved little (1.863-day increase per year). Overall, a stronger association was observed between MST and SPP (r(2) = 0.8917) than MST and MPFS time (r(2) = 0.2563), suggesting SPP and MPFS could account for 89% and 25% of the variation in MST, respectively. The association between MST and SPP became closer over the years (r(2) = 0.4428, 0.7242, and 0.9081 in 1988-1994, 1995-2001, and 2002-2007, respectively). CONCLUSIONS: SPP has become more closely associated with OS, potentially because of intensive post-study treatments. Even in advanced NSCLC, a PFS advantage is unlikely to be associated with an OS advantage any longer due to this increasing impact of SPP on OS, and that the prolongation of SPP might limit the original role of OS for assessing true efficacy derived from early-line chemotherapy in future clinical trials.

    DOI: 10.1371/journal.pone.0026646

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  • Early palliative care in non-small-cell lung cancer. 国際誌

    Eiki Ichihara, Junji Matsuoka, Katsuyuki Kiura

    The New England journal of medicine   363 ( 23 )   2263; author reply 2264-5 - 2263   2010年12月

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    記述言語:英語   出版者・発行元:MASSACHUSETTS MEDICAL SOC  

    DOI: 10.1056/NEJMc1010529

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  • Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice. 国際誌

    Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Eiki Ichihara, Hiromasa Takeda, Toshio Kubo, Seiki Hirano, Tadashi Yoshino, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer research   69 ( 17 )   7088 - 95   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer.

    DOI: 10.1158/0008-5472.CAN-08-4205

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  • Effects of vandetanib on lung adenocarcinoma cells harboring epidermal growth factor receptor T790M mutation in vivo. 国際誌

    Eiki Ichihara, Kadoaki Ohashi, Nagio Takigawa, Masahiro Osawa, Atsuko Ogino, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer research   69 ( 12 )   5091 - 8   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Vandetanib is a novel multitarget tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), with additional inhibition of epidermal growth factor receptor (EGFR) and rearranged during transfection receptor signaling, which has shown promising results in clinical trials for advanced non-small cell lung cancer. However, the mechanisms of acquired resistance to vandetanib remain unclear. Therefore, we established in vitro vandetanib-resistant PC-9/VanR cells from PC-9, a vandetanib-sensitive lung adenocarcinoma cell line, by chronic exposure to this agent. PC-9/VanR cells were 50-fold more resistant to vandetanib than PC-9 cells in vitro. Compared with PC-9 cells, PC-9/VanR cells showed emergence of an EGFR T790M mutation, moderately elevated MET amplification, and similar VEGFR-2 inhibition by vandetanib. Note that phospho-MET in PC-9/VanR was suppressed following EGFR inhibition by an irreversible EGFR-TKI, indicating that MET signaling of PC-9/VanR was dependent on EGFR signaling and that MET amplification was not the primary mechanism of resistance to vandetanib. In contrast to the in vitro experiment, vandetanib effectively inhibited the growth of PC-9/VanR tumors in an in vivo xenograft model through the antiangiogenesis effects of VEGFR-2 inhibition. In conclusion, the multitarget TKI vandetanib induced or selected for the EGFR T790M mutation as observed previously with highly selective EGFR-TKIs. However, vandetanib retained significant efficacy in vivo against xenografts harboring the T790M mutation, providing a strong scientific rationale for investigating vandetanib in clinical settings where acquired resistance through emergence of EGFR T790M mutations limits the effectiveness of highly selective EGFR-TKIs.

    DOI: 10.1158/0008-5472.CAN-08-4204

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  • Synchronous pulmonary MALT lymphoma and pulmonary adenocarcinoma after metachronous gastric MALT lymphoma and gastric adenocarcinoma. 国際誌

    Eiki Ichihara, Masahiro Tabata, Nagio Takigawa, Yumiko Sato, Eisaku Kondo, Motoi Aoe, Katsuyuki Kiura, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   3 ( 11 )   1362 - 3   2008年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1097/JTO.0b013e31818b1b07

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  • Pseudoprogression of lung cancer after concomitant chemoradiotherapy. 国際誌

