2022/12/01 更新

写真a

サイジョウ ヤスオ
西條 康夫
SAIJYO Yasuo
所属
教育研究院 医歯学系 医学系列 教授
医学部 医学科 教授
医歯学総合研究科 分子細胞医学専攻 遺伝子制御 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 1995年3月   東北大学 )

研究分野

  • ライフサイエンス / 腫瘍診断、治療学

  • ライフサイエンス / 生体材料学

  • ライフサイエンス / 生体医工学

  • ライフサイエンス / 呼吸器内科学

経歴(researchmap)

  • 新潟大学医学部医学科卒業   School of Medicine, Faculty of Medicine

    1984年3月 - 現在

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経歴

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻 遺伝子制御   教授

    2012年1月 - 現在

  • 新潟大学   医学部 医学科   教授

    2012年1月 - 現在

所属学協会

 

論文

  • Efficacy of BRAF inhibitor and anti-EGFR antibody in colorectal neuroendocrine carcinoma.

    Mae Nakano, Yoshifumi Shimada, Yoshifumi Matsumoto, Takuro Saiki, Qiliang Zhou, Kenta Sasaki, Masato Moriyama, Kosuke Yoshihara, Manabu Natsumeda, Yoko Kuriyama, Yasumasa Takii, Gen Watanabe, Hajime Umezu, Shujiro Okuda, Takeshi Ikeuchi, Toshifumi Wakai, Yasuo Saijo

    Clinical journal of gastroenterology   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

    DOI: 10.1007/s12328-022-01599-4

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  • Analysis of Pharmacokinetics in the Cochlea of the Inner Ear

    Seishiro Sawamura, Genki Ogata, Kai Asai, Olga Razvina, Takeru Ota, Qi Zhang, Sasya Madhurantakam, Koei Akiyama, Daisuke Ino, Sho Kanzaki, Takuro Saiki, Yoshifumi Matsumoto, Masato Moriyama, Yasuo Saijo, Arata Horii, Yasuaki Einaga, Hiroshi Hibino

    Frontiers in Pharmacology   12   2021年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    Hearing loss affects >5% of the global population and therefore, has a great social and clinical impact. Sensorineural hearing loss, which can be caused by different factors, such as acoustic trauma, aging, and administration of certain classes of drugs, stems primarily from a dysfunction of the cochlea in the inner ear. Few therapeutic strategies against sensorineural hearing loss are available. To develop effective treatments for this disease, it is crucial to precisely determine the behavior of ototoxic and therapeutic agents in the microenvironment of the cochlea in live animals. Since the 1980s, a number of studies have addressed this issue by different methodologies. However, there is much less information on pharmacokinetics in the cochlea than that in other organs; the delay in ontological pharmacology is likely due to technical difficulties with accessing the cochlea, a tiny organ that is encased with a bony wall and has a fine and complicated internal structure. In this review, we not only summarize the observations and insights obtained in classic and recent studies on pharmacokinetics in the cochlea but also describe relevant analytical techniques, with their strengths, limitations, and prospects.

    DOI: 10.3389/fphar.2021.633505

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  • Analysis of Pharmacokinetics in the Cochlea of the Inner Ear. 国際誌

    Seishiro Sawamura, Genki Ogata, Kai Asai, Olga Razvina, Takeru Ota, Qi Zhang, Sasya Madhurantakam, Koei Akiyama, Daisuke Ino, Sho Kanzaki, Takuro Saiki, Yoshifumi Matsumoto, Masato Moriyama, Yasuo Saijo, Arata Horii, Yasuaki Einaga, Hiroshi Hibino

    Frontiers in pharmacology   12   633505 - 633505   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hearing loss affects >5% of the global population and therefore, has a great social and clinical impact. Sensorineural hearing loss, which can be caused by different factors, such as acoustic trauma, aging, and administration of certain classes of drugs, stems primarily from a dysfunction of the cochlea in the inner ear. Few therapeutic strategies against sensorineural hearing loss are available. To develop effective treatments for this disease, it is crucial to precisely determine the behavior of ototoxic and therapeutic agents in the microenvironment of the cochlea in live animals. Since the 1980s, a number of studies have addressed this issue by different methodologies. However, there is much less information on pharmacokinetics in the cochlea than that in other organs; the delay in ontological pharmacology is likely due to technical difficulties with accessing the cochlea, a tiny organ that is encased with a bony wall and has a fine and complicated internal structure. In this review, we not only summarize the observations and insights obtained in classic and recent studies on pharmacokinetics in the cochlea but also describe relevant analytical techniques, with their strengths, limitations, and prospects.

    DOI: 10.3389/fphar.2021.633505

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  • 分子標的治療・臨床試験 未治療EGFR遺伝子変異陽性肺癌に対するオシメルチニブ+プラチナ併用療法の第2相試験

    朝比奈 肇, 田中 謙太郎, 齋藤 良太, 菅原 俊一, 高 遼, 守田 亮, 東 公一, 森田 智視, 西條 康夫, 前門戸 任, 岡本 勇, 清家 正博, 杉尾 賢二, 小林 国彦

    日本癌治療学会学術集会抄録集   58回   WS22 - 2   2020年10月

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    記述言語:英語   出版者・発行元:(一社)日本癌治療学会  

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  • Age-Based Comparison of Hematological Toxicity in Patients with Lung Cancer

    Yuki Sakai, Qiliang Zhou, Yoshifumi Matsumoto, Takuro Saiki, Masato Moriyama, Akira Toyama, Yasuo Saijo

    Oncology   1 - 8   2020年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:S. Karger AG  

    DOI: 10.1159/000507864

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  • Generation of Lungs by Blastocyst Complementation in Apneumic Fgf10-Deficient Mice. 査読 国際誌

    Akihiko Kitahara, Qingsong Ran, Kanako Oda, Akihiro Yasue, Manabu Abe, Xulu Ye, Toshikuni Sasaoka, Masanori Tsuchida, Kenji Sakimura, Yoichi Ajioka, Yasuo Saijo, Qiliang Zhou

    Cell reports   31 ( 6 )   107626 - 107626   2020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)  

    The shortage of donor lungs hinders lung transplantation, the only definitive option for patients with end-stage lung disease. Blastocyst complementation enables the generation of transplantable organs from pluripotent stem cells (PSCs) in animal models. Pancreases and kidneys have been generated from PSCs by blastocyst complementation in rodent models. Here, we report the generation of lungs using mouse embryonic stem cells (ESCs) in apneumic Fgf10 Ex1mut/Ex3mutmice by blastocyst complementation. Complementation with ESCs enables Fgf10-deficient mice to survive to adulthood without abnormalities. Both the generated lung alveolar parenchyma and the interstitial portions, including vascular endothelial cells, vascular and parabronchial smooth muscle cells, and connective tissue, largely originate from the injected ESCs. These data suggest that Fgf10 Ex1mut/Ex3mutblastocysts provide an organ niche for lung generation and that blastocyst complementation could be a viable approach for generating whole lungs.

    DOI: 10.1016/j.celrep.2020.107626

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  • ベセスダ力価と対応したFVIII-binding IgMの動態 インヒビター発生前後の先天性血友病Aでの経験

    松田 将門, 小宮山 豊, 野上 恵嗣, 古川 晶子, 西條 康夫, 森山 雅人

    日本血栓止血学会誌   31 ( 2 )   266 - 266   2020年5月

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    記述言語:日本語   出版者・発行元:(一社)日本血栓止血学会  

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  • A case of severe hepatotoxicity induced by cisplatin and 5-fluorouracil. 査読 国際誌

    Ayaka Yaegashi, Kensuke Yoshida, Naoto Suzuki, Izumi Shimada, Yusuke Tani, Yasuo Saijo, Akira Toyama

    International cancer conference journal   9 ( 1 )   24 - 27   2020年1月

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    記述言語:英語  

    Severe hepatotoxicity from combination chemotherapy with cisplatin and 5-fluorouracil is a rare adverse effect. In this case report, we present a case with severe hepatotoxicity immediately following chemotherapy with cisplatin and 5-fluorouracil. This female patient had previously been treated with this combination with no hepatotoxicity. The elevated liver enzymes quickly normalized after chemotherapy was stopped. There were no specific changes in liver imaging. As hepatotoxicity occurred after repeated administration of cisplatin, we suggest that this hepatotoxicity might represent a case of allergic hepatitis caused by cisplatin. Severe hepatotoxicity should be watched for with repeated administration of cisplatin.

    DOI: 10.1007/s13691-019-00394-2

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  • Generation of Thyroid Tissues From Embryonic Stem Cells via Blastocyst Complementation In Vivo. 国際誌

    Qingsong Ran, Qiliang Zhou, Kanako Oda, Akihiro Yasue, Manabu Abe, Xulu Ye, Yingchun Li, Toshikuni Sasaoka, Kenji Sakimura, Yoichi Ajioka, Yasuo Saijo

    Frontiers in endocrinology   11   609697 - 609697   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The generation of mature, functional, thyroid follicular cells from pluripotent stem cells would potentially provide a therapeutic benefit for patients with hypothyroidism, but in vitro differentiation remains difficult. We earlier reported the in vivo generation of lung organs via blastocyst complementation in fibroblast growth factor 10 (Fgf10), compound, heterozygous mutant (Fgf10 Ex1mut/Ex3mut) mice. Fgf10 also plays an essential role in thyroid development and branching morphogenesis, but any role thereof in thyroid organogenesis remains unclear. Here, we report that the thyroids of Fgf10 Ex1mut/Ex3mut mice exhibit severe hypoplasia, and we generate thyroid tissues from mouse embryonic stem cells (ESCs) in Fgf10 Ex1mut/Ex3mut mice via blastocyst complementation. The tissues were morphologically normal and physiologically functional. The thyroid follicular cells of Fgf10 Ex1mut/Ex3mut chimeric mice were derived largely from GFP-positive mouse ESCs although the recipient cells were mixed. Thyroid generation in vivo via blastocyst complementation will aid functional thyroid regeneration.

    DOI: 10.3389/fendo.2020.609697

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  • Treatments and outcomes of older patients with esophageal cancer: Comparison with younger patients. 査読

    Matsumoto Y, Kimura K, Zhou Q, Sasaki K, Saiki T, Moriyama M, Saijo Y

    Molecular and clinical oncology   11 ( 4 )   383 - 389   2019年10月

  • 【二次出版】ANL Secondary Publication 日本人頭頸部扁平上皮癌に対する高用量シスプラチン併用化学放射線療法の多施設共同第I/II相試験

    松山 洋, 山崎 恵介, 岡部 隆一, 植木 雄志, 正道 隆介, 尾股 丈, 佐藤 雄一郎, 太田 久幸, 高橋 剛史, 富田 雅彦, 横山 侑輔, 富樫 孝文, 青山 英史, 阿部 英輔, 西條 康夫, 勝良 剛詞, 曽我 麻里恵, 杉田 公, 松本 康男, 土田 恵美子, 堀井 新

    日本耳鼻咽喉科学会会報   122 ( 9 )   1269 - 1270   2019年9月

  • Treatment of Gastric and Gastroesophageal Cancer Patients with Hemodialysis by CapeOX. 査読

    Sasaki K, Zhou Q, Matsumoto Y, Saiki T, Moriyama M, Saijo Y

    Internal medicine (Tokyo, Japan)   2019年6月

  • MicroRNAs control eyelid development through regulating Wnt signaling. 査読 国際誌

    Takahiro Nagai, Supaluk Trakanant, Maiko Kawasaki, Katsushige Kawasaki, Yurie Yamada, Momoko Watanabe, James Blackburn, Yoko Otsuka-Tanaka, Mitsue Hishinuma, Atsushi Kitatmura, Fumiya Meguro, Akane Yamada, Yasumitsu Kodama, Takeyasu Maeda, Qiliang Zhou, Yasuo Saijo, Akihiro Yasue, Paul T Sharpe, Robert Hindges, Ritsuo Takagi, Atsushi Ohazama

    Developmental dynamics : an official publication of the American Association of Anatomists   248 ( 3 )   201 - 210   2019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: The timing, location, and level of gene expression are crucial for normal organ development, because morphogenesis requires strict genetic control. MicroRNAs (miRNAs) are noncoding small single-stranded RNAs that play a critical role in regulating gene expression level. Although miRNAs are known to be involved in many biological events, the role of miRNAs in organogenesis is not fully understood. Mammalian eyelids fuse and separate during development and growth. In mice, failure of this process results in the eye-open at birth (EOB) phenotype. RESULTS: It has been shown that conditional deletion of mesenchymal Dicer (an essential protein for miRNA processing; Dicer fl/fl ;Wnt1Cre) leads to the EOB phenotype with full penetrance. Here, we identified that the up-regulation of Wnt signaling resulted in the EOB phenotype in Dicer mutants. Down-regulation of Fgf signaling observed in Dicer mutants was caused by an inverse relationship between Fgf and Wnt signaling. Shh and Bmp signaling were down-regulated as the secondary effects in Dicer fl/fl ;Wnt1Cre mice. Wnt, Shh, and Fgf signaling were also found to mediate the epithelial-mesenchymal interactions in eyelid development. CONCLUSIONS: miRNAs control eyelid development through Wnt. Developmental Dynamics 248:201-210, 2019. © 2019 Wiley Periodicals, Inc.

