2021/12/27 更新

写真a

シエン カズヒコ
枝園 和彦
SHIEN Kazuhiko
所属
岡山大学病院 講師
職名
講師
ホームページ
外部リンク

学位

  • 博士(医学) ( 岡山大学 )

研究キーワード

  • Lung Cancer

  • Mesothelioma

  • 胸部外科

  • 呼吸器外科

  • 肺癌

  • 悪性胸膜中皮腫

  • Thoracic Surgery

研究分野

  • ライフサイエンス / ゲノム生物学

  • ライフサイエンス / 呼吸器外科学

  • ライフサイエンス / 腫瘍生物学

経歴

  • 岡山大学病院   新医療研究開発センター   講師

    2021年4月 - 現在

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  • 厚生労働省   医政局研究開発振興課   課長補佐

    2019年4月 - 2021年3月

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  • 岡山大学病院呼吸器外科   助教

    2016年4月 - 2019年3月

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  • 日本学術振興会   海外特別研究員

    2014年4月 - 2016年3月

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  • テキサス大学MDアンダーソンがんセンター   博士研究員

    2014年4月 - 2016年3月

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

    2013年4月 - 2014年3月

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

    2010年4月 - 2013年3月

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▼全件表示

所属学協会

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論文

  • YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development. 国際誌

    Miwa Fujihara, Tadahiko Shien, Kazuhiko Shien, Ken Suzawa, Tatsuaki Takeda, Yidan Zhu, Tomoka Mamori, Yusuke Otani, Ryo Yoshioka, Maya Uno, Yoko Suzuki, Yuko Abe, Minami Hatono, Takahiro Tsukioki, Yuko Takahashi, Mariko Kochi, Takayuki Iwamoto, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

    International journal of molecular sciences   22 ( 23 )   2021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)  

    Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

    DOI: 10.3390/ijms222312809

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  • Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. 国際誌

    Akihiro Miura, Daisuke Yamada, Masahiro Nakamura, Shuta Tomida, Dai Shimizu, Yan Jiang, Tomoka Takao, Hiromasa Yamamoto, Ken Suzawa, Kazuhiko Shien, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka, Takeshi Takarada

    International journal of cancer   149 ( 8 )   1593 - 1604   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

    DOI: 10.1002/ijc.33713

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  • Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice

    Kentaro Nakata, Mikio Okazaki, Dai Shimizu, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Daiki Ousaka, Toshiaki Ohara, Akihiro Matsukawa, Masahiro Nishibori, Shinichi Toyooka

    Biochemical and Biophysical Research Communications   573   164 - 170   2021年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.bbrc.2021.08.015

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  • Lung transplantation for idiopathic multicentric Castleman disease: potential efficacy and tolerability of a humanized anti-interleukin-6 receptor monoclonal antibody. 国際誌

    Yasuaki Tomioka, Shinji Otani, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Surgical case reports   7 ( 1 )   209 - 209   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease caused by the overrepresentation of interleukin-6 (IL-6). Tocilizumab (TCZ) is a humanized monoclonal antibody that binds to the IL-6 receptor and is approved for the treatment of iMCD. The efficacy and tolerability of TCZ in patients with iMCD undergoing lung transplantation (LTx) remain unknown. CASE PRESENTATION: We present the case of a 48-year-old iMCD patient with end-stage lung disease (ESLD) who was successfully treated with cadaveric single-LTx. Intravenous TCZ was used to stabilize the iMCD patient every 2 weeks, except for withdrawal immediately after LTx. At 32 month post-transplant, the patient remained asymptomatic without evidence of rejection, development of de novo donor-specific antibody (DSA), and recurrent iMCD in the native lung. CONCLUSIONS: Single-LTx can be a feasible treatment option for ESLD caused by iMCD. TCZ can be used safely and may be beneficial in recipients with iMCD, and TCZ in combination with usual immunosuppression can be helpful in stabilizing iMCD patients pre- and post-LTx.

    DOI: 10.1186/s40792-021-01297-2

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  • Robot-assisted thoracoscopic lobectomy for severe incomplete interlober fissure. 国際誌

    Mikio Okazaki, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

    Journal of surgical case reports   2021 ( 8 )   rjab336   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An incomplete interlobar fissure makes thoracoscopic lobectomy difficult and is predictive of morbidity after thoracoscopic lobectomy. This report demonstrates the robot-assisted thoracoscopic (RATS) lobectomy technique for patients with severe incomplete interlobar fissures. A fissureless approach was chosen for pulmonary resection. Near-infrared fluorescence imaging with intravenous indocyanine green (ICG) was used to detect the interlobar line after transection of the bronchus, pulmonary artery and vein. Interlobar fissure was identified and divided by robotic staplers. This combined technique using ICG and fissureless lobectomy made RATS lobectomy safe for patients with severe incomplete interlobar fissures.

    DOI: 10.1093/jscr/rjab336

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  • Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Non-small-cell Lung Cancer Treated with Trimodality Therapy. 国際誌

    Tsudaka S, Yamamoto H, Sato H, Katsui K, Suzawa K, Shien K, Miyoshi K, Otani S, Okazaki M, Sugimoto S, Yamane M, Kiura K, Kanazawa S, Toyooka S

    Annals of surgical oncology   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Current evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in several types of cancer. In this study, we aimed to evaluate the prognostic impact of clinicopathological factors, including postoperative NLR, in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) who underwent surgery after chemoradiotherapy (CRT) with or without postoperative adjuvant chemotherapy. METHODS: The medical records of LA-NSCLC patients treated with trimodality therapy at our institution between June 1999 and May 2019 were reviewed. The association between several clinicopathological factors and overall survival (OS) was analyzed. RESULTS: A total of 168 patients were included in this study. Regarding the prognosis, the 5-year OS rate was 68.1%, and the 2-year recurrence-free survival rate was 66.1% in the entire population. In multivariate analysis, we identified that high postoperative NLR, not pretreatment or preoperative NLR, was one of the independent factors for unfavorable OS (NLR high vs NLR low; hazard ratio = 2.45, 95% confidence interval: 1.53-3.94, p < 0.001). In addition, among patients with high postoperative NLR, patients who received postoperative adjuvant chemotherapy showed significantly better 5-year OS compared with those who did not (p = 0.016). On the other hand, postoperative adjuvant chemotherapy had no impact on the prognosis in patients with low NLR (p = 0.19). CONCLUSIONS: Our results suggest that high postoperative NLR was not only an independent unfavorable prognostic factor in patients with LA-NSCLC who were treated with trimodality therapy, but also a promising indicator for postoperative treatment in this population.

    DOI: 10.1245/s10434-021-09690-9

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  • Covalent N-arylation by the pollutant 1,2-naphthoquinone activates the EGF receptor

    Kengo Nakahara, Kyohei Hamada, Tomoki Tsuchida, Nobumasa Takasugi, Yumi Abiko, Kazuhiko Shien, Shinichi Toyooka, Yoshito Kumagai, Takashi Uehara

    Journal of Biological Chemistry   296   100524 - 100524   2021年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier {BV}  

    DOI: 10.1016/j.jbc.2021.100524

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  • The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. 国際誌

    Araki K, Kinoshita R, Tomonobu N, Gohara Y, Tomida S, Takahashi Y, Senoo S, Taniguchi A, Itano J, Yamamoto KI, Murata H, Suzawa K, Shien K, Sakaguchi M

    Journal of molecular medicine (Berlin, Germany)   99 ( 1 )   131 - 145   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

    DOI: 10.1007/s00109-020-02001-x

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  • A Giant Thymic Cyst Accompanied by Acute Mediastinitis.

    Miura A, Shien K, Toji T, Otani S, Yamamoto H, Okazaki M, Sugimoto S, Soh J, Yamane M, Toyooka S

    Acta medica Okayama   74 ( 5 )   431 - 433   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis.

    DOI: 10.18926/amo/60804

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  • Chronic lung injury after trimodality therapy for locally advanced non-small cell lung cancer.

    Soh J, Sugimoto S, Namba K, Miura A, Shiotani T, Yamamoto H, Suzawa K, Shien K, Yamamoto H, Okazaki M, Katsui K, Yamane M, Kiura K, Kanazawa S, Toyooka S

    The Annals of thoracic surgery   2020年10月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.athoracsur.2020.07.068

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  • Effectiveness of scheduled intravenous acetaminophen in the postoperative pain management of video-assisted thoracic surgery.

    Shikatani Y, Soh J, Shien K, Kurosaki T, Ohtani S, Yamamoto H, Taniguchi A, Okazaki M, Sugimoto S, Yamane M, Oto T, Morimatsu H, Toyooka S

    Surgery today   51 ( 4 )   589 - 594   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: The scheduled administration of intravenous acetaminophen (scheduled-IV-AcA) is one of the more effective multimodal analgesic approaches for postoperative pain in abdominal/orthopedic surgeries. However, there is little evidence concerning scheduled-IV-AcA after general thoracic surgery, especially when limited to video-assisted thoracoscopic surgery (VATS). We investigated the efficacy of scheduled-IV-AcA administration in patients after undergoing VATS. METHODS: Ninety-nine patients who underwent VATS lobectomy or segmentectomy via an 8-cm access window and 1 camera port were retrospectively reviewed by categorizing them into groups either with scheduled-IV-AcA (Group AcA: n = 29) or without it (Group non-AcA: n = 70). Group AcA received 1 g of IV-AcA every 6 h from the end of the operation until the end of POD2. Postoperative pain was measured using a numeric rating scale (NRS) three times per day until discharge. RESULTS: NRS scores were significantly lower in Group AcA with motion (on POD1 to the first point of POD2) than in Group non-AcA. Group non-AcA was also more likely to use additional analgesics than Group AcA (39% vs. 17%, p = 0.058). CONCLUSIONS: Scheduled-IV-AcA administration is a safe and effective multimodal analgesic approach in patients undergoing VATS pulmonary resection via an 8-cm access window.

    DOI: 10.1007/s00595-020-02127-y

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  • Prognostic nutrition index affects the prognosis of patients undergoing trimodality therapy for locally advanced non-small cell lung cancer.

    Soh J, Suzawa K, Shien K, Otani S, Yamamoto H, Okazaki M, Sugimoto S, Katsui K, Yamane M, Kiura K, Kanazawa S, Toyooka S

    Surgery today   50 ( 12 )   1610 - 1618   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Trimodality therapy, comprised of induction chemoradiotherapy (iCRT) followed by surgery, is a highly invasive treatment option for locally advanced non-small cell lung cancers (LA-NSCLCs; defined as a heterogenous disease). We conducted this study to investigate the prognostic nutritional index (PNI) of LA-NSCLC patients undergoing trimodality therapy, which has not been studied in detail before. METHODS: The subjects of this retrospective study were 127 patients who underwent trimodality therapy between 1999 and 2016. We measured the PNI at three points: before iCRT (pre-iCRT), before the operation, and after the operation. RESULTS: PNIs decreased significantly as treatment progressed. Patients with clinical T3/4 (cT3/4) disease had a significantly lower PNI than those with cT1/2 disease, but the extent of lymph-node metastasis did not affect the PNI at any point. Using the cut-off values of receiver-operating curve analyses, multivariable analyses revealed that a high PNI pre-iCRT correlated significantly with a better survival of LA-NSCLC patients, especially those with cT3/4 disease (hazard ratio 3.84; 95% confidential interval 1.34-12.5, P = 0.012). CONCLUSIONS: Measuring the PNI before trimodality therapy is important for predicting the clinical outcome of patients with LA-NSCLC, with differing predictive ability according to the disease extent. Perioperative intensive nutritional intervention must be considered for patients who undergo trimodality therapy for LA-NSCLC.