    Eiki Ichihara, Katsuyuki Kiura, Nagio Takigawa, Masako Omori, Motoi Aoe, Mitsune Tanimoto, Hiroshi Date

    Japanese journal of clinical oncology   38 ( 2 )   140 - 2   2008年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    We observed re-enlargement of a squamous cell carcinoma without recurrence. The tumour regressed markedly after concomitant chemoradiotherapy, but within 1 month, we supposed that the tumour had enlarged again and resection was performed. The resected tissue showed evidence of haemorrhage and several lymphocytes and macrophages, but no malignant cells were detected. We herein report a rare case of lung cancer showing a pathological complete response despite re-enlargement of tumour lesion.

    DOI: 10.1093/jjco/hym166

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  • [Coinfection with Mycoplasma pneumoniae and Chlamydophila pneumoniae in a middle-aged adult].

    Toshio Kubo, Nagio Takigawa, Yasushi Tanimoto, Eiki Ichihara, Masahiro Tabata, Nobuaki Miyahara, Arihiko Kanehiro, Katsuyuki Kiura, Mitsune Tanimoto

    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society   45 ( 10 )   808 - 11   2007年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A 47-year-old man who suffered from fever and dry cough visited a local clinic. His symptoms temporarily improved with oral administration of ciprofloxacin, however, he was admitted to our hospital because of exacerbation. IgM antibody for Mycoplasma pneumoniae was positive and IgM antibody titer for Chlamydophila pneumoniae showed a high value of 7.12 index. Thus, coinfection was diagnosed. The findings of chest X-ray and computed tomography were compatible with atypical pneumonia. Clarithromycin improved his condition, and 10 weeks later, antibody values for Mycoplasma pneumoniae by the particle agglutination test decreased from 10,240 times to 640 times and those by the complement-fixation test also decreased from 1024 times to 256 times. The IgM antibody for Chlamydophila pnetumoniae decreased to 0.13. This is the first case developing coinfection with Mycoplasma pneumoniae and Chlamydophila pneumoniae in a middle-aged patient to date.

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  • [Azygos vein aneurysm occurring simultaneously with hemoptysis].

    Eiki Ichihara, Masahiro Kaneko, Hiroshi Fujii, Kyousuke Ishihara

    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society   45 ( 6 )   479 - 82   2007年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    A 64-year-old man was admitted with hemoptysis. A chest X-ray showed a well-defined round nodule at the right tracheobronchial angle. Enhanced computed tomography revealed the superior vena cava to be completely occluded while the azygos vein was also observed to have formed an aneurysm. Bronchoscopy showed the submucosal bronchial vessels at the right second carina to be markedly dilated, and thus considered them to be the likely cause of hemoptysis. Based on the above findings, we considered the following events as the most likely to have taken place: The superior vena cava was completely occluded due to the long-term placement of a pacemaker. The blood flow of head and upper limbs could not sufficiently return to the heart, but instead flowed into the azygos vein via the collateral circulation. This resulted in both the formation of the azygos vein aneurysm and an elevated venous pressure of the bronchial vein. Due to this pressure elevation, the bronchial vein and small vessels had both ruptured, thereby inducing the onset of hemoptysis.

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  • Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells. 国際誌

    Nagio Takigawa, Masami Takeyama, Toshiyuki Kozuki, Takuo Shibayama, Akiko Hisamoto, Katsuyuki Kiura, Atsuhiko Tada, Katsuyuki Hotta, Shigeki Umemura, Kadoaki Ohashi, Yoshiro Fujiwara, Saburo Takata, Eiki Ichihara, Masahiro Osawa, Masahiro Tabata, Mitsune Tanimoto, Kiyoshi Takahashi