    DOI: 10.1002/dvdy.10

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  • Cancers among adolescents and young adults at one institution in Japan. 査読

    Kamimura K, Matsumoto Y, Zhou Q, Moriyama M, Saijo Y

    Oncology letters   16 ( 6 )   7212 - 7222   2018年12月

  • Multicenter phase I/II study of chemoradiotherapy with high-dose CDDP for head and neck squamous cell carcinoma in Japan 査読

    Hiroshi Matsuyama, Keisuke Yamazaki, Ryuichi Okabe, Yushi Ueki, Ryusuke Shodo, Jo Omata, Yuichiro Sato, Hisayuki Ota, Takeshi Takahashi, Masahiko Tomita, Yusuke Yokoyama, Takafumi Togashi, Hidefumi Aoyama, Eisuke Abe, Yasuo Saijo, Kouji Katsura, Marie Soga, Tadashi Sugita, Yasuo Matsumoto, Emiko Tsuchida, Arata Horii

    Auris Nasus Larynx   45 ( 5 )   1086 - 1092   2018年10月

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

    Objective: Recent data indicated that concurrent chemoradiotherapy (CCRT) using high dose cisplatin (CDDP) is the most useful treatment for advanced head and neck squamous cell carcinoma (SCC). Regarding the dose of CDDP, 100 mg/m2 is most recommended in Western countries. However, in terms of a balance of efficacy and adverse events, appropriate dose of cytotoxic drugs such as CDDP may be different among the different ethnic groups. In this multicenter phase I/II study, we aimed to identify the optimal dose of CDDP in CCRT for patients with advanced head and neck SCC in the Japanese. Methods: Patients were eligible for inclusion if they had head and neck SCC that was treated with radical CCRT comprising whole-neck irradiation of the primary lesion and level II–IV lymph nodes on both sides. For the phase I study, a CDDP dose was 70 mg/m2 for level 0, 80 mg/m2 for level 1, and 100 mg/m2 for level 2. Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) were examined by phase I trial, by which CDDP dose for phase II was determined. The primary endpoint for the phase II was CCRT completion rate, and the secondary endpoint was full-dose-CCRT completion rate, the percentage of patients receiving a total CDDP dose of ≥200 mg/m2, response rate, and incidences of adverse events. Results: A CDDP dose of 100 mg/m2 was the MTD for phase I, and the recommended dose for phase II was 80 mg/m2. Forty-seven patients were evaluated in the phase II trial. CCRT completion rate, full-dose-CCRT rate, and the percentage of patients receiving a total CDDP dose of ≥200 mg/m2, were 93.6%, 78.7%, and 93.6%, respectively. One patient (2.1%) developed grade 2 renal dysfunction, and no patient developed febrile neutropenia or a grade 4 adverse event. Conclusion: The present phase I study indicated that a CDDP dose of 80 mg/m2 is the optimal dose in terms of safety. The phase II study revealed that CCRT completion rate, response rate, and rates of adverse events were not inferior for a CDDP dose of 80 mg/m2 as compared with a dose of 100 mg/m2, and a dose of 80 mg/m2 is therefore recommended in CCRT for the Japanese. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR
    identification No. UMIN000010369).

    DOI: 10.1016/j.anl.2018.02.008

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  • Trachea Engineering Using a Centrifugation Method and Mouse-Induced Pluripotent Stem Cells. 査読

    Zhou Q, Ye X, Ran Q, Kitahara A, Matsumoto Y, Moriyama M, Ajioka Y, Saijo Y

    Tissue engineering. Part C, Methods   24 ( 9 )   524 - 533   2018年9月

  • The Prognostic Nutrition Index Predicts the Development of Hematological Toxicities in and the Prognosis of Esophageal Cancer Patients Treated with Cisplatin Plus 5-Fluorouracil Chemotherapy 査読

    Yoshifumi Matsumoto, Qiliang Zhou, Kensuke Kamimura, Masato Moriyama, Yasuo Saijo

    Nutrition and Cancer   70 ( 3 )   447 - 452   2018年4月

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

    The prognostic nutrition index (PNI), calculated based on serum albumin and lymphocyte counts, predicts the prognosis of several cancers, including operated esophageal cancers. In this study, we determined whether PNI could predict the occurrence of severe adverse events by chemotherapy and chemoradiotherapy, and overall survival in esophageal cancer. We collected data from 191 patients with esophageal cancer treated with at least one course of cisplatin and 5-fluorouracil from 2005 to 2016. We compared the incidences of severe adverse events and overall survival between a high- and a low-PNI group. The optimal cut-off value of the Onodera PNI was 43.2. Patients with low PNIs suffered more frequent severe adverse events than did those with high PNIs, and the latter patients survived longer. The PNI was independently prognostic of overall survival and stage. The PNI predicted the development of severe adverse events caused by chemotherapy or chemoradiotherapy, and overall survival, in esophageal cancer patients.

    DOI: 10.1080/01635581.2018.1445765

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  • 胚盤胞補完法を利用したマウスES細胞による肺再生

    北原 哲彦, 周 啓亮, 冉 慶松, 叶 許緑, 小田 佳奈子, 笹岡 俊邦, 阿部 学, 崎村 建司, 味岡 洋一, 泰江 章博, 土田 正則, 西條 康夫

    日本外科学会定期学術集会抄録集   118回   1340 - 1340   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 新潟大学医学科新カリキュラムの概要と実施状況について

    澁谷 雅子, 伊藤 正洋, 鈴木 利哉, 遠藤 直人, 佐藤 昇, 土田 正則, 西條 康夫, 牛木 辰男

    日本シミュレーション医療教育学会雑誌   5   127 - 128   2017年8月

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    記述言語:日本語   出版者・発行元:日本シミュレーション医療教育学会  

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  • A highly specific and sensitive massive parallel sequencer-based test for somatic mutations in non-small cell lung cancer 査読

    Yoshiaki Inoue, Jun Shiihara, Hitoshi Miyazawa, Hiromitsu Ohta, Megumi Higo, Yoshiaki Nagai, Kunihiko Kobayashi, Yasuo Saijo, Masanori Tsuchida, Mitsuo Nakayama, Koichi Hagiwara

    PLOS ONE   12 ( 4 )   e0176525   2017年4月

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

    Molecular targeting therapy for non-small cell lung cancer (NSCLC) has clarified the importance of mutation testing when selecting treatment regimens. As a result, multiple-gene mutation tests are urgently needed. We developed a next-generation sequencer (NGS)-based, multi-gene test named the MINtS for investigating driver mutations in both cytological specimens and snap-frozen tissue samples. The MINtS was used to investigate the EGFR, KRAS, BRAF genes from DNA, and the ERBB2, and the ALK, ROS1, and RET fusion genes from RNA. We focused on high specificity and sensitivity (>= 0.99) and even included samples with a cancer cell content of 1%. The MINtS enables testing of more than 100 samples in a single run, making it possible to process a large number of samples submitted to a central laboratory, and reducing the cost for a single sample. We investigated 96 cytological samples and 190 surgically resected tissues, both of which are isolated in daily clinical practice. With the cytological samples, we compared the results for the EGFR mutation between the MINtS and the PNA-LNA PCR clamp test, and their results were 99% consistent. In the snap-frozen tissue samples, 188/190 (99%) samples were successfully analyzed for all genes investigated using both DNA and RNA. Then, we used 200 cytological samples that were serially isolated in clinical practice to assess RNA quality. Using our procedure, 196 samples (98%) provided high-quality RNA suitable for analysis with the MINtS. We concluded that the MINtS test system is feasible for analyzing ''druggable'' genes using cytological samples and snap-frozen tissue samples. The MINtS will fill a needs for patients for whom only cytological specimens are available for genetic testing.

    DOI: 10.1371/journal.pone.0176525

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  • Chromosomal rearrangements in myoepithelial carcinoma of the breast that presented as metachronic double cancer with invasive ductal carcinoma in the ipsilateral breast 査読

    Hiroyuki Kawashima, Takashi Ariizumi, Yasuo Saijo, Masato Moriyama, Hajime Umezu, Yoshiyuki Ikeda, Akira Ogose, Naoto Endo

    CANCER GENETICS   209 ( 11 )   501 - 505   2016年11月

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

    Myoepithelial carcinoma of the breast is an extremely rare tumor composed entirely of malignant spindle cells with myoepithelial differentiation. The majority of previously reported cases have mainly described the clinicopathological features of the disease, and few have presented cytogenetic data. We herein present the case of a 48-year-old woman who was admitted with a left sided breast lump in the inner upper quadrant that was initially diagnosed as a myoepithelioma with potentially malignant disorder. At 12 months after resection, she complained about a newly developed solid mass in the subareolar region of the ipsilateral breast that was diagnosed as an invasive ductal carcinoma. In addition, 16 months after the initial admission, a re-growing remnant lesion recurred in the inner upper quadrant and was ultimately diagnosed as a myoepithelial carcinoma. Lymph node metastasis of the myoepithelial carcinoma was also observed in her left axillary region 11 months after local recurrence. A cytogenetic analysis showed recurring specific chromosomal alterations both in the locally recurrent and in the lymph-node metastatic lesion: 48, XX, t(5;18)(q13;q23),del(6)(q?),+14. + marl. To our knowledge, this is the first published report of clonal chromosomal rearrangements in myoepithelial carcinoma of the breast that presented as metachronic double cancer with invasive ductal carcinoma in the ipsilateral breast.

    DOI: 10.1016/j.cancergen.2016.10.005

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  • Inhibition of Glutaminolysis Inhibits Cell Growth via Down-regulating Mtorc1 Signaling in Lung Squamous Cell Carcinoma 査読

    Xulu Ye, Qiliang Zhou, Yoshifumi Matsumoto, Masato Moriyama, Shun Kageyama, Masaaki Komatsu, Seijiro Satoh, Masanori Tsuchida, Yasuo Saijo

    ANTICANCER RESEARCH   36 ( 11 )   6021 - 6029   2016年11月

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

    Background/Aim: Inhibition of glutaminolysis has been reported as a promising therapeutic strategy to target several solid carcinomas. We aimed to investigate the effects of glutaminolysis on cell proliferation in lung squamous cell carcinoma cell lines and to explore the potential of targeting glutaminolysis as an anticancer strategy. Materials and Methods: Glutamine (Gln) dependence was assessed in six lung squamous cell carcinoma cell lines. Cell proliferation, mammalian target of rapamycin complex 1 (mTORC1) activity and the induction of autophagy were assessed after inhibition of glutaminolysis via Gln depletion or glutaminase (GLS) inhibition. Results: Five of six lung squamous cell carcinoma cell lines exhibited glutamine- dependence. The extent of dependence was correlated with the mRNA levels of GLS1/GLS2. Inhibition of glutaminolysis inhibited cell proliferation by down-regulating of mTORC1 signaling and inducing autophagy in Gln-dependent lung squamous cell carcinoma cell lines. Conclusion: Targeting glutaminolysis may represent a potential therapeutic strategy for the treatment of Gln-dependent lung squamous cell carcinomas.

    DOI: 10.21873/anticanres.11191

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  • Myelosuppression by chemotherapy in obese patients with gynecological cancers 査読

    Kensuke Kamimura, Yoshifumi Matsumoto, Qiliang Zhou, Masato Moriyama, Yasuo Saijo

    CANCER CHEMOTHERAPY AND PHARMACOLOGY   78 ( 3 )   633 - 641   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)   出版者・発行元:SPRINGER  

    The American Society of Clinical Oncology provides clinical practice guidelines for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. The panel recommends that actual body weight should be used when selecting cytotoxic chemotherapy doses regardless of obesity status. However, there have been no reports regarding the appropriate cytotoxic chemotherapy dosing for obese Japanese patients with cancer.
    We collected data from 216 gynecological cancer patients who were treated with at least one course of a paclitaxel and carboplatin (TC) regimen or a docetaxel and carboplatin (DC) regimen at Niigata University Medical and Dental Hospital from July 2006 to April 2014. Patients were divided into three groups according to body mass index (BMI): obese (BMI aeyen 25), normal (BMI 18.5-24.9), and underweight (BMI < 18.5), as defined by the Japan Society for the Study of Obesity. We analyzed hematological toxicities by full weight-based chemotherapy in each group.
    The rates of grade 3/4 leukocytopenia, neutropenia, and thrombocytopenia were not significantly different among the three BMI groups on all patient analyses. For the TC regimen, the obese and normal groups had significantly lower leukocytopenia (grade 3/4) rates than did the underweight group. Also, significant positive correlations between BMI and the nadirs of leukocytes, neutrophils, platelets, and hemoglobin were observed. For the DC regimen, no significant difference was observed among the BMI groups and the rate of grade 3/4 hematological toxicities.
    We did not observe stronger myelosuppression in obese cancer patients compared with non-obese cancer patients. Therefore, the cytotoxic chemotherapy dose should be calculated by the actual body weight and unnecessary dose reduction should be avoided.

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  • A case of pancreatic neuroendocrine tumors 査読 国際誌

    Moriyama Masato, Matsumoto Yoshifumi, Zhou Qiliang, Yamana Kanako, Ikeda Yohei, Ayukawa Fumio, Abe Eisuke, Sato Seijiro, Takano Kabuto, Kaidu Motoki, Aoyama Hidefumi, Saijo Yasuo

    INTERNATIONAL CANCER CONFERENCE JOURNAL   5 ( 1 )   1 - 4   2016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)  

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  • Randomized Phase II Study of Docetaxel plus Personalized Peptide Vaccination versus Docetaxel plus Placebo for Patients with Previously Treated Advanced Wild Type EGFR Non-Small-Cell Lung Cancer 査読

    Koichi Takayama, Shunichi Sugawara, Yasuo Saijo, Makoto Maemondo, Atsushi Sato, Shinzo Takamori, Taishi Harada, Tetsuro Sasada, Tatsuyuki Kakuma, Junji Kishimoto, Akira Yamada, Masanori Noguchi, Kyogo Itoh, Yoichi Nakanishi

    JOURNAL OF IMMUNOLOGY RESEARCH   2016   1745108   2016年

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

    Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients andMethods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed.

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  • Possible Involvement of Lung Cells Harboring an Abnormal Karyotype in the Pathogenesis of Pulmonary Alveolar Proteinosis Associated with Myelodysplastic Syndrome. 査読

    Moriyama M, Yano T, Furukawa T, Takada T, Ushiki T, Masuko M, Takizawa J, Sone H, Tazawa R, Saijo Y, Ishii H, Nakata K

    Annals of the American Thoracic Society   12 ( 8 )   1251 - 1253   2015年8月

  • Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer - data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002) 査読

    Eisaku Miyauchi, Akira Inoue, Kunihiko Kobayashi, Makoto Maemondo, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Yasuo Saijo, Hirohisa Yoshizawa, Koichi Hagiwara, Toshihiro Nukiwa

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   45 ( 7 )   670 - 676   2015年7月

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

    Objective: Epidermal growth factor receptor tyrosine kinase inhibitors are effective as first-line therapy for advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutations. However, it is unknown whether second-line platinum-based chemotherapy after epidermal growth factor receptor tyrosine kinase inhibitor therapy could lead to better outcomes. We evaluated the efficacy of second-line platinum-based chemotherapy after gefitinib for advanced non-small cell lung cancers harboring epidermal growth factor receptormutations (the NEJ002 study).
    Methods: Seventy-one non-small cell lung cancers, treated with gefitinib as first-line therapy and then receiving platinum-based chemotherapy as second-line therapy were evaluated in NEJ002. Patients were evaluated for antitumor response to second-line chemotherapy by computed tomography according to the criteria of the Response Evaluation Criteria in Solid Tumors group (version 1.0).
    Results: Of the 71 patients receiving platinum-based chemotherapy after first-line gefitinib, a partial response was documented in 25.4% (18/71), stable disease in 43.7% (31/71) and progression of disease in 21.1% (15/71). The objective response and disease control rates were 25.4% (18/71) and 69% (49/71), respectively. There was no significant difference between first-and second-line chemotherapy in objective response and disease control rates for advanced non-small cell lung cancer harboring activating epidermal growth factor receptor mutations. In the analysis of epidermal growth factor receptor mutation types, the objective responses of deletions in exon 19 and a point mutation in exon 21 (L858R) were 27.3% (9/33) and 28.1% (9/32), respectively, but these differences between objective response rates were not significant.
    Conclusions: The efficacy of second-line platinum-based chemotherapy followed at progression by gefitinib was similar to first-line platinum-based chemotherapy, and epidermal growth factor receptor mutation types did not influence the efficacy of second-line platinum-based chemotherapy.

