2021/12/26 更新

写真a

タバタ マサヒロ
田端 雅弘
TABATA Masahiro
所属
岡山大学病院 教授
職名
教授
外部リンク

学位

  • 博士(医学) ( 1993年12月   岡山大学 )

  • 博士(医学) ( 1991年4月   岡山大学 )

研究分野

  • ライフサイエンス / 腫瘍診断、治療学

所属学協会

  • 日本サルコーマ治療研究会

    2017年3月 - 現在

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  • 日本臨床腫瘍学会

    2002年12月 - 現在

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  • 日本癌治療学会

    2001年6月 - 現在

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  • 日本呼吸器学会

    1990年4月 - 現在

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  • 日本肺癌学会

    1989年10月 - 現在

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  • 日本内科学会

    1987年10月 - 現在

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委員歴

  • 岡山県医師会   禁煙推進部会委員会  

    2018年11月 - 2019年12月   

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    団体区分:学協会

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  • 日本サルコーマ治療研究学会   評議員  

    2017年10月   

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    団体区分:学協会

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  • 岡山労働局   地域両立支援推進チーム委員  

    2017年7月 - 現在   

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    団体区分:政府

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  • 日本臨床腫瘍学会   倫理委員会委員  

    2017年7月 - 現在   

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    団体区分:学協会

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  • 岡山県生活習慣病検診等管理指導協議会   がん診療拠点部会委員  

    2011年12月 - 現在   

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    団体区分:自治体

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  • 岡山市がん対策推進委員会   委員(議長)  

    2011年9月 - 現在   

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    団体区分:自治体

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  • 日本臨床腫瘍学会   協議員  

    2009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   評議員  

    2002年11月 - 現在   

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    団体区分:学協会

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  • 日本癌治療学会   評議員  

    2001年6月 - 2021年9月   

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    団体区分:学協会

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  • 日本内科学会中国支部   評議員  

    1987年10月 - 現在   

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    団体区分:学協会

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論文

  • Cancer care for people with mental disorders: A qualitative survey among cancer care and psychiatric care professionals in Japan. 国際誌

    Tsuyoshi Etoh, Masaki Fujiwara, Yuto Yamada, Riho Wada, Yuji Higuchi, Shinichiro Inoue, Masafumi Kodama, Takanori Matsushita, Yusaku Yoshimura, Shigeo Horii, Maiko Fujimori, Kyoko Kakeda, Taichi Shimazu, Naoki Nakaya, Masahiro Tabata, Yosuke Uchitomi, Norihito Yamada, Masatoshi Inagaki

    Psycho-oncology   30 ( 12 )   2060 - 2066   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)  

    OBJECTIVE: It is widely assumed that there are multiple levels (from individual to policy level) of problems involving disparities in cancer care for people with mental disorders. However, few studies have comprehensively investigated issues as perceived by medical professionals. The purpose of the present study was to identify a wide range of issues in cancer care for people with mental disorders and offer corresponding solutions for both cancer care professionals and psychiatric care professionals. METHODS: We distributed open-ended questionnaires to 754 healthcare professionals in various medical facilities, including designated cancer hospitals, psychiatric hospitals, and other local healthcare/welfare facilities. Participants were asked to describe issues in cancer care for people with mental disorders. RESULTS: Of the 754 recruited professionals, 439 (58.2%) responded to the questionnaire. Sixty-one issues were extracted and categorized into 10 categories: patient factors; isolation and lack of support; obstacles to transport; socioeconomic factors; attitudes of psychiatric professionals; medical system of psychiatric hospitals; attitudes of cancer care professionals; medical system of designated cancer hospitals; regional cancer medical systems; and lack of coordination among multidisciplinary healthcare professionals. Forty-eight specific solutions were summarized into 12 goals. CONCLUSIONS: The present study widely identified issues causing disparities in cancer care for patients with mental disorders. We found that the issues extended from the patient level to the public-policy level. Our findings suggest the need for a multidisciplinary approach that includes both cancer and psychiatric care professionals to address the gap in cancer care for people with mental disorders.

    DOI: 10.1002/pon.5780

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  • 濾胞性樹状細胞肉腫に合併した腫瘍随伴性天疱瘡の1例

    前 琴絵, 芦田 日美野, 三宅 智子, 森実 真, 西 達也, 田端 雅弘, 石井 文人

    日本皮膚科学会雑誌   131 ( 11 )   2446 - 2446   2021年10月

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    記述言語:日本語   出版者・発行元:(公社)日本皮膚科学会  

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  • Dramatic Response to Carboplatin Plus Paclitaxel in Pancreatic Mucinous Cystadenocarcinoma with Liver Metastasis.

    Naohiro Oda, Masahiro Tabata, Masatoshi Uno, Yuzo Umeda, Hironari Kato, Toshio Kubo, Satoru Senoo, Takahito Yagi, Toshiyoshi Fujiwara, Yoshinobu Maeda, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   60 ( 18 )   2967 - 2971   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)  

    Mucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA+PTX). CBDCA+PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma.

    DOI: 10.2169/internalmedicine.6730-20

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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)  

    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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  • 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)  

    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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  • 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)  

    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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  • 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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  • A case of interstitial pneumonia associated with systemic sclerosis and primary peritoneal serous carcinoma successfully treated with cyclophosphamide. 国際誌

    Shunichi Kawamura, Toshio Kubo, Kenji Takada, Ryota Sunami, Sachi Okawa, Yoshitaka Iwamoto, Atsuko Hirabae, Akihiko Taniguchi, Yoshinobu Maeda, Katsuyuki Kiura, Masahiro Tabata

    International cancer conference journal   10 ( 3 )   197 - 200   2021年7月

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    記述言語:英語  

    A 62-year-old woman with edema and color changes in her fingers underwent computed tomography (CT); slight interstitial changes were detected in the lungs with multiple tumors in the anterior and hilar region of the liver. Based on the blood test findings, she was diagnosed with interstitial pneumonia associated with systemic sclerosis. Ultrasound-guided biopsy from the hepatic hilar lymph node revealed poorly differentiated serous adenocarcinoma cells. High serum CA-125 levels suggested primary peritoneal serous carcinoma (PPSC). Owing to increased interstitial shadows on chest CT images and worsening respiratory distress, intravenous cyclophosphamide and oral prednisolone treatment was started. The skin-related symptoms, respiratory distress, and interstitial shadows improved, and the tumor size reduced. Eighteen months later, the patient has had no exacerbation of interstitial pneumonia, and the PPSC is well controlled.

    DOI: 10.1007/s13691-021-00475-1

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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)  

    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.

    DOI: 10.1093/jjco/hyab048

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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)  

    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.

    DOI: 10.1111/cas.14801

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  • A Multicenter Study of Docetaxel at a Dose of 100 mg/m2 in Japanese Patients with Advanced or Recurrent Breast Cancer.

    Taizo Hirata, Shinji Ozaki, Masahiro Tabata, Takayuki Iwamoto, Shiro Hinotsu, Akinobu Hamada, Takayuki Motoki, Tomohiro Nogami, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara

    Internal medicine (Tokyo, Japan)   60 ( 8 )   1183 - 1190   2021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)  

    Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.

    DOI: 10.2169/internalmedicine.5089-20

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  • 【骨・軟部腫瘍のマネジメント(その1)】総論 診療体制 サルコーマセンター設立と腫瘍内科医との連携 集約化と地域連携

    国定 俊之, 中田 英二, 藤原 智洋, 久保 寿夫, 西森 久和, 田端 雅弘, 尾崎 敏文

    別冊整形外科   ( 79 )   7 - 12   2021年4月

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    記述言語:日本語   出版者・発行元:(株)南江堂  

    <文献概要>はじめに わが国では歴史的に整形外科が中心となって肉腫(サルコーマ)の治療方針を決め,主に手術と化学療法を担当してきた.一方,欧米では腫瘍内科が肉腫の化学療法を担当することが一般的であり,わが国の治療状況とは大きく異なる.肉腫治療例の増加とともに進行例が増加し,新規治療薬も開発され,整形外科医のみで治療していくことがむずかしくなってきた.また,化学療法以外にも,肉腫の診断,手術には多くの診療科の協力が必要で,多職種による集学的医療チームによる治療が重要である.当院では肉腫患者によりよい治療を提供する目的で,2014年4月に大学病院の診療部門としては日本ではじめてサルコーマセンターを設立した.本稿では,当院サルコーマセンターの活動を紹介する.

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04037&link_issn=&doc_id=20210514600002&doc_link_id=10.15106%2Fj_besei79_7&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_besei79_7&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

  • Demand for weekend outpatient chemotherapy among patients with cancer in Japan. 国際誌

    Hideki Katayama, Masahiro Tabata, Toshio Kubo, Katsuyuki Kiura, Junji Matsuoka, Yoshinobu Maeda

    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer   29 ( 3 )   1287 - 1291   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)  

    BACKGROUND: Advanced cancer therapeutics have improved patient survival, leading to an increase in the number of patients who require long-term outpatient chemotherapy. However, the available schedule options for chemotherapy are generally limited to traditional business hours. METHOD: In 2017, we surveyed 721 patients with cancer in Okayama, Japan, regarding their preferences for evening and weekend (Friday evening, Saturday, and Sunday) chemotherapy appointments. RESULTS: A preference for evening and weekend appointment options was indicated by 37% of the respondents. Patients who requested weekend chemotherapy were younger, female, with no spouse or partner, living alone, employed, and currently receiving treatment. Among these factors, age and employment status were significantly associated with a preference for weekend chemotherapy, according to multivariate analysis. CONCLUSION: Our findings reveal a demand for evening and weekend outpatient chemotherapy, especially among young, employed patients.

    DOI: 10.1007/s00520-020-05575-x

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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)  

    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.

    DOI: 10.1016/j.resinv.2020.12.001

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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)  

    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.

    DOI: 10.1111/ajco.13423

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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)  

    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.

    DOI: 10.1093/jjco/hyaa152

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  • Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. 国際誌

    Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

    Oncology letters   20 ( 6 )   393 - 393   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)  

    The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

    DOI: 10.3892/ol.2020.12256

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  • 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)  

    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.

    DOI: 10.1016/j.bbrc.2020.07.055

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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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  • 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)  

    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.

    DOI: 10.1080/0284186X.2019.1695062

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  • Recurring radiation-induced angiosarcoma of the breast that was treated with paclitaxel chemotherapy: a case report. 国際誌

    Yoko Suzuki, Kohei Taniguchi, Minami Hatono, Yukiko Kajiwara, Yuko Abe, Kengo Kawada, Takahiro Tsukioki, Mariko Kochi, Keiko Nishiyama, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Masahiro Tabata, Hiroyuki Yanai, Hiroyoshi Doihara

    Surgical case reports   6 ( 1 )   25 - 25   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)  

    BACKGROUND: Angiosarcoma of the breast is very rare and can be divided into primary and secondary angiosarcoma. Radiation-induced angiosarcoma (RIAS) is classified as secondary angiosarcoma. Diagnosis of RIAS is difficult due to its rarity, and the interpretation of pathological imaging is complicated. In the National Comprehensive Care Network (NCCN) guidelines, the first choice of treatment is surgery with negative margins. Adjuvant radiotherapy (RT) for close soft tissue margins should be considered. Preoperative or adjuvant chemotherapy of nonmetastatic disease is not recommended for angiosarcoma. We report a case of RIAS, which was impossible to diagnose with core needle biopsy (CNB) but was diagnosed by excisional biopsy. The patient was then administered adjuvant chemotherapy using conjugated paclitaxel (PTX). CASE PRESENTATION: A 62-year-old woman noticed a tumor in her right breast. She had a history of right breast cancer and had undergone breast-conserving surgery, RT, and tamoxifen therapy 8 years previously. CNB, which was performed twice, was inconclusive. The tumor was surgically excised and pathological analysis yielded a diagnosis of angiosarcoma. She then underwent a right mastectomy. One month after she underwent right mastectomy, a nodule reappeared on the skin of her right breast, and excisional biopsy revealed recurrence of angiosarcoma. A few weeks later another nodule reappeared near the post-operative scar and excisional biopsy revealed recurrence of angiosarcoma. We assumed that surgical therapy was insufficient because the patient experienced relapse of angiosarcoma after complete mastectomy. After the second recurrence, we treated her with systemic chemotherapy using PTX. There was no evidence of recurrence 8 months after chemotherapy. CONCLUSION: Although angiosarcoma is difficult to diagnose, many patients have a poor prognosis. Therefore, prompt treatment intervention is desired. Moreover, there is little evidence regarding adjuvant therapy of angiosarcoma since it is a rare disease. We consider that adjuvant therapy helped to effectively prevent recurrence in the patient after complete excision.

    DOI: 10.1186/s40792-020-0790-7

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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)  

    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.

    DOI: 10.1016/j.jtho.2019.07.017

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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)  

    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.

    DOI: 10.1016/j.resinv.2019.04.004

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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)  

    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.

    DOI: 10.1093/jjco/hyz066

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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)  

    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.

    DOI: 10.1016/j.lungcan.2019.02.021

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  • Successful Treatment of Metastatic Urothelial Carcinoma after Accurate Diagnosis by Immunohistochemistry.

    Go Makimoto, Hisakazu Nishimori, Reiko Kondo, Hiroyuki Yanai, Morito Sugimoto, Naohiro Oda, Toshio Kubo, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Yoshinobu Maeda

    Acta medica Okayama   73 ( 3 )   279 - 284   2019年6月

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    記述言語:英語  

    Urothelial carcinoma usually presents with hematuria, but cases of multiple lymphadenopathy with elevated S-pancreas-1 antigen (SPan-1) levels have not been reported. A 62-year-old Japanese man with lymphadenopathies was diagnosed with an adenocarcinoma of unknown origin and transferred to our hospital for further diagnosis. Serum carbohydrate antigen 19-9 and SPan-1 levels were extremely elevated. Uroplakin III immunostaining was positive in the inguinal lymph node, and cystoscopy revealed the presence of invasive urothelial carcinoma. Treatment with cisplatin and gemcitabine promoted a complete metabolic response for > 4 years. The detection of uroplakin III and serum SPan-1 might help diagnose urothelial carcinoma.

    DOI: 10.18926/AMO/56873

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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)  

    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.

    DOI: 10.1093/jjco/hyz016

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  • A case of pulmonary artery intimal sarcoma successfully treated using concurrent chemoradiotherapy and subsequent chemotherapy. 国際誌

    Terumi Aso, Masako Terao, Hisashi Endo, Masahiro Tabata

    International cancer conference journal   8 ( 2 )   71 - 76   2019年4月

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    記述言語:英語  

    Pulmonary artery intimal sarcoma (PAIS) is a rare malignancy with an extremely poor prognosis. A 43-year-old man visited our hospital with shortness of breath and suddenly experienced cardiopulmonary arrest before he could be examined. After prompt resuscitation, we diagnosed PAIS, but the patient refused to undergo surgery because of the high perioperative mortality risk. Thus, the patient was treated using concurrent chemoradiotherapy with weekly paclitaxel therapy, as well as subsequent chemotherapy. The patient continued chemotherapy for 36 months until he elected to discontinue treatment. To the best of our knowledge, this is the first case of PAIS, which is difficult to resect, that was successfully treated using concurrent chemoradiotherapy and subsequent chemotherapy.

    DOI: 10.1007/s13691-018-00356-0

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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)  

    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.

    DOI: 10.1111/cas.13752

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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.

    DOI: 10.18632/oncotarget.25705

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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)  

    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.

    DOI: 10.18926/AMO/56080

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  • Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery. 国際誌

    Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   48 ( 3 )   287 - 290   2018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)  

    The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

    DOI: 10.1093/jjco/hyy003

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  • 【緩和ケアは浸透しているか】最近の内科医からみた拠点病院の問題点

    田端 雅弘

    緩和医療   25 ( 1 )   114 - 135   2018年3月

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    記述言語:日本語   出版者・発行元:緩和医療研究会  

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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)  

    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.

    DOI: 10.1038/s41598-018-20326-z

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  • 喫煙再開後の発症が疑われた肺ランゲルハンス細胞組織球症の1例

    渡邉 洋美, 久保 寿夫, 田端 雅弘, 妹尾 賢, 秦 雄介, 木浦 勝行

    日本呼吸器学会誌   6 ( 4 )   255 - 259   2017年7月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器学会  

    68歳、男性。45年間の喫煙歴があったが、2012年の舌癌に対する手術後は禁煙していた。2014年12月より乾性咳嗽が出現し、2015年2月の単純CTで両肺野に多発する結節影を指摘された。舌癌の肺転移が疑われたが、CTガイド下肺生検の結果、肺ランゲルハンス細胞組織球症と診断された。診断後に喫煙を再開していたことが判明し、禁煙で軽快した。成人の肺ランゲルハンス細胞組織球症は喫煙との関連が深く、初回喫煙時に発症することが多いが、喫煙再開後の発症が疑われた症例を経験した。(著者抄録)

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  • ニボルマブ治療中にニューモシスチス肺炎を発症した肺多形癌の1例

    妹尾 賢, 久保 寿夫, 狩野 裕久, 西井 和也, 田端 雅弘, 木浦 勝行

    日本呼吸器学会誌   6 ( 4 )   283 - 286   2017年7月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器学会  

    症例は40歳、男性。右肺上葉原発の肺多形癌で、縦隔リンパ節転移、腹腔内転移を認めていた。化学療法を行われるも無効であり、4次治療としてニボルマブが投与された。ニボルマブにより胸部病変は縮小したが、経過中にニューモシスチス肺炎を発症した。肺多形癌に対するニボルマブは有用な可能性があるが、ニューモシスチス肺炎をはじめとした日和見感染症の顕性化も念頭に置いて治療する必要があると考えられた。(著者抄録)

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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)  

    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.