    Oncology reports   17 ( 5 )   983 - 7   2007年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxy-campthothecin (SN-38) is an active metabolite of irinotecan. Gefitinib and imatinib are tyrosine kinase inhibitors which have clinical activities in several malignancies and they are also potent inhibitors of breast cancer resistance protein (BCRP) transporter, which confers the resistance of topoisomerase I inhibitors including SN-38 and topotecan. The cytotoxicity of SN-38, gefitinib and imatinib for the SN-38-resistant cells (SBC-3/SN-38) from human SCLC cells, SBC-3, was evaluated using AlamarBlue assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96-h exposure was used to evaluate the cytotoxicity. BCRP expression was determined by Western blotting and immunofluorescence staining. Intracellular topotecan accumulation was evaluated by flow cytometry. No differences were observed in the IC50 values (mean +/- SD) of the tyrosine kinase inhibitors between the SBC-3 cells and the SBC-3/SN-38 cells: 15+/-1.6 and 12+/-2.8 microM of gefitinib, respectively; 15+/-0.51 and 14+/-3.9 microM of imatinib, respectively. The SBC-3/SN-38 was 9.5-fold more resistant to SN-38 than the parental SBC-3. The SBC-3/SN-38 restored sensitivity to SN-38 when combined with 8 microM gefitinib or 8 microM imatinib, even though the IC50 values of SN-38 combined with gefitinib or imatinib in the SBC-3 cells did not change. BCRP was equally overexpressed in the SBC-3/SN-38 with and without gefitinib or imatinib. In addition, the BCRP expression on the SBC-3/SN-38 cell membrane with and without gefitinib seemed to be equal. Gefitinib increased intracellular accumulation of topotecan in the SBC-3/SN-38 cells. Gefitinib or imatinib reversed SN-38-resistance in these SCLC cells, possibly due to intracellular accumulation of SN-38 without any change in BCRP quantity. Irinotecan with gefitinib or imatinib might be effective for SCLC refractory to irinotecan.

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  • [Characteristics of asthma patients who need repeated hospitalization; frequency of use of systemic corticosteroids, emergency and unscheduled hospital visits and habitual use of sleeping pills].

    Masahiro Kaneko, Kyousuke Ishihara, Takashi Hajiro, Hiroshi Fujii, Eiki Ichihara

    Arerugi = [Allergy]   56 ( 5 )   477 - 84   2007年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: This study aimed to analyze the characteristics of frequently hospitalized patients. METHODS: The clinical characteristics of 310 cases having hospitalization episodes (206 patients) for asthma attack analyzed retrospectively based on their clinical records. RESULTS: Nineteen out of the 206 patients were hospitalized more than just three times during the study period. Mean age (once hospitalization group 50.0+/-1.5 y.o., twice- 53.0+/-2.6 y.o., > or = 3 times- 56.6+/-2.0 y.o., p=0.02) and the ratio of female (once- 55.2%, twice- 61.5%, > or = 3 times- 78.9%, p=0.04) were higher among the groups. The frequency of use of systemic corticosteroids (once- 23.6%, twice- 50.0%, > or = 3 times- 59.8%, p<0.01), emergency and unscheduled hospital visits (once- 0.5+/-0.1 times/6M, twice- 1.3+/-0.3 times/6M, > or = 3 times- 2.7+/-0.2 times/6M, p<0.01), and habitual use of sleeping pills (once- 11.8%, twice- 30.8%, > or = 3 times- 47.4%, p<0.01) were significantly different among the groups. CONCLUSION: Among the patients who need repeated hospitalization, the frequency of use of systemic corticosteroids, emergency and unscheduled hospital visits, and habitual use of sleeping pills were higher.

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書籍等出版物

  • 肺癌薬物療法レジメン Expert’s Choice

    ( 担当: 分担執筆 ,  範囲: Chapter 3 非小細胞肺癌 非扁平上皮癌(IV期)PD-L1≧50%(PS良好)PD-L1≧50%(PS不良))

    メジカルビュー  2022年3月  ( ISBN:9784758318181

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  • 見る診るわかる!胸部画像診断

    市原英基, 木浦勝行( 担当: 分担執筆 ,  範囲: 大細胞癌、腫瘍塞栓症)

    中外医学社  2021年8月  ( ISBN:9784498013803

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    総ページ数:299p   記述言語:日本語

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  • 新臨床腫瘍学 : がん薬物療法専門医のために

    市原英基( 担当: 分担執筆 ,  範囲: 分子標的治療薬概論)