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  • Factors associated with a poor response to gefitinib in the NEJ002 study: Smoking and the L858R mutation 査読

    Tatsuro Fukuhara, Makoto Maemondo, Akira Inoue, Kunihiko Kobayashi, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Masao Harada, Hirohisa Yoshizawa, Ichiro Kinoshita, Yuka Fujita, Yasuo Saijo, Koichi Hagiwara, Satoshi Morita, Toshihiro Nukiwa

    LUNG CANCER   88 ( 2 )   181 - 186   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)   出版者・発行元:ELSEVIER IRELAND LTD  

    Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard therapy for non-small cell lung cancer (NSCLC) harbouring EGFR-activating mutations. The NEJ002 phase 3 clinical trial demonstrated the efficacy of EGFR-TKI; gefitinib was significantly superior in both progression-free survival (PFS) and objective response rate (ORR) than carboplatin plus paclitaxel. However, several cases showed no response. In this study, we performed further analysis of the characteristics of these non-responders.
    Methods: Available data from NEJ002 on maximum changes in tumour size were obtained from 103 cases (90.4%) and 110 cases (96.5%) in the carboplatin paclitaxel and gefitinib groups, respectively. Waterfall plots of maximum tumour size changes were created for non-responders.
    Results: Five (4.9%) and 9 (8.2%) cases in the carboplatin paclitaxel and gefitinib groups were non-responders, respectively. The mean pack years of the non-responders in the carboplatin paclitaxel and gefitinib groups were 0.33 and 31.7, respectively. The ORR of total smokers (61.5%) and heavy smokers (over 40 pack years, 52.6%) in the gefitinib group were significantly lower compared to people who have never smoked (80.0%) (P = 0.044 and P=0.020, respectively). Smoker cases also showed a tendency towards lower PFS and overall survival (05). In addition, the EGFR common mutation types did not affect PFS and OS in gefitinib-treated cases in NEJ002. However, in this study, the ORR and waterfall plots showed that gefitinib-treated non-responders who had a deletion in exon 19 in the EGFR gene exhibited a tendency towards a higher response compared to those with a L858R mutation.
    Conclusions: NSCLC patients with a smoking history or the EGFR L858R mutation may demonstrate a poorer response to gefitinib treatment. 0 2015 The Authors. Published by Elsevier Ireland Ltd.

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  • [Management of adverse effects of standard regimens for small cell lung cancer]. 査読

    Kagamu H, Saijo Y

    Nihon rinsho. Japanese journal of clinical medicine   73 Suppl 2   537 - 541   2015年2月

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  • A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: Re-evaluation of EGFR gene status (NEJ006/TCOG0903) 査読

    Yoshifumi Matsumoto, Makoto Maemondo, Yoshiki Ishii, Koichi Okudera, Yoshiki Demura, Kei Takamura, Kunihiko Kobayashi, Naoto Morikawa, Akihiko Gemma, Osamu Ishimoto, Kazuhiro Usui, Masao Harada, Satoru Miura, Yuka Fujita, Ikuro Sato, Yasuo Saijo

    LUNG CANCER   86 ( 2 )   195 - 200   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)   出版者・発行元:ELSEVIER IRELAND LTD  

    Objectives: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers.
    Patients and methods: Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry.
    Results: Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS.
    Conclusions: Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Differentiation of Mouse Induced Pluripotent Stem Cells Into Alveolar Epithelial Cells In Vitro for Use In Vivo 査読

    Qiliang Zhou, Xulu Ye, Ruowen Sun, Yoshifumi Matsumoto, Masato Moriyama, Yoshiya Asano, Yoichi Ajioka, Yasuo Saijo

    STEM CELLS TRANSLATIONAL MEDICINE   3 ( 6 )   675 - 685   2014年6月

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

    Alveolar epithelial cells (AECs) differentiated from induced pluripotent stem cells (iPSCs) represent new opportunities in lung tissue engineering and cell therapy. In this study, we modified a two-step protocol for embryonic stem cells that resulted in a yield of similar to 9% surfactant protein C (SPC)(+) alveolar epithelial type II (AEC II) cells from mouse iPSCs in a 12-day period. The differentiated iPSCs showed morphological characteristics similar to those of AEC II cells. When differentiated iPSCs were seeded and cultured in a decellularized mouse lung scaffold, the cells reformed an alveolar structure and expressed SPC or T1 alpha protein (markers of AEC II or AEC I cells, respectively). Finally, the differentiated iPSCs were instilled intratracheally into a bleomycin-induced mouse acute lung injury model. The transplanted cells integrated into the lung alveolar structure and expressed SPC and T1 alpha. Significantly reduced lung inflammation and decreased collagen deposition were observed following differentiated iPSC transplantation. In conclusion, we report a simple and rapid protocol for in vitro differentiation of mouse iPSCs into AECs. Differentiated iPSCs show potential for regenerating three-dimensional alveolar lung structure and can be used to abrogate lung injury.

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  • Consensus statement for the diagnosis and treatment of drug-induced lung injuries 査読

    Keishi Kubo, Arata Azuma, Minoru Kanazawa, Hideto Kameda, Masahiko Kusumoto, Akihiko Genma, Yasuo Saijo, Fumikazu Sakai, Yukihiko Sugiyama, Koichiro Tatsumi, Makoto Dohi, Hitoshi Tokuda, Shu Hashimoto, Noboru Hattori, Masayuki Hanaoka, Yuh Fukuda

    Respiratory Investigation   51 ( 4 )   260 - 277   2013年12月

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  • A change in the number of CCSPpos/SPCpos cells in mouse lung during development, growth, and repair 査読

    Ruowen Sun, Qiliang Zhou, Xulu Ye, Takenori Takahata, Atsushi Ishiguro, Hiroshi Kijima, Toshihiro Nukiwa, Yasuo Saijo

    Respiratory Investigation   51 ( 4 )   229 - 240   2013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: Putative resident stem/progenitor cells have been identified in the bronchoalveolar duct junction (BADJ) of the murine lung. However, the contribution of stem cells expressing both Clara cell secretory protein (CCSP) and pro-surfactant protein C (SP-C) to the repair and maintenance of normal homeostasis is still unclear. In this study, we identified and then quantified CD45neg/CCSPpos/SP-Cpos cell numbers in normal and lung-injured mice. Methods: Normal lung tissues of fetal, newborn, and adult mice were used to evaluate lung progenitor cells during development and growth. Mice treated with naphthalene were used for the bronchiolar epithelium injury model, and mice treated with bleomycin were used for the alveolar epithelium injury model. These lung tissues were stained with CD45, CCSP, and SP-C antibodies by immunofluorescence. The number of lung progenitor cells was counted as CD45neg/CCSPpos/SP-Cpos cells by flow cytometry. Results: CCSPpos/SP-Cpos epithelial cells in the BADJ were identified from E18 to 7 months after birth. The percentage of CD45neg/CCSPpos/SP-Cpos cells was relatively stable to 7 months (between 0.3±0.04% and 1.28±0.11%). When lungs were treated with naphthalene, the proliferation of CCSPpos/SP-Cpos cells was observed as patches of double-positive cells and preceded the recovery of bronchioles. In contrast, when lungs were treated with bleomycin, the proliferation of CCSPpos/SP-Cpos cells was observed, but the type II alveolar epithelial cells never recovered to baseline. Conclusions: CCSPpos/SP-Cpos lung cells were stable until 7 months after birth. These cells in the BADJ primarily regenerate bronchiolar epithelial cells and not alveolar epithelial cells. © 2013 The Japanese Respiratory Society.

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  • Randomized phase II trial of uracil/tegafur and cisplatin versus vinorelbine and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-small-cell lung cancer: NJLCG 0601 査読

    Shunichi Sugawara, Makoto Maemondo, Motoko Tachihara, Akira Inoue, Osamu Ishimoto, Tomohiro Sakakibara, Kazuhiro Usui, Hiroshi Watanabe, Nobumichi Matsubara, Kana Watanabe, Kenya Kanazawa, Takashi Ishida, Yasuo Saijo, Toshihiro Nukiwa

    LUNG CANCER   81 ( 1 )   91 - 96   2013年7月

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

    Introduction: The optimal chemotherapy with thoracic radiotherapy (TRT) for locally advanced non-small-cell lung cancer (NSCLC) remains to be established. This randomized phase II study of concurrent chemoradiotherapy was conducted to compare uracil/tegafur (UFT) and cisplatin with vinorelbine and cisplatin for stage III NSCLC.
    Patients and methods: Patients with unresectable stage III NSCLC were randomized to receive UP (400 mg/m(2) UFT on days 1-14 and 29-42 and 80 mg/m(2) cisplatin on days 8 and 36) or NP (20 mg/m(2) vinorelbine on days 1, 8, 29, and 36 and 80 mg/m(2) cisplatin on days 1 and 29). TRT began on day 1 (total 60 Gy in 30 fractions).
    Results: Of 70 enrolled patients, 66 were evaluable for efficacy and safety. The overall response rates were 80% (95% CI: 67-93%) and 71% (95% CI: 55-87%) for the UP arm and the NP arm. With a median follow-up of 20.2 months, the progression-free survival and median survival time were 8.8 and 26.9 months in the UP arm, and 6.8 and 21.7 months in the NP arm. The 2-/3-year survival rates were 51.0/34.3% and 46.9/33.4% for the UP arm and the NP arm, respectively. Grade 3/4 neutropenia occurred in 20% and 58% of patients in the UP and NP arms, respectively.
    Conclusion: Combined with concurrent TRT, the UP arm achieved better efficacy and safety compared with the NP arm, suggesting it to be a promising candidate as a standard regimen for locally advanced NSCLC. Further evaluation of the UP arm is warranted. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002) 査読

    A. Inoue, K. Kobayashi, M. Maemondo, S. Sugawara, S. Oizumi, H. Isobe, A. Gemma, M. Harada, H. Yoshizawa, I. Kinoshita, Y. Fujita, S. Okinaga, H. Hirano, K. Yoshimori, T. Harada, Y. Saijo, K. Hagiwara, S. Morita, T. Nukiwa

    Annals of Oncology   24 ( 1 )   54 - 59   2013年

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    記述言語:英語  

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  • Quality of Life with Gefitinib in Patients with EGFR-Mutated Non-Small Cell Lung Cancer: Quality of Life Analysis of North East Japan Study Group 002 Trial 査読

    Satoshi Oizumi, Kunihiko Kobayashi, Akira Inoue, Makoto Maemondo, Shunichi Sugawara, Hirohisa Yoshizawa, Hiroshi Isobe, Masao Harada, Ichiro Kinoshita, Shoji Okinaga, Terufumi Kato, Toshiyuki Harada, Akihiko Gemma, Yasuo Saijo, Yuki Yokomizo, Satoshi Morita, Koichi Hagiwara, Toshihiro Nukiwa

    ONCOLOGIST   17 ( 6 )   863 - 870   2012年6月

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

    Background. For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study. This report describes the quality of life (QoL) analysis of that study.
    Methods. Chemotherapy-naive patients with sensitive EGFR-mutated, advanced NSCLC were randomized to receive gefitinib or chemotherapy (carboplatin and paclitaxel). Patient QoL was assessed weekly using the Care Notebook, and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical, mental, and life well-being QoL scales. Kaplan-Meier probability curves and log-rank tests were employed to clarify differences.
    Results. QoL data from 148 patients (72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm) were analyzed. Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy (hazard ratio [HR] of time to deterioration, 0.34; 95% confidence interval [CI], 0.23-0.50; p < .0001 and HR, 0.43; 95% CI, 0.28-0.65; p < .0001, respectively).
    Conclusion. QoL was maintained much longer in patients treated with gefitinib than in patients treated with standard chemotherapy, indicating that gefitinib should be considered as the standard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage. The Oncologist 2012;17:863- 870

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  • Methylation of the KEAP1 gene promoter region in human colorectal cancer 査読

    Naoyuki Hanada, Takenori Takahata, Qiliang Zhou, Xulu Ye, Ruowen Sun, Jugoh Itoh, Atsushi Ishiguro, Hiroshi Kijima, Junsei Mimura, Ken Itoh, Shinsaku Fukuda, Yasuo Saijo

    BMC CANCER   12   66   2012年2月

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

    Background: The Keap1-Nrf2 pathway has been reported to be impaired in several cancers. However, the status of Keap1-Nrf2 system in human colorectal cancer (CRC) has not been elucidated.
    Methods: We used colorectal cancer (CRC) cell lines and surgical specimens to investigate the methylation status of the KEAP1 promoter region as well as expression of Nrf2 and its downstream antioxidative stress genes, NQO-1 and AKR1C1.
    Results: DNA sequencing analysis indicated that all mutations detected were synonymous, with no amino acid substitutions. We showed by bisulfite genomic sequencing and methylation-specific PCR that eight of 10 CRC cell lines had hypermethylated CpG islands in the KEAP1 promoter region. HT29 cells with a hypermethylated KEAP1 promoter resulted in decreased mRNA and protein expression but unmethylated Colo320DM cells showed higher expression levels. In addition, treatment with the DNA methyltransferase inhibitor 5-Aza-dC combined with the histone deacetylase inhibitor trichostatin A (TSA) increased KEAP1 mRNA expression. These result suggested that methylation of the KEAP1 promoter regulates its mRNA level. Time course analysis with the Nrf2-antioxidant response element (ARE) pathway activator t-BHQ treatment showed a rapid response within 24 h. HT29 cells had higher basal expression levels of NQO-1 and AKR1C1 mRNA than Colo320DM cells. Aberrant promoter methylation of KEAP1 was detected in 53% of tumor tissues and 25% of normal mucosae from 40 surgical CRC specimens, indicating that cancerous tissue showed increased methylation of the KEAP1 promoter region, conferring a protective effect against cytotoxic anticancer drugs.
    Conclusion: Hypermethylation of the KEAP1 promoter region suppressed its mRNA expression and increased nuclear Nrf2 and downstream ARE gene expression in CRC cells and tissues.