    DOI: 10.1093/jjco/hyx022

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  • Pneumocystis Pneumonia Concomitant with Ectopic ACTH Syndrome Caused by a Large Cell Neuroendocrine Carcinoma of the Thymus.

    Naohiro Oda, Nobuaki Miyahara, Masahiro Tabata, Daisuke Minami, Kiichiro Ninomiya, Arihiko Kanehiro, Motoshi Komatsubara, Kenichi Inagaki, Mitsune Tanimoto, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   56 ( 5 )   551 - 555   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We herein report the case of a 44-year-old man who was diagnosed with pneumocystis pneumonia (PCP) concomitant with ectopic adrenocorticotropic hormone (ACTH) syndrome, which had been caused by a large cell neuroendocrine carcinoma of the thymus. Chest computed tomography revealed ground-glass opacities in the lungs. PCP was diagnosed by a polymerase chain reaction with bronchoalveolar lavage. The levels of cortisol were slowly corrected with an adrenal enzyme inhibitor, and the exacerbation of PCP was successfully avoided. Our case indicates that in addition to prophylaxis, the early diagnosis of PCP and the slow correction of hypercortisolemia should be considered in order to prevent an exacerbation due to the reconstitution of the immune function in patients with ectopic ACTH syndrome.

    DOI: 10.2169/internalmedicine.56.7655

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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)  

    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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  • A phase II study of topotecan and cisplatin with sequential thoracic radiotherapy in elderly patients with small-cell lung cancer: Okayama Lung Cancer Study Group 0102. 国際誌

    Toshio Kubo, Keiichi Fujiwara, Katsuyuki Hotta, Toshiaki Okada, Shoichi Kuyama, Shingo Harita, Takashi Ninomiya, Haruhito Kamei, Shinobu Hosokawa, Akihiro Bessho, Tadashi Maeda, Toshiyuki Kozuki, Nobukazu Fujimoto, Kiichiro Ninomiya, Mitsuhiro Takemoto, Susumu Kanazawa, Nagio Takigawa, Masahiro Tabata, Mitsune Tanimoto, Hiroshi Ueoka, Katsuyuki Kiura

    Cancer chemotherapy and pharmacology   78 ( 4 )   769 - 74   2016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)  

    PURPOSE: The treatment outcome in elderly patients with limited-disease small-cell lung cancer (LD-SCLC) remains poor. We carried out a phase II trial of split topotecan and cisplatin (TP) therapy and sequential thoracic radiotherapy for elderly LD-SCLC patients as a follow-up to our previous phase I trial. METHODS: In total, 30 patients aged 76 years or older, with untreated LD-SCLC were enrolled. Four courses of topotecan (1.0 mg/m(2), days 1-3) and cisplatin (20 mg/m(2), days 1-3) were administered, followed by thoracic radiotherapy (1.8 Gy/day, total of 45 Gy). The primary end point was the overall response rate (ORR). RESULTS: The trial was terminated early with 22 patients because of slow accrual. Their median age was 79 years. The median number of courses of chemotherapy administered was three, and the actual completion rate of the entire treatment course was 41 %. The ORR was 68 % with a 95 % confidence interval of 47-89 % (15/22 cases). The median progression-free survival and overall survival were 9.1 and 22.2 months, respectively. The main toxicity was myelosuppression, with grades 3-4 neutropenia (96 %), thrombocytopenia (50 %), and febrile neutropenia (32 %). CONCLUSIONS: This regimen produced a favorable survival outcome, despite moderate-to-severe toxicity profiles. Further efforts are necessary to define an optimal regimen for elderly patients with limited SCLC.

    DOI: 10.1007/s00280-016-3135-2

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  • A Phase I Trial of 100 mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer.

    Tomoki Tamura, Taizo Hirata, Masahiro Tabata, Shiro Hinotsu, Akinobu Hamada, Takayuki Motoki, Takayuki Iwamoto, Taeko Mizoo, Tomohiro Nogami, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara

    Acta medica Okayama   70 ( 5 )   425 - 427   2016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)  

    Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.

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  • Safety and discomfort during bronchoscopy performed under sedation with fentanyl and midazolam: a prospective study. 国際誌

    Daisuke Minami, Nagio Takigawa, Hiromi Watanabe, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   46 ( 9 )   871 - 4   2016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)  

    OBJECTIVE: Although sedation with fentanyl and midazolam during bronchoscopic examination is widely accepted in the USA and Europe, it is not routine practice in Japan. The objective of the present study was to evaluate sedation with fentanyl and midazolam during bronchoscopy. METHODS: Thirty-seven patients were enrolled prospectively between November 2014 and July 2015 at Okayama University Hospital. Fentanyl (20 μg) was administered to the patients just before the examination, and fentanyl (10 μg) and midazolam (1 mg) were added as needed during the procedure. A questionnaire was administered 2 hours after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: great (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 used. Predefined matters for investigation (e.g. blood pressure, heart rate, oxygen saturation and complications) were recorded. RESULTS: The enrolled patients included 13 males and 24 females; the median age was 67 (range: 31-87) years. The patients received a median dose of fentanyl of 45.4 μg (range: 30-100 μg) and midazolam of 2.56 mg (range: 1-10 mg). Twenty-six patients (70.2%) agreed to undergo a second bronchoscopic examination, and the average levels of discomfort and re-examination were 2.02 points for each. Only 37.8% of the patients remembered the bronchoscopic examination. No severe complications were reported. CONCLUSIONS: Sedation with fentanyl and midazolam during bronchoscopic examination should be recommended for use in Japan.

    DOI: 10.1093/jjco/hyw083

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  • Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. 国際誌

    Daisuke Minami, Nagio Takigawa, Naohiro Oda, Takashi Ninomiya, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsumasa Kaji, Mitsune Tanimoto, Katsuyuki Kiura

    Japanese journal of clinical oncology   46 ( 6 )   529 - 33   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)  

    OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration is of diagnostic value in hilar/mediastinal (N1/N2) lymph node staging. We assessed the utility of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients with N1/N2 lymph nodes detected on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. METHODS: Fifty lung cancer patients with N1/N2 disease on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography underwent endobronchial ultrasound-guided transbronchial needle aspiration for pathological lymph nodes between November 2012 and April 2015. The diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration, lymph node site and size, number of needle passes and complications were evaluated retrospectively from patients' medical records. Malignancy was defined as a maximum standardized uptake value (SUVmax) >2.5. RESULTS: The median longest diameter of the 61 lymph nodes (29 subcarinal, 21 right lower paratracheal, 6 left lower paratracheal, 4 right hilar and 1 upper paratracheal) was 23.4 mm (range: 10.4-45.7); the median number of needle passes was 2 (range: 1-5). There were no severe complications. A definitive diagnosis was made by endobronchial ultrasound-guided transbronchial needle aspiration in 39 patients (31 adenocarcinomas, 3 small-cell carcinomas, 2 squamous-cell carcinomas, 3 large-cell neuroendocrine carcinomas). In the remaining 11 patients, the diagnosis was indefinite: insufficient endobronchial ultrasound-guided transbronchial needle aspiration material was collected in two patients and non-specific lymphadenopathy was confirmed by endobronchial ultrasound-guided transbronchial needle aspiration or thoracotomy in the other nine patients. The mean lymph node SUVmax was 7.09 (range: 2.90-26.9) and was significantly higher in true-positive than in false-positive nodes (P < 0.05, t-test). Non-specific lymphadenopathy was diagnosed by expert visual interpretation of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography images in five of the nine patients. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration accurately diagnoses N1/N2 disease detected on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography.

    DOI: 10.1093/jjco/hyw023

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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)  

    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.

    DOI: 10.1007/s10147-015-0860-1

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  • Efficacy of multimodal treatment for leptomeningeal metastases in a lung cancer harboring an EGFR mutation. 国際誌

    Daisuke Morichika, Toshio Kubo, Hiroko Gotoda, Tomoki Tamura, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Kazuhiko Kurozumi, Mitsune Tanimoto, Katsuyuki Kiura

    OncoTargets and therapy   9   1753 - 8   2016年

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    記述言語:英語  

    For lung cancer patients with epidermal growth factor receptor (EGFR) mutations, the advent of EGFR tyrosine kinase inhibitors (TKIs) has prolonged survival rates. Even though disease sites have been well controlled by EGFR-TKIs, some patients develop carcinomatous meningitis, which reduces their quality of life drastically. Although multidisciplinary approaches have improved patient survival and quality of life, the outcomes are not yet satisfactory. We report the case of a 54-year-old Japanese woman diagnosed with leptomeningeal metastases (LM) from a lung adenocarcinoma harboring an EGFR exon 21 L858R point mutation. She was treated with gefitinib for 2 months, and symptoms of LM emerged during the treatment period. Although the treatment was switched to erlotinib, disturbance of consciousness worsened because of progressive hydrocephalus. Because all extracranial lesions remained responsive to treatment, and the exon 20 T790M point mutation was not detected in cerebrospinal fluid, we placed a ventriculoperitoneal shunt. The patient's disturbed consciousness improved dramatically after the shunt was placed; however, the optic and auditory nerve impairments due to direct invasion of LM lesions into nerve canals persisted. Administration of bevacizumab subsequent to whole-brain radiotherapy reduced the cranial nerve impairment, and the patient survived for 10 months. In conclusion, a combination of erlotinib and ventriculoperitoneal shunt was effective for hydrocephalus, and the immediate administration of additional therapies, including bevacizumab and radiation therapy, was useful in a patient suffering from LM.

    DOI: 10.2147/OTT.S95721

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  • Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model. 国際誌

    Daisuke Minami, Nagio Takigawa, Yuka Kato, Kenichiro Kudo, Hideko Isozaki, Shinsuke Hashida, Daijiro Harada, Nobuaki Ochi, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Takehiro Tanaka, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer science   106 ( 10 )   1296 - 302   2015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)  

    Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2'-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

    DOI: 10.1111/cas.12752

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  • Endobronchial ultrasound-guided transbronchial biopsy with or without a guide sheath for diagnosis of lung cancer. 国際誌

    Daisuke Minami, Nagio Takigawa, Daisuke Morichika, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    Respiratory investigation   53 ( 3 )   93 - 7   2015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)  

    BACKGROUND: Endobronchial ultrasound-guided transbronchial biopsy with a guide sheath (EBUS-GS) is widely used for diagnosing lung cancers; however, the diagnostic yield varies widely. This study aimed to assess the efficiency of EBUS-GS. METHODS: We retrospectively evaluated the results of 110 patients who underwent transbronchial biopsy (TBB) for diagnosis of peripheral lung cancer. Bronchoscopy with and without EBUS-GS was performed in 60 (group A) and 50 patients (group B), respectively; their medical records were examined, and results from the two groups were compared by using the unpaired Student t-test. RESULTS: The diagnostic sensitivity for lung cancer was 83.3% in group A and 68% in group B (P=0.066) while using at least one of the following procedures: TBB, cytological brushing, and bronchial washing. The diagnostic sensitivity for lesions ≥20mm was 86.4% in group A and 76.7% in group B (P=0.263). Moreover, the diagnostic sensitivity for lesions 10-20mm was 60% in group A and 14.2% in group B (P=0.0004); the diagnostic sensitivity with TBB alone was 63.3% in group A and 44% in group B (P=0.043). The diagnostic sensitivity with TBB alone for lesions ≥20mm was 70.2% in group A and 44.8% in group B (P=0.051). Moreover, the diagnostic sensitivity for lesions 10-20mm in size was 45% in group A and 14.2% in group B with TBB alone (P=0.115). CONCLUSION: EBUS-GS with TBB, brushing, and bronchial washing is effective in diagnosing lung cancers sized <20mm.

    DOI: 10.1016/j.resinv.2014.10.003

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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)  

    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%.

    DOI: 10.1097/JTO.0000000000000434

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  • A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0501. 国際誌

    Naoyuki Nogami, Nagio Takigawa, Katsuyuki Hotta, Yoshihiko Segawa, Yuka Kato, Toshiyuki Kozuki, Isao Oze, Daizo Kishino, Keisuke Aoe, Hiroshi Ueoka, Shoichi Kuyama, Shingo Harita, Toshiaki Okada, Shinobu Hosokawa, Koji Inoue, Kenichi Gemba, Takuo Shibayama, Masahiro Tabata, Mitsuhiro Takemoto, Susumu Kanazawa, Mitsune Tanimoto, Katsuyuki Kiura

    Lung cancer (Amsterdam, Netherlands)   87 ( 2 )   141 - 7   2015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: Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S-1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective. METHODS: In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40mg/m(2) on days 1, 8, 29 and 36) and S-1 (80mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary endpoint was the response rate. RESULTS: A partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis. CONCLUSIONS: This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC.

    DOI: 10.1016/j.lungcan.2014.11.001

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  • Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review. 国際誌

    Katsuyuki Hotta, Yuka Kato, Natasha Leighl, Nagio Takigawa, Rabab Mohamed Gaafar, Hiroe Kayatani, Taizo Hirata, Kadoaki Ohashi, Toshio Kubo, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

    PloS one   10 ( 3 )   e0121211   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed. METHODS AND FINDINGS: We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; P<0.01). A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%). The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01). An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%. CONCLUSION: The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

    DOI: 10.1371/journal.pone.0121211

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  • Intramucosal gastric mixed adenoneuroendocrine carcinoma completely resected with endoscopic submucosal dissection.

    Yasushi Yamasaki, Junichiro Nasu, Kou Miura, Yoshiyasu Kono, Hiromitsu Kanzaki, Keisuke Hori, Takehiro Tanaka, Masahide Kita, Takao Tsuzuki, Minoru Matsubara, Seiji Kawano, Yoshiro Kawahara, Masahiro Tabata, Hiroyuki Okada, Kazuhide Yamamoto

    Internal medicine (Tokyo, Japan)   54 ( 8 )   917 - 20   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Composite tumors in the stomach composed of adenocarcinoma and neuroendocrine carcinoma are rare. We herein report a case of intramucosal gastric mixed adenoneuroendocrine carcinoma (MANEC) that was treated with endoscopic submucosal dissection (ESD). A 77-year-old man who had previously received ESD for early gastric adenocarcinoma underwent esophagogastroduodenoscopy for screening, which showed a depressed lesion on the lesser curvature of the antrum. The tumor was removed en bloc via ESD and pathologically diagnosed as MANEC. The tumor was located within the mucosal layer, and no lymphovascular invasion was evident. Seven months after the ESD procedure, the patient is currently feeling well without recurrence or metastasis.

    DOI: 10.2169/internalmedicine.54.3469

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  • A survey of Japanese thoracic oncologists' perception of diagnostic and treatment strategies for EGFR mutant or EML4-ALK fusion non-small cell lung cancer. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Mitsune Tanimoto, Hiroshi Ueoka

    Chest   146 ( 6 )   e222-e225   2014年12月

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    記述言語:英語  

    DOI: 10.1378/chest.14-2055

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  • A phase II study of S-1 chemotherapy with concurrent thoracic radiotherapy in elderly patients with locally advanced non-small-cell lung cancer: the Okayama Lung Cancer Study Group Trial 0801. 国際誌

    Keisuke Aoe, Nagio Takigawa, Katsuyuki Hotta, Tadashi Maeda, Daizo Kishino, Naoyuki Nogami, Masahiro Tabata, Shingo Harita, Toshiaki Okada, Toshio Kubo, Shinobu Hosokawa, Keiichi Fujiwara, Kenichi Gemba, Masayuki Yasugi, Toshiyuki Kozuki, Yuka Kato, Kuniaki Katsui, Susumu Kanazawa, Hiroshi Ueoka, Mitsune Tanimoto, Katsuyuki Kiura

    European journal of cancer (Oxford, England : 1990)   50 ( 16 )   2783 - 90   2014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)  

    BACKGROUND: Although thoracic irradiation (TRT) is a standard treatment for elderly patients with locally advanced non-small-cell lung cancer (LA-NSCLC), treatment outcomes are poor. We previously reported a phase I trial combining S-1, an oral 5-fluorouracil derivative, and thoracic radiation, which yielded safe and effective outcomes. METHODS: In this phase II trial, 30 patients aged 76 years or older with LA-NSCLC received S-1 (80 mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary end-point was the response rate. RESULTS: The median age and pre-treatment Charlson score were 79 years and 1, respectively. The mean proportions of the actual doses of S-1 and TRT delivered relative to the planned doses were 95% and 98%, respectively. Partial responses were observed in 19 patients (63%; 95% confidence interval: 45-82%), which did not attain the end-point. At a median follow-up time of 23.7 months, the median progression-free survival and median survival times were 13.0 months and 27.9 months, respectively. No difference in efficacy was observed upon stratification by tumour histology. Toxicities were generally mild, except for grade 3 or greater febrile neutropenia and pneumonitis in 7% and 10% of patients, respectively. No patient developed severe oesophagitis. CONCLUSIONS: Although the primary end-point was not met, concurrent S-1 chemotherapy and radiotherapy yielded favourable survival data. Also, the combined treatment was well-tolerated in elderly patients with LA-NSCLC.