    DOI: 10.1007/s00595-020-02067-7

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  • Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer 査読 国際誌

    Kosuke Ochi, Ken Suzawa, Shuta Tomida, Kazuhiko Shien, Jui Takano, Shunsaku Miyauchi, Tatsuaki Takeda, Akihiro Miura, Kota Araki, Kentaro Nakata, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Masaomi Yamane, Kazuo Azuma, Yoshiharu Okamoto, Shinichi Toyooka

    Biochemical and Biophysical Research Communications   529 ( 3 )   760 - 765   2020年8月

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

    BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

    DOI: 10.1016/j.bbrc.2020.06.077

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  • Fibrosis or Necrosis in Resected Lymph Node Indicate Metastasis Before Chemoradiotherapy in Lung Cancer Patients. 査読 国際誌

    Takahashi Y, Soh J, Shien K, Yamamoto H, Yamane M, Kiura K, Kanazawa S, Yanai H, Toyooka S

    Anticancer research   40 ( 8 )   4419 - 4423   2020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)  

    BACKGROUND/AIM: The histological features of lymph nodes (LNs) treated by chemoradiotherapy (CRT) in non-small cell lung cancer (NSCLC) have not been well studied. The purpose of this study was to evaluate the histological findings of LNs affected by CRT. PATIENTS AND METHODS: Among 107 clinically N2 NSCLC patients who underwent induction CRT followed by surgery from 1999 to 2017, 24 patients who received pathological evaluation of mediastinal LN before CRT were enrolled in this study. Postoperatively, we histologically reviewed all resected LNs (n=117) of the station evaluated before CRT. RESULTS: Fibrosis and/or necrosis were observed in all investigated LN stations. Histological observation of fibrosis and/or necrosis in the resected LNs after CRT indicated the presence of LN metastasis before CRT. CONCLUSION: The metastatic LNs that responded to CRT showed specific histological features, which enabled us to know the accurate clinical stage of the patient even though cancer cells were not found in the post-treated LNs.

    DOI: 10.21873/anticanres.14447

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  • The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas. 査読

    Yamamoto H, Namba K, Yamamoto H, Toji T, Soh J, Shien K, Suzawa K, Kurosaki T, Otani S, Okazaki M, Sugimoto S, Yamane M, Takahashi K, Kunisada T, Oto T, Toyooka S

    Surgery today   51 ( 1 )   127 - 135   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. METHODS: The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan-Meier method and prognostic factors were evaluated by multivariate analysis. RESULTS: Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. CONCLUSION: The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy.

    DOI: 10.1007/s00595-020-02093-5

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  • Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. 査読 国際誌

    Miyauchi S, Shien K, Takeda T, Araki K, Nakata K, Miura A, Takahashi Y, Kurihara E, Ogoshi Y, Namba K, Suzawa K, Yamamoto H, Okazaki M, Soh J, Toyooka S

    Anticancer research   40 ( 5 )   2667 - 2673   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)  

    BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

    DOI: 10.21873/anticanres.14237

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  • YES1 activation induces acquired resistance to neratinib in HER2 ‐amplified breast and lung cancers 査読 国際誌

    Tatsuaki Takeda, Hiromasa Yamamoto, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Kei Namba, Kazuhiko Shien, Junichi Soh, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

    Cancer Science   111 ( 3 )   849 - 856   2020年3月

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

    Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

    DOI: 10.1111/cas.14289

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  • 頭頸部癌治療歴を有する非小細胞肺がん患者に対する手術症例の検討

    高津 史明, 諏澤 憲, 枝園 和彦, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   711 - 711   2019年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • サルベージ治療・オリゴ再発に対する局所治療戦略 術前化学放射線療法後手術を行った局所進行肺癌術後再発症例の臨床経過

    諏澤 憲, 枝園 和彦, 三好 健太郎, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 6 )   586 - 586   2019年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 妊婦に合併した縦隔成熟奇形腫に対して手術を行った1例

    宮内 俊策, 枝園 和彦, 宗 淳一, 山本 寛斉, 山根 正修, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 6 )   624 - 628   2019年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

    縦隔成熟奇形腫は無症状で検診発見されることが多いが、時に急速に増大することがある。今回我々は、妊婦に合併し急速に増大したため妊娠中に手術を施行した症例を経験した。症例は27歳、女性。検診で胸部異常陰影を指摘され当科受診となった。初診時、患者は妊娠10週の妊婦であった。胸部X線写真で右上肺野中枢側に8cm大の腫瘤影、単純MRIで前縦隔に10cm大の多房性嚢胞性病変を認め、成熟奇形腫が疑われた。右前胸部痛が出現しており、腫瘍の急速な増大が考えられ手術の方針とした。手術は妊娠15週に胸骨正中切開で縦隔腫瘍摘出術、右肺上葉・心膜合併部分切除術を施行した。腫瘍は成熟奇形腫の診断で未熟成分や悪性所見は認めなかった。術後経過は良好で、妊娠40週で正常分娩に至った。妊娠と急速増大との因果関係は不明であるが、本症例のような場合でも術前検査や手術時期・方法に注意すれば妊娠中でも安全に手術が行えると考える。(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=2019&ichushi_jid=J02256&link_issn=&doc_id=20190920300008&doc_link_id=10.2995%2Fjacsurg.33.624&url=https%3A%2F%2Fdoi.org%2F10.2995%2Fjacsurg.33.624&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • 非小細胞肺癌におけるモネンシン併用療法によるEMT関連薬剤耐性の克服(Overcoming EMT-mediated drug resistance with Monensin-based combined therapy in non-small cell lung cancer)

    大智 宏祐, 諏澤 憲, 冨田 秀太, 荒木 恒太, 宮内 俊策, 三浦 章博, 武田 達明, 難波 圭, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 枝園 忠彦, 豊岡 伸一

    日本癌学会総会記事   78回   P - 1139   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Acquired resistance mechanisms to afatinib in HER 2 ‐amplified gastric cancer cells 査読 国際誌

    Takahiro Yoshioka, Kazuhiko Shien, Tatsuaki Takeda, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Junichi Soh, Toshiyoshi Fujiwara, Shinichi Toyooka

    Cancer Science   110 ( 8 )   2549 - 2557   2019年8月

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

    Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan-HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)-amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2-amplified gastric cancer cells. Two afatinib-resistant gastric cancer cell lines were established from 2 HER2-amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87-derived resistant cells, whereas it was upregulated in SNU216-derived resistant cells. In the N87-derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216-derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2-driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance.

    DOI: 10.1111/cas.14089

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  • 災害ボランティア活動に参加した喘息患者の血痰精査中に発見された右胸部異常陰影の一例

    鹿谷 芳伸, 黒崎 毅史, 大谷 真二, 中田 憲太郎, 難波 圭, 諏澤 憲, 枝園 和彦, 久保 寿夫, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    岡山医学会雑誌   131 ( 2 )   113 - 113   2019年8月

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    記述言語:日本語   出版者・発行元:岡山医学会  

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  • Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. 査読 国際誌

    Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Sakaguchi M

    Neoplasia (New York, N.Y.)   21 ( 7 )   627 - 640   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

    DOI: 10.1016/j.neo.2019.04.006

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  • Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma. 査読 国際誌

    Sato H, Soh J, Aoe K, Fujimoto N, Tanaka S, Namba K, Torigoe H, Shien K, Yamamoto H, Tomida S, Tao H, Okabe K, Kishimoto T, Toyooka S

    International journal of oncology   54 ( 6 )   2139 - 2148   2019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: 10.3892/ijo.2019.4768

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  • Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer. 査読 国際誌

    Kurihara E, Shien K, Torigoe H, Takeda T, Takahashi Y, Ogoshi Y, Yoshioka T, Namba K, Sato H, Suzawa K, Yamamoto H, Soh J, Okazaki M, Shien T, Tomida S, Toyooka S

    Anticancer research   39 ( 4 )   1767 - 1775   2019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)  

    BACKGROUND: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. MATERIALS AND METHODS: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition. RESULTS: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. CONCLUSION: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

    DOI: 10.21873/anticanres.13283

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  • EGFR-TKI耐性NSCLCに対するHSP90阻害剤ganetespibの有用性の検討

    栗原 英祐, 枝園 和彦, 鳥越 英次郎, 武田 達明, 荒木 恒太, 宮内 俊策, 三浦 章博, 高橋 優太, 諏澤 憲, 山本 寛斉, 宗 淳一, 冨田 秀太, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   O17 - 4   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • Pulmonary resection in a prone position for lung cancer invading the spine. 査読

    Miyauchi S, Soh J, Shien K, Tanaka M, Yamamoto H, Ozaki T, Toyooka S

    General thoracic and cardiovascular surgery   68 ( 3 )   298 - 301   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)  

    The prone position is usually not selected for pulmonary resection. The intraoperative body position is an important issue in surgery for non-small cell lung cancer invading the spine because the standard intraoperative body position for a vertebrectomy is a prone position, while that for a pulmonary resection is a lateral decubitus position. Intraoperative changes in body position can cause several complications. Using an O-arm with a navigation system, a partial vertebrectomy was completed with the patient in a prone position thanks to the recognition of accurate surgical margins in the vertebral body; then, without changing the patient's body position, a lobectomy with systemic lymph node dissection was performed via a posterior approach. Especially for procedures requiring a wide resection of the chest wall, a prone position can be selected for a lobectomy with systemic lymph node dissection via a posterior approach without any significant difficulties.

    DOI: 10.1007/s11748-019-01113-7

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  • Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. 査読 国際誌

    Chen Y, Sumardika IW, Tomonobu N, Winarsa Ruma IM, Kinoshita R, Kondo E, Inoue Y, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Sakaguchi M

    Cancer letters   452   178 - 190   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)  

    Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

    DOI: 10.1016/j.canlet.2019.03.023

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  • Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non–Small Cell Lung Cancer Cells 査読 国際誌

    Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hidejiro Torigoe, Hiroki Sato, Takahiro Yoshioka, Tatsuaki Takeda, Eisuke Kurihara, Yusuke Ogoshi, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka

    Molecular Cancer Research   17 ( 2 )   499 - 507   2019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:American Association for Cancer Research ({AACR})  

    Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.