    南江堂  2021年5月  ( ISBN:9784524227396

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    総ページ数:xix, 757p   記述言語:日本語

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  • COVID-19の病態・診断・治療 : 現場の知恵とこれからの羅針盤

    市原英基( 担当: 分担執筆 ,  範囲: 肺癌とCOVID-19)

    医学書院  2021年1月  ( ISBN:9784260045858

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    総ページ数:xiv, 225p   記述言語:日本語

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  • 癌と化学療法 第47巻第12号(2020年12月) 特集・COVID-19パンデミックとがん医療への影響

    工藤健一郎, 市原英基( 担当: 分担執筆 ,  範囲: COVID-19における肺炎)

    2020年12月 

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  • コロナ禍におけるがん患者・家族への支援 看護技術2020年12月号

    西達也, 市原英基( 担当: 分担執筆 ,  範囲: 外来での化学療法、緩和医療、化学療法を継続するか否かを迷う患者・家族への支援と感染対策のために)

    2020年12月 

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  • 肺がん化学療法副作用マネジメント

    市原英基( 担当: 分担執筆 ,  範囲: 7 神経 (2) 末梢神経障害)

    メジカルビュー社  2019年7月  ( ISBN:9784758318051

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    総ページ数:395p   記述言語:日本語

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  • カレントセラピー バイオマーカーを用いたがんの診断と治療

    渡邉洋美, 市原英基( 担当: 分担執筆 ,  範囲: ALK融合遺伝子・ROS1融合遺伝子におけるコンパニオン診断薬)

    ライフメディアコム  2018年9月 

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  • 新臨床腫瘍学(改訂第5版): がん薬物療法専門医のために

    市原英基( 担当: 分担執筆 ,  範囲: 分子標的治療薬概論)

    南江堂  2018年7月  ( ISBN:4524237887

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    総ページ数:840   記述言語:日本語

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    ASIN

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  • 肺癌診療Q&A : 一つ上を行く診療の実践

    市原英基, 木浦勝行( 担当: 分担執筆 ,  範囲: 薬物療法副作用への対応)

    中外医学社  2017年10月  ( ISBN:9784498131002

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    総ページ数:vii, 521p   記述言語:日本語

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  • 肺癌診療Q&A : 一つ上を行く診療の実践

    市原英基( 担当: 分担執筆 ,  範囲: G-CSFの使用の適応)

    中外医学社  2017年10月  ( ISBN:9784498131002

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    総ページ数:vii, 521p   記述言語:日本語

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  • 内科學 第11版

    市原英基、二宮崇、久保寿夫、大橋圭明、木浦勝行( 担当: 分担執筆 ,  範囲: 呼吸器系の疾患 縦隔疾患)

    朝倉書店  2017年3月  ( ISBN:9784254322712

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    総ページ数:5冊   記述言語:日本語

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  • エビデンスに基づいた癌化学療法ハンドブック2012

    加藤有加, 市原英基, 木浦勝行( 担当: 分担執筆 ,  範囲: Elrotinib)

    2012年8月 

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  • 医学のあゆみ 肺癌UPDATE

    市原英基、木浦勝行( 担当: 分担執筆 ,  範囲: IV期非小細胞肺癌におけるセカンドライン・サードラインのエビデンスと今後の展望)

    医歯薬出版株式会社  2012年3月 

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  • インフォームドコンセントのための図説シリーズ 肺がん 抗悪性腫瘍薬 改訂4版

    柳瀬香葉, 市原英基, 木浦勝行( 担当: 分担執筆 ,  範囲: セカンドライン,サードライン化学療法の定義)

    医薬ジャーナル社  2011年11月 

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  • がんの新しいバイオマーカー/予測因子による個別化医療時代に求められる抗がん剤開発

    市原英基( 担当: 分担執筆 ,  範囲: がんバイオマーカー/予測因子)

    技術情報協会  2011年6月 

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  • がんの分子標的と治療薬事典

    市原英基( 担当: 分担執筆 ,  範囲: EpCAM, Adecatumumab)