    DOI: 10.1016/j.ejca.2014.07.024

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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)  

    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)  

    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.

    DOI: 10.1016/j.yexcr.2014.01.007

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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)  

    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.

    DOI: 10.1093/jjco/hyt128

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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)  

    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.

    DOI: 10.1093/jjco/hyt123

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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)  

    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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  • 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)  

    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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  • 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)  

    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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  • 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)  

    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)  

    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.

    DOI: 10.1371/journal.pone.0042798

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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)  

    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.

    DOI: 10.1159/000338532

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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)  

    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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  • A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401. 国際誌

    Naoyuki Nogami, Katsuyuki Hotta, Shoichi Kuyama, Katsuyuki Kiura, Nagio Takigawa, Kenichi Chikamori, Takuo Shibayama, Daizo Kishino, Shinobu Hosokawa, Akihiko Tamaoki, Shingo Harita, Masahiro Tabata, Hiroshi Ueoka, Tetsu Shinkai, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   74 ( 1 )   80 - 4   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)  

    BACKGROUNDS: Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. METHODS: Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases. RESULTS: Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths. CONCLUSION: This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.

    DOI: 10.1016/j.lungcan.2011.01.018

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  • Benefits and adverse events among elderly patients receiving concurrent chemoradiotherapy for locally advanced non-small cell lung cancer: analysis of the Okayama Lung Cancer Study Group trial 0007. 国際誌

    Nagio Takigawa, Katsuyuki Kiura, Yoshihiko Segawa, Katsuyuki Hotta, Akihiko Tamaoki, Yoshiyuki Tokuda, Takuya Nagata, Kazuhiko Watanabe, Kenichi Gemba, Tomonori Moritaka, Naokatsu Horita, Hiromasa Takeda, Niro Okimoto, Mitsuhiro Takemoto, Keitaro Matsuo, Tetsu Shinkai, Masahiro Tabata, Hiroshi Ueoka, Susumu Kanazawa, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   6 ( 6 )   1087 - 91   2011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)  

    INTRODUCTION: Thoracic radiotherapy (RT) with concurrent chemotherapy may be offered to selected elderly patients with locally advanced non-small cell lung cancer. The Okayama Lung Cancer Study Group (OLCSG) 0007 trial with patients up to 75 years showed that with concurrent RT, docetaxel and cisplatin (DP) chemotherapy was an alternative to mitomycin C, vindesine, and cisplatin (MVP) chemotherapy. METHODS: Of the 99 patients in the DP arm, 73 were younger than 70 years and 26 were 70 years or older. Of the 101 patients in the MVP arm, 75 were younger than 70 years and 26 were 70 years or older. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared using an early period weighted log-rank test. Toxicities and treatment intensities were compared by χ(2) and t tests, respectively. RESULTS: OS and PFS tended to be longer in the DP arm versus MVP arm: median OS (months), 27.5 versus 22.9 (p = 0.109) and 25.6 versus 23.4 (p = 0.064) in the ≥70-year and <70-year groups, respectively; median PFS (months), 19.0 versus 11.5 (p = 0.175) and 12.0 versus 9.3 (p = 0.132) in the ≥70-year and less than 70-year groups, respectively. Severe toxicity (neutropenia, esophagitis, and pneumonitis) rates did not differ between age groups. Nevertheless, the absence of statistically significant differences in this retrospective analysis might be due to the small number of patients. Radiation intensity was similar between the groups, but chemotherapy intensity was lower in the ≥70-year group. CONCLUSION: Chemotherapy with concurrent RT may be effective and tolerable in elderly patients with locally advanced non-small cell lung cancer.

    DOI: 10.1097/JTO.0b013e318213f86a

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  • A phase I study of S-1 with concurrent thoracic radiotherapy in elderly patients with localized advanced non-small cell lung cancer. 国際誌

    Nagio Takigawa, Katsuyuki Kiura, Katsuyuki Hotta, Shinobu Hosokawa, Naoyuki Nogami, Keisuke Aoe, Kenichi Gemba, Keiichi Fujiwara, Shingo Harita, Mitsuhiro Takemoto, Kengo Himei, Tetsu Shinkai, Yoshirou Fujiwara, Saburo Takata, Masahiro Tabata, Susumu Kanazawa, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   71 ( 1 )   60 - 4   2011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)  

    S-1, an oral 5-fluorouracil derivative, is effective against advanced non-small cell lung cancer (NSCLC) with mild toxicity and synergistic effects with radiation in preclinical trials. In this phase I study, we evaluated the dose-limiting toxicity and recommended dose of S-1 for a future phase II study when administered concurrently with thoracic radiation (total dose of 60 Gy at 2 Gy per daily fraction) in elderly patients (>75 years old) with localized advanced NSCLC. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. Twenty-two previously untreated patients were enrolled in this study. Dose-limiting toxicity included febrile neutropenia, thrombocytopenia, stomatitis, and pneumonitis. One patient had grade 5 radiation pneumonitis. No other patient experienced radiation pneumonitis or esophagitis exceeding grade 2. The recommended dose for S-1 was determined to be 80 mg/m(2)/day, which produced an overall response rate of 75% (n=12). The median progression-free survival time was 11.5 months (95% confidence interval: 7.1-15.8 months) with a median follow-up time of 27.9 months. These results indicate that concurrent treatment with S-1 and thoracic radiation is a feasible option for NSCLC in the elderly. A phase II study is currently under way.

    DOI: 10.1016/j.lungcan.2010.04.012

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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)  

    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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  • Association between poor performance status and risk for toxicity during erlotinib monotherapy in Japanese patients with non-small cell lung cancer: Okayama Lung Cancer Study Group experience. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Etsuji Suzuki, Hiroshige Yoshioka, Toshiaki Okada, Daizo Kishino, Hiroshi Ueoka, Koji Inoue, Masahiro Tabata, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   70 ( 3 )   308 - 12   2010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)  

    BACKGROUND: The relationship between poor performance status (PS) and toxicity during chemotherapy is controversial. We examined this for erlotinib monotherapy in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Toxicity during the first month of therapy was recorded in 209 patients receiving erlotinib for NSCLC, and its association with PS was assessed. RESULTS: Of 209 patients, 52, 115, 30 and 12 had a PS of 0, 1, 2 and 3-4, respectively. Treatment was discontinued in 26% of patients within 1 month, with a higher rate in poorer PS patients (17%, 25%, 37% and 42%). Discontinuation was predominantly due to disease progression, rather than adverse events, in both the whole cohort (82% vs. 18%) and the poorest PS subgroup (100% vs. 0%). Three, two, and four patients with a PS of 1, 2 and 3-4, respectively, died within 1 month; all six deaths of PS 2-4 patients were attributed to disease progression. Treatment interruption and dose reduction rates were similar among the subgroups. The principal adverse event was skin rash, with identical incidence in all PS subgroups. CONCLUSIONS: Poor PS is unlikely to increase the risk for toxicity during erlotinib monotherapy, but was related to low compliance, probably because of disease progression rather than treatment-related toxicity.

    DOI: 10.1016/j.lungcan.2010.03.008

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  • Desire for information and involvement in treatment decisions: lung cancer patients' preferences and their physicians' perceptions: results from Okayama Lung Cancer Study Group Trial 0705. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Hiroshige Yoshioka, Hidetoshi Hayashi, Hajime Fukuyama, Akihiro Nishiyama, Toshihide Yokoyama, Shoichi Kuyama, Shigeki Umemura, Yuka Kato, Naoyuki Nogami, Yoshihiko Segawa, Masayuki Yasugi, Masahiro Tabata, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   5 ( 10 )   1668 - 72   2010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)  

    INTRODUCTION: This study explores patient preferences for involvement in lung cancer treatment decisions and the extent of concordance between the views of patients and physicians on decisional roles. The impact of demographic and psychosocial characteristics on the decisional role of patients is also examined. METHODS: Patients with relapsed non-small cell lung cancer who were candidates for a phase II trial of erlotinib monotherapy were recruited. Patients were interviewed after they had learned of their relapse and the treatment decision had been made but before pharmacologic intervention. RESULTS: Most of the 28 participants were married, had a smoking history, and were well educated. They reported moderate levels of depression and anxiety. Initially, 14% of the patients reported a preference for active decision making; later, 29% believed that the primary responsibility for the treatment decision had been theirs. Only 54% of the patients agreed with the physician's assessment of how the treatment decision was made (κ = 0.31; test of symmetry, p = 0.23). The depression score was significantly associated with a patient's preferred level of control (p < 0.01). CONCLUSIONS: The limited concordance between patient preference and perception and between patient and physician perceptions regarding how the treatment decision was made suggests that physicians should more accurately identify patient preferences by directly asking patients at the beginning of each clinical encounter.

    DOI: 10.1097/JTO.0b013e3181f1c8cb

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  • A randomized phase II study of a combination of docetaxel and S-1 versus docetaxel monotherapy in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy: results of Okayama Lung Cancer Study Group (OLCSG) Trial 0503. 国際誌

    Yoshihiko Segawa, Katsuyuki Kiura, Katsuyuki Hotta, Nagio Takigawa, Masahiro Tabata, Keitaro Matsuo, Hiroshige Yoshioka, Hidetoshi Hayashi, Haruyuki Kawai, Keisuke Aoe, Tadashi Maeda, Hiroshi Ueoka, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   5 ( 9 )   1430 - 4   2010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)  

    BACKGROUND: The survival impact of single-agent treatment with docetaxel, the standard regimen for relapsed patients with non-small cell lung cancer (NSCLC), remains modest. We conducted a randomized phase II study to evaluate the efficacy and safety of the combination of docetaxel and S-1 in the second-line setting. METHODS: Patients with relapse of NSCLC after first-line platinum-based chemotherapy were randomly assigned to docetaxel alone (60 mg/m, day 1, q3 weeks; arm A) or a combination of docetaxel (40 mg/m, day 1, q3 weeks) and S-1 (80 mg/m, days 1-15; arm B). The primary end point was response rate, whereas secondary endpoints included overall survival, progression-free survival, and toxicity. RESULTS: Between 2005 and 2008, a total of 60 patients were enrolled in the study. The objective response rates were 20.7% and 16.1% in arms A and B, respectively (p = 0.81). Progression-free survival was comparable in the two arms (median: 3.7 versus 3.4 months, p = 0.27), whereas overall survival time was longer in arm A (22.9 versus 8.7 months, p = 0.02). The major toxicity was myelosuppression with grade > or =3 neutropenia in 89.7% of patients versus 64.5% in arms A and B, respectively. CONCLUSIONS: This study suggests that docetaxel monotherapy should continue to be considered the standard for second-line chemotherapy against NSCLC.

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  • Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. 国際誌

    Yoshihiko Segawa, Katsuyuki Kiura, Nagio Takigawa, Haruhito Kamei, Shingo Harita, Shunkichi Hiraki, Yoichi Watanabe, Keisuke Sugimoto, Takuo Shibayama, Toshiro Yonei, Hiroshi Ueoka, Mitsuhiro Takemoto, Susumu Kanazawa, Ichiro Takata, Naoyuki Nogami, Katsuyuki Hotta, Akio Hiraki, Masahiro Tabata, Keitaro Matsuo, Mitsune Tanimoto

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   28 ( 20 )   3299 - 306   2010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)  

    PURPOSE: To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT. RESULTS: Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056). CONCLUSION: DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

    DOI: 10.1200/JCO.2009.24.7577

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  • Triplet chemotherapy with cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer.

    Nobukazu Fujimoto, Katsuyuki Kiura, Nagio Takigawa, Yoshiro Fujiwara, Shinichi Toyooka, Shigeki Umemura, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

    Acta medica Okayama   64 ( 1 )   33 - 7   2010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)  

    We examined the feasibility of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer (NSCLC), retrospectively. Twenty-five patients (21 men and 4 women) with NSCLC and good performance status who were < or = 70 years old were analyzed. The median age was 58 years. Most patients had performance status 1 (16/25), stage IV disease (18/25) and adenocarcinoma-histology (16/25). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2; the cycle was repeated every 3 weeks. The objective response rate was 39.1% (95% confidence interval: 18.7-59.5%). The median survival time and actual 2-, 3-, and 5-year survival rates were 14.3 months, 32%, 20%, and 8%, respectively. Of note, only 6 patients were treated with gefitinib at the recurrence after triplet chemotherapy; of these, 4 (67%) achieved a partial response, which might result in favorable survival. Grade 3/4 toxicities consisted of neutropenia (100%), neutropenic fever (56%), nausea/vomiting (40%), and diarrhea (16%); no cases of treatment-related death occurred. Triplet chemotherapy showed impressive survival data in our clinical trial, but proved too toxic for use in treating patients with NSCLC in the clinical practice.

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  • Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Hiroshige Yoshioka, Shingo Harita, Shoichi Kuyama, Toshiro Yonei, Keiichi Fujiwara, Tadashi Maeda, Keisuke Aoe, Hiroshi Ueoka, Haruhito Kamei, Shigeki Umemura, Tomonori Moritaka, Yoshihiko Segawa, Haruyuki Kawai, Akihiro Bessho, Katsuya Kato, Masahiro Tabata, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   5 ( 2 )   179 - 84   2010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: Data comparing the incidence and pattern of interstitial lung disease (ILD) in non-small cell lung cancer patients receiving treatment with gefitinib versus erlotinib, both of which are epidermal growth factor receptor tyrosine kinase inhibitors, are scarce. We investigated the incidence of ILD in Japanese patients treated with gefitinib or erlotinib. METHODS: We reviewed the clinical records of 209 patients treated with erlotinib in 2008 (cohort A) and 330 treated with gefitinib between 2000 and 2003 (cohort B). Toxicity within the first month of treatment was investigated. RESULTS: The patients in cohort A had fewer known risk factors for ILD (e.g., poor performance status and prior pulmonary fibrosis). ILD was detected in two patients (1.0%) from cohort A and eight patients (2.4%) from cohort B during the first month of treatment. The events were graded as follows: one patient each in grades 1 and 2 (cohort A), and one, one, and six patients in grades 3, 4, and 5, respectively (cohort B). Multivariate analysis revealed that poor performance status and prior pulmonary fibrosis were significantly correlated with the occurrence of ILD, but the type of epidermal growth factor receptor tyrosine kinase inhibitor administered was not. CONCLUSION: There was a somewhat lower incidence of ILD with erlotinib therapy than with gefitinib therapy, despite no statistically significant difference. Patient selection based on awareness by Japanese physicians of the risk factors for ILD, rather than the type of agent, may explain the difference in ILD incidence between the two treatments.

    DOI: 10.1097/JTO.0b013e3181ca12e0

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  • A phase II trial of erlotinib monotherapy in pretreated patients with advanced non-small cell lung cancer who do not possess active EGFR mutations: Okayama Lung Cancer Study Group trial 0705. 国際誌

    Hiroshige Yoshioka, Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Hidetoshi Hayashi, Shingo Harita, Shoichi Kuyama, Yoshihiko Segawa, Haruhito Kamei, Shigeki Umemura, Akihiro Bessho, Masahiro Tabata, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   5 ( 1 )   99 - 104   2010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)  

    BACKGROUNDS: Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR)-mutation status in Asian patients with non-small cell lung cancer. Recently, the survival advantage of erlotinib, another tyrosine kinase inhibitor, was not affected by EGFR mutation status in a phase III trial, indicating that patients with EGFR-wild-type (EGFR-wt) tumors might also benefit from this tyrosine kinase inhibitor. The aim of this trial was to evaluate the efficacy and toxicity of erlotinib in Japanese patients with EGFR-wt tumors. METHODS: The primary end point was an objective response. Patients with EGFR-wt tumors previously receiving one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Erlotinib was administered (150 mg/d) until disease progression or unacceptable toxicities occurred. RESULTS: Thirty patients were enrolled between January and December 2008. Objective response was observed in one patient (3.3%), and the disease became stable in 18 patients (60.0%). Skin rash was the most common side effect. Grades 3-4 adverse events included pulmonary embolism, keratitis, and anemia. Two other patients developed interstitial lung disease (grades 1 and 2). Nevertheless, all these events were reversible, resulting in no treatment-related deaths. With a median follow-up time of 10.7 months, the median survival time and median progression-free survival times were 9.2 and 2.1 months, respectively. CONCLUSION: This is the first prospective biomarker study showing that erlotinib therapy for pretreated patients with EGFR-wt tumors seems to have a modest activity with no irreversible toxicity.