    DOI: 10.1158/1541-7786.MCR-18-0628

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  • Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma. 査読 国際誌

    Namba K, Tomida S, Matsubara T, Takahashi Y, Kurihara E, Ogoshi Y, Yoshioka T, Takeda T, Torigoe H, Sato H, Shien K, Yamamoto H, Soh J, Tsukuda K, Toyooka S

    BMC cancer   19 ( 1 )   175 - 175   2019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)  

    DOI: 10.1186/s12885-019-5374-1

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  • Clinical outcome of patients with recurrent non-small cell lung cancer after trimodality therapy. 査読

    Suzawa K, Soh J, Takahashi Y, Sato H, Shien K, Yamamoto H, Kanazawa S, Kiura K, Miyoshi S, Toyooka S

    Surgery today   49 ( 7 )   601 - 609   2019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)  

    PURPOSES: The purpose of this study was to review the clinical course of patients with recurrence after induction chemoradiotherapy followed by surgery (trimodality therapy) for locally advanced non-small cell lung cancer (LA-NSCLC) and to identify the factors associated with favorable clinical outcome after recurrence. METHODS: We analyzed the records of 140 patients with LA-NSCLC who were treated with trimodality therapy between 1999 and 2014. RESULTS: Recurrence developed after trimodality therapy in 48 patients. A yp-N positive status was associated with a high risk of recurrence (HR, 2.05; P = 0.048). Of the 45 of these patients able to be assessed retrospectively, 18 had oligometastatic recurrence and 20 underwent local treatment with curative intent. Local treatment was most frequently given to patients with oligometastatic recurrence (P < 0.001). The median post-recurrence survival (PRS) was 41.4 months, and the 2-year PRS rate was 62%. Patients who received local treatment showed better PRS (P = 0.009). The presence of liver metastasis (P = 0.008), bone metastasis (P = 0.041), or dissemination (P < 0.0001) were associated with worse PRS. CONCLUSION: The survival of patients who received aggressive local treatment for postoperative recurrence after trimodality therapy for LA-NSCLC was better than that of patients who did not.

    DOI: 10.1007/s00595-019-1774-8

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  • Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. 査読 国際誌

    Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

    Molecular carcinogenesis   58 ( 6 )   980 - 995   2019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)  

    DOI: 10.1002/mc.22987

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  • NEUROPLASTIN-β MEDIATES S100A8/A9-INDUCED LUNG CANCER DISSEMINATIVE PROGRESSION 査読

    Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

    Molecular Carcinogenesis   2019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)  

    Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers. This article is protected by copyright.

    DOI: 10.1002/mc.22987

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  • Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations. 査読 国際誌

    Ogoshi Y, Shien K, Yoshioka T, Torigoe H, Sato H, Sakaguchi M, Tomida S, Namba K, Kurihara E, Takahashi Y, Suzawa K, Yamamoto H, Soh J, Toyooka S

    Oncology letters   17 ( 3 )   2729 - 2736   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. Numerous studies have reported the amplification and overexpression of HER2 in several types of cancer, including non-small cell lung cancer (NSCLC). However, the benefits of HER2-targeted therapy have not been fully established. In the present study, the anti-tumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), against NSCLC cells harboring HER2 alterations was investigated. The sensitivity of normal bronchial epithelial cells (BEAS-2B) ectopically overexpressing wild-type or mutant HER2 to neratinib was assessed. Furthermore, the anti-tumor activity of neratinib in several NSCLC cell lines harboring HER2 alterations was determined in vitro and in vivo, and the association between their genetic alterations and sensitivity to neratinib treatment was investigated. BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D and S310F) exhibited constitutive autophosphorylation of HER2, as determined by western blotting. While these BEAS-2B cells were sensitive to neratinib, they were insensitive to erlotinib, a first-generation epidermal growth factor receptor-TKI. Neratinib also exerted anti-proliferative effects on HER2-altered (H2170, Calu-3 and H1781) NSCLC cell lines. Neratinib was also demonstrated to exert strong tumor growth inhibitory activity in mouse xenograft models using HER2-altered lung cancer cells. The results of the present study strongly suggest that neratinib has potential as a promising therapeutic option for the treatment of HER2-altered NSCLC.

    DOI: 10.3892/ol.2019.9908

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  • exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. 査読 国際誌

    Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Sakaguchi M

    International journal of cancer   144 ( 12 )   3138 - 3145   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNβ, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

    DOI: 10.1002/ijc.31945

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  • Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. 査読 国際誌

    Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Sakaguchi M

    International journal of cancer   145 ( 2 )   569 - 575   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

    DOI: 10.1002/ijc.31982

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  • Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis 査読 国際誌

    Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Shinsuke Oda, Takehiro Matsubara, Hiroki Sato, Ken Suzawa, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Torigoe, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

    Cancer Science   109 ( 11 )   3634 - 3642   2018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  

    In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

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  • 肺癌におけるPrecision Medicineの現状と今後の展開 肺癌のゲノム異常と治療の課題

    豊岡 伸一, 枝園 和彦, 山本 寛斉, 宗 淳一, 冨田 秀太

    日本癌治療学会学術集会抄録集   56回   PD3 - 2   2018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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  • Myoepithelioma occurring in the posterior mediastinum harboring EWSR1 rearrangement: a case report. 査読 国際誌

    Habu T, Soh J, Toji T, Shien K, Niman E, Namba K, Sato H, Yamamoto H, Sugimoto S, Yamane M, Toyooka S

    Japanese journal of clinical oncology   48 ( 9 )   851 - 854   2018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)  

    Myoepithelioma is a rare neoplasm usually occurring in the salivary glands or the mammary glands but also, more rarely, in the thoracic cavity. The diagnosis of myoepithelioma is based on the presence of histological and immunohistochemical characteristics of myoepithelioma, but in unusual locations, the diagnosis is challenging. For such cases, cytogenetic approaches have been developed as helpful tools for the diagnosis. We report a surgical case of 51-year-old woman with myoepithelioma occurring in the posterior mediastinum that harbored the Ewing sarcoma breakpoint region1 (EWSR1) gene rearrangement. To the best of our knowledge, this is the first report of a myoepithelioma occurring in the posterior mediastinum. In this case, the patient underwent the thoracoscopic surgery for a diagnostic tumorectomy and was diagnosed as myoepithelioma based on the following immunohistological findings. Considering the unusual location, we additionally performed a cytogenetic analysis to confirm the presence of the EWSR1 gene rearrangement, which is a genetic characteristic of myoepithelioma.

    DOI: 10.1093/jjco/hyy100

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  • Concomitant targeting of the mTOR/MAPK pathways: novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer. 査読 国際誌

    Ruder D, Papadimitrakopoulou V, Shien K, Behrens C, Kalhor N, Chen H, Shen L, Lee JJ, Hong WK, Tang X, Girard L, Minna JD, Diao L, Wang J, Mino B, Izzo JG

    Oncotarget   9 ( 74 )   33995 - 34008   2018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)  

    Despite a therapeutic paradigm shift into targeted-driven medicinal approaches, resistance to therapy remains a hallmark of lung cancer, driven by biological and molecular diversity. Using genomic and expression data from advanced non-small cell lung cancer (NSCLC) patients enrolled in the BATTLE-2 clinical trial, we identified RICTOR alterations in a subset of lung adenocarcinomas and found RICTOR expression to carry worse overall survival. RICTOR-altered cohort was significantly enriched in KRAS/MAPK axis mutations, suggesting a co-oncogenic driver role in these molecular settings. Using NSCLC cell lines, we showed that, distinctly in KRAS mutant backgrounds, RICTOR blockade impairs malignant properties and generates a compensatory enhanced activation of the MAPK pathway, exposing a unique therapeutic vulnerability. In vitro and in vivo concomitant pharmacologic inhibition of mTORC1/2 and MEK1/2 resulted in synergistic responses of anti-tumor effects. Our study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations.

    DOI: 10.18632/oncotarget.26129

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  • Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. 査読 国際誌

    Sato H, Yamamoto H, Sakaguchi M, Shien K, Tomida S, Shien T, Ikeda H, Hatono M, Torigoe H, Namba K, Yoshioka T, Kurihara E, Ogoshi Y, Takahashi Y, Soh J, Toyooka S

    Cancer science   109 ( 10 )   3183 - 3196   2018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)  

    Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

    DOI: 10.1111/cas.13763

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  • EGFR変異陽性肺癌におけるLRIG1の抗腫瘍効果(Tumor-suppressive effect of LRIG1 in non-small cell lung cancer harboring mutant EGFR)

    鳥越 英次郎, 山本 寛斉, 阪口 政清, 難波 圭, 佐藤 博紀, 枝園 和彦, 諏澤 憲, 宗 淳一, 冨田 秀太, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   77回   940 - 940   2018年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • HER増幅胃癌におけるアファチニブ耐性機序(Acquired resistant mechanism to afatinib in HER2 amplified gastric cancer cells)

    吉岡 貴裕, 枝園 和彦, 難波 圭, 冨田 秀太, 山本 寛斉, 宗 淳一, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   77回   1449 - 1449   2018年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • 悪性胸膜中皮腫に対するREIC/Dkk-3遺伝子治療

    山本 寛斉, 諏澤 憲, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本がん免疫学会総会プログラム・抄録集   22回   146 - 146   2018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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  • 腫瘍浸潤リンパ球(TIL)を含んだ腫瘍解離細胞(DTC)の保存

    渡邊 元嗣, 高橋 優太, 冨田 秀太, 宗 淳一, 松原 岳大, 難波 圭, 佐藤 博紀, 森田 瑞樹, 枝園 和彦, 山本 寛斉, 鵜殿 平一郎, 豊岡 伸一

    日本がん免疫学会総会プログラム・抄録集   22回   161 - 161   2018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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  • Therapeutic strategies for afatinib‐resistant lung cancer harboring HER 2 alterations 査読 国際誌

    Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Cancer Science   109 ( 5 )   1493 - 1502   2018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  

    Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

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  • β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. 査読 国際誌

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Sato H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

    Oncology research   26 ( 3 )   431 - 444   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)  

    DOI: 10.3727/096504017X15031557924123

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  • [Induction Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer]. 査読

    Miura A, Soh J, Shien K, Yamamoto H, Toyooka S

    Kyobu geka. The Japanese journal of thoracic surgery   71 ( 4 )   270 - 277   2018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)  

    The management of locally advanced non-small cell lung cancer (LA-NSCLC) is still controversial, because of complicated patient status and poor prognosis. The purpose of this study was to evaluate the treatment results for induction chemoradiotherapy (iCRT) followed by surgery for LA-NSCLC. From 1999 to 2016, 157 patients were surgically treated after iCRT in our hospital, and their median follow-up was 43 months. Overall survival( OS) was 66.8%, and relapse-free survival( RFS) was 52.0%. The poor prognostic factor in OS by multivariate analysis was lower-lobe origin, incomplete radiotherapy, reoperation, and RFS was lower-lobe origin. The result of our hospital was feasible compared with definitive CRT. The definitive CRT is mainstream for treatment of LA-NSCLC and adjuvant anti-programmed death ligand 1 antibody will influence the treatment strategy, however there are some patients who can get benefit only by iCRT followed by surgery. iCRT followed by surgery is one of the feasible treatment for LA-NSCLC.