    羊土社  2010年10月  ( ISBN:9784758120166

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    総ページ数:346p   記述言語:日本語

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  • 腫瘍内科

    市原英基, 木浦勝行( 担当: 分担執筆 ,  範囲: 小分子物質と抗体の違い)

    科学評論社  2010年6月 

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MISC

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講演・口頭発表等

  • 肺癌薬物療法の更なる治療効果を 目指した基礎・臨床研究(篠井・河合賞受賞記念講演) 招待

    市原英基

    第62回日本肺癌学会学術集会  2021年11月27日 

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    開催年月日: 2021年11月26日 - 2021年11月28日

    記述言語:日本語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

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  • 肺小細胞がんの薬剤開発 分子標的治療開発からの教訓と 免疫チェックポイント阻害剤への期待

    市原英基

    第62回日本肺癌学会学術集会  2021年11月26日 

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    開催年月日: 2021年11月26日 - 2021年11月28日

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • がん患者と コロナワクチン

    市原英基

    がん患者学会2021  2021年8月22日 

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    開催年月日: 2021年8月22日

    記述言語:日本語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

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  • 間質性肺炎合併症例に対する 細胞傷害性抗がん剤をどう考えるか

    市原英基

    第61回日本呼吸器学会学術集会  2021年4月25日 

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    開催年月日: 2021年4月23日 - 2021年4月25日

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20.

    Eiki Ichihara, Hiroyuki Yasuda, Yuta Takashima, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katuyuki Kiura, Hideki Terai, Shinnosuke Ikemura, Ryo Takemura, Koichi Goto, Kenzo Soejima

    AACR Annual Meeting 2021  2021年4月10日 

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    開催年月日: 2021年4月10日 - 2021年4月15日

    記述言語:英語   会議種別:ポスター発表  

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  • 免疫チェックポイント阻害薬が有効なEGFR遺伝子変異陽性肺癌の特徴

    市原 英基, 原田大二郎, 井上 考司, 柴山 卓夫, 細川 忍, 岸野 大蔵, 張田 信吾, 越智 宣昭, 小田 尚廣, 原 尚史, 堀田 勝幸, 前田 嘉信, 木浦 勝行

    第61回日本肺癌学会学術集会  2020年11月14日 

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    開催年月日: 2020年11月12日 - 2020年11月14日

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • EGFR-TKIと血管新生阻害薬の併用 今後の展望

    市原英基

    第61回日本肺癌学会学術集会  2020年11月13日 

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    開催年月日: 2020年11月12日 - 2020年11月14日

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Resistant mechanisms to ALK TKIs

    市原英基

    第59回日本肺癌学会学術集会  2018年11月30日 

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    開催年月日: 2018年11月29日 - 2018年12月1日

    記述言語:日本語  

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  • I. 一部改訂について: 「泌尿器がん」 「肉腫」 「呼吸器がん」の 一部改訂について

    市原英基, 三浦裕司

    第55回日本癌治療学会学術集会  2017年10月21日 

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    開催年月日: 2017年10月20日 - 2017年10月22日

    記述言語:日本語  

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  • Significance of repeating rebiopsy for detecting T790M mutation

    第58回日本肺癌学会学術集会  2017年10月14日 

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    開催年月日: 2017年10月14日 - 2017年10月15日

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • Possibility of combination therapy using EGFR TKIs 招待

    市原英基

    第15回日本臨床腫瘍学会学術集会  2017年7月27日 

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    開催年月日: 2017年7月27日 - 2017年7月29日

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • 英文化にむけて

    市原英基

    第54回日本癌治療学会学術集会  2016年10月21日 

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    開催年月日: 2016年10月20日 - 2016年10月22日

    記述言語:日本語  

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受賞

  • 楷の木賞特別賞

    2022年3月   岡山大学病院  

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  • 篠井・河合賞

    2021年11月   日本肺癌学会  

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  • 楷の木賞特別賞

    2021年3月   岡山大学病院  

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  • 肺癌研究助成

    2020年11月   日本肺癌学会  

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  • プロジェクト未来

    2019年12月   日本対がん協会  

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  • 海外留学助成

    2013年12月   上原記念生命科学財団  

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  • 岡山医学会賞(山田賞)