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  • Mesenchymal Stromal Cells Protect Cancer Cells From ROS-induced Apoptosis and Enhance the Warburg Effect by Secreting STC1 査読

    Shinya Ohkouchi, Gregory J. Block, Ahmed M. Katsha, Masahiko Kanehira, Masahito Ebina, Toshiaki Kikuchi, Yasuo Saijo, Toshihiro Nukiwa, Darwin J. Prockop

    MOLECULAR THERAPY   20 ( 2 )   417 - 423   2012年2月

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

    Previous studies have demonstrated that mesenchymal stromal cells (MSCs) enhance cell survival through upregulation and secretion of stanniocalcin-1 (STC1). This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation, reducing intracellular reactive oxygen species (ROS), and shifting metabolism towards a more glycolytic metabolic profile. MSC-derived STC1 upregulated uncoupling protein 2 (UCP2) in injured A549 cells in an STC1-dependent manner. Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 (rSTC1) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS, mitochondrial membrane potential (MMP), and increased lactate production, all of which were dependent on the upregulation of UCP2. Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1.

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  • Sequential irinotecan hydrochloride/S-1 for S-1-resistant inoperable gastric cancer: A feasibility study 査読

    Takenori Takahata, Jugoh Itoh, Taroh Satoh, Atsush Ishiguro, Yoshifumi Matsumoto, Satoshi Tanaka, Soh Saitoh, Hiroshi Tohno, Shinsaku Fukuda, Yasuo Saijo, Yuh Sakata

    ONCOLOGY LETTERS   3 ( 1 )   89 - 93   2012年1月

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

    Irinotecan hydrochloride (CPT-11) is reported to be involved in the downregulation of thymidylate synthase (TS), a target molecule of 5-fluorouracil (5-FU) and oral fluoropyrimidine S-1. Therefore, we hypothesized that a preceding administration of CPT-11 against S-1-resistant tumors may recover sensitivity to S-1. To this end, we planned a S-1/CPT-11 sequential therapy as a feasibility study in S-1-refractory gastric cancer patients. In the first course, CPT-11 was administered intravenously at 150 mg/m(2) on days 1 and 15. Subsequently, S-1 was administered orally for 4 weeks from day 29 to 57, followed by a 2-week interval (sequential S-1/CPT-11). When the tumor showed a complete response (CR) or partial response (PR), the same dose of S-1 monotherapy was continued unless progressive disease (PD) was observed. When the response was stable disease (SD), S-1 was administered at the same dose for just 2 weeks (days 1-15), no drug was administered for the following 2 weeks (4-week cycle) and CPT-11 was administered intravenously at 100 mg/m(2) on days I and 15 (concurrent S-1/CPT-11) unless PD was observed. In the case of PD, the study was terminated. The primary endpoint was an antitumor effect and secondary endpoints were median survival time (MST), progression-free survival (PFS), time-to-treatment failure (TTF) and safety. The response rate (RR) following the first course was only 5.9% and the most positive RR was 11.8%. The MST, median TTF and PFS were 381, 69 and 71 days, respectively. Leukocytopenia was observed in more than half of the patients. Since the RR was lower than estimated in an interim analysis, the trial was terminated and the protocol was concluded to be unfeasible.

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  • A case of gastric cancer treated with modified docetaxel, cisplatin and 5-fluorouracil (mDCF) with ingestion inability 査読

    Atsushi Ishiguro, Takenori Takahata, Yoshifumi Matsumoto, Satoshi Tanaka, Jugoh Itoh, Hitoshi Kawasaki, Yasuyuki Kudoh, Hiroshi Kijima, Sen Shimaya, Yasuo Saijo

    Japanese Journal of Cancer and Chemotherapy   39 ( 3 )   465 - 467   2012年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    The standard regimen of S-1 and cisplatin is not adaptable for patients with gastric cancer with an ingestion inability. A 74-year-old man was revealed to have unresectable gastric cancer with severe pyloric stenosis (cT4, cN3, cH1, cP0, cStage IV). He was treated with systemic chemotherapy using modified docetaxel, cisplatin and 5-fluorouracil (mDCF). He had manageable neutropenia (grade 3 and 4) during his treatment. CT findings after 3 courses showed reduced primary tumor and metastatic lesions. A curative operation was performed based on the effective response with downstaging. Palliative surgery was considered before receiving chemotherapy. mDCF therapy is one of the recommended options for gastric cancer with an ingestion inability.

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  • Low-Dose Gefitinib Treatment for Patients with Advanced Non-small Cell Lung Cancer Harboring Sensitive Epidermal Growth Factor Receptor Mutations 査読

    Hironori Satoh, Akira Inoue, Kunihiko Kobayashi, Makoto Maemondo, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Yasuo Saijo, Hirohisa Yoshizawa, Koichi Hagiwara, Toshihiro Nukiwa

    JOURNAL OF THORACIC ONCOLOGY   6 ( 8 )   1413 - 1417   2011年8月

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

    Introduction: Although standard schedule of gefitinib was the administration of 250 mg tablet every day, many patients need dose reduction because of toxicities. However, the efficacy of such low-dose gefitinib for patients with epidermal growth factor receptor-mutated non-small cell lung cancer has rarely been evaluated.
    Methods: A post hoc comparison of the efficacy (response rate and survival) in patients treated with gefitinib with or without any dose reduction in NEJ002 study was performed.
    Results: Among 114 patients treated with first-line gefitinib in NEJ002, 61 (54%) continued gefitinib without any dose reduction until their diseases progressed, and 53 (46%) reduced their dose of gefitinib because of some toxicities. There was no significant difference of patient characteristics between the two groups. The progression-free survival of low-dose group tended to be better than that of standard-dose group (median progression-free survival, 11.8 versus 9.9 months; p = 0.144), and the overall survival of low-dose group was also better than that of standard-dose group (median survival time, 32.7 versus 25.3 months; p = 0.049).
    Conclusions: The results suggest that low-dose gefitinib may be clinically not inferior to standard-dose gefitinib for non-small cell lung cancer with sensitive epidermal growth factor receptor mutations. Prospective study of low-dose gefitinib is warranted especially for frail patients who need less toxic treatment.

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  • Mesenchymal Stromal Cells Promote Tumor Growth through the Enhancement of Neovascularization 査読

    Kazuhiro Suzuki, Ruowen Sun, Makoto Origuchi, Masahiko Kanehira, Takenori Takahata, Jugoh Itoh, Akihiro Umezawa, Hiroshi Kijima, Shinsaku Fukuda, Yasuo Saijo

    MOLECULAR MEDICINE   17 ( 7-8 )   579 - 587   2011年7月

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

    Mesenchymal stromal cells (MSCs), also called mesenchymal stem cells, migrate and function as stromal cells in tumor tissues. The effects of MSCs on tumor growth are controversial. In this study, we showed that MSCs increase proliferation of tumor cells in vitro and promote tumor growth in vivo. We also further analyzed the mechanisms that underlie these effects. For use in in vitro and in vivo experiments, we established a bone marrow-derived mesenchymal stromal cell line from cells isolated in C57BL/6 mice. Effects of murine MSCs on tumor cell proliferation in vitro were analyzed in a coculture model with B16-LacZ cells. Both coculture with MSCs and treatment with MSC-conditioned media led to enhanced growth of B16-LacZ cells, although the magnitude of growth stimulation in cocultured cells was greater than that of cells treated with conditioned media. Co-injection of B16-LacZ cells and MSCs into syngeneic mice led to increased tumor size compared with injection of B16-LacZ cells alone. Identical experiments using Lewis lung carcinoma (LLC) cells instead of B16-LacZ cells yielded similar results. Consistent with a role for neovascularization in MSC-mediated tumor growth, tumor vessel area was greater in tumors resulting from co-injection of B16-LacZ cells or LLCs with MSCs than in tumors induced by injection of cancer cells alone, Co-injected MSCs directly supported the tumor vasculature by localizing close to vascular walls and by expressing an endothelial marker. Furthermore, secretion of leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2 and vascular endothelial growth factor was increased in cocultures of MSCs and B16-LacZ cells compared with B16-LacZ cells alone. Together, these results indicate that MSCs promote tumor growth both in vitro and in vivo and suggest that tumor promotion in vivo may be attributable in part to enhanced angiogenesis. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org

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  • Paracrine Factors of Multipotent Stromal Cells Ameliorate Lung Injury in an Elastase-induced Emphysema Model 査読

    Ahmed M. Katsha, Shinya Ohkouchi, Hong Xin, Masahiko Kanehira, Ruowen Sun, Toshihiro Nukiwa, Yasuo Saijo

    MOLECULAR THERAPY   19 ( 1 )   196 - 203   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)   出版者・発行元:NATURE PUBLISHING GROUP  

    Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury.

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  • FIRST-LINE GEFITINIB VS CARBOPLATIN/PACLITAXEL IN NON-SMALL CELL LUNG CANCER WITH EGFR MUTATION: PHASE III STUDY NEJ002 査読

    Osamu Ishimoto, Kobayashi Kunihiko, Inoue Akira, Maemondo Makoto, Sugawara Shunichi, Oizumi Satoshi, Saijo Yasuo, Gemma Akihiko, Morita Satoshi, Hagiwara Koichi, Nukiwa Toshihiro

    ANNALS OF ONCOLOGY   21   11   2010年11月

  • A case of gastric adenosquamous carcinoma successfully treated with second-line chemotherapy (CPT-11 and CDDP) 査読

    Atsushi Ishiguro, Takenori Takahata, Katsumi Hirose, Yoshifumi Matsumoto, Satoshi Tanaka, Kazuhiro Suzuki, Naoyuki Hanada, Jugoh Itoh, Hitoshi Kawasaki, Hiroshi Kijima, Shinsaku Fukuda, Yasuo Saijo

    Japanese Journal of Cancer and Chemotherapy   37 ( 8 )   1579 - 1582   2010年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    Gastric adenosquamous carcinoma is known as an infrequent histological cancer with a poor prognosis. A 69-year-old man was revealed to have gastric squamous carcinoma on the gastric body remote from esophagus (cT4 cN3, cStage IV). A curative operation was impossible so he was treated with systemic chemotherapy using S-1+docetaxel. After 1 course, we changed to second-line chemotherapy combining CPT-11+CDDP because of heterochronic multiple hepatic metastases. PET-CT and CT findings after 5 courses of second-line therapy showed reduced primary tumor and metastatic lesions. The curative operation was performed based on the effective response with downstaging. The final histological diagnosis showed gastric adenosquamous carcinoma. The adjuvant chemotherapy of CPT-11 was continued without relapse for almost 2 years.

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  • [Respiratory diseases]. 査読

    Saijo Y

    Nihon rinsho. Japanese journal of clinical medicine   68 Suppl 8   374 - 377   2010年8月

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  • Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR. 査読

    Makoto Maemondo, Akira Inoue, Kunihiko Kobayashi, Shunichi Sugawara, Satoshi Oizumi, Hiroshi Isobe, Akihiko Gemma, Masao Harada, Hirohisa Yoshizawa, Ichiro Kinoshita, Yuka Fujita, Shoji Okinaga, Haruto Hirano, Kozo Yoshimori, Toshiyuki Harada, Takashi Ogura, Masahiro Ando, Hitoshi Miyazawa, Tomoaki Tanaka, Yasuo Saijo, Koichi Hagiwara, Satoshi Morita, Toshihiro Nukiwa

    NEW ENGLAND JOURNAL OF MEDICINE   362 ( 25 )   2380 - 2388   2010年6月

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

    Background: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy.
    Methods: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects.
    Results: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease.
    Conclusions: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)
    N Engl J Med 2010;362:2380-8.

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  • Survey on the compliance of patients with continuous infusion of 5-fluorouracil via portable infusion pumps 査読

    Junya Sato, Kazufumi Terui, Akemi Awatsu, Motoi Koyama, Jugoh Itoh, Yasuo Saijo, Makoto Hayakari

    Japanese Journal of Cancer and Chemotherapy   37 ( 4 )   671 - 675   2010年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    A portable infusion pump is essential to sustain the 46-hour continuous administration of 5-fluorouracil in the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and folinic acid, fluorouracil, and irinotecan (FOLFIRI) protocols in colorectal cancer chemotherapy. However, the accuracy of the 5-fluorouracil dose administered via the infusion pump and patient compliance varies because the infusion rate changes depending on the viscosity of the drug, temperature, etc. In addition, the termination of administration based on the patient's judgment may influence these factors. In the present study, the amount of 5-fluorouracil remaining in the infusion pump and the administration time were investigated. As a result, the median amount that was found to remain in the pump was 49 mg, which was 2.0% of the average dosage, and an median administration time delay of 70 min was obtained. A questionnaire survey revealed that a majority of the patients felt insecurity about inadequate administration and administration time delays. These results indicate that customizing capacity modulation in the infusion pump corresponding to the patient's usage or seasonal variability of air temperature, and patient education may be important to improve patient compliance.