    DOI: 10.15106/j_kyobu71_270

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  • Antitumor activity of pan‐ HER inhibitors in HER 2‐positive gastric cancer 査読 国際誌

    Takahiro Yoshioka, Kazuhiko Shien, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Hiroaki Asano, Junichi Soh, Kazunori Tsukuda, Takeshi Nagasaka, Toshiyoshi Fujiwara, Shinichi Toyooka

    Cancer Science   109 ( 4 )   1166 - 1176   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:Wiley  

    Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer.

    DOI: 10.1111/cas.13546

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  • 【肺癌の集学的治療の現況】局所進行肺癌における集学的治療 局所進行非小細胞肺癌に対する術前導入化学放射線療法後手術

    三浦 章博, 宗 淳一, 枝園 和彦, 山本 寛斉, 豊岡 伸一

    胸部外科   71 ( 4 )   270 - 277   2018年4月

  • IV期肺癌における呼吸器外科の役割は拡大しているか? 手術を契機に診断した胸膜播種・悪性胸水を伴うIVA期肺癌は切除非適応か? 多施設共同後方視的解析

    藤原 俊哉, 松浦 求樹, 宗 淳一, 枝園 和彦, 山本 寛斉, 牧 佑歩, 上野 剛, 杉本 龍士郎, 岡崎 幹生, 田尾 裕之, 葉山 牧夫, 片岡 正文, 佐野 由文, 岡部 和倫, 山下 素弘, 川真田 修, 片岡 和彦, 森山 重治, 豊岡 伸一, 岡山大学呼吸器外科研究会

    日本呼吸器外科学会雑誌   32 ( 3 )   PD3 - 1   2018年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR. 査読 国際誌

    Torigoe H, Yamamoto H, Sakaguchi M, Youyi C, Namba K, Sato H, Shien K, Soh J, Suzawa K, Tomida S, Tsukuda K, Miyoshi S, Toyooka S

    Carcinogenesis   39 ( 5 )   719 - 727   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues. Next, we focused on the effect of LRIG1 in NSCLC. For this purpose, we established clones stably overexpressing LRIG1, using EGFR-mutant (HCC827, HCC4011 and NCI-H1975) and wild-type (A549) cells. Transfection of LRIG1 was associated with a decrease in the expression and phosphorylation levels of EGFR in the HCC827, HCC4011 and NCI-H1975 cells. It was also associated with strong suppression of the cell proliferative, invasive, migratory and tumorigenic potential of the HCC827 cells. On the other hand, no such effects were observed in the A549 cells. In addition, LRIG1 also downregulated the expression and phosphorylation levels of other tyrosine kinase receptors, such as HER2, HER3, MET and IGF-1R, and prevented the epithelial-to-mesenchymal transition induced by TGF-β in the HCC827 cells. These findings suggest that LRIG1 exerts important tumor-suppressive effects in EGFR-mutant NSCLC and has the potential to become a novel therapeutic target for EGFR-mutant NSCLC.

    DOI: 10.1093/carcin/bgy044

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  • Development of novel biologics for cancer metastasis via prevention of extracellular S100A8/A9 function 査読

    Kinoshita Rie, Yamauchi Akira, Shien Kazuhiko, Tomida Shuta, Toyooka Shinichi, Kondo Eisaku, Sakaguchi Masakiyo

    CANCER SCIENCE   109   1017   2018年1月

  • Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma 査読 国際誌

    Hiroki Sato, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Keisuke Aoe, Kazuhiko Shien, Takahiro Yoshioka, Kei Namba, Hidejiro Torigoe, Junichi Soh, Kazunori Tsukuda, Hiroyuki Tao, Kazunori Okabe, Shinichiro Miyoshi, Harvey I. Pass, Shinichi Toyooka

    Oncogenesis   7 ( 1 )   11 - 11   2018年1月

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

    Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

    DOI: 10.1038/s41389-017-0017-3

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  • JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer. 査読 国際誌

    Kazuhiko Shien

    Molecular cancer therapeutics   16 ( 10 )   2234 - 2245   2017年10月

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

    Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234-45. ©2017 AACR.

    DOI: 10.1158/1535-7163.mct-17-0148

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  • Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer. 査読 国際誌

    Kazuhiko Shien

    Oncology letters   14 ( 4 )   4349 - 4354   2017年10月

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

    Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxel-resistant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

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  • Induction chemoradiotherapy using docetaxel and cisplatin with definitive-dose radiation followed by surgery for locally advanced non-small cell lung cancer. 査読 国際誌

    Torigoe H, Soh J, Tomida S, Namba K, Sato H, Katsui K, Hotta K, Shien K, Yamamoto H, Yamane M, Kanazawa S, Kiura K, Miyoshi S, Toyooka S

    Journal of thoracic disease   9 ( 9 )   3076 - 3086   2017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:AME PUBL CO  

    Background: Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (LA-NSCLC). Typically, around 40-50 Gy of radiation is applied as the induction-dose; however, a definitive-dose (DD) of radiation (60 Gy or higher) is occasionally applied to increase local control. We investigated the impact of induction CRT with DD radiation in LA-NSCLC patients treated with a single regimen of docetaxel and cisplatin. Methods: We reviewed 110 patients with LA-NSCLC who underwent induction CRT followed by surgery using a single regimen (docetaxel and cisplatin) between January 1999 and December 2014 at our hospital. The clinical outcomes of a DD group (60 Gy or higher, n=11) and a non-DD group (less than 60 Gy, n=99) were investigated using a propensity score (PS)-matched analysis. Results: An advanced clinical stage was significantly more common in the DD group than in the non-DD group (P=0.033). Before and after the PS-matching based on seven factors including clinical stage, there was no significant difference in the rates of postoperative (PO) complication, mortality, 5-year overall survival (OS), or 5-year recurrence-free survival (RFS) between the two groups. After the PS-matching, the pathological complete response (CR) rate was significantly higher in the DD group than in the non-DD group [50% (n=5/10) vs. 0% (n=0/10), P=0.033]. Conclusions: Induction CRT followed by surgery using docetaxel and cisplatin with DD radiation can be performed safely and is associated with a higher pathological CR rate than that attained using non-DD radiation in LA-NSCLC patients.

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  • ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. 査読 国際誌

    Oncology research   26 ( 3 )   431 - 444   2017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)  

    DOI: 10.3727/096504017x15031557924123

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  • Advantage of Induction Chemoradiotherapy for Lung Cancer in Securing Cancer-Free Bronchial Margin. 査読 国際誌

    Kazuhiko Shien

    The Annals of thoracic surgery   104 ( 3 )   971 - 978   2017年9月

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

    BACKGROUND: Bronchoplasty is a useful procedure for preserving pulmonary function. For this procedure, it is critical to secure the negative surgical margin for avoiding local recurrence. In this study, we examined the status of the surgical bronchial margin as well as the clinical outcomes in bronchoplasty with or without induction chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). METHODS: The medical records of NSCLC patients who underwent bronchoplasty at our institution between January 1999 and September 2014 were reviewed. We compared the clinical outcomes of bronchoplasty with or without induction CRT. RESULTS: A total of 58 NSCLC patients were included in this study. Among these, 38 patients underwent primary surgical procedure with bronchoplasty and 20 patients underwent bronchoplasty after induction CRT. Intraoperative pathologic diagnosis for the surgical margin of the bronchus revealed that the patients in the primary surgical procedure group had a significantly higher rate of positive surgical margin than the induction CRT group (p = 0.023), requiring an additional bronchial resection to secure the negative margin. After additional resection of positive bronchial stumps, no significant difference was found in the rate of positive margin with postoperative histologic diagnosis between the two groups. In addition, no significant differences in the postoperative complication rate and overall and recurrence-free survivals were observed between the two groups. CONCLUSIONS: Our results suggest that induction CRT before surgical procedure may help ensure the intraoperative negative surgical margin of the bronchus. Our study also indicates that bronchoplasty after induction CRT is feasible in comparison with bronchoplasty in primary surgical procedure.

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  • 第3世代EGFR-TKI Osimertinib耐性肺癌細胞株における獲得耐性機構の解明

    難波 圭, 枝園 和彦, 吉岡 貴裕, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 和憲, 豊岡 伸一

    肺癌   57 ( 5 )   440 - 440   2017年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • HER2陽性胃癌に対するアファチニブ・ネラチニブの抗腫瘍効果

    吉岡 貴裕, 枝園 和彦, 高橋 優太, 栗原 英祐, 難波 圭, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 憲徳, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   76回   P - 2336   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 分子バーコード技術を用いた低頻度多重変異の同定

    難波 圭, 冨田 秀太, 枝園 和彦, 山本 寛斉, 宗 淳一, 佃 和憲, 豊岡 伸一

    日本癌学会総会記事   76回   P - 3052   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 肺がん新治療の展望 HER2異常肺癌に対する治療戦略

    豊岡 伸一, 諏澤 憲, 二宮 崇, 山本 寛斉, 枝園 和彦, 宗 淳一, 冨田 秀太, 木浦 勝行

    日本癌学会総会記事   76回   SST6 - 3   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 分子標的薬への耐性機構の解明 肺がんにおける分子標的薬耐性メカニズムの解明

    枝園 和彦, 佐藤 博紀, 鳥越 英次郎, 難波 圭, 吉岡 貴裕, 山本 寛斉, 宗 淳一, 豊岡 伸一

    肺癌   57 ( 5 )   377 - 377   2017年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 抗HER2療法耐性におけるYes1の重要性

    武田 達明, 山本 寛斉, 諏澤 憲, 冨田 秀太, 難波 圭, 渡邉 元嗣, 枝園 和彦, 宗 淳一, 佃 和憲, 豊岡 伸一

    日本癌学会総会記事   76回   P - 3366   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • HER2遺伝子異常肺癌に対するマルチキナーゼ阻害剤Afatinb耐性獲得機序の解明

    鳥越 英次郎, 枝園 和彦, 吉岡 貴裕, 難波 圭, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 冨田 秀太, 佃 和憲, 豊岡 伸一

    肺癌   57 ( 5 )   441 - 441   2017年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Erratum to "Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer" [Lung Cancer 76 (1) (2012) 32-38]. 査読 国際誌

    Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

    Lung cancer (Amsterdam, Netherlands)   108   254 - 255   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.lungcan.2016.04.016

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  • Is tumor location an independent prognostic factor in locally advanced non-small cell lung cancer treated with trimodality therapy? 査読 国際誌

    Kazuhiko Shien

    Journal of thoracic disease   9 ( 5 )   E489-E491 - E491   2017年5月

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

    DOI: 10.21037/jtd.2017.03.183

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  • Lung Cancer Panelを用いた多発小型肺癌のマルチプレックス遺伝子変異解析

    枝園 和彦, 冨田 秀太, 佐藤 博紀, 高橋 優太, 諏澤 憲, 山本 寛斉, 宗 淳一, 三好 新一郎, 豊岡 伸一

    日本呼吸器外科学会雑誌   31 ( 3 )   RO16 - 4   2017年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer (vol 12, e0171356, 2017) 査読

    T. Takeda, H. Yamamoto, H. Kanzaki, K. Suzawa, T. Yoshioka, S. Tomida

    PLOS ONE   12 ( 3 )   e0171356   2017年3月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    DOI: 10.1371/journal.pone.0174493