    2010年6月   岡山医学会  

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  • 第二内科同門会賞

    2009年11月   第二内科同門会  

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  • 若手奨励賞

    2005年10月   日本内科学会 中国支部会  

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共同研究・競争的資金等の研究

  • SHP2による薬剤toleranceを標的とした肺がん根治的治療の開発

    研究課題/領域番号:21K08179  2021年04月 - 2024年03月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    市原 英基, 久保 寿夫

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • SHP2シグナル経路を標的としたEGFR/ALK肺がんの根治的新規肺がん治療法の開発

    2020年11月 - 2021年10月

    公益財団法人岡山医学振興会  医学研究助成

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    担当区分:研究代表者 

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  • SHP2を標的としたEGFR/ALK/ROS1肺がんにおける根治的新規治療法の開発

    2020年10月 - 2023年03月

    日本肺癌学会  肺癌研究助成

    市原英基

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    担当区分:研究代表者 

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  • EGFR/ALK変異陽性肺がんにおけるSHP2シグナル経路を標的とする根治的新規肺がん治療法の開発

    2020年10月 - 2021年09月

    公益財団法人両備檉園記念財団  研究助成

    市原英基

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    担当区分:研究代表者 

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  • EGFR遺伝子変異陽性肺がん分子標的治療におけるtolerant細胞を標的とした 根治的新規肺がん治療法の開発

    2019年10月 - 2020年09月

    公益財団法人 日本対がん協会  「プロジェクト未来」研究助成

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    担当区分:研究代表者 

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  • 上原記念生命科学財団 海外留学助成

    2013年12月 - 2014年11月

    上原記念生命科学財団 

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  • ALK遺伝子変異陽性肺癌に対するALK阻害薬と血管新生阻害薬の併用効果の検討

    研究課題/領域番号:24790813  2012年04月 - 2013年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    市原 英基

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    1. ALK 遺伝子変異陽性肺癌に対するALK 阻害薬+血管新生阻害薬の有効性の検討 我々は、ALK融合遺伝子を持つ肺癌細胞株であるH2228およびABC-11を用いて、ALK阻害薬であるAF802(CH5424802)の持続的暴露を行うことで、AF802耐性株であるH2228CHRおよびABC11CHRを樹立した。親株であるH2228およびABC-11はAF802に高い感受性を示す(IC50: H2228 0.030±0.020μM, ABC11 0.32± 0.087μM)のに対し、H2228CHR・ABC-11CHRはAF802に高い耐性を示した(IC50: H2228CHR 3.9±0.84μM, ABC-11CHR 5.3±0.91 μM)。しかし、これら細胞株に対して血管新生阻害薬であるbevacizumabはin vitroでの効果を認めなった。
    2. ALK 遺伝子変異陽性肺癌に対するALK 阻害薬+EGFR 阻害薬の有効性の検討
    上記、H2228CHRはALKだけでなくEGFRが活性化していることをwesernblottingにて証明した。H2228CHRに対するAF802単剤での細胞増殖率は87%であったのに対し、EGFR阻害薬(erlotinib)+ AF802の併用では47%と有意に増殖を抑制していた。
    3. EGFR 遺伝子変異陽性肺癌に対するEGFR 阻害薬+血管新生阻害薬の有効性の検討
    EGFR遺伝子変異を要する肺癌細胞株H1975のゼノグラフトを作製し、腫瘍抑制効果を検討した。EGFR阻害薬であるBIBW2992+cetuximabの2剤併用療法と比較し、血管新生阻害薬であるbevacizumabを加えた3剤併用療法で腫瘍縮小効果が強い傾向を認めた。

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  • 遺伝子改変マウスを利用したEGFR遺伝子変異陽性肺癌の基礎的臨床的検討

    研究課題/領域番号:23390221  2011年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    木浦 勝行, 瀧川 奈義夫, 堀田 勝幸, 高田 穣, 中別府 雄作, 吉野 正, 市原 英基

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    配分額:19500000円 ( 直接経費:15000000円 、 間接経費:4500000円 )