    DOI: 10.1097/JTO.0b013e3181c20063

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  • Twenty-seven years of phase III trials for patients with extensive disease small-cell lung cancer: disappointing results. 国際誌

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

    PloS one   4 ( 11 )   e7835   2009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)  

    BACKGROUND: Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials. METHODS AND FINDINGS: We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. RESULTS: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine-based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome. CONCLUSIONS AND SIGNIFICANCE: The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.

    DOI: 10.1371/journal.pone.0007835

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  • A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer. 国際誌

    Kenichi Chikamori, Daizo Kishino, Nagio Takigawa, Katsuyuki Hotta, Naoyuki Nogami, Haruhito Kamei, Shoichi Kuyama, Kenichi Gemba, Mitsuhiro Takemoto, Susumu Kanazawa, Hiroshi Ueoka, Yoshihiko Segawa, Saburo Takata, Masahiro Tabata, Katsuyuki Kiura, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   65 ( 1 )   74 - 9   2009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)  

    A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

    DOI: 10.1016/j.lungcan.2008.10.019

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  • Time to progression as a surrogate marker for overall survival in patients with advanced non-small cell lung cancer. 国際誌

    Katsuyuki Hotta, Yoshiro Fujiwara, Keitaro Matsuo, Katsuyuki Kiura, Nagio Takigawa, Masahiro Tabata, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   4 ( 3 )   311 - 7   2009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)  

    PURPOSE: With the increasing number of active compounds available for advanced non-small cell lung cancer, it is useful to evaluate whether surrogate end points can replace survival in randomized trials for the rapid and efficient assessment of efficacy. We examined the association between differences in overall survival and time to progression (TTP) using a literature survey. METHODS: We used median TTP (MTTP) and median survival time (MST) from 54 phase III trials of first-line chemotherapy involving 23,457 advanced non-small cell lung cancer patients in a multiple linear regression analysis. The MST ratio in each trial was defined as the ratio of MST in the investigational arm to that in the reference arm. The MTTP ratio was defined similarly. RESULTS: The degree of the association between the MST and MTTP ratios was only moderate both in the overall cohort (R(2) = 0.33) and various trial settings (R(2) = 0.16-0.51), although the MTTP ratio was an independent factor influencing the MST ratio in the multiple regression model (p < 0.01). This means that the MTTP ratio could account for less than half of the variance in the MST ratio. CONCLUSIONS: The TTP potentially acts as a surrogate marker, but may not be still a definitive alternative in the first-line setting.

    DOI: 10.1097/JTO.0b013e3181989bd2

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  • Sex difference in the influence of smoking status on the responsiveness to gefitinib monotherapy in adenocarcinoma of the lung: Okayama Lung Cancer Study Group experience. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Shoichi Kuyama, Yoshihiko Segawa, Toshiro Yonei, Kenichi Gemba, Keisuke Aoe, Takuo Shibayama, Keisuke Matsuo, Haruhito Kamei, Yoshiro Fujiwara, Akihiko Bessho, Tomonori Moritaka, Keisuke Sugimoto, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

    Journal of cancer research and clinical oncology   135 ( 1 )   117 - 23   2009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)  

    BACKGROUND: Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma. METHODS: We reviewed the clinical records of 260 Japanese patients with lung adenocarcinoma who received gefitinib therapy (250 mg/day), and whose smoking status was known. Tumour response and survival were evaluated and stratified by smoking status and gender. RESULTS: Among the 260 patients, 157 were male (60%). Median pack-years was 40 (range 8-160) and 23 (range 1-74) in male and female smokers, respectively. Objective response was observed in 62 (23.8%) of the 260 patients, and 1-year overall survival and progression-free survival were 45.1 and 24.3%, respectively. Multivariate analysis revealed that smoking status (pack-years) was an independent predictive factor for response to gefitinib [odds ratio (OR) = 0.971, 95% confidence interval (CI) = 0.947-0.995; P = 0.0159] in male patients, but not in female patients (OR = 0.999, 95%CI = 0.957-1.042). Additionally, pack-years significantly influenced the overall survival in males (hazard ratio = 1.010; 95%CI = 1.002-1018, P = 0.0169), while differential survival of females was not significantly predicted by this factor (P = 0.7639). CONCLUSIONS: In male patients with lung adenocarcinoma, cumulative smoking significantly affected response and survival following gefitinib treatment, while in female patients, responsiveness to gefitinib was independent of smoking status. These results suggest that the influence of smoking habit on responsiveness to gefitinib is gender specific.

    DOI: 10.1007/s00432-008-0431-1

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  • A case of advanced non-small-cell lung cancer who responded slowly to gefitinib monotherapy after long-term disease stabilization. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Akinori Shirahige, Saburo Takata, Nagio Takigawa, Masahiro Tabata, Hirokazu Watanabe, Mitsune Tanimoto

    Acta oncologica (Stockholm, Sweden)   48 ( 3 )   471 - 3   2009年

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  • Paradoxical clinical effects of epidermal growth factor receptor-tyrosine kinase inhibitors for acute myelogenous leukemia. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Keitaro Matsuo, Masahiro Tabata, Yoshiro Fujiwara, Mitsune Tanimoto

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   26 ( 35 )   5826 - 7   2008年12月

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  • Association of the benefit from gefitinib monotherapy with smoking status in Japanese patients with non-small-cell lung cancer. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Yoshiro Fujiwara, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   62 ( 2 )   236 - 41   2008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)  

    BACKGROUND: Gefitinib has been reported to be more effective in patients with non-small-cell lung cancer (NSCLC) who had low or never-smoking history than for heavier smokers. However, this has been criticized because the better survival in such subpopulation might be attributable simply to their favorable natural history, rather than any treatment effect. METHODS: We retrospectively reviewed the clinical records of 155 Japanese patients with relapsed NSCLC who received gefitinib (gefitinib-treated patients; n=83) and those who did not receive it, but were treated with other cytotoxic agents (gefitinib-untreated patients; n=72). A light smoker was defined as one with <20 pack-years. Survival was assessed stratified by gefitinib treatment and smoking status using stepwise proportional hazard modeling. RESULTS: Among the 155 relapsed patients, 58 (37%) had low or never-smoking history. The benefit from gefitinib monotherapy was associated with smoking status (test for interaction, p=0.01). Gefitinib monotherapy, as compared to the cytotoxic agents, significantly prolonged survival among patients with low or never-smoking history (hazard ratio [HR]=0.377; 95% confidence interval [CI]=0.181-0.785; p=0.01), but not among the heavier smokers. Additionally, among gefitinib-treated patients, those with low or never-smoking history survived longer than heavier smokers (HR=0.461; 95% CI=0.244-0.871; p=0.02), while the survival benefit of cytotoxic agents was comparable between those with low or never-smoking history and with heavy smoking habits among the gefitinib-untreated group. CONCLUSIONS: Patients with relapsed NSCLC and low or never-smoking habits appeared to benefit from gefitinib monotherapy, while patients with heavy smoking habits did not.

    DOI: 10.1016/j.lungcan.2008.03.025

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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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  • Aberrant promoter hypermethylation in serum DNA from patients with silicosis. 国際誌

    Shigeki Umemura, Nobukazu Fujimoto, Akio Hiraki, Kenichi Gemba, Nagio Takigawa, Keiichi Fujiwara, Masanori Fujii, Hiroshi Umemura, Mamoru Satoh, Masahiro Tabata, Hiroshi Ueoka, Katsuyuki Kiura, Takumi Kishimoto, Mitsune Tanimoto

    Carcinogenesis   29 ( 9 )   1845 - 9   2008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)  

    It is well established that patients with silicosis are at high risk for lung cancer; however, it is difficult to detect lung cancer by chest radiography during follow-up treatment of patients with silicosis because of preexisting diffuse pulmonary shadows. The purpose of this study is to evaluate the usefulness of detection of serum DNA methylation for early detection of lung cancer in silicosis. Serum samples from healthy controls (n = 20) and silicosis patients with (n = 11) and without (n = 67) lung cancer were tested for aberrant hypermethylation at the promoters of the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), p16(INK4a), ras association domain family 1A (RASSF1A), the apoptosis-related gene death-associated protein kinase (DAPK) and retinoic acid receptor beta (RARbeta) by methylation-specific polymerase chain reaction. Aberrant promoter methylation in at least one of five tumor suppressor genes was detected more frequently in the serum DNA of silicosis patients with lung cancer than in that of patients without it (P = 0.006). Furthermore, the odds ratio of having lung cancer was 9.77 (P = 0.009) for those silicosis patients with methylation of at least one gene. Extended exposure to silica (>30 years) was correlated with an increased methylation frequency (P = 0.017); however, methylation status did not correlate with age, smoking history or radiographic findings of silicosis. These results suggest that testing for aberrant promoter methylation of tumor suppressor genes using serum DNA may facilitate early detection of lung cancer in patients with silicosis.

    DOI: 10.1093/carcin/bgn169

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  • Impact of HER2 gene and protein status on the treatment outcome of cisplatin-based chemoradiotherapy for locally advanced non-small cell lung cancer. 国際誌

    Shoichi Kuyama, Katsuyuki Hotta, Masahiro Tabata, Yoshihiko Segawa, Yoshiro Fujiwara, Nagio Takigawa, Katsuyuki Kiura, Hiroshi Ueoka, Kenji Eguchi, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   3 ( 5 )   477 - 82   2008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)  

    BACKGROUND: It has not been fully evaluated whether both HER2 gene copy number and HER2 protein expression are related to the outcome of chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this study was to evaluate their relationships. METHODS: HER2 gene copy number determined by fluorescence in situ hybridization (FISH) and HER2 protein expression determined by immunohistochemistry (IHC) were assessed in 68 patients with LA-NSCLC enrolled in our previous phase II trials of concurrent cisplatin-based chemoradiotherapy, and a multivariate analysis was conducted for response and survival. RESULTS: HER2-IHC-positive tumors were detected in 23 patients (34%), and the median ratio of HER2 to chromosome 17 copy number was 0.93 (range, 0.55-2.00). The HER2-FISH results were marginally correlated with the IHC results (p = 0.0715). When the median ratio in the FISH analysis was used as a cut-off level for its positivity, there was no association between either HER2-FISH or IHC status and objective response to chemoradiotherapy. Contrary, a multivariate analysis revealed HER2-FISH result but not IHC result was an independent poor prognostic factor for both overall survival and progression-free survival (hazard ratio = 2.568, 95% confidence interval [CI] = 1.117-5.903, p = 0.0264 and hazard ratio = 2.283, 95% CI = 1.005-5.189, p = 0.0487, respectively). CONCLUSIONS: Patients with HER2 FISH-positive LA-NSCLC had a poorer outcome even when treated with cisplatin-based chemoradiotherapy, despite the strong need for validation assessment of these observations. Development of more effective treatment for these high-risk patients is needed to improve their poor prognosis.

    DOI: 10.1097/JTO.0b013e31816e2ea3

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  • Remarkable shrinkage of sarcomatoid renal cell carcinoma with single-agent gemcitabine. 国際誌

    Yoshiro Fujiwara, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Katsuyuki Hotta, Shigeki Umemura, Masako Omori, Kenichi Gemba, Hiroshi Ueoka, Mitsune Tanimoto

    Anti-cancer drugs   19 ( 4 )   431 - 3   2008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)  

    A 60-year-old Japanese man presented to our hospital with a painful left hip. Computed tomography showed a tumor in the left kidney and metastases in the left gluteus maximus muscle and lung. The pathological diagnosis of a biopsy specimen obtained from a metastatic lesion in the left gluteus maximus muscle was sarcomatoid renal cell carcinoma. On admission, his general condition was extremely poor. He was confined to bed because of severe left hip pain and confusion, possibly caused by hypercalcemia. This seriously ill patient suffering from advanced sarcomatoid renal cell carcinoma was treated with single-agent gemcitabine, resulting in symptom relief and a dramatic improvement in his status; all of the tumors had regressed significantly by the 11th dose of gemcitabine. These findings indicate that single-agent gemcitabine is one of the few chemotherapeutic agents effective for palliation in patients with sarcomatoid renal cell carcinoma, even those with poor performance status.

    DOI: 10.1097/CAD.0b013e3282f5d336

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  • Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib. 国際誌

    Yoshiro Fujiwara, Katsuyuki Kiura, Shinichi Toyooka, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Junichi Soh, Yasushi Tanimoto, Arihiko Kanehiro, Katsuya Kato, Hiroshi Date, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   59 ( 1 )   81 - 7   2008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)  

    PURPOSE: The factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases; however, it was first discovered as a lung cancer-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status. PATIENTS AND METHODS: Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods. RESULTS: The serum KL-6 levels ranged from 199 to 9080U/ml (median, 550U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p=0.040) as well as OS (hazard ratio: 4.858, p=0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p=0.0194). CONCLUSION: Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when treated with gefitinib.

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  • Point mutation of K-ras gene in cisplatin-induced lung tumours in A/J mice. 国際誌

    Akiko Hisamoto, Eisei Kondo, Katsuyuki Kiura, Toshiaki Okada, Shinobu Hosokawa, Junko Mimoto, Nagio Takigawa, Masahiro Tabata, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   58 ( 1 )   15 - 20   2007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)  

    The risks of secondary lung cancer in patients with early stage non-small and small cell lung cancers are estimated to be 1-2% and 2-10% per patient per year, respectively. Surprisingly, the incidence of second primary cancer in locally advanced non-small cell lung cancer at 10 years, following cisplatin-based chemotherapy with concurrent radiotherapy, increases to 61%. Those patients, on the road to being cured, cannot overlook the possibility of developing a second primary cancer. We developed a second primary lung cancer model using cisplatin as a carcinogen in A/J mice to screen for chemopreventive agents for a second malignancy. In the primary lung tumour model, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo(a)pyrene (BaP), urethane induces specific K-ras mutations in codon 12, codon 12, and codon 61, respectively, in the A/J mice. In this study, we investigated the mechanisms of carcinogenicity by cisplatin in the A/J mice. In the cisplatin-induced tumours, we found no K-ras codon 12 mutation, which is the major mutation induced by NNK or BaP. K-ras gene mutations in codon 13 and codon 61 were found in one tumour (4%) and five tumours (17.8%), respectively. These findings suggest that cisplatin is partially related to K-ras codon 61 mutations, and that the mechanism of carcinogenicity by cisplatin is different from that by NNK or BaP.

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  • Isolated metastasis of lung cancer to the thyroid gland. 国際誌

    Masahiro Osawa, Nagio Takigawa, Katsuyuki Kiura, Kouichi Ichimura, Junji Matsuoka, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   58 ( 1 )   156 - 8   2007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)  

    A 67-year-old man with lung cancer developed an isolated metastasis to the thyroid gland. The patient had undergone a right upper lobectomy, followed by chemotherapy consisting of cisplatin and etoposide based on post-surgical diagnosis of small cell lung cancer. Four years later, he had an isolated metastasis to the thyroid gland. The patient underwent a metastasectomy and adjuvant chemotherapy including cisplatin and irinotecan. The cancer cells in resected thyroid tumor had large nuclei and cytoplasm, and expressed the neuroendocrine markers, CD56 and chromogranin A. Retrospectively, the primary lung cancer consisted of both small cell and large cell cancer, and the latter was consistent with the pathological finding of the thyroid tumor. This is the first report to document an isolated recurrence of the lung cancer to the thyroid.

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  • Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung. 国際誌

    Toshiyuki Kozuki, Akiko Hisamoto, Masahiro Tabata, Nagio Takigawa, Katsuyuki Kiura, Yoshihiko Segawa, Masao Nakata, Koichi Mandai, Kenji Eguchi, Hiroshi Ueoka, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   58 ( 1 )   30 - 5   2007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)  

    Recently, a mutation of the epidermal growth factor receptor (EGFR) gene has been reported to be implicated in the development of pulmonary adenocarcinoma. However, the involvement of the mutation in atypical adenomatous hyperplasia (AAH) and multiple adenocarcinomas still remains unclear. We herein examined the EGFR mutations in 9 AAH and 31 adenocarcinoma lesions obtained from 30 Japanese patients. Nine patients had synchronous or metachronous multiple adenocarcinomas and/or AAH. Mutations in exons 18-21 of EGFR gene were analysed using polymerase chain reaction and direct sequence methods. EGFR mutations were detected in 4 (44%) of 9 AAH and in 7 (23%) of 31 adenocarcinomas. A gefitinib-resistant point mutation (T790M) in exon 20 without gefitinib treatment was detected in 1 AAH and 1 adenocarcinoma. The patient with T790M mutated AAH, which also had an exon 19 mutation of D761Y, had synchronous adenocarcinoma, which had only an exon 19 mutation of D761Y. The other exon 19 mutations were all in-frame deletions. In the two patients with synchronous AAH and adenocarcinoma, AAH had mutations at exon 19 although adenocarcinoma did not have any mutations. In the patient with synchronous 2 adenocarcinomas, each had different mutations (exons 19 and 21). In two patients with double adenocarcinomas, 1 adenocarcinoma harbored exon 21 mutations, while the other demonstrated no mutations. Although EGFR mutations appeared to be partially associated with the early steps of adenocarcinoma development, such mutations may possibly occur randomly even in multiple lesions in a single patient.