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    その他リンク: http://orcid.org/0000-0002-4959-4220

  • Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features. 査読 国際誌

    Kazuhiko Shien

    Scientific reports   7   40847 - 40847   2017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  

    MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

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  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. 査読 国際誌

    Kazuhiko Shien

    Anticancer research   37 ( 1 )   301 - 307   2017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  

    BACKGROUND: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. MATERIALS AND METHODS: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. RESULTS: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. CONCLUSION: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer. 査読 国際誌

    Kazuhiko Shien

    PloS one   12 ( 2 )   e0171356   2017年

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

    BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumab-resistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. METHODS: We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. RESULTS: Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. CONCLUSION: Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

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  • Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. 査読 国際誌

    Kazuhiko Shien

    Scientific reports   6   39557 - 39557   2016年12月

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

    HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

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  • 腸型肺腺癌の1切除例

    清水 大, 三好 健太郎, 目崎 久美, 枝園 和彦, 杉本 誠一郎, 山本 寛斉, 宗 淳一, 豊岡 伸一, 大藤 剛宏, 三好 新一郎

    肺癌   56 ( 6 )   682 - 682   2016年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • NSCLCにおける分子バーコードシークエンス分析による複数の低頻度変異の検出(Detection of multiple low-frequency mutations by molecular-barcode sequencing in NSCLC)

    難波 圭, 冨田 秀太, 枝園 和彦, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 佃 和憲, 三好 新一郎, 豊岡 伸一

    肺癌   56 ( 6 )   639 - 639   2016年11月

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    記述言語:英語   出版者・発行元:(NPO)日本肺癌学会  

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  • 悪性胸膜中皮腫におけるS100A11の働き

    佐藤 博紀, 山本 寛斉, 難波 圭, 鳥越 英次郎, 下田 篤志, 吉岡 貴裕, 枝園 和彦, 宗 淳一, 豊岡 伸一

    日本癌学会総会記事   75回   J - 1061   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer. 査読 国際誌

    Shien K, Papadimitrakopoulou VA, Wistuba II

    Lung cancer (Amsterdam, Netherlands)   99   79 - 87   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:ELSEVIER IRELAND LTD  

    Inhibitors of the programmed cell death 1 (PD-1) pathway show the potential to substantially increase the efficacy of therapy for various malignancies, including non-small cell lung cancer (NSCLC). At the same time, substantial effort has been invested in finding biomarkers predicting which patients will respond best to this immune checkpoint inhibition. PD-L1 expression in tumor cells and the tumor microenvironment, genetic alterations and mutational load in tumor cells, and pre-existing immunity and its enhancement during treatment through tumor-infiltrating immune cells have been associated with outcomes of immune checkpoint inhibition. Here, we review the reported predictive biomarkers of response to PD-1 pathway immune checkpoint inhibitors in NSCLC, mainly focusing on results obtained with clinical trials.

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  • Role of surgery in N2 NSCLC: pros. 査読 国際誌

    Shien K, Toyooka S

    Japanese journal of clinical oncology   46 ( 12 )   1168 - 1173   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:OXFORD UNIV PRESS  

    The optimal management of clinical N2 Stage IIIA non-small cell lung cancer is still controversial. For a cure of locally advanced IIIA/N2 non-small cell lung cancer, the control of both local regions and possible distant micrometastases is crucial. Chemotherapy is generally expected to prevent distant recurrence. For local tumor control, radiotherapy or surgery has been adopted singly or in combination. If a complete resection can be safely performed, surgery remains the strongest modality for 'eradicating' local disease. Many retrospective studies have reported a possible survival benefit of induction treatment followed by surgery in selected patients with IIIA/N2 non-small cell lung cancer; however, randomized Phase III trials have failed to demonstrate the superiority of induction treatment followed by surgery over chemoradiotherapy, mainly because of the heterogeneity of the N2 status. IIIA/N2 non-small cell lung cancer consists of a heterogeneous group of disease ranging from microscopically single station to radiologically bulky ipsilateral multi-station mediastinal lymph node involvement. A recent definition proposed by the American College of Chest Physicians classified non-small cell lung cancer based on the N2 status, such as discrete or infiltrative type, and recommendations were made according to this N2 status, with definitive chemoradiotherapy recommended for infiltrative clinical N2 and definitive chemoradiotherapy or induction treatment followed by surgery recommended for other cases. Thus, the introduction of a multimodality treatment strategy seems to be necessary for the improved prognosis of non-small cell lung cancer patients with IIIA/N2 disease. In this review, we discuss the role of surgery and the optimal surgical management for patients with IIIA/N2 non-small cell lung cancer.

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  • Study about the Efficacy of Metformin to Immune Function in Cancer Patients. 査読

    Watanabe M, Yamamoto H, Eikawa S, Shien K, Shien T, Soh J, Hotta K, Wada J, Hinotsu S, Fujiwara T, Kiura K, Doihara H, Miyoshi S, Udono H, Toyooka S

    Acta medica Okayama   70 ( 4 )   327 - 30   2016年8月

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

    A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8+ T cells, which produce multiple cytokines.

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  • The proliferative effects of asbestos-exposed peripheral blood mononuclear cells on mesothelial cells. 査読 国際誌

    Maki Y, Nishimura Y, Toyooka S, Soh J, Tsukuda K, Shien K, Furukawa M, Muraoka T, Ueno T, Tanaka N, Yamamoto H, Asano H, Maeda M, Kumagai-Takei N, Lee S, Matsuzaki H, Otsuki T, Miyoshi S

    Oncology letters   11 ( 5 )   3308 - 3316   2016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)  

    Malignant mesothelioma (MM) is thought to arise from the direct effect of asbestos on mesothelial cells. However, MM takes a long time to develop following exposure to asbestos, which suggests that the effects of asbestos are complex. The present study examined the effects of asbestos exposure on the cell growth of MeT-5A human mesothelial cells via cytokines produced by immune cells. Peripheral blood mononuclear cells (PBMCs) were stimulated with antibodies against cluster of differentiation (CD)3 and CD28 upon exposure to the asbestos chrysotile A (CA) or crocidolite (CR); the growth of MeT-5A cells in media supplemented with PBMC culture supernatants was subsequently examined. MeT-5A cells exhibited an increase in proliferation when grown in supernatant from the 7-day PBMC culture exposed to CA or CR. Analysis of cytokine production demonstrated increased levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-3, IL-5, IL-13 and IL-17A in supernatants. Individual administration of these cytokines, excluding G-CSF and GM-CSF, led to an increase in cell growth of MeT-5A, whereas this effect was not observed following the combined administration of these cytokines. The results indicate that cytokines secreted by immune cells upon exposure to asbestos cause an increase in the growth activity of mesothelial cells, suggesting that alterations in the production of cytokines by immune cells may contribute to tumorigenesis in individuals exposed to asbestos.

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  • Genetic alterations in lung adenocarcinoma with a micropapillary component. 査読 国際誌

    Furukawa M, Toyooka S, Ichimura K, Yamamoto H, Soh J, Hashida S, Ouchida M, Shien K, Asano H, Tsukuda K, Miyoshi S

    Molecular and clinical oncology   4 ( 2 )   195 - 200   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pulmonary adenocarcinoma (PA) with a micropapillary component (PA-MPC) is known as an aggressive subtype of PA. The molecular profiles of PA-MPC have not been well characterized. the pathological reports of patients who underwent surgical resection for lung cancer between April, 2004 and May, 2012 were reviewed. Of the 674 patients diagnosed with PA, 28 were found to have MPC. A total of 138 resected PAs without MPC were selected in the same period to serve as age-, gender- and smoking status-matched controls to the PA-MPC group. Mutational status was determined by the following two methods: SNaPshot assay based on multiplex polymerase chain reaction (PCR), primer extension and capillary electrophoresis that was designed to assess 38 somatic mutations in 8 genes [AKT1, BRAF, endothelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1, neuroblastoma RAS viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) and phosphatase and tensin homolog]; and a PCR-based sizing assay that assesses EGFR exon 19 (deletions), EGFR exon 20 (insertions) and human epidermal growth factor receptor 2 exon 20 (insertions). echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK) was screened by ALK immunohistochemistry and confirmed using the reverse transcription PCR assay and the break-apart fluorescence in situ hybridization assay. Regarding genetic alterations, 13 (46.4%) of the 28 PA-MPCs harbored mutually exclusive mutations: 9 (32.1%) EGFR mutations, 1 (3.6%) KRAS mutation and 3 (10.7%) EML4-ALK fusion genes. PAs without MPC harbored 42 (30.4%) EGFR mutations, 17 (12.3%) KRAS mutations, 3 (2.2%) EML4-ALK fusion genes and 1 (0.7%) PIK3CA mutation. EML4-ALK fusion genes appeared to occur significantly more frequently in PA-MPCs compared with PAs without MPC (P=0.027). Although the sample size was small, our study suggests that the molecular pathogenesis of PA-MPC may be different from that of other adenocarcinomas.

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  • Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma. 査読 国際誌

    Suzawa K, Yamamoto H, Murakami T, Katayama H, Furukawa M, Shien K, Hashida S, Okabe K, Aoe K, Soh J, Asano H, Tsukuda K, Mimura Y, Toyooka S, Miyoshi S

    Oncology letters   11 ( 1 )   705 - 712   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)   出版者・発行元:SPANDIDOS PUBL LTD  

    Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS, HER2, BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies.

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  • DNA copy number gains in malignant pleural mesothelioma. 査読 国際誌

    Furukawa M, Toyooka S, Hayashi T, Yamamoto H, Fujimoto N, Soh J, Hashida S, Shien K, Asano H, Aoe K, Okabe K, Pass HI, Tsukuda K, Kishimoto T, Miyoshi S

    Oncology letters   10 ( 5 )   3274 - 3278   2015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:SPANDIDOS PUBL LTD  

    Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an extremely poor prognosis. The incidence of MPM is increasing as a result of widespread exposure to asbestos. The molecular pathogenesis of MPM remains unclear. The present study analyzed the frequency of various genomic copy number gains (CNGs) in MPM using reverse transcription-quantitative polymerase chain reaction. A total of 83 primary MPMs and 53 primary lung adenocarcinomas were analyzed to compare the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2. In MPM, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 12 (14.5%), 8 (9.6%), 5 (6.0%), 4 (4.8%) and 1 (1.2%) of the samples, respectively. In lung adenocarcinomas, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 21 (39.6%), 12 (22.6%), 5 (9.4%), 10 (18.9%) and 0 (0.0%) of the samples, respectively. The CNGs of EGFR, KRAS and FGFR1 were significantly less frequent in the MPMs compared with the lung adenocarcinomas (P=0.0018, 0.048 and 0.018, respectively). Overall, the MPMs exhibited these CNGs less frequently compared with the lung adenocarcinomas (P=0.0002). The differences in CNGs between the two tumor types suggested that they are genetically different.