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  • Randomized phase II trial of weekly paclitaxel combined with carboplatin versus standard paclitaxel combined with carboplatin for elderly patients with advanced non-small-cell lung cancer. 査読

    Sakakibara T, Inoue A, Sugawara S, Maemondo M, Ishida T, Usui K, Abe T, Kanbe M, Watanabe H, Saijo Y, Nukiwa T

    Ann Oncol   21 ( 4 )   795 - 799   2010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)  

    DOI: 10.1093/annonc/mdp401

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  • Phase II Study of Gefitinib Readministration in Patients with Advanced Non-Small Cell Lung Cancer and Previous Response to Gefitinib 査読

    Hajime Asahina, Satoshi Oizumi, Akira Inoue, Ichiro Kinoshita, Takashi Ishida, Yuka Fujita, Noriaki Sukoh, Masao Harada, Makoto Maemondo, Yasuo Saijo, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Toshihiro Nukiwa, Masaharu Nishimura

    ONCOLOGY   79 ( 5-6 )   423 - 429   2010年

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

    Objective: Salvage treatment for acquired resistance to gefitinib has yet to be developed. We conducted the first prospective phase II study of gefitinib readministration in previous gefitinib responders. Methods: Gefitinib (250 mg/day) was readministered to patients with advanced/metastatic non-small cell lung cancer who had achieved objective response to initial gefitinib and subsequently received cytotoxic chemotherapy after disease progression with initial gefitinib. The primary endpoint was the objective response rate with gefitinib readministration. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), quality of life, and toxicity. Changes in lung cancer-related symptoms were evaluated using the seven-item lung cancer subscale of the questionnaire. Results: Sixteen patients were enrolled between February 2005 and January 2008. Most had received >= 3 regimens of chemotherapy. Response and disease-control rates for all patients were 0 and 44%. Median PFS and OS were 2.5 and 14.7 months, respectively. Four of 7 patients with stable disease experienced a long duration (>= 6 months) of disease control without severe toxicity. Symptom improvement was observed in 2 of 12 patients (17%) for whom quality of life was evaluable. Conclusion: Gefitinib represents a useful therapeutic option for selected previous gefitinib responders. Copyright (C) 2011 S. Karger AG, Basel

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  • Intratracheal Delivery of CX3CL1-Expressing Mesenchymal Stem Cells to Multiple Lung Tumors 査読

    Hong Xin, Ruowen Sun, Masahiko Kanehira, Takenori Takahata, Jugoh Itoh, Hiroyuki Mizuguchi, Yasuo Saijo

    MOLECULAR MEDICINE   15 ( 9-10 )   321 - 327   2009年9月

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

    The lung is one of the organs to which cancers from solid tumors frequently metastasize. Multiple tumors in the lung are usually treated by systemic chemotherapy because of the lack of efficient methods of targeting antitumor agents to the lung. Although intratracheal administration is an ideal route for targeting multiple lung tumors, antitumor agents are often harmful to the organ or induce inflammation. Mesenchymal stem cells (MSCs), nonhematopoietic stem cells capable of differentiating into various mesoderm-type cells, have a propensity to migrate to and proliferate in tumor tissues after systemic administration. We intratracheally injected MSCs expressing CX3CL1 (MSC/RGDFKN) into the lung of lung tumor-bearing mice with multiple metastases of C26 or Lewis lung carcinoma (LLC). Antitumor effects were evaluated by counting the number of lung metastases and survival. We demonstrated the tropism of mouse MSCs to lung tumor tissues after intratracheal administration of GFP-positive MSCs. Intratracheal injection of MSC/RGDFKN strongly inhibited growth of lung metastases of 026 or LLC, and thus prolonged survival. Intratracheal injection of MSC/RGDFKN did not induce an inflammatory reaction in the lung. These results suggest that MSCs expressing antitumor agents can be delivered intratracheally into multiple lung tumor tissues without causing inflammation. (C) 2009 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2009.00059

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  • [Standard chemotherapy of solid tumors. 1) Cancers of the respiratory system and breast]. 査読

    Saijo Y

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   98 ( 8 )   1860 - 1865   2009年8月

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  • Retrospective analysis of acquired resistance during the treatment with gefitinib in non-small cell lung cancer patients with epidermal growth factor receptor mutations 査読

    Teruyuki Sato, Akira Inoue, Tatsuro Fukuhara, Tomohiro Sakakibara, Hiromitsu Ohta, Masahito Ebina, Yasuo Saijo, Toshihiro Nukiwa

    Japanese Journal of Lung Cancer   49 ( 3 )   257 - 261   2009年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Background. Gefitinib, a selective inhibitor of tyrosine kinase of the epidermal growth factor receptor (EGFR), can be effective in patients with non-small-cell lung cancer (NSCLC) harboring somatic mutations of EGFR. However, the clinical resistance to gefitinib is an unsolved problem. Methods. We analyzed patients with advanced NSCLC with EGFR mutations treated with gefitinib between June 2004 and June 2007 in our institution. The effectiveness of gefitinib, the pattern of relapse, progression-free survival (PFS), and overall survival were assessed retrospectively. EGFR mutations were all examined by DNA direct sequence or peptide nucleic acid-locked nucleic acid (PNA-LNA) polymerase chain reaction (PCR) clamp method by using the tumor specimen before treatment, and re-examination of EGFR mutations by using relapsed tumor sample was performed for some patients. Results. From June 2004 to June 2007, 51 patients with advanced NSCLC harboring EGFR mutations started treatment with gefitinib, and 36 had partial response and 8 had stable disease. The overall response rate and disease control rate were 71% and 86%, respectively. Among 44 responders to gefitinib, disease progression was observed in 33 patients by April 2008. The initial sites of relapse were thoracic (primary lung tumor, pleural effusion, etc) in 21 patients, and distant (brain, bone, etc) in 12 patients. There was no statistical difference in PFS among the initial sites of recurrence. T790M, a resistant mutation of EGFR, was detected in 3 specimens obtained after relapse. Interestingly, most of patients with initial relapse in the thorax had to change the treatment from gefitinib within 3 months, however, more than half of the patients with brain relapse could be managed by radiation therapy with gefitinib for over 3 months. The median survival time of patients with initial relapse in the brain was 28.2 months, which is quite better than that of general NSCLC patients with brain metastasis. Conclusion. Different patterns of relapse were observed in NSCLC patients treated with gefitinib. The new therapeutic strategy according to the mechanism of resistance to EGFR-TKI is warranted. © 2009 The Japan Lung Cancer Society.

    DOI: 10.2482/haigan.49.257

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  • First-Line Gefitinib for Patients With Advanced Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Without Indication for Chemotherapy 査読

    Akira Inoue, Kunihiko Kobayashi, Kazuhiro Usui, Makoto Maemondo, Shoji Okinaga, Iwao Mikami, Masahiro Ando, Koichi Yamazaki, Yasuo Saijo, Akihiko Gemma, Hitoshi Miyazawa, Tomoaki Tanaka, Kenji Ikebuchi, Toshihiro Nukiwa, Satoshi Morita, Koichi Hagiwara

    JOURNAL OF CLINICAL ONCOLOGY   27 ( 9 )   1394 - 1400   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)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    This multicenter phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations without indication for chemotherapy as a result of poor performance status (PS).
    Patients and Methods
    Chemotherapy-naive patients with poor PS (patients 20 to 74 years of age with Eastern Cooperative Oncology Group PS 3 to 4, 75 to 79 years of age with PS 2 to 4, and >= 80 years of age with PS 1 to 4) who had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method were enrolled and received gefitinib (250 mg/d) alone.
    Results
    Between February 2006 and May 2007, 30 patients with NSCLC and poor PS, including 22 patients with PS 3 to 4, were enrolled. The overall response rate was 66% (90% CI, 51% to 80%), and the disease control rate was 90%. PS improvement rate was 79% (P < .00005); in particular, 68% of the 22 patients improved from >= PS 3 at baseline to <= PS 1. The median progression-free survival, median survival time, and 1-year survival rate were 6.5 months, 17.8 months, and 63%, respectively. No treatment-related deaths were observed.
    Conclusion
    This is the first report indicating that EGFR mutation-positive patients with extremely poor PS benefit from first-line gefitinib. Because there previously has been no standard treatment for these patients with short life expectancy other than best supportive care, examination of EGFR mutations as a biomarker is recommended in this patient population.

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  • Change in patient satisfaction in outpatient chemotherapy unit - Comparison in 2005 and 2008 査読

    Junya Sato, Kazufumi Terui, Akemi Awatsu, Jugo Ito, Yasuo Saijo

    Japanese Journal of Cancer and Chemotherapy   36 ( 11 )   1935 - 1940   2009年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    We investigated the influences of the treatment environment, in terms of the increased number of treatments, introduction of regimen assessment and registration system, and the levels of specialization of the concerned medical professionals on patient satisfaction. We compared our results with those of a previous survey conducted in the outpatient chemotherapy unit of Hirosaki University Hospital. The patients were satisfied with respect to the privacy considerations and waiting time. However, a decrease in the patient instruction time led to slightly lower patient satisfaction. We concluded that it is useful to evaluate the quality of treatment in terms of patient satisfaction in a hospital.

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  • Randomized Phase II Trial Comparing Amrubicin With Topotecan in Patients With Previously Treated Small-Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 0402 査読

    Akira Inoue, Shunichi Sugawara, Koichi Yamazaki, Makoto Maemondo, Toshiro Suzuki, Kazunori Gomi, Shingo Takanashi, Chieko Inoue, Minoru Inage, Hiroshi Yokouchi, Hiroshi Watanabe, Toumei Tsukamoto, Yasuo Saijo, Osamu Ishimoto, Fumihiro Hommura, Toshihiro Nukiwa

    JOURNAL OF CLINICAL ONCOLOGY   26 ( 33 )   5401 - 5406   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)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation.
    Patients and Methods
    Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m(2) on days 1 through 3) or topotecan (1.0 mg/m(2) on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile.
    Results
    From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival.
    Conclusion
    Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

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  • Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation 査読

    Akira Inoue, Hong Xin, Takuji Suzuki, Masahiko Kanehira, Yoshio Kuroki, Tatsuro Fukuhara, Toshiaki Kikuchi, Makoto Maemondo, Toshihiro Nukiwa, Yasuo Saijo

    CANCER SCIENCE   99 ( 8 )   1679 - 1684   2008年8月

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

    Interstitial lung disease (ILD) is reported as a serious adverse event in lung cancer patients treated with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the mechanisms of ILD associated with gefitinib remain unknown. To address the molecular mechanisms of ILD-associated gefitinib, we determined the effect of gefitinib treatment on surfactant protein expression in vitro and in vivo. Gefitinib treatment suppressed surfactant protein (SP)-A expression in H441 human lung adenocarcinoma cells expressing SP-A, -B, -C and -D by inhibiting epidermal growth factor signal. Next, gefitinib (200 mg/kg) was given p.o. to the mice daily for 1 week. Daily administration of gefitinib gradually reduced SP-A level in the bronchoalveolar lavage fluid. When lipopolysaccharide (LPS) was instilled intratracheally to the mice pretreated with gefitinib for 1 week, lung inflammation by LPS was exacerbated and prolonged. This exacerbation of lung inflammation was rescued by intranasal administration of SP-A. These results demonstrated that pretreatment with gefitinib exacerbated LPS-induced lung inflammation by reducing SP-A expression in the lung. This study suggests that epidermal growth factor receptor tyrosine kinase inhibitor may reduce SP-A expression in the lungs of lung cancer patients and thus patients treated with epidermal growth factor receptor tyrosine kinase inhibitor may be susceptible to pathogens. (Cancer Sci 2008; 99: 1679-1684)

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  • Successful treatment of carcinomatous meningitis with gefitinib in a patient with lung adenocarcinoma harboring a mutated EGF receptor gene 査読

    Tatsuro Fukuhara, Yasuo Saijo, Tomohiro Sakakibara, Akira Inoue, Naoto Morikawa, Masayuki Kanamori, Ichiro Nakashima, Toshihiro Nukiwa

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE   214 ( 4 )   359 - 363   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)   出版者・発行元:TOHOKU UNIV MEDICAL PRESS  

    Carcinomatous meningitis is a severe complication of lung cancer. Although treatment with gefitinib, a tyrosine kinase inhibitor of epidermal growth factor (EGF) receptor, has been reported to be highly effective against lung cancers harboring a mutated EGF gene, its effect against carcinomatous meningitis is unknown. Here, we report successful treatment of carcinomatous meningitis with gefitinib in a lung cancer patient suffered from meningeal metastasis. A 62-year-old, non-smoking, Japanese male was admitted for headache, failing vision, and temporary loss of consciousness and was subsequently diagnosed with stage IV lung adenocarcinoma and carcinomatous meningitis. A tumor sample revealed the in-frame deletion of codons 746 to 750 (E746 to A750) in exon 19 of the EGF gene, which leads to constitutive activation of the tyrosine kinase domain and high-affinity binding of gefitinib. The patient's performance status was poor owing to progression of the meningitis and elevated cerebrospinal fluid (CSF) pressure. Combined treatment with gefitinib (250 mg/day) and whole-brain irradiation (36 Gray total) proved to be effective. It is noteworthy that the level of gefitinib in the CSF was less than 1% of the serum level (serum: 117 nM before drug re-administration and 132 nM 2 hrs later; CSF: 0.9 nM both before and 2 hrs after drug re-administration). Gefitinib treatment should be considered for patients with carcinomatous meningitis and lung adenocarcinoma harboring a mutated EGF gene.

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  • Opioid rotation from oral morphine to oral oxycodone in cancer patients with intolerable adverse effects: An open-label trial 査読

    Masaru Narabayashi, Yasuo Saijo, Seiichi Takenoshita, Masayuki Chida, Naohito Shimoyama, Takeshi Miura, Kazuhiko Tani, Kousuke Nishimura, Yusuke Onozawa, Toyoshi Hosokawa, Toshiyuki Kamoto, Tomoyasu Tsushima

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   38 ( 4 )   296 - 304   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)   出版者・発行元:OXFORD UNIV PRESS  

    Objective: We prospectively investigated the efficacy of opioid rotation from oral morphine to oral oxycodone in cancer patients who had difficulty in continuing oral morphine treatment because of inadequate analgesia and/or intolerable side effects.
    Methods: Twenty-seven patients were enrolled and 25 were evaluated. The rate of patients who achieved adequate pain control, which provided an indication of treatment success, was evaluated as primary endpoint. The acceptability and pharmacokinetics of oxycodone were evaluated in addition to the assessment of analgesic efficacy and safety during the study period.
    Results: In spite of intense pain, the morphine daily dose could not be increased in most patients before the study because of intolerable side effects. However, switching to oral oxycodone allowed similar to 1.7-fold increase as morphine equivalent dose. Consequently, 84.0% (21/25) of patients achieved adequate pain control. By the end of the study, all patients except one had tolerated the morphine-induced intolerable side effects (i.e. nausea, vomiting, constipation, drowsiness). Common side effects (> 10%) that occurred during the study were typically known for strong opioid analgesics, and most were mild to moderate in severity. A significant negative correlation between creatinine clearance (CCr) value and the trough concentrations of the morphine metabolites was observed. On the other hand, no significant correlation was found between CCr value and the pharmacokinetic parameters of oxycodone or its metabolites.
    Conclusions: For patients who had difficulty in continuing oral morphine treatment, regardless of renal function, opioid rotation to oral oxycodone may be an effective approach to alleviate intolerable side effects and pain.

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  • Adenocarcinoma with epidermal growth factor receptor gene mutations in three siblings 査読

    Tomohiro Sakakibara, Yasuo Saijo, Tatsuro Fukuhara, Kazunori Gomi, Akira Inoue, Osamu Ishimoto, Shunichi Sugawara, Toshihiro Nukiwa

    JOURNAL OF THORACIC ONCOLOGY   3 ( 3 )   311 - 313   2008年3月

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

    Sensitivity to an inhibitor of epidermal growth factor receptor (EGFR) kinase strongly correlates with EGFR somatic mutations in non-small cell lung cancer. These mutations are frequently found in patients with adenocarcinoma, never- or light-smokers, women, and East Asians. In this study, we show an aggregation of three non-small cell lung cancer cases with EGFR gene mutations in one family. The subjects were all female, never- or light-smokers with adenocarcinoma. Two of the patients responded to treatment with gefitimb. A genetic study of these cases would be useful in elucidating genetic susceptibility to lung cancer in persons with EGFR mutations.