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  • Presentation of Garcin syndrome due to lung cancer. 国際誌

    Masanori Fujii, Katsuyuki Kiura, Nagio Takigawa, Tetsuya Yumoto, Yoshihide Sehara, Masahiro Tabata, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2 ( 9 )   877 - 8   2007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)  

    Garcin syndrome consists of unilateral palsies of almost all cranial nerves without either sensory or motor long-tract disturbances and without intracranial hypertension, and it is caused by a malignant osteoclastic lesion at the skull base. A 60-year-old woman presented with dizziness and left facial palsy. Progressive left cranial nerve palsies developed over 2 months until gadolinium-enhanced magnetic resonance imaging of the brain revealed an intracranial extension of a tumor from the left skull base. A systemic survey revealed adenocarcinoma of the lung, which had metastasized along the skull base. We experienced a rare case of Garcin syndrome due to skull base metastases from lung cancer.

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  • Serum level of arginine-vasopressin influences the prognosis of extensive-disease small-cell lung cancer. 国際誌

    Shigeki Umemura, Yoshihiko Segawa, Hiroshi Ueoka, Katsuyuki Hotta, Katsuyuki Kiura, Nagio Takigawa, Masahiro Tabata, Akihiro Bessho, Tetsu Shinkai, Mitsune Tanimoto

    Journal of cancer research and clinical oncology   133 ( 8 )   519 - 24   2007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)  

    PURPOSE: The purpose of this study is to elucidate the influence of serum arginine-vasopressin (AVP) level on prognosis of extensive-disease small-cell lung cancer (ED-SCLC). METHODS: We retrospectively investigated the clinical records of 163 patients with ED-SCLC, who were admitted to Okayama University Hospital or National Shikoku Cancer Center Hospital. The influence of 14 pretreatment variables on survival was analyzed. RESULTS: In a multivariate analysis of 163 patients, elevation of serum LDH level (P = 0.028) and poor performance status (PS > or = 2, P = 0.002) were independent poor prognostic factors. In 34 patients whose serum AVP levels were available, high serum AVP level was related to the poor prognosis (P < 0.001). The serum-sodium level did not affect the survival. Median serum level of osmotic pressure in 34 patients was normal (284.9 mOsm/kg), although, serum osmotic pressure was low in four of six patients with high serum AVP level. In all patients with high serum AVP level, serum LDH level was elevated. CONCLUSIONS: The data from the current study suggested that serum LDH level and PS were the poor prognostic factors for ED-SCLC. But we additionally identified the prognostic significance of serum AVP level, which may be a more useful factor than serum-sodium level.

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  • Radiation necrosis mimicking progressive brain metastasis in a patient with non-small cell lung cancer. 国際誌

    Kadoaki Ohashi, Kastuyuki Kiura, Nagio Takigawa, Shigeki Umemura, Naruhito Kondo, Mistuhiro Takemoto, Kensuke Onoda, Motoi Aoe, Masahiro Tabata, Mistune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2 ( 8 )   762 - 3   2007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)  

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  • Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after first-line cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Shinichi Toyooka, Nagio Takigawa, Junichi Soh, Yoshiro Fujiwara, Masahiro Tabata, Hiroshi Date, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2 ( 7 )   632 - 7   2007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)  

    INTRODUCTION: The relationship between the EGFR gene mutation status and clinical outcome has not fully been assessed in patients with non-small cell lung cancer (NSCLC) who received cytotoxic agents. The aim of this study was to clarify its association. We also examined whether this association could be affected by previous gefitinib treatment. METHODS: Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy in their treatment course were included in this study. An EGFR mutation was determined in exons 19 and 21 by direct sequencing. RESULTS: Of 194 Japanese patients with advanced or relapsed NSCLC assessable for mutation analysis, 60 received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment courses. EGFR mutations significantly affected progression-free survival (PFS) in the first-line cytotoxic chemotherapy regimens in the multivariate analysis (hazard ratio for PFS = 0.422; p = 0.0422). In contrast, in 28 (47%) of the 60 patients who also received cytotoxic chemotherapy after the relapse to gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status, and its sensitivity was retained even in the second-line treatment setting in patients with EGFR mutations. CONCLUSIONS: EGFR mutations were therefore significantly associated with a better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, whereas gefitinib sensitivity was associated with an EGFR mutation even in the second-line or later treatment settings.

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  • A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study. 国際誌

    Masahiro Tabata, Toshiyuki Kozuki, Hiroshi Ueoka, Katsuyuki Kiura, Shingo Harita, Atsuhiko Tada, Takuo Shibayama, Nagio Takigawa, Toshiro Yonei, Kenichi Gemba, Yoshihiko Segawa, Daizo Kishino, Shinya Tada, Shunkichi Hiraki, Mitsune Tanimoto

    Cancer chemotherapy and pharmacology   60 ( 1 )   53 - 9   2007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)  

    PURPOSE: We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m(2) and 30 mg/m(2), respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m(2) was conducted and primary objective in the phase II portion was response rate. RESULTS: The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m(2) because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C (max) and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. CONCLUSION: These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.

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  • A phase II trial of cisplatin and irinotecan alternating with doxorubicin, cyclophosphamide and etoposide in previously untreated patients with extensive-disease small-cell lung cancer. 国際誌

    Masahiro Tabata, Katsuyuki Kiura, Niro Okimoto, Yoshihiko Segawa, Tetsu Shinkai, Toshiro Yonei, Shoichi Kuyama, Shingo Harita, Katsuyuki Hotta, Hiroshi Ueoka, Mitsune Tanimoto

    Cancer chemotherapy and pharmacology   60 ( 1 )   1 - 6   2007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)  

    PURPOSE: The aim of this trial was to investigate the efficacy and safety of cisplatin (P) and irinotecan (I) (PI) alternating with doxorubicin (A), cyclophosphamide (C) and etoposide (E) (ACE) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Patients with previously untreated ED-SCLC were enrolled in this trial. In the first, third and fifth cycles, PI (P: 60 mg/m(2) on day 1; I: 60 mg/m(2)/day on days 1, 8 and 15) was administered, whereas ACE (A: 50 mg/m(2) on day 1; C: 750 mg/m(2) on day 1; E 80 mg/m(2)/day on days 1-3) was given in the second, fourth and sixth cycles. Each cycle was repeated every 4 weeks. At the end of six cycles, patients who had obtained a complete response were given prophylactic cranial irradiation. RESULTS: In total, 28 patients were enrolled, of whom 27 were assessable for efficacy and safety. Objective responses, including 4 (15%) complete responses, were observed in 25 patients (93%). Median survival time was 12.9 months. The principal toxicity was myelosuppression; grade 4 neutropenia and thrombocytopenia were observed in 89 and 4%, respectively. Febrile neutropenia occurred in 30% of patients. Diarrhea was mild (grade 3-4; 4%). All toxicities were reversible and there were no treatment-related deaths. The mean percentage of the delivered doses, relative to the projected doses, of PI and ACE were 84.6 and 91.1%, respectively. CONCLUSIONS: These results indicate the PI-ACE regimen to have promising activity against ED-SCLC with moderate toxicities.

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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)  

    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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  • Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials. 国際誌

    Katsuyuki Hotta, Yoshiro Fujiwara, Katsuyuki Kiura, Nagio Takigawa, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2 ( 5 )   402 - 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)  

    BACKGROUND: The association between the objective response to chemotherapy and survival has not yet been fully evaluated using large cohorts in advanced non-small cell lung cancer. METHODS: We searched for phase III trials conducted between 1991 and 2006 to investigate the role of systemic chemotherapy for advanced non-small cell lung cancer. Associations were tested by multiple regression analysis. RESULTS: Of the 1255 trials screened, 143 met our criteria, involving 50,569 patients with 309 chemotherapy regimens. In the first-line setting, the median intention-to-treat objective response rate (ORR) and disease control rate (DCR) were 26.4% and 62.5%, respectively (43,551 randomized patients; 290 trials). The median of the median survival time (MST) was 8.5 months in the first-line setting, and both the ORR and DCR were significantly associated with the MST in the multivariate analysis (regression coefficient = 0.0788 [p < 0.0001] and 0.0794 [p < 0.0001], respectively). Subgroup analysis showed no correlation between the ORR and MST in patients receiving chemotherapy containing molecular-targeted agents (p = 0.3817). In the second-line or later setting, the median ORR was only 6.8%, whereas the median DCR was 42.4% (4318 randomized patients; 19 trials). The median MST (6.6 months) was not associated with the ORR (p = 0.6992), but was associated with the DCR (p = 0.0129), despite the small sample size. CONCLUSIONS: We found that survival was associated with both the ORR and DCR in the first-line setting, although it should be interpreted cautiously because of the abstracted data-based analysis. Regarding chemotherapy regimens containing molecular-targeted agents and salvage chemotherapy regimens, further assessments are warranted to clarify the association between the parameters.

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  • Recent improvement in the survival of patients with advanced nonsmall cell lung cancer enrolled in phase III trials of first-line, systemic chemotherapy. 国際誌

    Katsuyuki Hotta, Yoshiro Fujiwara, Keitaro Matsuo, Takeshi Suzuki, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Hiroshi Ueoka, Mitsune Tanimoto

    Cancer   109 ( 5 )   939 - 48   2007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)  

    BACKGROUND: Few studies have assessed formally whether treatment outcomes have improved substantially over the years for patients with advanced nonsmall cell lung cancer (NSCLC) enrolled in Phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials. METHODS: The literature was searched to identify trials that addressed the role of chemotherapy regimens in the first-line setting for the treatment of advanced NSCLC. Trends were tested by using multiple regression analysis. RESULTS: In total, 121 Phase III trials were identified that involved 42,768 patients with 263 chemotherapy arms and 11 best supportive care (BSC) arms, all of which were initiated between 1982 and 2002. Although the number of randomized patients and the proportion of patients with metastatic disease had increased over the years, the number of patients with a poor performance status who were accrued into the trials had decreased. Cisplatin-based chemotherapy was been investigated most frequently during the period. The multiple regression analysis revealed a significant improvement in median survival and in the median time to disease progression over the years, with annual prolongations of 0.1203 months (3.609 days) and 0.0617 months (1.851 days), respectively (P< .0001 and P < .0130, respectively). In addition, the use of cisplatin and carboplatin was associated significantly with survival prolongation. The median survival for patients who received BSC also increased progressively over the years (P = .0487). CONCLUSIONS: The survival of patients with NSCLC in Phase III trials improved slowly but steadily over time, although the main factors responsible for this improvement remain unknown. Nonetheless, the current results also suggested that novel targets and new agents will be required in the future fight against advanced NSCLC.

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  • Being overweight influences the development of hepatic dysfunction in Japanese patients with non-small-cell lung cancer undergoing cytotoxic chemotherapy. 国際誌

    Yoshiro Fujiwara, Katsuyuki Kiura, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   55 ( 3 )   343 - 8   2007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)  

    PURPOSE: The aim of this study was to identify risk factors for hepatic dysfunction during cytotoxic chemotherapy in Japanese patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively reviewed the medical records of patients with NSCLC who received cytotoxic chemotherapy at Okayama University Hospital between January 2003 and March 2006. "Overweight" was defined as a body mass index (BMI) of 25 or more, according to the World Health Organization (WHO) criteria. We investigated the incidence and pattern of hepatic dysfunction during chemotherapy and evaluated the possible associations between hepatic dysfunction and several clinical factors, including BMI. RESULTS: Of the 155 Japanese patients enrolled in this study, 19 (12%) were overweight. Grade 2 or worse hepatic dysfunction was observed in 5 of the 19 overweight patients (26%) but in only 13 of the 136 non-overweight patients (10%). A multivariate analysis demonstrated that a higher BMI significantly increased the risk of grade 2 or worse hepatic dysfunction after the initiation of cytotoxic chemotherapy (odds ratio=4.04, 95% confidence intervals: 1.13-14.5, p=0.032). CONCLUSION: Our data suggest that being overweight can influence the development of hepatic dysfunction in Japanese patients receiving cytotoxic chemotherapy for the treatment of NSCLC, although further investigation is required.

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  • Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation. 国際誌

    Akiko Uchida, Seiki Hirano, Hiroyuki Kitao, Atsuko Ogino, Kanmei Rai, Shinichi Toyooka, Nagio Takigawa, Masahiro Tabata, Minoru Takata, Katsuyuki Kiura, Mitsune Tanimoto

    Cancer science   98 ( 3 )   357 - 63   2007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)  

    Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.

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  • Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation. 国際誌

    Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Toshiyuki Kozuki, Akiko Hisamoto, Hideki Katayama, Nagio Takigawa, Nobukazu Fujimoto, Keiichi Fujiwara, Hiroshi Ueoka, Mitsune Tanimoto

    Oncology reports   17 ( 2 )   313 - 7   2007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)  

    Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.

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  • Triple combination chemotherapy with cisplatin, docetaxel, and irinotecan for advanced non-small cell lung cancer: a phase I/II trial. 国際誌

    Katsuyuki Kiura, Nagio Takigawa, Yoshihiko Segawa, Masahiro Tabata, Takuo Shibayama, Kenichi Gemba, Akihiro Bessho, Nobukazu Fujimoto, Ichiro Takata, Katsuyuki Hotta, Keiichi Fujiwara, Yoshiyuki Tokuda, Shoichi Kuyama, Tetsu Shinkai, Hiroshi Ueoka, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   2 ( 1 )   44 - 50   2007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)  

    BACKGROUND: To determine the recommended dose and evaluate the response rate and toxicity of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for non-small cell lung cancer (NSCLC) patients with stage IIIB or IV. METHODS: A total of 65 patients (33 men and 32 women) with advanced NSCLC, a good performance status, and 65 years of age or younger were included in these phase I/II studies. The median age was 52 years. Most patients had performance status 1 (49/65) and stage IV disease (49/65). Adenocarcinoma was the most common tumor histology (55 patients). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2; the cycles were repeated every 3 weeks. RESULTS: In the phase I study, the maximum tolerated doses of combination cisplatin/docetaxel/irinotecan were, respectively, 80/60/60 (mg/m) and the recommended doses for the phase II study were determined to be 60/60/60 (mg/m), respectively. The dose-limiting toxicities were neutropenia, neutropenic fever, and diarrhea. In the phase II study, 157 cycles of chemotherapy were delivered to 49 patients (median three cycles per patient). The objective response rate was 57.1% (95% confidence interval: 43.1%-71.1%). The median survival time and the actual 2-, 3- and estimated 5-year survival rates were 17 months, 33%, 25%, and 18%, respectively. Grade 3/4 toxicities consisted of neutropenia (92%), neutropenic fever (45%), nausea/vomiting (27%), diarrhea (35%), and hepatic toxicity (2%); there were no cases of treatment-related death. CONCLUSION: This triplet chemotherapy has shown a promising activity against advanced NSCLC according to admission-based treatment with adequate supportive care. The principal toxicity was neutropenic fever, but supportive care should be explored to reduce this incidence.

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  • Fractionated administration of irinotecan and cisplatin in Japanese patients with extensive-stage-disease small-cell lung cancer. 国際誌

    Nagio Takigawa, Katsuyuki Kiura, Masahiro Tabata, Mitsune Tanimoto

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   24 ( 32 )   5175; author reply 5175-6   2006年11月

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    記述言語:英語  

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  • Clinical factors affecting acquired resistance to gefitinib in previously treated Japanese patients with advanced nonsmall cell lung cancer. 国際誌

    Yoshihiko Segawa, Katsuyuki Hotta, Shigeki Umemura, Yoshiro Fujiwara, Tetsu Shinkai, Hiroshi Ueoka, Nagio Takigawa, Masahiro Tabata, Katsuyuki Kiura, Mitsune Tanimoto

    Cancer   107 ( 8 )   1866 - 72   2006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)  

    BACKGROUND: The risk factors for the development of acquired resistance in nonsmall cell lung cancer (NSCLC) patients responding to gefitinib are unclear. The current study assessed clinicopathologic factors affecting acquired resistance to gefitinib in previously treated patients with advanced NSCLC. METHODS: Between 2000 and 2004, 197 consecutive Japanese patients with advanced NSCLC underwent treatment with gefitinib. Of these patients, 56 who had continued gefitinib treatment without disease progression for at least 6 months were included in the study. RESULTS: At a median follow-up time of 21.6 months (range, 7.7-59.7 months), the median time to disease progression was 19.5 months, with progression-free survival rates of 68.5% at 1 year, 33.6% at 2 years, and 21.2% at 3 years. In a multivariate analysis using a Cox regression model, baseline brain metastasis was the strongest prognostic factor affecting acquired resistance to gefitinib (hazards ratio, 2.14; 95% confidence interval, 1.10- 4.17 [P = .025]). In addition, a decreased baseline hemoglobin level (P = .074) and the administration of >1 chemotherapy regimen before gefitinib treatment (P = .069) tended to be significant negative prognostic factors. CONCLUSIONS: In patients undergoing treatment with gefitinib, the presence of brain metastasis was strongly associated with the emergence of acquired resistance in the current series of NSCLC patients. The finding requires confirmation in a large cohort of patients with advanced NSCLC, including a non-Japanese/Asian population.