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  • REIC/Dkk-3遺伝子治療の胸部悪性腫瘍に対する免疫刺激を介する抗腫瘍効果

    諏澤 憲, 枝園 和彦, 阪口 政清, 渡部 昌実, 橋田 真輔, 宗 淳一, 山本 寛斉, 牧 祐歩, 佃 和憲, 那須 保友, 公文 裕巳, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   74回   J - 1224   2015年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies 査読

    Suzawa Ken, Shien Kazuhiko, Huang Peng, Sakaguchi Masakiyo, Watanabe Masami, Hashida Shinsuke, Soh Junichi, Yamamoto Hiromasa, Maki Yuho, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro, Toyooka Shinichi

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S599   2015年9月

  • 悪性胸膜中皮腫におけるDNAコピー数の増加(DNA copy number gains in malignant pleural mesothelioma)

    古川 公之, 豊岡 伸一, 林 達朗, 山本 寛斉, 宗 淳一, 橋田 真輔, 枝園 和彦, 浅野 博昭, 岡部 和倫, 佃 和憲, 三好 新一郎

    日本呼吸器外科学会雑誌   29 ( 3 )   O56 - 6   2015年4月

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    記述言語:英語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib 査読 国際誌

    Hashida, S., Yamamoto, H., Shien, K., Miyoshi, Y., Ohtsuka, T., Suzawa, K., Watanabe, M., Maki, Y., Soh, J., Asano, H., Tsukuda, K., Miyoshi, S., Toyooka, S.

    Cancer Sci   106 ( 10 )   1377 - 84   2015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:WILEY-BLACKWELL  

    Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs.

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  • Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors 査読 国際誌

    Hashida, S., Yamamoto, H., Shien, K., Ohtsuka, T., Suzawa, K., Maki, Y., Furukawa, M., Soh, J., Asano, H., Tsukuda, K., Miyoshi, S., Kanazawa, S., Toyooka, S.

    Oncol Rep   33 ( 3 )   1499 - 504   2015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:SPANDIDOS PUBL LTD  

    Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a critical issue that needs to be overcome in the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. EGFR and AKT are client proteins of the 90-kDa heat shock protein (Hsp90). Therefore, it was hypothesized that the use of Hsp90 inhibitors might allow the resistance to EGFR-TKIs to be overcome. Furthermore, Hsp90 inhibitors are known to function as radiosensitizers in various types of cancer. In the present study, we evaluated the radiosensitizing effect of the novel Hsp90 inhibitor, NVP-AUY922 (AUY), on NSCLC cell lines harboring EGFR activating mutations and showing acquired resistance to EGFR-TKIs via any of several mechanisms. We used HCC827 and PC-9, which are NSCLC cell lines harboring EGFR exon 19 deletions, and gefitinib-resistant sublines derived from the same cell lines with T790M mutation, MET amplification or stem-cell like properties. AUY was more effective against the gefitinib-resistant sublines with T790M mutation and MET amplification than against the parental cell lines, although the subline with stem cell-like properties showed more than a 10-fold higher resistance to AUY than the parental cell line. AUY exerted a significant radiosensitizing effect on the parental cell line and the MET-amplified subline through inducing G2/M arrest and inhibition of non-homologous end joining (NHEJ). In contrast, the radiosensitizing effect of AUY was limited on the subline with stem cell-like properties, in which it did not induce G2/M arrest or inhibition of NHEJ. In conclusion, combined inhibition of Hsp90 plus radiation was effective, and therefore a promising treatment alternative for overcoming major EGFR-TKI resistance, such as that induced by T790M mutation or MET amplification. However, other approaches are required to overcome minor resistance to EGFR-TKIs, such as that observed in cells with stem cell-like properties.

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  • Lower lobe origin is a poor prognostic factor in locally advanced non-small-cell lung cancer patients treated with induction chemoradiotherapy 査読 国際誌

    Shien, K., Toyooka, S., Soh, J., Hotta, K., Katsui, K., Oto, T., Kanazawa, S., Kiura, K., Date, H., Miyoshi, S.

    Mol Clin Oncol   3 ( 3 )   706 - 712   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The AIM of this study was to identify prognostic factors in patients receiving trimodality therapy for locally advanced non-small-cell lung cancer (NSCLC). Among patients who underwent induction chemoradiotherapy (CRT) followed by surgery between 1999 and 2011 at our institution, 76 NSCLC patients with clinical (c) N2/3 stage III were enrolled in this retrospective study. Induction CRT consisted of docetaxel and cisplatin with concurrent 40-60 Gy radiation therapy. In total, 76 patients were assessed (53 men and 23 women) with 43 adenocarcinomas and 33 non-adenocarcinomas. Of the 76 patients, 44 had cStage IIIA and 32 had cStage IIIB disease. The primary tumors were located in the right upper lobe (N=33), right middle lobe (N=5), right lower lobe (N=11), left upper lobe (N=20s) and left lower lobe (N=7). For all 76 patients, lower lobe tumors were associated with a significantly shorter overall survival (OS) and disease-free survival (DFS) compared to non-lower lobe tumors (OS, P=0.022; and DFS, P=0.0007). When the analysis was limited to pathologically proven N2/3 disease prior to induction CRT (n=36), lower lobe location, compared to other locations, tended to be a poor prognostic factor (OS, P=0.068; and DFS, P=0.0075). Our results indicated that a lower lobe tumor origin is associated with unfavorable prognosis in NSCLC patients treated with induction CRT, strongly suggesting the significance of appropriate patient selection in order to maximize the benefits of trimodality therapy.

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  • Clinicopathological characteristics and lymph node metastasis pathway of non-small-cell lung cancer located in the left lingular division 査読 国際誌

    Shien, K., Toyooka, S., Soh, J., Okami, J., Higashiyama, M., Kadota, Y., Maeda, H., Hayama, M., Chida, M., Funaki, S., Okumura, M., Miyoshi, S.

    Interact Cardiovasc Thorac Surg   20 ( 6 )   791 - 6   2015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:OXFORD UNIV PRESS  

    OBJECTIVES: The purpose of this study is to assess the clinicopathological characteristics of non-small-cell lung cancer (NSCLC) occurring in the left lingular division (LLD) in association with a proposal of the LLD-specific regional lymph node stations. METHODS: Medical records of patients, who underwent complete tumour resection with mediastinal lymph node dissection (MLND) for LLD-NSCLC from 2000 to 2009 in multiple institutions, were retrospectively examined. We analysed patient clinicopathological characteristics and obtained the LLD-specific regional lymph node stations, and then the validity of intraoperative navigation in lymphadenectomy for LLD-NSCLC was investigated. RESULTS: One hundred and eighty-four LLD-NSCLC patients (97 males and 87 females, and 128 adenocarcinomas and 56 non-adenocarcinomas) were studied. The 5-year overall survival (OS) and disease-free survival (DFS) rates for all LLD-NSCLC patients were 72.9 and 58.3%, respectively. We examined the lymph node metastasis patterns in 42 node-positive tumours. The frequent metastatic lymph node stations were #12u lobar node (n = 22), #5 subaortic node (n = 15) and #11 interlobar node (n = 13) in order. These three node stations were also single metastatic sites in some patients. Metastases to sub-carinal (#7) or inferior mediastinal nodes (#8) were rare. Thus, we assigned the three stations (#5, #11, #12u) as the regional lymph node stations for LLD-NSCLC. If these regional lymph node stations had been examined pathologically during surgery for a total of 160 LLD-NSCLC patients with c-T2N1M0 or lower stage disease, 125 p-N0 and 5 p-N1 patients diagnosed with no metastasis would have been subjected to selective MLND, while 14 p-N1 and all 16 p-N2 patients diagnosed with metastasis would have had complete MLND carried out. As a result, these regional lymph node stations could accurately predict the existence of p-N2 metastasis, and appropriately lead to a selective or complete MLND. CONCLUSIONS: An intraoperative pathological examination using our proposed LLD-specific regional lymph node stations may accurately diagnose the status of node metastasis, and appropriately lead to selective or complete MLND in LLD-NSCLC patients with c-T2N1M0 or lower stage disease.

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  • Extended sleeve lobectomy after induction chemoradiotherapy for non-small cell lung cancer 査読

    Toyooka, S., Soh, J., Yamamoto, H., Yamane, M., Hattori, S., Shien, K., Miyoshi, K., Sugimoto, S., Oto, T., Miyoshi, S.

    Surg Today   45 ( 9 )   1121 - 6   2015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  

    PURPOSE: Extended sleeve lobectomy is a challenging surgery. While induction chemoradiotherapy (ChRT) followed by surgery is one of the therapeutic strategies used for locally advanced non-small cell lung cancer (NSCLC), ChRT can impair the anastomotic healing potential. We herein present our experience with cases who underwent an extended sleeve lobectomy after induction ChRT. METHODS: The medical records of patients who underwent a surgery for NSCLC after ChRT were reviewed. RESULTS: Between December 2007 and January 2013, nine patients underwent an extended sleeve lobectomy; the left lingular division and lower lobe in four patients, the right upper lobe and trachea in one patient, the carina and trachea in one patient, the right middle and lower lobes in one patient, the right upper and middle lobes and carina in one patient and the right upper lobe and superior segment of the lower lobe in one patient. While no postoperative 90-day deaths occurred, one case developed a bronchopleural fistula on postoperative day (POD) 25 and one case developed a bronchovascular fistula on POD 163. No cases of local recurrence developed. CONCLUSIONS: Our experience suggests that an extended sleeve lobectomy after induction ChRT is feasible, but careful patient selection and perioperative management are mandatory.

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  • Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma 査読

    Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-LB-291

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  • 家族性・孤発性肺腺癌におけるHER2膜貫通領域の新規遺伝子変異(Novel functional mutations in the transmembrane domain of HER2 gene in familial and sporadic lung adenocarcinomas)

    山本 寛斉, 日笠 幸一郎, 阪口 政清, 枝園 和彦, 宗 淳一, 市村 浩一, 佃 和憲, 瀧川 奈義夫, 松尾 恵太郎, 木浦 勝行, 三好 新一郎, 松田 文彦, 豊岡 伸一

    日本癌学会総会記事   73回   E - 2012   2014年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • アファチニブ耐性を獲得した非小細胞肺癌細胞株の分子生物学的特徴(The molecular characters of acquired resistant non-small cell lung cancer cells to afatinib)

    橋田 真輔, 枝園 和彦, 渡邉 元嗣, 大塚 智昭, 諏澤 憲, 牧 佑歩, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   73回   J - 1044   2014年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Preclinical evaluation of microRNA-34b/c delivery for malignant pleural mesothelioma. 査読

    Ueno T, Toyooka S, Fukazawa T, Kubo T, Soh J, Asano H, Muraoka T, Tanaka N, Maki Y, Shien K, Furukawa M, Sakaguchi M, Yamamoto H, Tsukuda K, Miyoshi S

    Acta medica Okayama   68 ( 1 )   23 - 6   2014年1月

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

    The microRNA-34s (miR-34s) have p53 response elements in their 5'-flanking regions and demonstrate tumor-suppressive functions. In malignant pleural mesothelioma (MPM), we previously reported that expression of miR-34b and miR-34c (miR-34b/c) was frequently downregulated by methylation in MPM cell lines and primary tumors. The forced overexpression of miR-34b/c showed significant antitumor effects with the induction of apoptosis in MPM cells. In this study, we examined the in vivo antitumor effects of miR-34b/c using adenovirus vector on MPM. We subcutaneously transplanted NCI-H290, a human MPM cell line, into BALB/C mice and injected adenovirus vector expressing miR-34b/c, luciferase driven by the cytomegalovirus promoter (Ad-miR-34b/c or Ad-Luc), or PBS control into tumors over 5mm in diameter. A statistically significant growth inhibition of the tumor volume was observed in the Ad-miR-34b/c group from day 6 onward compared to the Ad-Luc group. The inhibition rate of Ad-miR-34b/c, compared to the tumor volume treated with Ad-Luc, was 58.6% on day 10 and 54.7% on day13. Our results indicate that adenovirus-mediated miR-34b/c gene therapy could be useful for the clinical treatment of MPM.