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  • OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice 査読

    Jamal Zaini, Sita Andarini, Minoru Tahara, Yasuo Saijo, Naoto Ishii, Kazuyoshi Kawakami, Masaru Taniguchi, Kazuo Sugamura, Toshihiro Nukiwa, Toshiaki Kikuchi

    JOURNAL OF CLINICAL INVESTIGATION   117 ( 11 )   3330 - 3338   2007年11月

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

    The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-alpha-stimulated DC maturation was accompanied by increased expression of OX40 ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4(+) T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-gamma production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-gamma. production and CD69 expression, indicated that NKT cell activation by DCs presenting cc-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4(+) T cells, in the induction of antitumor immunity in tumor-bearing mice.

    DOI: 10.1172/JCI32693

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  • Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. 査読

    Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T, Matsumoto K, Nakamura T, Nukiwa T, Saijo Y

    Cancer Gene Therapy   14 ( 11 )   894 - 903   2007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)  

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  • Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. 査読

    Xin H, Kanehira M, Mizuguchi H, Hayakawa T, Kikuchi T, Nukiwa T, Saijo Y

    Stem cells (Dayton, Ohio)   25 ( 7 )   1618 - 1626   2007年7月

  • Phase II study of carboplatin combined with biweekly docetaxel for advanced non-small cell lung cancer 査読

    Osamu Ishimoto, Shunichi Sugawara, Akira Inoue, Takashi Ishida, Mitsuru Munakata, Sadahiro Koinumaru, Yukihiro Hasegawa, Toshiro Suzuki, Hiroshi Miki, Yasuo Saijo, Toshihiro Nukiwa

    JOURNAL OF THORACIC ONCOLOGY   1 ( 9 )   979 - 983   2006年11月

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

    Background: The combination of carboplatin and docetaxel has been considered one of the standard treatments for advanced nonsmall cell lung cancer (NSCLC). To investigate a safer and more convenient schedule for outpatient, we conducted a phase II study to evaluate the efficacy and the safety of carboplatin plus biweekly docetaxel for advanced NSCLC.
    Patients and Methods: Patients with stage IIIB, IV, or postoperative recurrent NSCLC with good performance status were administered docetaxel at a dose of 35 mg/m(2) on days 1 and 15 and carboplatin at an area under the curve (AUC) of 6 on day 1 every 4 weeks for at least three cycles.
    Results: Fifty patients were treated with median of three cycles (range 1-6). Grade 3/4 toxicities included neutropenia in 18 patients (36%), thrombocytopenia in 4 patients (8%), and anemia in 10 patients (20%). No patient experienced febrile neutropenia. Nonhematological toxicities were also mild to moderate, and there were no treatment-related deaths. The overall response rate was 30%, and the disease control rate was 70%. Among the elderly population, 54% of patients achieved partial response. Median progression-free survival was 4.8 months, and median overall survival was 11.8 months.
    Conclusions: Biweekly docetaxel plus carboplatin has a similar efficacy and lower toxicity compared with a standard triweekly regimen of docetaxel plus carboptatin, which is a suitable regimen for outpatients, including elderly patients.

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  • [A case of pulmonary Langerhans cell histiocytosis discovered by CT mass screening and followed by bronchoalveolar lavage]. 査読

    Watanabe H, Maemondo M, Okouchi S, Suzuki T, Kikuchi T, Tazawa R, Ebina M, Saijo Y, Hoshikawa Y, Nukiwa T

    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society   44 ( 11 )   869 - 873   2006年11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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  • CT検診で発見され、BALにより経過を観察したPulmonary Langerhans Cell Histiocytosisの1例

    渡辺 洋, 前門戸 任, 大河内 眞也, 鈴木 拓児, 菊地 利明, 田澤 立之, 海老名 雅仁, 西條 康夫, 星川 康, 貫和 敏博

    日本呼吸器学会雑誌   44 ( 11 )   869 - 873   2006年11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42歳女性。喫煙指数420。CT検診で両側上肺野に最大7mmの空洞性病変を多数認めた。気管支肺胞洗浄液中のCD1a陽性細胞数が高値であり、病理組織学的に気道周囲の線維化包巣内にS-100陽性細胞を認め、Pulmonary Langerhans Cell Histiocytosis(以下PLCH)と診断した。禁煙を励行し、3ヵ月後には瘢痕を残し空洞性病変は消失した。禁煙による画像所見の改善に伴い、気管支肺胞洗浄液中のCD1a陽性細胞数は減少し(4.9%→1.8%)、CD4/CD8比は上昇した(1.66→6.16)。PLCHの禁煙後のBAL経過の報告はなく、病態理解上、興味深い所見であった。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J03150&link_issn=&doc_id=20061120300016&doc_link_id=10018400949&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F10018400949&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

  • A phase I study of amrubicin combined with carboplatin for elderly patients with small-cell lung cancer 査読

    Akira Inoue, Koichi Yamazaki, Makoto Maemondo, Takuji Suzuki, Yuichiro Kimura, Mariko Kanbe, Hiroshi Isobe, Masaharu Nishimura, Yasuo Saijo, Toshihiro Nukiwa

    JOURNAL OF THORACIC ONCOLOGY   1 ( 6 )   551 - 555   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)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background: Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) with acceptable toxicities in previous studies. However, a combination regimen of platinum and amrubicin for elderly patients has not been reported. In this phase I study, the dose-limiting toxicity (DLT), the maximal tolerable dose (NITD), and the antitumor activity of a combination of amrubicin and carboplatin in elderly patients with SCLC were evaluated.
    Patients and Methods: Previously untreated elderly patients (>= 70 years old) with SCLC were enrolled in this study. Amrubicin was administered from day 1 to day 3, and carboplatin was administered on day 1 intravenously. The treatment was repeated every 3 weeks. Three escalating dose levels of amrubicin (mg/m(2))/carboplatin (area under the curve; AUC) (40/4.0, 40/5.0, and 45/5.0) were initially planned.
    Results: Twelve patients were enrolled. At level 1 (amrubicin 40 mg/m(2) and carboplatin AUC 4.0), all three patients experienced DLTs (grade 4 neutropenia >= 4 days, thrombocytopenia <20,000/mm(3), or grade 3 diarrhea), and this dose level was determined to be the MTD. At the reduced dose of level 0 (amrubicin 35 mg/m(2) and carboplatin AUC 4.0), although DLTs were observed in three of the nine patients, they were considered to be clinically not severe and could be managed. Non-hematological toxicities were mild or moderate and reversible. The objective response rate was 83%, and the median survival time was 12.7 months.
    Conclusions: The MTD of this combination was amrubicin 40 mg/m(2) and carboplatin AUC 4.0, and the recommended dose for a phase II trial is a combination of amrubicin 35 mg/m(2) and carboplatin AUC 4.0. We are now conducting a multicenter phase II trial of this regimen to determine the activity of this combination for elderly patients with SCLC.

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  • Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations 査読

    Akira Inoue, Takuji Suzuki, Tatsuro Fukuhara, Makoto Maemondo, Yuichiro Kimura, Naoto Morikawa, Hiroshi Watanabe, Yasuo Saijo, Toshihiro Nukiwa

    JOURNAL OF CLINICAL ONCOLOGY   24 ( 21 )   3340 - 3346   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)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    This study was undertaken to investigate the efficacy and the feasibility of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations.
    Patients and Methods
    The EGFR gene status in various tumor samples obtained from chemotherapy-naive advanced NSCLC patients was examined by DNA sequencing of EGFR exons 18 to 23. Patients harboring EGFR mutations received gefitinib (250 mg/d) alone. The response rate, progression-free survival (PFS), and toxicity profile were assessed prospectively.
    Results
    Between June 2004 and October 2005, 75 patients were examined for the EGFR status, and 25 patients (33%) harbored EGFR mutations. EGFR mutations were significantly frequent in females (P <.01) and never or light smokers (P <.001). Sixteen patients with EGFR mutations were enrolled onto the study. The overall response rate in these patients was 75% (95% Cl, 54% to 96%), and the disease control rate was 88% (95% Cl, 71% to 100%). The median PFS time of these patients was 9.7 months (95% Cl, 7.4 to 9.9 months). No life-threatening toxicity was observed.
    Conclusion
    Treatment with gefitinib alone for chemotherapy-naive NSCLC patients with EGFR mutations could achieve a high efficacy with acceptable toxicity. To assess the proper timing of gefitinib in such patients, a subsequent randomized trial comparing gefitinib with standard chemotherapy is warranted.

    DOI: 10.1200/JCO.2005.05.4692

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  • A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer 査読

    A Inoue, K Usui, O Ishimoto, N Matsubara, M Tanaka, M Kanbe, K Gomi, S Koinumaru, Y Saijo, T Nukiwa

    LUNG CANCER   52 ( 1 )   83 - 87   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)   出版者・発行元:ELSEVIER IRELAND LTD  

    We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small. cell lung cancer (NSCLC). Elderly patients (>= 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel. at a dose of 70 mg/m(2) on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2005.11.014

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  • Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer 査読

    T Fujiwara, N Tanaka, S Kanazawa, S Ohtani, Y Saijo, T Nukiwa, K Yoshimura, T Sato, Y Eto, S Chada, H Nakamura, H Kato

    JOURNAL OF CLINICAL ONCOLOGY   24 ( 11 )   1689 - 1699   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)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC).
    Patients and Methods
    Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 X 10(9) to 1 X 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m(2)). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response.
    Results
    Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the Carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease.
    Conclusion
    Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

    DOI: 10.1200/JCO.2005.03.4116

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  • Dendritic cells modified to express fractalkine/CX3CLI in the treatment of preexisting tumors 査読

    M Nukiwa, S Andarini, J Zaini, H Xin, M Kanehira, T Suzuki, T Fukuhara, H Mizuguchi, T Hayakawa, Y Saijo, T Nukiwal, T Kikuchi

    EUROPEAN JOURNAL OF IMMUNOLOGY   36 ( 4 )   1019 - 1027   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)   出版者・発行元:WILEY-V C H VERLAG GMBH  

    Fractalkine (CX3CL1) is a unique membrane-bound CX3C chemokine that serves as a potent chemoattractant for lymphocytes. The hypothesis of this study is that dendritic cells (DC) genetically modified ex vivo to overexpress fractalkine would enhance the T cell-mediated cellular immune response with a consequent induction of anti-tumor immunity to suppress tumor growth. To prove this hypothesis, established tumors of different mouse cancer cells (B16-F10 melanoma, H-2(b), and Colon-26 colon adenocarcinoma, H-2(d)) were treated with intratumoral injection of bone marrow-derived DC that had been modified in vitro with an RGD fiber-mutant adenovirus vector expressing mouse fractalkine (Ad-FKN). In both tumor models tested, treatment of tumor-bearing mice with Ad-FKN-transduced DC gave rise to a significant suppression of tumor growth along with survival advantages in the treated mice. Immunohistochemical analysis of tumors treated with direct injection of Ad-FKN-transduced DC demonstrated that the treatment prompted CD8(+) T cells and CD4(+) T cells to accumulate in the tumor milieu, leading to activation of immune-relevant processes. Consistent with the finding, the intratumoral administration of Ad-FKN-transduced DC evoked tumor-specific cytotoxic T lymphocytes, which ensued from in vivo priming of Th1 immune responses in the treated host. In addition, the anti-tumor effect provided by intratumoral injection of Ad-FKN-transduced DC was completely abrogated in CD4+ T cell-deficient mice as well as in CD8(+) T cell-deficient mice. These results support the concept that genetic modification of DC with a recombinant fractalkine adenovirus vector may be a useful strategy for cancer immunotherapy protocols.

    DOI: 10.1002/eji.200535549

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  • [Gene-based testing for respiratory disease]. 査読

    Saijo Y

    Nihon rinsho. Japanese journal of clinical medicine   63 Suppl 12   212 - 216   2005年12月

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  • Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth 査読

    S Nakao, T Kuwano, C Tsutsumi-Miyahara, S Ueda, YN Kimura, S Hamano, KH Sonoda, Y Saijo, T Nukiwa, RM Strieter, T Ishibashi, M Kuwano, M Ono

    JOURNAL OF CLINICAL INVESTIGATION   115 ( 11 )   2979 - 2991   2005年11月

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

    Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1 beta promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1 beta-induced angiogenesis and cell inflammation. IL-1 beta induced neovascularization in the mouse cornea at rates comparable to those of VEGF. Neutrophil infiltration occurred on day 2. Macrophage infiltration occurred on days 4 and 6. The anti-Gr-1 Ab-induced depletion of infiltrating neutrophils did not affect IL-1 beta- or VEGF-induced angiogenesis. The former was reduced in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice compared with wild-type mice. After day 4, clodronate liposomes, which kill macrophages, reduced IL-1 beta-induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1 beta-induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1 beta (LLC/IL-1 beta) developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1(-/-) mice. A COX-2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration in LLC/IL-1 beta . Thus, macrophage involvement might be a prerequisite for IL-1 beta-induced neovascularization and tumor progression.

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  • Involvement of fractalkine/CX3CL1 expression by dendritic cells in the enhancement of host immunity against Legionella pneumophila 査読

    T Kikuchi, S Andarini, H Xin, K Gomi, Y Tokue, Y Saijo, T Honjo, A Watanabe, T Nukiwa

    INFECTION AND IMMUNITY   73 ( 9 )   5350 - 5357   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)   出版者・発行元:AMER SOC MICROBIOLOGY  

    Legionnaires' disease is clinically manifested as severe pneumonia caused by Legionella pneumophila. However, the dendritic cell (DC)-centered immunological framework of the host defense against L. pneumophila has not been fully delineated. For this study, we focused on a potent chemoattractant for lymphocytes, fractalkine/CX3CL1, and observed that the fractalkine expression of DCs was somewhat up-regulated when they encountered L. pneumophila. We therefore hypothesized that fractalkine expressed by Legionella-capturing DCs is involved in the induction of T-cell-mediated immune responses against Legionella, which would be enhanced by a genetic modulation of DCs to overexpress fractalkine. In vivo immunization-challenge experiments demonstrated that DCs modified with a recombinant adenovirus vector to overexpress fractalkine (AdFKN) and pulsed with heat-killed Legionella protected immunized mice from a lethal Legionella infection and that the generation of in vivo protective immunity depended on the host lymphocyte subsets, including CD4(+) T cells, CD8(+) T cells, and B cells. Consistent with this, immunization with AdFKN/Legionella/DC induced significantly higher levels of serum anti-Legionella antibodies of several isotypes than those induced by control immunizations. Further analysis of spleen cells from the immunized mice indicated that the AdFKN/Legionella/DC immunization elicited Th1-dominated immune responses to L. pneumophila. These observations suggest that fractalkine may play an important role in the DC-mediated host defense against intracellular pathogens such as L. pneumophila.