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  • Severe interstitial pneumonia induced by paclitaxel in a patient with adenocarcinoma of the lung.

    Noriyuki Suzaki, Akio Hiraki, Nagio Takigawa, Hiroshi Ueoka, Yasushi Tanimoto, Toshiyuki Kozuki, Masahiro Tabata, Arihiko Kanehiro, Katsuyuki Kiura, Mitsune Tanimoto

    Acta medica Okayama   60 ( 5 )   295 - 8   2006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)  

    A 71-year-old Japanese man with adenocarcinoma of the lung developed interstitial pneumonia after treatment with paclitaxel. The patient had acute chills and fever on the fourth day after the second exposure to paclitaxel, rapidly got worse despite empiric therapies, and developed prolonged respiratory failure requiring mechanical ventilation. Four months later, he died of respiratory failure due to progression of both interstitial pneumonia and lung cancer. This is the first case developing fatal paclitaxel-induced pulmonary toxicity to date. Interstitial pneumonia should be considered one of the possible life-threatening complications during treatment with paclitaxel.

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  • A phase I and pharmacological study of amrubicin and topotecan in patients of small-cell lung cancer with relapsed or extensive-disease small-cell lung cancer. 国際誌

    Takuo Shibayama, Katsuyuki Hotta, Nagio Takigawa, Atsuhiko Tada, Hiroshi Ueoka, Shingo Harita, Katsuyuki Kiura, Masahiro Tabata, Yoshihiko Segawa, Naoyuki Nogami, Shoichi Kuyama, Tetsu Shinkai, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   53 ( 2 )   189 - 95   2006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)  

    Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.

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  • Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. 国際誌

    Masaki Tokumo, Shinichi Toyooka, Shuji Ichihara, Kadoaki Ohashi, Kazunori Tsukuda, Kouichi Ichimura, Masahiro Tabata, Katsuyuki Kiura, Motoi Aoe, Yoshifumi Sano, Hiroshi Date, Nobuyoshi Shimizu

    Lung cancer (Amsterdam, Netherlands)   53 ( 1 )   117 - 21   2006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)  

    Mutations of the epidermal growth factor receptor (EGFR) gene have been reported in non-small-cell lung cancer (NSCLC), especially in patients with adenocarcinoma and never smokers. Some common somatic mutations in EGFR, including deletion mutations in exon 19 and leucine-to-arginine substitution at amino acid position 858 (L858R) in exon 21, have been examined for their ability to predict sensitivity to gefitinib or erlotinib, which are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). On the other hand, reports have shown that the threonine-to-methionine substitution at amino acid position 790 (T790M) in exon 20 is related to gefitinib resistance. Some studies have indicated that high copy numbers of the EGFR gene may be a more effective molecular predictor to responsiveness and prolonged survival in patients treated with EGFR-TKIs. Here, we describe two NSCLC patients with the L858R mutation who did not respond to gefitinib. Case 1 harbored both the T790M and L858R mutations, and fluorescence in situ hybridization showed EGFR gene amplification. Case 2 harbored both the L858R and aspartic acid-to-tyrosine substitution at amino acid position 761 in exon 19 of EGFR mutations and had a high polysomy status for EGFR. In these two cases, tumors showed resistance to gefitinib treatment despite the presence of EGFR L858R mutation and increased copy number. Our findings encourage further molecular analysis to elucidate the relationship between the EGFR status, including mutations and amplifications, and the responsiveness of NSCLC to gefitinib.

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  • A phase I study of 3-day topotecan and cisplatin in elderly patients with small-cell lung cancer. 国際誌

    Keiichi Fujiwara, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Katsuyuki Hotta, Shigeki Umemura, Keisuke Sugimoto, Takuo Shibayama, Haruhito Kamei, Shingo Harita, Niro Okimoto, Mitsune Tanimoto

    Cancer chemotherapy and pharmacology   57 ( 6 )   755 - 60   2006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)  

    PURPOSE: The aim of this phase I study was to determine the maximum-tolerated dose (MTD) in elderly patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients aged over 75 years with previously untreated SCLC were enrolled in this study. Both topotecan and cisplatin were administered on days 1-3 and repeated every 3 weeks. The starting dose of topotecan was 0.5 mg/m2/day, while cisplatin was fixed at the dose of 20 mg/m2/day. Patients with limited disease (LD) SCLC received thoracic irradiation after the completion of chemotherapy. RESULTS: Twenty-one elderly patients were enrolled in this study and received a total of 59 cycles. The major hematological toxicity was neutropenia and non-hematological toxicities including diarrhea were generally mild and reversible. The MTD of topotecan was determined as 1.2 mg/m2/day. The recommended phase II study dose of topotecan was determined as 1.0 mg/m2/day with cisplatin 20 mg/m2/day daily for 3 days. An objective response was observed in 6 of 10 patients (60%) with LD-SCLC and 6 of 11 (55%) with extensive disease (ED) SCLC. The median survival time in patients with LD-SCLC and those with ED-SCLC were 16.0 and 11.0 months, respectively. CONCLUSION: The combination chemotherapy of 3-day topotecan and cisplatin appears to be tolerable and effective in elderly patients with SCLC.

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  • Recent improvement in lung cancer screening: a comparison of the results carried out in two different time periods.

    Takuji Kitajima, Kenji Nishii, Hiroshi Ueoka, Takuo Shibayama, Kenichi Gemba, Tsuyoshi Kodani, Katsuyuki Kiura, Masahiro Tabata, Katsuyuki Hotta, Mitsune Tanimoto, Tomotaka Sobue

    Acta medica Okayama   60 ( 3 )   173 - 9   2006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)  

    To evaluate recent improvements in lung cancer screening, we compared the results of recently conducted lung cancer screening with those of a previous screening. This study compared the survival of lung cancer patients detected by lung cancer screening conducted between 1976 and 1984 (early period) with that conducted between 1989 and 1997 (late period). Two hundred seventy-six patients with lung cancer were detected in the early period and 541 patients with lung cancer were detected in the late period. The median survival time (late : 49.8 vs. early : 27.8 months) and the 5-year survival rate (late : 47.8 vs. early : 34.8%) of the patients with lung cancer detected in the late period were significantly better than those in the early period (p = 0.0054). Among patients undergoing resection, the proportion of pathological stage I patients in the late period was significantly higher than that in the early period (late : 60.8 vs. early : 54.9%, p = 0.005). Multivariate analysis showed that the screening time period was a significant prognostic factor (hazard ratio = 0.685, 95% confidence interval : 0.563-0.832, p = 0.0002). These results were consistent with the findings of case-control studies of lung cancer screening programs in the late period recently conducted in Japan, which also showed a greater efficacy for screening than for previous case-control studies in the early period.

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  • Clustered incidence of acute promyelocytic leukemia during gefitinib treatment for non-small-cell lung cancer: experience at a single institution. 国際誌

    Keitaro Matsuo, Katsuyuki Kiura, Masahiro Tabata, Akiko Uchida, Katsuyuki Hotta, Daigo Niiya, Shiro Kubonishi, Atsuko Ogino, Yoshiro Fujiwara, Hiromi Nakajima, Katsuji Shinagawa, Fumihiko Ishimaru, Hiroshi Ueoka, Mitsune Tanimoto

    American journal of hematology   81 ( 5 )   349 - 54   2006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)  

    Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.

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  • Relationship between epidermal growth factor receptor gene mutations and the severity of adverse events by gefitinib in patients with advanced non-small cell lung cancer. 国際誌

    Yoshiro Fujiwara, Katsuyuki Kiura, Shinichi Toyooka, Nagio Takigawa, Masaki Tokumo, Katsuyuki Hotta, Motoi Aoe, Masahiro Tabata, Keitaro Matsuo, Hiroshi Date, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   52 ( 1 )   99 - 103   2006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)  

    PURPOSE: Recent reports have demonstrated that mutation of epidermal growth factor receptor (EGFR) gene is predictive factor for tumor responsiveness to gefitinib suggesting the importance of EGFR status for the treatment of the patients with non-small cell lung cancer (NSCLC). However, the relationship between EGFR mutation and adverse events of gefitinib is still unknown. The aim of this study was to evaluate its correlation. PATIENTS AND METHODS: Twenty-six tumor samples from Japanese NSCLC patients who received gefitinib in Okayama University Hospital between November 2000 and October 2004 were examined exons 18-21 of EGFR using direct sequence method. We retrospectively reviewed the clinical records and compared EGFR mutation status with adverse events during gefitinib treatment. RESULTS: Of all 26 patients, EGFR mutation (exon 19 in-frame deletion, 6; exon 21 L858R, 5), were detected in 11 patients (42.3%). The principal adverse event was skin rash (89%), diarrhea (39%), and liver injury (39%). Grade 3 or more adverse events were not common. EGFR mutation status was correlated with neither its frequency nor severity of adverse events during gefitinib treatment including skin rash, diarrhea, liver injury, and interstitial lung disease. As expected, objective response rate of those with EGFR mutations was significantly higher than those without EGFR mutations (78% versus 21%, P<0.001). CONCLUSION: Our study did not demonstrate the presence of close relationships between EGFR mutation status and adverse events during gefitinib treatment.

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  • The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells. 国際誌

    Nagio Takigawa, Masako Takeyama, Takuo Shibayama, Atsuhiko Tada, Noriko Kawata, Chiharu Okada, Keisuke Aoe, Toshiyuki Kozuki, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura, Hiroshi Ueoka, Mitsune Tanimoto, Kiyoshi Takahashi

    Oncology reports   15 ( 4 )   837 - 42   2006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)  

    The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

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  • Induction chemotherapy, surgical resection, and high-dose chemotherapy for mediastinal nonseminomatous germ-cell tumor. 国際誌

    Hiroshi Date, Kiura Katsuyuki, Hiroshi Ueoka, Masahiro Tabata, Katsuyuki Hotta, Hideki Katayama, Itaru Kataoka, Mitsune Tanimoto

    The Journal of thoracic and cardiovascular surgery   130 ( 4 )   1205 - 6   2005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)  

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  • Systemic tumor embolism mimicking gefitinib ('IRESSA')-induced interstitial lung disease in a patient with lung cancer.

    Shigeki Umemura, Daizo Kishino, Masahiro Tabata, Katsuyuki Kiura, Katsuyuki Hotta, Kenji Nishii, Yasushi Tanimoto, Arihiko Kanehiro, Kenji Notohara, Hiroshi Ueoka, Mitsune Tanimoto

    Internal medicine (Tokyo, Japan)   44 ( 9 )   979 - 82   2005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)  

    We describe a 55-year-old man with advanced adenocarcinoma of the lung who received gefitinib ('IRESSA'). After gefitinib administration for 7 months, computed tomography scan of the chest demonstrated diffuse ground glass opacity and he was suspected to have developed gefitinib-induced interstitial lung disease (ILD). However, transbronchial lung biopsy (TBLB) revealed tumor cells in the middle-size lung vessels. Afterwards, multiple infarctions of the brain, spleen and left kidney were detected. Then, he was considered to have developed systemic tumor emboli, a rare complication. The clinical presentation of this patient was difficult to discriminate from that of ILD, and TBLB was useful in the differential diagnosis.

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  • Serum hemoglobin level determined at the first presentation is a poor prognostic indicator in patients with lung cancer.

    Keisuke Aoe, Akio Hiraki, Tadashi Maeda, Hideki Katayama, Keiichi Fujiwara, Masahiro Tabata, Katsuyuki Kiura, Hiroshi Ueoka, Mitsune Tanimoto

    Internal medicine (Tokyo, Japan)   44 ( 8 )   800 - 4   2005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)  

    OBJECTIVES: Anemia is observed in various malignancies including lung cancer and is recently considered to be a poor prognostic indicator. We investigated whether there is a correlation between anemia, other clinicopathologic factors, and survival. METHODS: We retrospectively examined the clinical records of 611 patients with lung cancer. RESULTS: Of those, 298 (48.8%) patients had anemia at the time of their first visit to our hospital. There was a significant correlation between anemia and age (p=0.0006) or ECOG performance status (p=0.0002), however, there was no correlation of anemia with gender, histological type, clinical stage, or serum level of lactate dehydrogenase. Survival was significantly shorter in 298 patients with anemia (median survival time (MST): 7.5 months) compared with 313 patients without anemia (MST: 11.8 months, p<0.0001). Multivariate analysis of prognostic factors using the Cox proportional hazards model revealed that anemia appeared to be an independent prognostic indicator. CONCLUSION: Anemia observed at the first presentation is an independent poor prognostic indicator in patients with lung cancer.

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  • Successful treatment of pulmonary artery sarcoma by a two-drug combination chemotherapy consisting of ifosfamide and epirubicin. 国際誌

    Akiko Uchida, Masahiro Tabata, Katsuyuki Kiura, Yasushi Tanimoto, Arihiko Kanehiro, Motoi Aoe, Nobuya Ohohara, Hiroshi Ueoka, Mitsune Tanimoto

    Japanese journal of clinical oncology   35 ( 7 )   417 - 9   2005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)  

    We describe a case of 63-year-old woman with pulmonary artery sarcoma successfully treated with chemotherapy. She developed acute shortness of breath, and left chest and shoulder pain. Although a diagnosis of acute pulmonary embolism was made at a local hospital and she received anticoagulation and thrombolysis therapy, no improvement was achieved. Thereafter, she underwent a pulmonary thromboectomy in our hospital, and the histological diagnosis was intimal sarcoma of the pulmonary artery. Since post-operative computed tomography (CT) scans of the chest showed obvious persistence of an intraluminal hypoattenuated area in the left main pulmonary artery, the patient was treated with four cycles of a doublet chemotherapy consisting of ifosfamide (2.5 g/m(2)/day) on days 1-5 and epirubicin (45 mg/m(2)/day) on days 2 and 3. CT scans of the chest after four cycles showed marked regression of the intraluminal hypoattenuated area in the left main pulmonary artery. This is the first case of pulmonary artery sarcoma responding to chemotherapy. Surgical resection is currently the most hopeful treatment for pulmonary artery sarcoma. However, intensive chemotherapy is worth trying in unresectable patients.

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  • Complexity in the treatment of pulmonary large cell neuroendocrine carcinoma. 国際誌

    Toshiyuki Kozuki, Nobukazu Fujimoto, Hiroshi Ueoka, Katsuyuki Kiura, Keiichi Fujiwara, Katsuhiko Shiomi, Koichi Mizobuchi, Masahiro Tabata, Shuji Hamazaki, Mitsune Tanimoto

    Journal of cancer research and clinical oncology   131 ( 3 )   147 - 51   2005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)  

    PURPOSE: According to the World Health Organization (WHO) classification of pulmonary large cell neuroendocrine carcinoma (LCNEC), one of the neuroendocrine tumors of the lung, is considered as a variant of non-small cell lung carcinoma. The objective of this study was to investigate the treatment strategy for LCNEC. METHODS: We retrospectively reviewed the clinical information of 12 patients with LCNEC. RESULTS: Three patients with stage I disease underwent curative resection but all relapsed within 20 months. One with stage IIA disease underwent non-curative resection received adjuvant chemoradiotherapy (cisplatin plus etoposide) and is well with no evidence of recurrence. Two with stage IIIB disease received concurrent chemoradiotherapy. Both achieved partial response (PR) but relapsed within 2 months. One elderly patient with stage IIIA disease received vinorelbine alone and did not respond. Of five patients with stage IV disease, three received platinum-based chemotherapy but no patient achieved PR. Of five patients with gefitinib as salvage therapy, one achieved PR. CONCLUSIONS: The prognosis of LCNEC is poor. To improve the outcome, we must evaluate the effectiveness of adjuvant or neoadjuvant therapy in patients with resectable disease. In addition, the evaluation of systemic and multimodality treatment strategies similar as in small cell lung cancer is worthy of consideration.