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  • Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer. 査読

    Shien K, Yamamoto H, Soh J, Miyoshi S, Toyooka S

    Acta medica Okayama   68 ( 4 )   191 - 200   2014年1月

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

    Non-small cell lung cancer (NSCLC) harboring an activating mutation within the epidermal growth factor receptor (EGFR) was defined as a clinically distinct molecular group. These lesions show oncogene addiction to EGFR and dramatic responses to the EGFR tyrosine kinase inhibitors (TKIs). Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy. However, the long-term effectiveness of EGFR-TKIs is usually limited because of acquired drug resistance. To overcome this resistance to EGFR-TKIs, it will be essential to identify the specific mechanisms underlying the resistance. Many investigators have attempted to identify the mechanisms using preclinical models and drug-resistant clinical samples. As a result, several mechanisms have been showed to be responsible for the resistance, but not all of the relevant mechanisms have been uncovered. In this review, we provide an overview of mechanisms underlying drug-resistance to EGFR-TKIs, focusing on results obtained with preclinical models, and we present some possible strategies to overcome the EGFR-TKI resistance.

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  • Validity of using lobe-specific regional lymph node stations to assist navigation during lymph node dissection in early stage non-small cell lung cancer patients 査読

    Miyoshi, S., Shien, K., Toyooka, S., Miyoshi, K., Yamamoto, H., Sugimoto, S., Soh, J., Hayama, M., Yamane, M., Oto, T.

    Surg Today   44 ( 11 )   2028 - 36   2014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  

    PURPOSE: The validity of our proposed lobe-specific regional lymph node stations (LSRLNS) was evaluated as a method for navigation during lymphadenectomy in patients with early stage non-small cell lung cancer (NSCLC). METHODS: A total of 725 NSCLC patients with c-T2N1M0 or less extensive disease who had undergone a curative operation with complete mediastinal lymph node dissection (MLND) were studied. The LSRLNS were #2, #3, #4 and #10 for the right upper lobe, #11i, #11s, #7 and #8 for the right lower lobe, #4, #5 and #6 for the left superior division, #11, #5 and #7 for the left lingular division and #11, #7 and #8 for the left lower lobe. RESULTS: If the LSRLNS were used for pathological examinations during surgery, 599 p-N0 and 39 p-N1 patients diagnosed with no metastasis would have been subjected to a selective MLND, while 20 p-N1 and 65 p-N2 patients who had a diagnosis of metastasis would have been navigated to a complete MLND. Two p-N2 patients with a diagnosis of no metastasis would have inappropriately undergone a selective MLND, resulting in the false negative rate at 0.3 %. CONCLUSION: Intra-operative pathological examination using our LSRLNS may accurately reveal the status of metastasis, and appropriately lead to a selective or complete MLND in patients with c-T2N1M0 or less extensive disease.

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  • Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients 査読 国際誌

    Hashida, S., Soh, J., Toyooka, S., Tanaka, T., Furukawa, M., Shien, K., Yamamoto, H., Asano, H., Tsukuda, K., Hagiwara, K., Miyoshi, S.

    Oncol Rep   32 ( 1 )   145 - 52   2014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:SPANDIDOS PUBL LTD  

    The T790M mutation in the epidermal growth factor receptor (EGFR) gene is known to be associated with the acquired resistance of lung adenocarcinoma patients to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The minor T790M mutant allele is occasionally detected in EGFR-TKI-naive tumor samples, yet findings concerning the clinical impact of the minor T790M mutation vary among previous studies. In the present study, we assessed the clinical impact of the minor T790M mutation using a novel, highly sensitive assay combining high-resolution melting (HRM), mutant-enriched PCR and co-amplification at a lower denaturation temperature (COLD)-PCR. We determined the T790M mutational status in 146 surgically resected lung adenocarcinomas without a history of EGFR-TKI treatment using mutant-enriched COLD-HRM (MEC-HRM) and standard HRM assays. The sensitivities of the MEC-HRM and standard HRM assays for the detection of T790M-mutant alleles among wild-type alleles were 0.01 and 10%, respectively. Although the T790M mutation was not detected using a standard HRM assay, we identified 19 (13%) T790M mutations using the MEC-HRM assay and defined these 19 mutations as minor T790M mutations. The proportion of T790M alleles was <0.1% in 17 (84%) of the 19 samples. Multivariate analyses revealed that a minor T790M mutation was significantly associated with the presence of EGFR exon 19 deletions or the L858R mutation (both of which are drug-sensitive EGFR mutations) (P=0.04). In conclusion, the minor EGFR T790M mutations were present in 13% of EGFR-TKI-naive surgically resected lung adenocarcinomas and were associated with drug-sensitive EGFR mutations.

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  • Density of tumor-infiltrating FOXP3+ T cells as a response marker for induction chemoradiotherapy and a potential prognostic factor in patients treated with trimodality therapy for locally advanced non-small cell lung cancer 査読

    Tao, H., Shien, K., Soh, J., Matsuda, E., Toyooka, S., Okabe, K., Miyoshi, S.

    Ann Thorac Cardiovasc Surg   20 ( 6 )   980 - 6   2014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:MEDICAL TRIBUNE INC  

    PURPOSE: To examine the relationship between the density of tumor-infiltrating T cell subpopulations and the pathological response to induction chemoradiotherapy (CRT) in patients with locally advanced NSCLC, and to assess the impact of T cell density on patient prognosis. METHODS: A total of 64 patients with c-stages IIA-IIIB NSCLC who underwent induction CRT followed by R0 surgery were enrolled. Tumor-infiltrating T cells expressing either FOXP3 or CD8 were detected by immunohistochemical staining. RESULTS: Mean numbers of tumor-infiltrating FOXP3+ T cells were 39.9 for patients with minor pathological responses (n = 9), 18.4 for those with major pathological responses (n = 25), and 12.9 for those with complete pathological responses (n = 30; P &lt;0.001). The number of CD8+ T cells was not associated with pathological responses. Patients with lower FOXP3+ T cell densities showed better survival, although the difference was not statistically significant. CONCLUSION: Our study demonstrated that the density of tumor-infiltrating FOXP3+ T cells indicated the degree of response for induction CRT and prognosis in patients treated with trimodality therapy for locally advanced NSCLC, suggesting that FOXP3+ T cells may be target for adjunct immunotherapy.

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  • Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer 査読 国際誌

    Shien, K., Tanaka, N., Watanabe, M., Soh, J., Sakaguchi, M., Matsuo, K., Yamamoto, H., Furukawa, M., Asano, H., Tsukuda, K., Nasu, Y., Huh, N. H., Miyoshi, S., Kumon, H., Toyooka, S.

    PLoS One   9 ( 2 )   e87900   2014年

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

    OBJECTIVES: REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines. RESULTS: Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a non-malignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells. CONCLUSION: Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.

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  • Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas 査読 国際誌

    Yamamoto, H., Higasa, K., Sakaguchi, M., Shien, K., Soh, J., Ichimura, K., Furukawa, M., Hashida, S., Tsukuda, K., Takigawa, N., Matsuo, K., Kiura, K., Miyoshi, S., Matsuda, F., Toyooka, S.

    J Natl Cancer Inst   106 ( 1 )   djt338   2014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:OXFORD UNIV PRESS INC  

    We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.

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  • Micropapillary componentを有する肺腺癌の遺伝子異常

    古川 公之, 豊岡 伸一, 市村 浩一, 宗 淳一, 橋田 真輔, 多田 龍平, 枝園 和彦, 山本 寛斎, 浅野 博昭, 佃 和憲, 三好 新一郎

    日本外科学会雑誌   114 ( 臨増2 )   552 - 552   2013年3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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  • Silenced expression of NFKBIA in lung adenocarcinoma patients with a never-smoking history. 査読

    Furukawa M, Soh J, Yamamoto H, Ichimura K, Shien K, Maki Y, Muraoka T, Tanaka N, Ueno T, Asano H, Tsukuda K, Toyooka S, Miyoshi S

    Acta medica Okayama   67 ( 1 )   19 - 24   2013年1月

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

    Nuclear factor of κ-light polypeptide gene enhancer in B cells inhibitor α (NFKBIA), which is a tumor suppressor gene, was found to be silenced in lung adenocarcinomas. We examined NFKBIA expression, mutations in the EGFR and K-ras genes, and EML4-ALK fusion in 101 resected lung adenocarcinoma samples from never-smokers. NFKBIA expression was evaluated using immunohistochemistry. NFKBIA expression was negative in 16 of the 101 samples (15.8%). EGFR and K-ras mutations and EML4-ALK fusion were detected in 61 (60.5%), 1 (1.0%), and 2 (2.0%) of the 101 samples, respectively, in a completely mutually exclusive manner. Negative NFKBIA expression was observed significantly more frequently among the tumors with none of the three genetic alterations compared to those with such alterations (p = 0.009). In addition, negative NFKBIA expression was significantly more frequent among the EGFR-wild type samples compared to the EGFR-mutant samples (p = 0.013). In conclusion, NFKBIA expression was silenced in adenocarcinomas without EGFR/K-ras mutations or EML4-ALK fusion, suggesting that the silencing of NFKBIA may play an important role in the carcinogenesis of adenocarcinomas independent of EGFR/K-ras mutations or EML4-ALK fusion.

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  • Use of a vessel sealing system versus conventional electrocautery for lung parenchymal resection: a comparison of the clinicopathological outcomes in porcine lungs 査読

    Sugimoto, S., Toyooka, S., Iga, N., Furukawa, M., Sugimoto, R., Shien, K., Nishikawa, H., Soh, J., Yamane, M., Oto, T., Miyoshi, S.