    DOI: 10.1128/IAI.73.9.5350-5357.2005

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  • Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells 査読

    H Xin, T Kikuchi, S Andarini, S Ohkouchi, T Suzuki, T Nukiwa, Huqun, K Hagiwara, T Honjo, Y Saijo

    EUROPEAN JOURNAL OF IMMUNOLOGY   35 ( 5 )   1371 - 1380   2005年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-V C H VERLAG GMBH  

    The CX3C chemokine fractalkine (CX3CL1) exists as both a membrane-bound form promoting firm cell-cell adhesion and a soluble form chemoattracting leukocytes expressing its receptor CX3CR1. When adenoviral vector expressing mouse fractalkine (AdFKN) was transduced to the tumor cells, fractalkine was expressed as both membrane-bound form on the tumor cells and soluble form in the supernatant in vitro. Intratumoral injection of AdFKN (1x10(9)PFU/tumor) into C26 and B16F10 tumors resulted in marked reduction of tumor growth compared to control (C26: 86.5%, p< 0.001; B16F10: 85.5%,p< 0.001). Histological examination of tumor tissues revealed abundant infiltration of NK cells, dendritic cells, and CD8(+) T lymphocytes 3 and/or 6 days after treatment with AdFKN. Splenocytes from mice treated by AdFKN developed tumor-specific cytotoxic T cells, and thereby protected from rechallenging with parental tumor cells. Antitumor effects by AdFKN were completely abrogated in both NK cell-depleted mice and CD8(-/-) mice, and partially blocked in CD4(-/-) mice. These data indicated that fractalkine mediates antitumor effects by both NK cell-dependent and T cell-dependent mechanisms. This study suggests that fractalkine can be a suitable candidate for immunogene therapy of cancer because fractalkine induces both innate and adaptive immunity.

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  • Vaccination of dendritic cells loaded with interleukin-12-secreting cancer cells augments in vivo antitumor immunity: Characteristics of syngeneic and allogeneic antigen-presenting cell cancer hybrid cells 査読

    T Suzuki, T Fukuhara, M Tanaka, A Nakamura, K Akiyama, T Sakakibara, D Koinuma, T Kikuchi, R Tazawa, M Maemondo, K Hagiwara, Y Saijo, T Nukiwa

    CLINICAL CANCER RESEARCH   11 ( 1 )   58 - 66   2005年1月

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

    Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-p resenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.

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  • 肺癌形成過程におけるHGF antagonist NK4による血管新生抑制機序の検討 骨髄由来細胞の動態解析を中心として

    大河内 眞也, 秋山 健一, 太田 洋充, 前門戸 任, 菊池 利明, 田澤 立之, 海老名 雅仁, 辛 紅, 西條 康夫, 貫和 敏博

    日本癌学会総会記事   63回   496 - 497   2004年9月

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    記述言語:日本語   出版者・発行元:(一社)日本癌学会  

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  • Gene therapy with secretory leukoprotease inhibitor promoter-controlled replication-competent adenovirus for non-small cell lung cancer 査読

    M Maemondo, Y Saijo, K Narumi, T Kikuchi, K Usui, R Tazawa, K Matsumoto, T Nakamura, K Sasaki, M Takahashi, Y Niitsu, T Nukiwa

    CANCER RESEARCH   64 ( 13 )   4611 - 4620   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)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Secretory leukoprotease inhibitor (SLPI) is highly expressed in almost all non-small cell lung cancers (NSCLCs), but not in the majority of other tumor types. In an attempt to create a specific gene therapy for NSCLC, we constructed AdSLPI.E1AdB, an adenovirus vector with a double expression cassette consisting of E1A driven by the SLPI promoter gene followed by E1B-19K under the control of the cytomegalovirus (CMV) promoter that can selectively replicate only in NSCLC cells. Infection with AdSLPI.E1AdB yielded E1A protein expression and adenovirus replication resulting in a >100-fold increase of the virus titers only in SLPI-producing NSCLC cells (A549, H358, and HS24 cells). In contrast, neither E1A protein nor replication was detected in non-SLPI-producing HepG2 cells. Treatment with AdSLPI.E1AdB significantly inhibited the proliferation of NSCLC cells in vitro in a dose-dependent manner, whereas the cell growth of HepG2 or normal human bronchial epithelial cells was not affected by AdSLPI.E1AdB infection. Direct injection of AdSLPI.E1AdB into A549 and H358 tumors in nude mice resulted in a marked reduction in tumor growth compared with controls (A549, 57%, P < 0.02; H358, 67%, P < 0.03). Histological examination revealed the replication of AdSLPI.E1AdB and strong induction of necrosis and apoptosis. In addition, we evaluated the combination of AdSLPI.E1AdB and AdCMV.NK4 encoding NK4 protein, which has strong antiangiogenic activity. E1A expressed by AdSLPI.E1AdB trans-acts on the replication of AdCMV.NK4 and thus increases the expression of NK4. Injection of these two vectors into H358 tumors resulted in a more striking reduction of tumor growth compared with single injection of each vector. These results suggest that AdSLPI.E1AdB could provide a selective therapeutic modality for NSCLC and that the combination of AdSLPI.E1AdB and AdCMV.NK4 may be a more effective gene therapy for NSCLC.

    DOI: 10.1158/0008-5472.CAN-03-2549

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  • Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts 査読

    S Andarini, T Kikuchi, M Nukiwa, P Pradono, T Suzuki, S Ohkouchi, A Inoue, M Maemondo, N Ishii, Y Saijo, K Sugamura, T Nukiwa

    CANCER RESEARCH   64 ( 9 )   3281 - 3287   2004年5月

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

    OX40 ligand (OX40L), the ligand for OX40 on activated CD4(+) T cells, has adjuvant properties for establishing effective T-cell immunity, a potent effector arm of the immune system against cancer. The hypothesis of this study is that in vivo genetic engineering of tumor cells to express OX40L will stimulate tumor-specific T cells by the OX40L-OX40 engagement, leading to an induction of systemic antitumor immunity. To investigate this hypothesis, s.c. established tumors of three different mouse cancer cells (B16 melanoma, H-2(b); Lewis lung carcinoma, H-2(b); and Colon-26 colon adenocarcinoma, H-2(d)) were treated with intratumoral injection of a recombinant adenovirus vector expressing mouse OX40L (AdOX40L). In all tumor models tested, treatment of tumor-bearing mice with AdOX40L induced a significant suppression of tumor growth along with survival advantages in the treated mice. The in vivo AdOX40L modification of tumors evoked tumor-specific cytotoxic T lymphocytes in the treated host correlated with in vivo priming of T helper 1 immune responses in a tumor-specific manner. Consistent with the finding, the antitumor effect provided by intratumoral injection of AdOX40L was completely abrogated in a CD4(+) T cell-deficient or CD8(+) T cell-deficient condition. In addition, ex vivo AdOX40L-transduced B16 cells also elicited B16-specific cytotoxic T lymphocyte responses, and significantly suppressed the B16 tumor growth in the immunization-challenge experiment. All of these results support the concept that genetic modification of tumor cells with a recombinant OX40L adenovirus vector may be of benefit in cancer immunotherapy protocols.

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  • 高齢者進行非小細胞肺癌に対するカルボプラチン,パクリタキセル(毎週投与)併用療法の第2相試験

    井上 彰, 臼井 一裕, 西條 康夫, 田中 昌史, 石本 修, 大河内 眞也, 木村 雄一郎, 小犬丸 貞裕, 前門戸 任, 貫和 敏博

    日本呼吸器学会雑誌   42 ( 増刊 )   180 - 180   2004年3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  

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  • Pharmacokinetic analysis of combination chemotherapy with carboplatin and etoposide in small-cell lung cancer patients undergoing hemodialysis. 査読

    Inoue A, Saijo Y, Kikuchi T, Gomi K, Suzuki T, Maemondo M, Miki M, Sato T, Nukiwa T

    Ann Oncol   15 ( 1 )   51 - 54   2004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)  

    DOI: 10.1093/annonc/mdh008

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  • Identification of a CTL-directed epitope encoded by an intron of the putative tumor suppressor gene testin of the common fragile site 7G region: a peptide vaccine candidate for HLA-B52(+) and HLA-62(+) cancer patients 査読

    S Ohkouchi, N Kawamoto, M Koga, F Sakanashi, S Shichijo, Y Saijo, T Nukiwa, K Itoh, A Yamada

    EUROPEAN JOURNAL OF IMMUNOLOGY   33 ( 11 )   2964 - 2973   2003年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-V C H VERLAG GMBH  

    Although cytotoxic T lymphocyte (CTL)-directed epitopes binding to human histocompatibility leukocyte antigen (HLA)-A molecules have been well characterized, those binding to HLA-B molecules have not, largely due to their large diversity. In this study we report a unique cancer antigen gene, tentatively named Testin-related gene (TRG), which encodes CTL-directed epitopes on the HLA-B52 molecules most frequently expressed in Asians. TRG is located in an intron of the putative tumor suppressor gene Testin in the common fragile site 7G region at 7q31.2. TRG mRNA was expressed in the majority of cancer cells and cancer tissue tested, whereas it was scarcely expressed in the majority of normal tissues, and only low-level expression of TRG was detected in the heart, liver, and pancreas. One TRG peptide had the ability to induce HLA-B52-restricted CTL cytotoxic to TRG(+) tumor cells in peripheral blood mononuclear cells (PBMC) of epithelial cancer patients. This peptide also induced HLA-B62-restricted and tumor-reactive CTL in PBMC of cancer patients. Therefore, this TRG-derived peptide might be appropriate for use in peptide-based immunotherapy for relatively large numbers of cancer patients throughout the world, given that 34% of Japanese, 27% of Chinese, and 13% of Caucasians express either HLA-B52 or HLA-B62 molecules.

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  • IL-12産生遺伝子改変癌細胞及びallogeneic樹状細胞の融合細胞による癌免疫療法

    鈴木 拓児, 福原 達朗, 中村 晃, 田中 昌史, 西條 康夫, 田澤 立之, 前門戸 任, 菊地 利明, 萩原 弘一, 貫和 敏博

    基盤的癌免疫研究会総会抄録   7回   49 - 49   2003年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers 査読

    K Usui, Y Saijo, K Narumi, S Koyama, M Maemondo, T Kikuchi, R Tazawa, K Hagiwara, Y Ishibashi, S Ohta, T Nukiwa

    ONCOGENE   22 ( 17 )   2655 - 2663   2003年5月

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

    Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to be a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (DeltaN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-x(L) owing to the lack of the BH3 domain needed to interact with the antiapoptotic Bcl-2 family molecules. In this study, we used the Cre-loxP system that allowed us to propagate adenoviruses expressing DeltaN Bax, and investigated the effects of the DeltaN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell tines. DeltaN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the DeltaN Bax-induced cell death was not inhibited by the pan-caspase inhibitor z-VAD-fmk, suggesting that DeltaN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing AN Bax into A549 tumors in Balb/c nude mice showed a significantly stronger suppression of tumor growth (74%) than full-length Bax (25%) compared to the control. Our results suggest that DeltaN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.

    DOI: 10.1038/sj.onc.1206331

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  • Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules. 査読 国際誌

    Seiji Yano, Hiroshi Nokihara, Akihiko Yamamoto, Hisatsugu Goto, Hirohisa Ogawa, Takanori Kanematsu, Toyokazu Miki, Hisanori Uehara, Yasuo Saijo, Toshihiro Nukiwa, Saburo Sone

    Cancer science   94 ( 3 )   244 - 52   2003年3月

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    記述言語:英語  

    We examined whether interleukin-1 (IL-1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL-1beta enhanced expression of various cytokines (IL-6, IL-8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule-1 (ICAM-1) by A549, PC14, RERF-LC-AI, and SBC-3 cells expressing IL-1 receptors. A549 cells transduced with human IL-1beta-gene with the growth-hormone signaling-peptide sequence (A549/IL-1beta) secreted a large amount of IL-1beta protein. Overexpression of IL-1beta resulted in augmentation of expression of the cytokines, ICAM-1, and matrix metalloproteinase-2 (MMP-2). A549/IL-1beta cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti-IL-1beta antibody inhibited formation of lung metastasis by A549/IL-1beta cells. Moreover, A549/IL-1beta cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL-1beta cells. Histological analyses showed that more host-cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL-1beta cells, compared with tumors derived from control A549 cells. These findings suggest that IL-1beta facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis.

    DOI: 10.1111/j.1349-7006.2003.tb01428.x

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  • 癌細胞と抗原提示細胞の融合細胞を用いた抗腫瘍効果の検討 syngeneicとallogeneic及び樹状細胞とマクロファージの比較

    鈴木 拓児, 福原 達朗, 中村 晃, 田中 昌史, 西條 康夫, 菊地 利明, 前門戸 任, 田澤 立之, 萩原 弘一, 貫和 敏博

    加齢医学研究所雑誌   54 ( 1〜2 )   54 - 54   2003年3月

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    記述言語:日本語   出版者・発行元:東北大学加齢医学研究所  

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  • 肺腺癌由来新規癌精巣抗原TRG(TESTIN related gene)ペプチドを用いたHLA-B52拘束性CTLの誘導

    大河内 眞也, 山田 亮, 七條 茂樹, 西條 康夫, 貫和 敏博, 伊東 恭悟

    日本呼吸器学会雑誌   41 ( 増刊 )   178 - 178   2003年3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  

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  • Gefitinib(イレッサ)投与後に間質性肺炎を発症した進行非小細胞肺癌の4例

    清水川 稔, 井上 彰, 海老名 雅仁, 小西 一央, 大河内 眞也, 五味 和紀, 前門戸 任, 西條 康夫, 貫和 敏博

    日本呼吸器学会雑誌   41 ( 増刊 )   104 - 104   2003年3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  

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  • Severe acute interstitial pneumonia and gefitinib 査読

    A Inoue, Y Saijo, M Maemondo, K Gomi, Y Tokue, Y Kimura, M Ebina, T Kikuchi, T Moriya, T Nukiwa

    LANCET   361 ( 9352 )   137 - 139   2003年1月

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

    Gefitinib is an oral selective inhibitor of the epidermal growth factor receptor tyrosine kinase that is an effective treatment for patients with advanced non-small cell lung cancer who do not respond to platinum-based chemotherapy. We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities In chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.