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  • The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. 国際誌

    Masaki Tokumo, Shinichi Toyooka, Katsuyuki Kiura, Hisayuki Shigematsu, Kunitoshi Tomii, Motoi Aoe, Kouichi Ichimura, Toshihide Tsuda, Masaaki Yano, Kazunori Tsukuda, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto, Hiroshi Date, Adi F Gazdar, Nobuyoshi Shimizu

    Clinical cancer research : an official journal of the American Association for Cancer Research   11 ( 3 )   1167 - 73   2005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)  

    PURPOSE: Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features. EXPERIMENTAL DESIGN: EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters. RESULTS: EGFR mutations were present in 38 cases (32%) and the majority of mutations were in-frame deletions of exon 19 (19 cases) and a missense mutation in exon 21 (18 cases). EGFR mutations were frequently associated with adenocarcinoma (P < 0.0001), never smoker (P < 0.0001), and female gender (P = 0.0001). Of interest, increasing smoke exposure was inversely related to the rate of EGFR mutation (P < 0.0001). Multivariate analysis showed that smoking and histology were independent variables. Furthermore, gender difference was observed for the mutational location (P = 0.01) dominance of exon 19 for males and exon 21 for females. Twenty-one cases were treated with gefitinib and found that EGFR mutation was significantly related to gefitinib responsiveness (P = 0.002). In addition, median survival times of patients with and without EGFR mutations treated with gefitinib were 25.1 and 14.0 months, respectively. Patients with EGFR mutations had approximately 2-fold survival advantage; however, the difference was not significant. CONCLUSIONS: We show that EGFR mutations were significantly related to histology and smoke exposure and were a strong predictive factor for gefitinib responsiveness in NSCLC.

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  • Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer. 国際誌

    Keiichi Fujiwara, Nobukazu Fujimoto, Masahiro Tabata, Kenji Nishii, Keitaro Matsuo, Katsuyuki Hotta, Toshiyuki Kozuki, Motoi Aoe, Katsuyuki Kiura, Hiroshi Ueoka, Mitsune Tanimoto

    Clinical cancer research : an official journal of the American Association for Cancer Research   11 ( 3 )   1219 - 25   2005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)  

    PURPOSE: The purpose of this study is to evaluate the usefulness of serum DNA methylation of five tumor suppressor genes for early detection of lung cancer. EXPERIMENTAL DESIGN: Methylation status in serum DNA from 200 patients undergoing bronchofiberscopic examination for abnormal findings on chest radiograph detected by lung cancer screening or surveillance was examined using methylation-specific PCR. RESULTS: Ninety-one patients were given a pathologic diagnosis of lung cancer, 9 other malignant diseases, and 100 nonmalignant pulmonary diseases. In patients with lung cancer, methylation was detected in 18.7% for MGMT, 15.4% for p16(INK4a), 12.1% for RASSF1A, 11.0% for DAPK, and 6.6% for RAR-beta, which was higher compared with that in patients with nonmalignant diseases. Age and smoking status seemed to associate with methylation status. Sensitivity, specificity, and predictive value of methylation in at least one gene for diagnosis of lung cancer were 49.5%, 85.0%, and 75.0%, respectively. Adjusted odds ratio (95% confidence interval) for having lung cancer was 5.28 (2.39-11.7) for patients with methylation in one gene and 5.89 (1.53-22.7) for those with methylation in two or more genes. It is of note that methylation was identified in 50.9% of stage I lung cancer patients, whereas serum protein tumor markers were positive in 11.3% of them. CONCLUSIONS: These results suggest that identification of promoter methylation of tumor suppressor genes in serum DNA could be useful for early detection of lung cancer.

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  • Safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience. 国際誌

    Katsuyuki Hotta, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Atsuko Ogino, Shigeki Umemura, Shingo Harita, Kenichi Gemba, Toshiro Yonei, Akihiro Bessho, Tadashi Maeda, Mitsune Tanimoto

    Acta oncologica (Stockholm, Sweden)   44 ( 7 )   717 - 22   2005年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We evaluated the safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer (NSCLC). We retrospectively compared toxicity, response and survival outcomes for gefitinib in patients aged 75 years or older (elderly group) with the same outcomes in patients aged younger than 75 years. In total, 350 patients were eligible for this analysis, of whom 92 were in the elderly group and 258 in the non-elderly group. In the elderly group, adverse events were generally mild to moderate and grade 3-4 adverse events were observed in 8 (9%) patients. The objective response rate (17 vs. 21% for elderly vs. non-elderly, respectively) and median survival time (7.6 vs. 9.3 months) were also similar in the two groups. Multivariate analysis revealed elderly patients with lower Brinkman index tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence interval: 0.91-22.72, p = 0.0642). In this study, treatment with gefitinib appeared to be as safe and effective in elderly patients (aged 75 or older) with NSCLC as in non-elderly patients.

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  • Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. 国際誌

    Katsuyuki Hotta, Katsuyuki Kiura, Hiroshi Ueoka, Masahiro Tabata, Keiichi Fujiwara, Toshiyuki Kozuki, Toshiaki Okada, Akiko Hisamoto, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   46 ( 2 )   255 - 61   2004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)  

    BACKGROUND: Gefitinib ('Iressa', ZD1839), an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), has shown antitumor activity in refractory patients with non-small-cell lung cancer (NSCLC) in clinical trials. We have retrospectively analyzed the efficacy and tolerability of gefitinib in patients with advanced NSCLC treated at Okayama University Hospital. METHODS: We reviewed the clinical records of 57 patients with advanced NSCLC who had received 250 mg/day gefitinib at our hospital between November 2000 and May 2003. Correlations between the sensitivity of brain metastases and extracranial disease following treatment with gefitinib were also investigated. RESULTS: Extracranial objective responses were observed in 15 (27%; 95% confidence interval 15.8-40.3%) patients. Fourteen out of 57 patients had brain metastases; six experienced objective responses (one complete response, CR and five partial responses, PR) and eight had stable disease (SD) in the brain. Seven out of 14 patients with brain metastases experienced objective responses in their extracranial tumors and, interestingly, objective responses in the brain were observed in six (86%) of these patients. Multivariate analysis found that advanced age (> or = 70 years) and the presence of brain metastases were associated with clinical response to gefitinib (P = 0.01 and 0.05, respectively), and that female patients were more likely to respond. Median survival and median duration of response were 9.1 and 7.7 months, respectively. The majority of adverse events (AEs) were mild and reversible skin and gastrointestinal disorders, with grade 3 adverse events observed in six (11%) patients. CONCLUSIONS: This retrospective analysis has found that gefitinib is effective and well tolerated in patients with refractory NSCLC, confirming previous phase II trial data. Interestingly, gefitinib appeared to be effective for brain metastases as well as extracranial tumors. Further prospective trials are warranted to evaluate the efficacy of gefitinib in elderly patients and in patients with brain metastases.

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  • Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. 国際誌

    Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Mitsune Tanimoto

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   22 ( 19 )   3860 - 7   2004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)  

    PURPOSE: The role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials. METHODS: We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy. RESULTS: Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P =.001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P =.012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P =.015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild. CONCLUSION: This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.

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  • Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. 国際誌

    Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Mitsune Tanimoto

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   22 ( 19 )   3852 - 9   2004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)  

    PURPOSE: It remains undetermined whether cisplatin and carboplatin are equally effective for advanced non-small-cell lung cancer (NSCLC). We therefore did a meta-analysis of trials that compared cisplatin-based chemotherapy with carboplatin-based chemotherapy. METHODS: We performed a literature search to identify trials that had investigated the substitution of carboplatin for cisplatin in the treatment of advanced NSCLC. We evaluated these trials for inclusion, rated methodologic quality, and abstracted relevant data. RESULTS: Of 1,191 reports, eight trials (2,948 patients) were identified, five of which investigated drug regimens containing platinum plus a new agent. Cisplatin-based chemotherapy produced a higher response rate, but the survival advantage was not significant (hazard ratio = 1.050; 95% CI, 0.907 to 1.216; P =.515). Subgroup analysis revealed that combination chemotherapy consisting of cisplatin plus a new agent yields 11% longer survival than carboplatin plus the same new agent (hazard ratio = 1.106; 95% CI, 1.005 to 1.218; P =.039). Patients on cisplatin-based chemotherapy frequently developed nausea and vomiting; thrombocytopenia was more frequent during carboplatin-based chemotherapy. No significant difference in treatment-related mortality was observed. CONCLUSION: We found that combination chemotherapy consisting of cisplatin plus a new agent yields a substantial survival advantage compared with carboplatin plus a new agent in patients with advanced NSCLC, although we failed to find any survival difference in an analysis that included both new and old agents. The strength of our conclusion is limited because we used abstracted data, and careful interpretation is thus required. Nevertheless, our results raise a critical point that needs to be evaluated in future studies.

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  • An overview of 48 elderly-specific clinical trials of systemic chemotherapy for advanced non-small cell lung cancer. 国際誌

    Katsuyuki Hotta, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   46 ( 1 )   61 - 76   2004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)  

    PURPOSE: The aim of the present study was to identify elderly-specific clinical trials for advanced non-small cell lung cancer (NSCLC) and to clarify the study design and patient characteristics entered of each of these trials. METHODS: We used the MEDLINE database to select prospective clinical trials evaluating the efficacy of chemotherapy in elderly patients with advanced NSCLC. RESULTS: Our literature search yielded 48 prospective clinical trials between 1990 and 2003, involving a total of 2648 elderly patients with advanced NSCLC. The median number of patients treated per trial was 36. In 23 (48%) of the 48 trials, only the abstract was available. In 44 trials (92%), elderly patients were defined using their calendar age, and the age of 70 years was the most frequently used lower limit for inclusion. Vinorelbine was the most widely studied chemotherapy agent in elderly patients. CONCLUSIONS: Our review revealed that (i) the definition of "elderly" varied from trial to trial, and elderly patients were simply defined using calendar age in the clinical trials; (ii) the quality of elderly-specific trials were generally poor, mainly because of their small sample size.

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  • Clinical and pharmacokinetic study of docetaxel in elderly non-small-cell lung cancer patients. 国際誌

    Nagio Takigawa, Yoshihiko Segawa, Daizo Kishino, Keiichi Fujiwara, Yoshiyuki Tokuda, Nobuhiko Seki, Tetsu Shinkai, Yoichi Watanabe, Shunkichi Hiraki, Toshiyuki Kozuki, Kenichi Gemba, Masahiro Tabata, Katsuyuki Kiura, Hiroshi Ueoka, Mitsune Tanimoto

    Cancer chemotherapy and pharmacology   54 ( 3 )   230 - 6   2004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)  

    PURPOSE: To evaluate the usefulness and pharmacokinetics of docetaxel in the treatment of elderly patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive elderly patients (aged at least 76 years) with locally advanced or metastatic non-small-cell lung cancer were accrued. Eligible patients received at least two cycles of docetaxel at a dose of 60 mg/m2 on day 1 over 1 h every 3 weeks. Patients who were considered ineligible for this study were also registered. Symptom control was assessed using a questionnaire during the treatment period. The pharmacokinetics of docetaxel were evaluated in the first cycle of chemotherapy. RESULTS: Of 35 elderly patients, 15 (43%) met the study eligibility criteria. The reasons for ineligibility consisted mainly of poor performance status, poor bone marrow function, and hypoxemia (six patients each). A total of 49 cycles of chemotherapy (median 2 cycles, range 1-12 cycles) were administered to the eligible patients, six of whom achieved a partial response (overall response rate 40%, 95% confidence interval 15-65%). The major toxicity was hematologic, with grade 3 or greater neutropenia and grade 3 neutropenic fever developing in 13 patients (87%) and five patients (33%), respectively. Symptoms, as assessed in terms of the symptom control score, did not clearly decline during the treatment period. The values (mean+/-SD) of Cmax, AUC(0-->inf), and t(1/2) were 1.35+/-0.32 microg/ml, 1.79+/-0.52 microg h/ml, and 4.1+/-2.3 h, respectively. CONCLUSIONS: Although the validity of the results of this study is limited due to the small sample size, docetaxel appears effective in selected elderly patients with advanced non-small-cell lung cancer.

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  • A phase I study and pharmacokinetics of irinotecan (CPT-11) and paclitaxel in patients with advanced non-small cell lung cancer. 国際誌

    Katsuyuki Hotta, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Shoichi Kuyama, Ken Satoh, Toshiyuki Kozuki, Akiko Hisamoto, Shinobu Hosokawa, Keiichi Fujiwara, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   45 ( 1 )   77 - 84   2004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)  

    PURPOSE: To determine the maximum-tolerated dose (MTD) of irinotecan and paclitaxel in this two-drug combination, and to investigate a sequence-dependent effect in the pharmacokinetics of these drugs, we conducted a phase I study in chemo-naïve patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled in this study. Both irinotecan and paclitaxel were administered on days 1 and 8, and repeated every 3 weeks. The starting dose of both drugs was 40 mg/m2 which was then alternately increased by 10 mg/m2 increments. In the first cycle, irinotecan was initially administered and followed by paclitaxel infusion, while the sequence of drug administration was reversed in the second cycle. Blood samples for pharmacokinetic analysis were obtained on day 1 of the first and second cycles. RESULTS: Nine patients received a total of 12 cycles, which were evaluated for toxicity and efficacy. The main hematological toxicity was neutropenia. Grades 3 or more neutropenia was observed in 67% of cycles at dose level 2. The main non-hematological toxicities were grade 3 febrile neutropenia, supraventricular arrhythmia, and grade 2 hepatic dysfunction. The MTD of irinotecan and paclitaxel were 40 and 50 mg/m2, respectively. In the pharmacokinetic analysis, the maximum concentration of paclitaxel was elevated in a dose-dependent manner. There was a trend toward elevation of the area under the plasma concentration-time curve (AUC) of irinotecan and a decline of the AUC of paclitaxel in cycle 1 (irinotecan followed by paclitaxel), compared with those in cycle 2 (paclitaxel followed by irinotecan). Hepatic toxicity was strongly associated with the AUC of irinotecan (r = 0.894, P < 0.0001). The objective response was not observed in the nine patients. CONCLUSION: The combination of irinotecan and paclitaxel with this schedule produced considerable toxicities without any antitumor effect for advanced NSCLC. The different schedule of administration or other combinations should be investigated.

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  • Phase I study of docetaxel and irinotecan in patients with advanced non-small-cell lung cancer. 国際誌

    Naoyuki Nogami, Shingo Harita, Hiroshi Ueoka, Toshiro Yonei, Katsuyuki Kiura, Haruhito Kamei, Masahiro Tabata, Yoshihiko Segawa, Kenichi Gemba, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   45 ( 1 )   85 - 91   2004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)  

    The role of non-platinum combination chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan (CPT) in patients with advanced NSCLC were evaluated. Previously untreated patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV were eligible. Both drugs were administered by 1-h intravenous infusion on day 1, and repeated every 3 weeks. DCT was given before CPT administration. Five escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165 mg/m2) were studied. Eighteen patients received 44 courses. The DLT was considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or more was observed in three patients, which was accompanied with three episodes of febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred in three patients. Since all the three patients treated at the fifth dose level (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in two patients and grade 3 hepatic toxicity in one), this dose level was determined to be the MTD. The objective response rate was 33.3%, and the median survival time was 13.6 months. To confirm the effectiveness of this combination for advanced NSCLC which was suggested in the present study, a phase II study with the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.

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  • Successful treatment of limited disease-small cell lung cancer with multimodality treatment consisting of concurrent chemoradiotherapy, high-dose chemotherapy with autologous peripheral blood stem cell transplantation and surgical resection.

    Katsuyuki Hotta, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Eisei Kondoh, Yoshihiko Segawa, Hiroshi Date, Nobuyoshi Shimizu, Tadashi Yoshino, Mine Harada, Mitsune Tanimoto

    Internal medicine (Tokyo, Japan)   42 ( 12 )   1223 - 7   2003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)  

    A 65-year-old man with limited disease-small cell lung cancer was treated with concurrent chemoradiotherapy which resulted in a partial response. He further received high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Development of non-small cell carcinoma was, however, suspected at a site of the residual nodule in cytological examination using bronchoscopy. He then underwent lobectomy, which revealed that the nodule was composed of necrotic tissue. He has been alive without recurrence for seven years. This multimodality treatment appeared to be effective for this patient. However, further investigation is necessary to clarify the role of multimodality treatment.

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  • Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer. 国際誌

    Yoshihiko Segawa, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Yoshio Hiraki, Yoichi Watanabe, Toshiro Yonei, Tomonori Moritaka, Junichiro Hiyama, Shunkichi Hiraki, Mitsune Tanimoto, Mine Harada

    Lung cancer (Amsterdam, Netherlands)   41 ( 1 )   13 - 20   2003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)  

    To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage small-cell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily x 30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m(2), respectively. In the phase II study, the overall response rate was 100% (complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (>/=grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens.