    ① EGFR遺伝子改変マウスを使用し,afatinib (非可逆性TKI), everolimus (mTOR阻害薬), AZD1480 (JAK-1/2 阻害薬)の抗腫瘍効果を明らかにした。② マウス異種移植モデルで,T790Mを有する耐性細胞に対してafatinib + cetuximab + bevacizumab併用療法は,持続する病理学的完全奏効をもたらすことを証明した。③ Ogg1ホモノックアウトマウスに高用量タバコ特異的ニトロサミン(NNK)投与で9.3%に早期発癌を肺に認めたが,低用量では発癌を認めず,上皮成長因子受容体(EGFR)遺伝子異常との関連は不明である。

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  • 含鉄蛋白質に含まれるラジウムの体内被曝による悪性中皮腫発生機序に関する基礎的研究

    研究課題/領域番号:23659432  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    木浦 勝行, 瀧川 奈義夫, 市原 英基, 中村 栄三, 吉野 正, 高田 穣

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    健常雄性 Slc: Wistar ラット 10 匹に鉄およびキレート剤を腹腔内へ反復投与し,5 匹で悪性腹膜中皮腫を認めたが,コントロール群,キレート剤投与群では認めなった。免疫染色(Calretinin, CEA 染色),電子顕微鏡による観察を行い,いずれも上皮型中皮腫であることを確認した。また,DNA 酸化損傷マーカーである 8-hydroxy-2-deoxyguanosine による免疫染色は陽性であり,従来の学説は確認された。ラジウムを含む微量元素を最終解析中である。

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  • 上皮成長因子受容体遺伝子改変マウスを利用した肺癌化学予防に関する基礎的研究

    研究課題/領域番号:19590895  2007年 - 2008年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    木浦 勝行, 瀧川 奈義夫, 高田 穣, 吉野 正, 大橋 圭明, 頼 冠明, 市原 英基, 高田 三郎, 大澤 昌宏, 武田 洋昌, 藤井 昌学, 久保 寿夫, 柏原 宏美, 原田 大二郎, 越智 宣昭, 八杉 昌幸

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    肺癌の粗死亡数は増加しているが、喫煙率低下に伴い年齢調整死亡率は低下傾向にある。肺癌患者の男性30%、女性70%は非喫煙者である。非喫煙者肺癌の病因探求およびその予防の研究目的で、上皮成長因子受容体(EGFR)遺伝子改変マウスを作製し、非喫煙関連肺癌マウスモデルを樹立した。ヒトEGFR遺伝子改変マウスは5-6週で多発性の異型腺腫様過形成、肺腺癌が出現し、30週前後で腫瘍死する。これらの肺発癌をgefitinibが効果的に予防することを証明した。

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担当授業科目

  • 血液・腫瘍・呼吸器内科学(基本臨床実習) (2021年度) 特別  - その他

  • 血液・腫瘍・呼吸器内科学(基本臨床実習) (2020年度) 特別  - その他

 

社会貢献活動

  • がん患者団体向け講演「がん患者とコロナワクチン」

    役割:講師

    一般社団法人 全国がん患者団体連合会  がん患者学会2021  2021年8月22日

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    種別:講演会

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  • 市民公開講座 最新の肺がんのすべて 「肺がんの免疫療法 ーうそと本当ー」

    役割:講師

    独立行政法人国立病院機構 福山医療センター  市民公開講座  2020年2月8日

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    種別:対話型集会・市民会議

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  • NPO法人 中国四国呼吸器疾患関連事業包括的支援機構(CS-Lung)設立および事務局担当

    役割:運営参加・支援

    NPO法人 中国四国呼吸器疾患関連事業包括的支援機構(CS-Lung)  2018年4月 - 現在

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    種別:その他

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  • 市民公開講座 自分に合ったがん治療を受けるために~ライフステージ、ライフスタイルに沿った医療、福祉~ 「免疫治療の嘘と本当 ~まず知っておくべきこと~」

    役割:講師

    中国四国広域がんプロ養成コンソーシアム  市民公開講座  2018年1月19日

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    種別:対話型集会・市民会議

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  • 市民公開講座 ~きっと役立つがんの最新情