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  • 癌細胞と抗原提示細胞の融合細胞を用いた抗腫瘍効果の検討 syngeneicとallogeneic及び樹状細胞とマクロファージの比較

    鈴木 拓児, 福原 達朗, 中村 晃, 田中 昌史, 西條 康夫, 菊地 利明, 前門戸 任, 田澤 立之, 萩原 弘一, 貫和 敏博

    日本癌学会総会記事   61回   179 - 179   2002年10月

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    記述言語:日本語   出版者・発行元:日本癌学会  

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  • Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: In vivo analysis of tumor-stromal interaction 査読

    Y Saijo, M Tanaka, M Miki, K Usui, T Suzuki, M Maemondo, Hong, X, R Tazawa, T Kikuchi, K Matsushima, T Nukiwa

    JOURNAL OF IMMUNOLOGY   169 ( 1 )   469 - 475   2002年7月

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

    Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240 %, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and > 10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

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  • Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy 査読

    M Maemondo, K Narumi, Y Saijo, K Usui, M Tahara, R Tazawa, K Hagiwara, K Matsumoto, T Nakamura, T Nukiwa

    MOLECULAR THERAPY   5 ( 2 )   177 - 185   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)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Hepatocyte growth factor (HGF) affects tumor growth/invasion and tumor neovascularization. A proposed HGF antagonist, NK4 (an amino-terminal kringle-domain peptide of HGF), inhibits tumor growth/invasion through the competition of HGF binding to its receptor, c-Met, and acts as an angiogenesis inhibitor. To investigate the in vivo effect of NK4 gene transfer, we constructed an adenovirus vector expressing human NK4 (AdCMV.NK4). Human lung cancer cell lines (A549 and H358) infected in vitro with AdCMV.NK4 yielded NK4 protein without a change in the cell growth rate. In contrast, direct injection of AdCMV.NK4 (1 x 10(9) pfu, twice) into established subcutaneous tumors in BALB/c nu/nu mice resulted in suppression of the tumors by 64% for A549 or by 91% for H358 compared with controls (P < 0.02 or P < 0.01, respectively). Counting of the tumor vessels revealed suppressed vascularity by 57% in H358 tumors when using AdCMV.NK4 (P < 0.0001). Furthermore, systemic NK4 delivery by intraperitoneal injection of AdCMV.NK4 effectively suppressed both angiogenesis in the Matrigel assay (86% reduction, P < 0.032), subcutaneous tumor growth in vivo (by 65% for H358, P < 0.001), and hematogenous lung metastases without obvious side effects. These results indicate that NK4 elicits tumor-growth suppression in vivo through its anti-angiogenic activity and anti-HGF activity and that NK4 gene transfer can be an effective tool in the treatment of cancer.

    DOI: 10.1006/mthe.2002.0533

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  • Gene transfer of thromboxane A(2) synthase and prostaglandin I-2 synthase antithetically altered tumor angiogenesis and tumor growth 査読

    P Pradono, R Tazawa, M Maemondo, M Tanaka, K Usui, Y Saijo, K Hagiwara, T Nukiwa

    CANCER RESEARCH   62 ( 1 )   63 - 66   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)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Cyclooxygenase, involved in tumor growth and angiogenesis, converts arachidonic acid to prostaglandin (PG)H-2, which is immediately converted to bioactive prostanoids including PGE(2), PGD(2), thromboxane (TX)A(2) and PGI(2). To test the hypothesis that changes in the prostanoid profile alter cancer growth, we transduced the retroviral vectors carrying TXA(2) synthase cDNA or PGI(2) synthase cDNA to colon-26 adenocarcinoma cells and subsequently inoculated each transformant to syngeneic BALB/c mice. Tumors derived from TXA(2) synthase transformants grew faster (280%, day 8, versus null-vector control; P < 0.05) and showed more abundant vasculature (204%, versus null-vector control; P < 0.01), whereas tumors from PGI(2) synthase transformants presented opposite effects. These effects by the transgenes were reversed by administration of specific inhibitors. These results suggest that the profile of downstream metabolites of cyclooxygenase in cancer cells can be a determinant for tumor development.

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  • High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer 査読

    O Ishimoto, Y Saijo, K Narumi, Y Kimura, M Ebina, N Matsubara, N Asou, Y Nakai, T Nukiwa

    ONCOLOGY   63 ( 1 )   70 - 75   2002年

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

    Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than nonhemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion. Copyright (C) 2002 S. Karger AG, Basel.

    DOI: 10.1159/000065723

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  • 2.Bronchioloalveolar cell carcinomaに対してZD1839投与により著しい肺浸潤影の改善を認めた1例(支部会(記録))(第28回 日本気管支学会東北支部会)

    前門戸 任, 小西 一央, 西條 康夫, 榊原 智博, 田中 昌史, 田澤 立之, 萩原 弘一, 貫和 敏博, 蝦名 昭男

    気管支学   24 ( 7 )   564 - 564   2002年

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本呼吸器内視鏡学会  

    DOI: 10.18907/jjsre.24.7_564_2

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  • Administration of wild-type p53 adenoviral vector synergistically enhances the cytotoxicity of anti-cancer drugs in human lung cancer cells irrespective of the status of p53 gene. 査読

    Inoue A, Narumi K, Matsubara N, Sugawara S, Saijo Y, Satoh K, Nukiwa T

    Cancer Lett   157 ( 1 )   105 - 112   2000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)  

    DOI: 10.1016/S0304-3835(00)00480-8

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  • Expression of the 37-kDa laminin binding protein in murine lung tumor cell correlates with tumor angiogenesis. 査読

    Tanaka M, Narumi K, Isemura M, Abe M, Sato Y, Abe T, Saijo Y, Nukiwa T, Satoh K

    Cancer Lett   153 ( 1月2日 )   161 - 168   2000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)  

    DOI: 10.1016/S0304-3835(00)00365-7

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  • [Case of alveolar proteinosis associated with pulmonary aspergillosis]. 査読

    Kobayashi T, Ebina M, Oshima M, Shimizu M, Uchiyama M, Saijo Y, Watanabe A, Kanwa T

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   88   135 - 137   1999年1月

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    出版者・発行元:1  

    DOI: 10.2169/naika.88.135

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  • HGFcDNA組込みAdenovirus vectorによる薬剤性肺傷害に対する遺伝子治療

    中村 晃, 八重柏 政宏, 西條 康夫, 阿部 達也, 佐藤 研, 貫和 敏博

    加齢医学研究所雑誌   50 ( 1 )   46 - 46   1999年1月

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    記述言語:日本語   出版者・発行元:東北大学加齢医学研究所  

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  • [Gamma-knife radiosurgery for metastatic brain tumors from primary lung cancer]. 査読

    Uchiyama B, Satoh K, Saijo Y, Joukura E, Boku E, Fujimura S, Abe Y, Nakai Y, Ookuda K, Nukiwa T

    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society   36 ( 6 )   503 - 508   1998年6月

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  • Expression of nucleolar protein p120 in human lung cancer: Difference in histological types as a marker for proliferation 査読

    B Uchiyama, Y Saijo, N Kumano, T Abe, S Fujimura, K Ohkuda, M Handa, K Satoh, T Nukiwa

    CLINICAL CANCER RESEARCH   3 ( 10 )   1873 - 1877   1997年10月

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

    The function of proliferation-associated nucleolar protein p120 is unclear, A recent report that a yeast protein, NOP2, 67% homologous to human p120, is up-regulated during the onset of growth and influences the morphology of the nucleolus supports the notion that this protein could serve as a marker for proliferation in neoplastic cells, Lung cancer is characteristic in that different histological types show different biological features, We attempted to evaluate the levels of p120 expression in resected human lung cancer tissues of different histological types and the relation of p120 expression and cell proliferation using human lung cancer cell lines, When 37 frozen specimens of human lung cancer and normal lung were stained with a p120 monoclonal antibody, the nucleoli of cancer cells were positively stained, whereas a few macrophages in normal lung revealed only weak staining, The labeling index of p120 in squamous cell carcinoma (67.7 +/- 12.4%) was significantly higher than that in adenocarcinoma (35.3 +/- 12.6%) or in large cell carcinoma (30.1 +/- 17.3%; P < 0.01). In six human lung cancer cell lines and one normal lung fibroblast cell line cultured bt vitro, there was a significant correlation between S-phase fraction and p120 mRNA (r = 0.851, P < 0.02)/p120 protein (r = 0.869, P < 0.01) or between doubling time and p120 protein (r = -0.928, P < 0.01), In the context of the reports that indicate higher [H-3]thymidine incorporation and shorter doubling time in the squamous cell carcinoma, these results indicate that p120 can be a marker for proliferation in human lung cancer cells in vivo and in vitro, and that it has an important function in the cell cycle of tumor proliferation.

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  • Rapidly progressive primary adenocarcinoma of the lung with signet-ring cells responding to 5-fluorouracil and leucovorin: A case report 査読

    Makoto Maemondo, Yasuo Saijo, Masahito Ebina, Tatsuya Abe, Masahiro Yaekashiwa, Ken Satoh, Toshihiro Nukiwa

    International Journal of Clinical Oncology   2 ( 1 )   47 - 50   1997年

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

    A 47-year-old female patient with a tumor mass in the left upper lung was admitted to our hospital. Needle biopsy of the tumor revealed signet-ring cell carcinoma, which is relatively rare in the lung. Since no other primary site was found, she was diagnosed with primary lung adenocarcinoma with signet-ring cells. The primary tumor showed rapid growth. She was first treated with combination chemotherapy consisting of continuous 5-FU infusion, leucovorin, and CDDP. Although the size of the primary tumor was markedly diminished, a new metastatic lesion appeared after chemotherapy. Subsequent continuous 5-FU infusion and leucovorin without CDDP chemotherapy controlled aggressive growth of the primary tumor for several months. This case suggests that 5-FU should be included in the anticancer regimen for primary signet-ring cell carcinoma of the lung. © JSCO/CLJ 1997.

    DOI: 10.1007/BF02492597

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  • 33 HTLV-I 随伴性びまん性肺疾患 (HAB) 4 例における気管支肺胞洗浄 (BAL) の検討(BAL 3)

    新藤 哲, 内山 美寧, 西條 康夫, 大島 美和子, 堀越 理紀, 阿部 達也, 中井 祐之, 貫和 敏博

    気管支学   18 ( 3 )   271 - 271   1996年

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本呼吸器内視鏡学会  

    DOI: 10.18907/jjsre.18.3_271_1

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  • Protein Kinase C Activity in Human Leukemia Cell Lines with Reference to Sensitivity to Antineoplastic Agents.

    SUGAWARA SHUNICHI, KUMANO NOBUKO, SAIJO YASUO, SUZUKI SHUJI, NUMATA YUKA, SATO GEORGE, MOTOMIYA MASAKICHI

    The Tohoku Journal of Experimental Medicine   168 ( 2 )   393 - 396   1992年

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    記述言語:英語   出版者・発行元:Tohoku University Medical Press  

    SUGAWARA, S., KUMANO, N., SAIJO, Y., SUZUKI, S., NUMATA, Y., SATO, G. and MOTOMIYA, M. <i>Protein Kinase C Activity in Human Leukemia Cell Lines with</i> <i>Reference to Sensitivity to Antineoplastic Agents</i>. Tohoku J. Exp. Med., 1992, <b>168</b> (2), 393-396- Protein kinase C (PKC) regulates many cellular processes. In view of its possible relevance to the drug resistance, the levels of PKC activity were assessed in human leukemia cell lines with reference to the sensitivity to antineoplastic agents. K562/ADM exhibited approximately 2-fold higher levels of PKC activity as compared with the parental K562. After a 1-hr preincubation with Adriamycin (ADM) (0.5, 1, 10μM), PKC activity in K562 tended to increase dose-dependently, while no substantial alteration was found in K562/ADM. Cisplatin (CDDP) or etoposide was of no effect. The activity in THP-1/E was slightly lower than THP-1, and the basal level stayed unchanged with any one of the above durgs. These results suggest that in K562 increase in PKC activity with ADM may play a role in the process of acquisition of resistance.- protein kinase C; antineoplastic agents; human leukemia cell lines; drug resistance

    DOI: 10.1620/tjem.168.393

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  • REDUCED TOPOISOMERASE-II-MEDIATED DNA CLEAVAGE IN VP-16 RESISTANT HUMAN LEUKEMIC-CELL LINE 査読

    Y SAIJO, K SATOH, Y TOKUE, N KUMANO, M MOTOMIYA

    ANTICANCER RESEARCH   11 ( 1 )   445 - 448   1991年1月

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

    Drug resistance in the VP-16 resistant human leukemic cell line (THP-1/E) was studied the possible relavance of topoisomerase II activity. Strand - passing activity in crude nuclear extract from sensitive and resistant cells was comparable and equally sensitive to inhibition by VP-16. However, it was demonstrated that VP-16 - mediated pBR322 DNA cleavage in the presence of nuclear extract from resistant cells was reduced to one-tenth of that from sensitive cells. These results suggested that the resistance of THP-1/E cells to VP-16 was due to reduced DNA cleavage activity.

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  • ESTABLISHMENT OF AN ETOPOSIDE (VP-16)-RESISTANT SUBLINE OF THP-1 HUMAN MONOCYTIC LEUKEMIA-CELL LINE 査読

    Y SAIJO, N KUMANO, S SUZUKI, S KOINUMARU, S SUGAWARA, K OIZUMI, M MOTOMIYA

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE   157 ( 3 )   215 - 219   1989年3月

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

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  • Characterization of resistance to VP-16 in human leukemic cell line.

    SAIJO YASUO, KUMANO NOBUKO, TOKUE YUTAKA, SATOH KEN, OIZUMI KOTARO, MOTOMIYA MASAKICHI

    The Tohoku Journal of Experimental Medicine   159 ( 4 )   299 - 306   1989年

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    記述言語:英語   出版者・発行元:Tohoku University Medical Press  

    SAIJO, Y., KUMANO, N., TOKUE, Y., SATOH, K., OIZUMI, K. and MOTOMIYA, M. <i>Characterization of Resistance to VP-16 in Human Leukemic Cell Line</i>. Tohoku J. Exp. Med., 1989, <b>159</b> (4), 299-306-Resistance mechanism was studied in the VP-16-resistant human leukemic cell line (THP-1/E) which was developed by continuous drug exposure. The drug uptake and efflux studies revealed no decrease in net cellular drug accumulation. VP-16-induced DNA single- and double-strand breaks in the whole THP-1/E cells decreased significantly compared to the sensitive counterpart as assessed by alkaline elution methods. Decrease in DNA SSBs was also observable in the isolated nuclei from the THP-1/E cells. The resistance to VP-16 in THP-1/E appeared to be independent of altered membrane permeability, and more likely to be associated with decreased VP-16-mediated DNA cleavage.

    DOI: 10.1620/tjem.159.299

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