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  • Dramatic effect of ZD1839 ('Iressa') in a patient with advanced non-small-cell lung cancer and poor performance status. 国際誌

    Keiichi Fujiwara, Katsuyuki Kiura, Hiroshi Ueoka, Masahiro Tabata, Shuji Hamasaki, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   40 ( 1 )   73 - 6   2003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)  

    We describe the case of a 52-year-old Japanese woman with advanced adenocarcinoma of the lung, in whom once-daily treatment with 250 mg ZD1839 ('Iressa') demonstrated a marked antitumour effect. She had initially achieved a partial response with cisplatin-based combination chemotherapy, but had subsequently progressed and had failed to respond to salvage chemotherapy. She had also received whole-brain irradiation for brain metastases. On admission, the patient was confined to bed due to dyspnoea and had rapidly progressing hypoxia secondary to lymphangitis carcinomatosa and a massive right pleural effusion. She was treated with oxygen supplementation and oral ZD1839, which, within a week, led to marked tumour regression and gradually improving dyspnoea. The main adverse event observed was a grade 2 rash. A month after starting ZD1839 treatment, the patient was discharged without the need for oxygen supplementation and had since returned to full-time work. This is a demonstration of ZD1839 producing a dramatic clinical response when administered to a patient with poor performance status who had received extensive prior treatment with cytotoxic agents.'Iressa' is a trademark of the AstraZeneca group of companies.

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  • Daily low-dose cisplatin and concurrent thoracic irradiation for poor-risk patients with unresectable non-small-cell lung cancer.

    Ichiro Takata, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Hideki Katayama, Mitsuhiro Takemoto, Yoshio Hiraki, Mine Harada, Mitsune Tanimoto

    Acta medica Okayama   56 ( 5 )   261 - 6   2002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)  

    A pilot study was conducted to assess the efficacy and feasibility of daily low-dose cisplatin with concurrent thoracic irradiation for clinically unresectable non-small-cell lung cancer (NSCLC). Patients with inoperable NSCLC who had poor risk factors such as advanced age, poor performance status, poor lung function, or concomitant active malignancy were entered into the study. Low-dose cisplatin (6 mg/m2) was administered daily before concurrent thoracic irradiation (2 Gy/day; total dose of 60 Gy) was given. Twenty-five patients were registered. The majority of the patients had either stage IIIA (24.0%) or stage IIIB (60.0%) disease. Fifteen patients (60.0%) completed the planned treatment. Both chemotherapy and radiotherapy were stopped in 3 patients (12.0%) due to poor response, and 7 patients (28.0%) partly received radiotherapy alone as a result of their toxicity response. The proportion of total administered dose to planned dose was 90.9% for chemotherapy and 99.3% for radiotherapy, which were comparable to those in previous studies for LA-NSCLC patients without poor risk factors. Grade 3 leukopenia and neutropenia developed in 14 patients (56.0%) and 10 patients (40.0%), respectively, but grade 4 toxicity was not encountered. Grade 3 pneumonitis and esophagitis were observed in 4 patients (16.0%) and 2 patients (8.0%), respectively. The overall response rate was 60.0%. The median survival time was 22 months, and the 2-year survival rate was 50.3%. Daily low-dose cisplatin and concurrent thoracic irradiation were well tolerated even by poor-risk patients with NSCLC, and showed a therapeutic efficacy similar to that for good-risk patients.

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  • A phase III randomized trial comparing vindesine and cisplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer: long-term follow-up results and analysis of prognostic factors. 国際誌

    Tsuyoshi Kodani, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Yoshihiko Segawa, Tomonori Moritaka, Shunkichi Hiraki, Mine Harada, Mitsune Tanimoto

    Lung cancer (Amsterdam, Netherlands)   36 ( 3 )   313 - 9   2002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)  

    UNLABELLED: In order to evaluate the activity and toxicity of a three-drug combination of vindesine, ifosfamide and cisplatin (VIP) for inoperable non-small-cell lung cancer (NSCLC), we conducted a randomized trial comparing VIP with a two-drug combination of cisplatin and vindesine (VP). Between September 1987 and March 1992, a total of 132 patients with stage III or IV NSCLC were randomly allocated to either VIP or VP. The VIP regimen consisted of vindesine (VDS 3 mg/m(2) on days 1 and 8), ifosfamide (IFX 1300 mg/m(2) on days 1-5), and cisplatin (CDDP 20 mg/m(2) on days 1-5). The VP regimen consisted of VDS and CDDP with the same dose and schedule as the VIP regimen. Both regimens were repeated every 4 weeks. Objective response rates were 49.3% (95% confidence interval: 95%CI, 43.1-55.4%) in the VIP arm and 44.6% (95%CI, 38.4-50.2%) in the VP arm; the difference was not significant (P=0.5390). Median response duration, median survival time, and two-year survival rates were 26.5 weeks, 49.6 weeks, and 14.9% in the VIP arm and 28.7 weeks, 37.1 weeks, and 12.3% in the VP arm, respectively. There were also no significant differences between these two treatment arms. In comparison with the VP regimen, however, a survival advantage of the VIP regimen could be confirmed when the data were evaluated with Cox's multivariate analysis (P=0.0131). In both arms, the principal toxicity was myelosuppression, which was significantly more frequent in the VIP arm, although generally well tolerated. CONCLUSION: This study suggested the survival advantage of the VIP regimen over the VP regimen for treatment of patients with advanced NSCLC.

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  • Comparison of chemosensitivity tests: clonogenic assay versus MTT assay.

    Kazuhiko Kawada, Toshiro Yonei, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Nagio Takigawa, Mine Harada, Mitsune Tanimoto

    Acta medica Okayama   56 ( 3 )   129 - 34   2002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)  

    When the development of chemotherapeutic agents reaches the clinical trial stage, it is necessary to perform drug sensitivity tests quickly in order to select the most promising agents for the treatment of cancer. In order to assess the possibility of using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as a substitute for the human tumor clonogenic assay (HTCA), we evaluated the correlation between the results obtained by these 2 assays in 5 human lung cancer cell lines. The correlation coefficient between the results of the HTCA and the MTT assay was 0.673, indicating a relatively good correlation. The correlation was most prominent in platinum analogues (r = 0.939) and good in anthracyclines/anthracenedione (r = 0.611). However, no significant correlation was observed in vinca alkaloids, etoposide, irinotecan, SN-38 (an active metabolite of irinotecan), and rhizoxin. The results of the MTT assay showed a high degree of correlation with those of the HTCA in predicting the sensitivity of cancer cell lines to platinum analogues, and anthracyclines/anthracenedione. These results suggest that the MTT assay may be more convenient and quickly performed than the HTCA and can replace HTCA in evaluating the effects of anticancer agents, especially the platinum analogues and anthracyclines/anthracenedione.

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  • [Combination chemotherapy with carboplatin and etoposide for elderly patients aged 76 years or older with small cell lung cancer].

    Atsuhiko Tada, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Mitsuhiro Takemoto, Hiromichi Yamane, Junichiro Hiyama, Keisuke Aoe, Takuo Shibayama, Haruhito Kamei, Shin Kawahara, Shingo Harita, Toshio Sato, Makoto Kobayashi, Kenji Eguchi, Shunkichi Hiraki, Yoshio Hiraki, Mitsune Tanimoto

    Gan to kagaku ryoho. Cancer & chemotherapy   29 ( 5 )   751 - 6   2002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)  

    Eighteen elderly patients aged 76 years or older with small cell lung cancer were treated with carboplatin (AUC = 4 mg/ml.min, i.v. day 1) and etoposide (70 mg/m2 i.v. day 1-3) and 17 patients were evaluable. The median age of the study population was 77 years (range: 76-81). Eight patients had limited disease (LD) and nine did extensive disease (ED). The overall response rate was 88% for LD patients and 67% for ED patients. Median survival time was 219 days for LD patients and 158 days for ED patients. Grade 3 and 4 leukopenia, neutropenia, thrombocytopenia and anemia occurred in 41%, 76%, 24% and 6% of patients, respectively. There was one treatment-related death due to pneumonitis.

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  • Characterization of non-small-cell lung cancer cell lines established before and after chemotherapy. 国際誌

    Haruyuki Kawai, Katsuyuki Kiura, Masahiro Tabata, Tadashi Yoshino, Ichiro Takata, Akio Hiraki, Kenichi Chikamori, Hiroshi Ueoka, Mitsune Tanimoto, Mine Harada

    Lung cancer (Amsterdam, Netherlands)   35 ( 3 )   305 - 14   2002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)  

    We established several in vitro drug-resistant cell lines after continuous, long-term exposure of each drug to elucidate mechanisms of drug resistance. Whether drug resistance in these in vitro resistant cell lines reflects clinical drug resistance still remains unanswered. In this study, a pair of lung cancer cell lines was established from one patient with squamous cell carcinoma of the lung, with one line being established before and one line after combination chemotherapy (cisplatin/ifosfamide/vindesine). Combination chemotherapy selected resistant EBC-2/R cells, which showed cross-resistance to 4-hydroxyifosfamide (3.2-fold), cisplatin (2.3-fold), and methotrexate (3.7-fold) and collateral sensitivity to vindesine (0.77-fold) compared with parent EBC-2 cells. EBC-2/R cells showed decrease in intracellular accumulation of cisplatin, increase in intracellular concentration of glutathione (GSH), and overexpression of multidrug resistance-associated protein (MRP) 3 when compared with EBC-2 cells. A single cycle of chemotherapy was not sufficient to select other mechanisms of drug resistance, such as multidrug resistance-1/P-glycoprotein, MRPs 1, 2, 4, and 5, lung resistance-related protein, metallothionein IIa, glutathione S-transferase pi, gamma-glutamylcysteine synthetase (light and heavy chain), and excision repair cross complementing 1. Sequentially we established two cell lines, which cell lines showed the differences of the cisplatin resistance, expression level of MRP3, intracellular GSH level and intracellular accumulation of cisplatin. A pair of cell lines will be useful to elucidate resistant mechanisms of cisplatin in heterogeneous lung cancer cells.

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  • Interleukin-12 augments cytolytic activity of peripheral blood mononuclear cells against autologous lung cancer cells in combination with IL-2. 国際誌

    Akio Hiraki, Katsuyuki Kiura, Hiromichi Yamane, Naoyuki Nogami, Masahiro Tabata, Nagio Takigawa, Hiroshi Ueoka, Mitsune Tanimoto, Mine Harada

    Lung cancer (Amsterdam, Netherlands)   35 ( 3 )   329 - 33   2002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)  

    The majority of patients with advanced lung cancer die within a few years. Accordingly, new therapeutic modalities need to be developed. Interleukin (IL)-12 was previously known as natural killer (NK) cell stimulatory factor or cytotoxic lymphocyte maturation factor. By virtue of its effects on T cells and NK cells, IL-12 seems to be one of the key cytokines that regulates cell-mediated anti tumor immune responses. Recently, there has been a substantial interest in the potential applications of IL-12 in the treatment of lung cancer. However, there have been no reports about the effect of IL-12 on peripheral blood mononuclear cells (PBMCs) obtained from lung cancer patients in an autologous setting. In this study, we examined the cytotoxicity of PBMC activated by IL-2, IL-12 or both against K562 or autologous lung cancer cells. In contrast to the effect of IL-2 on NK activity, IL-12 alone augmented NK activity against K562 cells, but not against autologous lung cancer cells. IL-12 augmented the IL-2 mediated cytotoxicity of PBMC against both K562 and autologous lung cancer cells. In the absence of IL-2, IL-12 alone cannot induce an autologous anti-tumor effect in vivo. In summary, our results clearly demonstrated that IL-12 can augment the cytolytic activity of PBMC against K562 and autologous lung cancer cells when combined with IL-2, although, IL-12 alone was unable to induce a marked increase in the cytotoxicity against autologous lung cancer cells. These results suggest that an administration of IL-12 in combination with IL-2 may be a useful therapeutic option for solid tumors.

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  • Spontaneous regression of metastatic endometrial stromal sarcoma. 国際誌

    Seisuke Ota, Katsuji Shinagawa, Hiroshi Ueoka, Shinya Tada, Masahiro Tabata, Shuji Hamazaki, Eisaku Kondo, Katsuyuki Kiura, Tomohiko Mannami, Takuo Shibayama, Kenji Niiya, Mine Harada

    Japanese journal of clinical oncology   32 ( 2 )   71 - 4   2002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)  

    Spontaneous regression of malignancy is rare and there appear to be no reports of spontaneous regression of endometrial stromal sarcoma. We report a rare case of metastatic endometrial stromal sarcoma that regressed spontaneously. A 58-year-old woman was admitted to hospital in January 1996 when her chest radiograph showed multiple nodular shadows in the left lower lung field. Computed tomography of the chest revealed bilateral nodules. Segmentectomy of the left lower lobe was performed by thoracoscopy. She had a past history of uterine myoma with metrorrhagia for which she had undergone a hystero-oophorectomy 10 years earlier. She also had a vaginal polyp removed 1 year earlier. The lung pathology was studied and the surgical specimens of the uterus and vagina were re-examined. The diagnosis was endometrial stromal sarcoma primarily arising in the uterus. The vaginal polyp and the pulmonary nodules were considered to be metastases. Samples of lung and vaginal tissues were positive for both estrogen and progesterone receptors. The patient was discharged without treatment in February 1996 and followed up in the outpatient clinic. The tumor shadow measuring 2 mm in diameter on admission was enlarged to 4 mm in diameter 1 year later. Surprisingly, spontaneous regression of the lung disease occurred at 33 months, the tumor size decreasing to 2 mm in diameter and to 1 mm at 46 months. No evidence of tumor enlargement was detected at the last follow-up in July 2001. Although the precise mechanism of tumor regression is unknown, metastatic endometrial stromal sarcoma may spontaneously regress.

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  • Synergistic effects of topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin, and irradiation in a cisplatin-resistant human small cell lung cancer cell line. 国際誌

    Hiroyuki Kohara, Masahiro Tabata, Katsuyuki Kiura, Hiroshi Ueoka, Kazuhiko Kawata, Masakazu Chikamori, Keisuke Aoe, Kenichi Chikamori, Akio Matsushita, Mine Harada

    Clinical cancer research : an official journal of the American Association for Cancer Research   8 ( 1 )   287 - 92   2002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)  

    7-ethyl-10-[4-(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, a topoisomerase I (topo I) inhibitor, is one of the most active agent against lung cancer, and its radiosensitizing effect has been reported recently. We evaluated a combination in vitro effect of irradiation and 7-ethyl-10-hydroxy-CPT (SN-38), an active metabolite of 7-ethyl-10-[4- (1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, on a human small cell lung cancer cell line (SBC-3) and its cisplatin-resistant subline (SBC-3/CDDP). Growth-inhibitory effects of irradiation with or without SN-38 were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A modified isobologram method was used to evaluate the treatment interaction. The combination of irradiation and SN-38 showed a synergistic inhibitory effect on the growth of SBC-3/CDDP despite its cross-resistance to irradiation and SN-38. In contrast, the same combination showed only an additive effect on the growth of parental SBC-3 cells. There was no significant difference in topo I protein expression between these two cell lines. In SBC-3 cells, topo I catalytic activity was suppressed by 4 Gy of irradiation, without a decrease of nuclear topo I protein, whereas the exposure of SBC-3 cells to 1 microM SN-38 subsequent to irradiation showed no remarkable additional effects on both topo I activity and protein content. On the other hand, in SBC-3/CDDP cells, topo I activity was unchanged by irradiation, but the subsequent exposure to SN-38 gave rise to a decrease in topo I activity, which was accompanied by a significant decrease in the topo I protein content (P = 0.02). These observations may indicate that SN-38 induces sequestration of topo I onto DNA in radiation-treated SBC-3/CDDP cells and suggest that the synergistic effect of irradiation and SN-38 in SBC-3/CDDP cells was considered attributable to DNA repair-related enhanced recruitment of topo I onto the damaged DNA.

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  • Inhibition of NF-kappaB and proteasome activity in tumors: can we improve the therapeutic potential of topoisomerase I and topoisomerase II poisons. 国際誌

    Ram Ganapathi, Susan A J Vaziri, Masahiro Tabata, Nagio Takigawa, Dale R Grabowski, Ronald M Bukowski, Mahrukh K Ganapathi

    Current pharmaceutical design   8 ( 22 )   1945 - 58   2002年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Activation of signaling pathways following DNA damage induced by topoisomerase (topo) poisons can lead to cell death by apoptosis. NF-kappaB, a major regulator of the stress response and a negative regulator of apoptosis is often activated following treatment with topoisomerase poisons. Since activation of NF-kappaB is generally considered to relay an anti-apoptotic signal, inactivation of this signaling molecule is considered to represent an important strategy to improve therapeutic efficacy. Although this strategy seems to be effective in some model systems, our results in human non-small cell lung cancers differed. In this review we will discuss the role of NF-kappaB in mediating topoisomerase poison-induced DNA damage and apoptosis and the consequence of inhibiting its activity. Newer insights about the importance of proteasome inhibitors and anti-apoptotic genes in topoisomerase poison-induced signaling mechanisms leading to apoptosis will also be reviewed. The knowledge obtained from these studies may be useful for translation to a clinical setting for development of more effective therapeutic strategies.

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