    Surg Today   44 ( 3 )   540 - 5   2013年

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

    PURPOSE: LigaSure, a vessel sealing system, has been shown to have excellent hemostatic properties; however, its use for lung parenchymal resection has been limited. We herein examined the hemostatic properties and potential for inducing histological lung injury of the LigaSure system in non-anatomic pulmonary resection to estimate the feasibility of its clinical application. METHODS: Non-anatomic pulmonary wedge resections of the right cranial, middle, and caudal lobes were performed in four pigs using the LigaSure system (Group A) or electrocautery (Group B). In each resection, the resection time, blood loss, and weight of the resected lung were measured. The thermal effect on the lung tissue was examined by means of intraoperative thermography and histology. RESULTS: A total of 12 lung wedge resections were performed in each group. For an equivalent length of operation and weight of the resected lung parenchyma, Group A showed significantly lower blood loss and lower maximum and minimum temperatures of the lung tissue, as assessed by thermography, than Group B. The degree of thermal injury as estimated by a histological examination was lower in Group A than in Group B. CONCLUSION: Our study suggests that the LigaSure system may be superior to conventional electrocautery, indicating its clinical usefulness for non-anatomic pulmonary resection.

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  • The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma 査読 国際誌

    Muraoka, T., Soh, J., Toyooka, S., Aoe, K., Fujimoto, N., Hashida, S., Maki, Y., Tanaka, N., Shien, K., Furukawa, M., Yamamoto, H., Asano, H., Tsukuda, K., Kishimoto, T., Otsuki, T., Miyoshi, S.

    Lung Cancer   82 ( 3 )   485 - 90   2013年

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

    OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP). MATERIALS AND METHODS: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined. RESULTS: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 °C which was the mean ± 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P=0.03) or HVs (P<0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77. CONCLUSIONS: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM.

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  • Impact of GLUT1 and Ki-67 expression on early‑stage lung adenocarcinoma diagnosed according to a new international multidisciplinary classification. 査読 国際誌

    Maki Y, Soh J, Ichimura K, Shien K, Furukawa M, Muraoka T, Tanaka N, Ueno T, Yamamoto H, Asano H, Tsukuda K, Toyooka S, Miyoshi S

    Oncology reports   29 ( 1 )   133 - 40   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:1  

    DOI: 10.3892/or.2012.2087

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  • Sacrificing the pulmonary arterial branch to the spared lobe is a risk factor of bronchopleural fistula in sleeve lobectomy after chemoradiotherapy 査読 国際誌

    Toyooka, S., Soh, J., Shien, K., Sugimoto, S., Yamane, M., Oto, T., Date, H., Miyoshi, S.

    Eur J Cardiothorac Surg   43 ( 3 )   568 - 72   2013年

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

    OBJECTIVES: A sleeve lobectomy is a widely accepted procedure for enabling the pulmonary parenchyma to be spared. Induction chemoradiotherapy (CRT) followed by surgery is one treatment option for locally advanced non-small cell lung cancer (NSCLC), but CRT is considered to have a negative effect on subsequent surgery, especially for anastomotic healing. In this study, we describe our experience performing sleeve lobectomies and the associated anastomotic complications after induction CRT. METHODS: The medical records of NSCLC patients who underwent surgery after receiving CRT were reviewed. The relationships between anastomotic complications and clinicopathological factors were examined. RESULTS: Between December 1998 and October 2011, a total of 104 patients received CRT followed by surgery. Among them, 14 NSCLC patients underwent a bronchial sleeve resection: nine patients underwent a right upper lobe resection, two patients underwent a left lingular division and lower lobe resection and one patient each underwent a right lower lobe, a right upper and middle lobe and a right middle and lower lobe resection. A bronchopleural fistula at the anastomosis occurred in two patients. A pulmonary arterial (PA) branch to the spared lobe had been sacrificed in both of these patients because of tumour involvement. In contrast, the PA branches to the spared lobes were preserved in 11 of the 12 patients who did not exhibit anastomotic complications (P = 0.033). CONCLUSIONS: Our experience strongly suggests that the sacrifice of the PA branch to the spared lobe is a possible risk factor for anastomotic complications for a sleeve lobectomy after induction CRT.

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  • Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers 査読 国際誌

    Muraoka, T., Soh, J., Toyooka, S., Maki, Y., Shien, K., Furukawa, M., Ueno, T., Tanaka, N., Yamamoto, H., Asano, H., Tsukuda, K., Miyoshi, S.

    Mol Clin Oncol   1 ( 1 )   185 - 189   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MicroRNAs (miRs) contribute to cancer development and progression by acting as oncogenes and tumor suppressor genes. miR-9 family members (miR-9s), including miR-9-1, 9-2 and 9-3, have been shown to be oncogenically involved through the downregulation of E-cadherin expression, which promotes the epithelial-mesenchymal transition. Tumor suppressive roles of miR-9s have also been reported to silence miR-9 through methylation, which is associated with an shortened overall survival (OS) period in several types of cancer. In this study, the impact of miR-9s methylation on non-small cell lung cancers (NSCLC) was investigated. In total, 293 resected NSCLC samples were examined and the miR-9s methylation status was determined using a combined bisulfite restriction analysis. miR-9 expression was analyzed by in situ hybridization. Methylation of miR-9-1, 9-2 and 9-3 was present in 20 (7%), 33 (11%) and 34 (12%) of the cases, respectively. Methylation of any miR-9s (miR-9s methylation) was observed in 76 of the cases (26%), and miR-9 expression was silenced in cases with miR-9s methylation. Logistic regression analysis demonstrated that male gender [odds ratio (OR), 2.0; 95% confidence interval (95% CI), 1.1-3.6; P=0.01] and pathologically negative lymph node metastasis (OR, 4.8; 95% CI, 1.4-17.2; P=0.002) were independent relative factors for miR-9s methylation. Additionally, miR-9s methylation [hazard ratio (HR), 4.2; 95% CI, 1.2-27.0; P=0.026] and early pathological stage (HR, 8.3; 95% CI, 2.1-28.6; P=0.004) were found to be independent predictive factors for prolonged OS time by the Cox proportional hazard test. miR-9s methylation which induces expression silencing is common in NSCLC cases without lymph nodal metastasis, suggesting that miR-9s are oncogenically involved in NSCLC carcinogenesis through the promotion of tumor metastasis.

    DOI: 10.3892/mco.2012.18

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  • Acquired Resistance to EGFR Inhibitors Is Associated with a Manifestation of Stem Cell-like Properties in Cancer Cells 査読 国際誌

    Shien, K., Toyooka, S., Yamamoto, H., Soh, J., Jida, M., Thu, K. L., Hashida, S., Maki, Y., Ichihara, E., Asano, H., Tsukuda, K., Takigawa, N., Kiura, K., Gazdar, A. F., Lam, W. L., Miyoshi, S.

    Cancer Res   73 ( 10 )   3051 - 61   2013年

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

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

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  • Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells 査読 国際誌

    Tanaka, N., Toyooka, S., Soh, J., Tsukuda, K., Shien, K., Furukawa, M., Muraoka, T., Maki, Y., Ueno, T., Yamamoto, H., Asano, H., Otsuki, T., Miyoshi, S.

    Oncol Rep   29 ( 6 )   2169 - 74   2013年

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

    Malignant mesothelioma (MM) is an aggressive tumor with a dismal prognosis, and the molecular alterations involved in this disease remain unknown. We previously reported that microRNA-34s (miR-34s) are methylated and downregulated in MM and may play an important role in the carcinogenesis of MM. In this study, we downregulated miR-34s in human mesothelial cells to investigate the cellular effect of miR-34 knockdown. For the cell study, we used LP-9, a human mesothelial cell line, and three human primary-cultured mesothelial cell lines. RNA-based miR-34a, -34b and -34c inhibitors were transfected into these cells, and their effects on proliferation and invasion were evaluated. A scramble RNA oligonucleotide was used as a control. The protein expression status was estimated using western blotting. After miR-34 inhibitor transfection, miR-34a, -34b and -34c were downregulated in all the examined mesothelial cell lines. miR-34 inhibitor transfection significantly increased cell proliferation in all of the mesothelial cell lines, compared with the scramble control. The invasive ability also increased in the miR-34 inhibitor transfectants, compared with the scramble control, in the LP-9 cell line. Western blotting confirmed the upregulation of c-MET, phospho-c-MET, and bcl-2 proteins in LP-9 cells after miR-34 inhibitor transfection. In conclusion, our study showed that the downregulation of miR-34s induced an oncogenic phenotype in non-malignant mesothelial cells. The present study, together with the results of our previous report, strongly suggest that miR-34s play an important role in the early carcinogenic process involved in the transformation of human mesothelial cells to MM.

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  • DIRECT THERAPEUTIC EFFECT OF REIC/DKK-3-ENCODING ADENOVIRAL VECTOR FOR NON-SMALL CELL LUNG CANCER 査読

    Yamamoto Hiromasa, Tanaka Norimitsu, Toyooka Shinichi, Watanabe Masami, Sakaguchi Masakiyo, Soh Junichi, Shien Kazuhiko, Furukawa Masashi, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi, Miyoshi Shinichirou

    JOURNAL OF THORACIC ONCOLOGY   7 ( 11 )   S463   2012年11月

  • 新規に樹立した悪性胸膜中皮腫細胞株の分子生物学的解析

    山本 寛斉, 多田 龍平, 枝園 和彦, 古川 公之, 宗 淳一, 三村 雄輔, 片山 英樹, 青江 啓介, 岡部 和倫, 松本 常男, 豊岡 伸一, 三好 新一郎

    肺癌   52 ( 5 )   550 - 550   2012年10月

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  • 微小乳頭状肺腺癌におけるEGFR、K-ras、EML4-ALKの変異の様式(EGFR, K-ras and EML4-ALK mutational profile of lung adenocarcinomas with micropapillary component)

    古川 公之, 宗 淳一, 豊岡 伸一, 枝園 和彦, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎

    肺癌   52 ( 5 )   671 - 671   2012年10月

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    記述言語:英語   出版者・発行元:(NPO)日本肺癌学会  

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  • 正常中皮細胞におけるmicroRNA34の抑制効果 Tiny RNA drives mesothelial cell mad

    田中 則光, 豊岡 伸一, 宗 淳一, 佃 和憲, 枝園 和彦, 古川 公之, 村岡 孝幸, 牧 佑歩, 上野 剛, 久保 孝文, 山本 寛斎, 浅野 博昭, 大槻 剛巳, 三好 新一郎

    日本癌治療学会誌   47 ( 3 )   1275 - 1275   2012年10月

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  • Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer 査読

    Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

    Lung Cancer   108   254 - 255   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:Elsevier Ireland Ltd  

    The publisher regrets errors were introduced in Fig. 3 A of the article described above. The images for both p-Scramble and p-miR-34b/c in SBC5 were incorrect. An amended version of Fig. 3 is shown below. Note that the analyses for both migration and invasion assays were appropriate and thus it is not necessary to correct the bar graphs in Fig. 3 as well as the legends for Fig. 3. The authors also consider that there is no need to correct any other parts of this article. The publisher would like to apologise for any inconvenience caused.

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  • 中葉肺癌のリンパ節転移様式に関する検討

    枝園 和彦, 豊岡 伸一, 沢田 茂樹, 山下 素弘, 森山 重治, 林 達朗, 岡部 和倫, 西 英行, 重松 久行, 安藤 陽夫, 岡崎 幹生, 佐野 由文, 井野川 英利, 前田 宏也, 片岡 正文, 水谷 尚雄, 三好 新一郎

    日本呼吸器外科学会雑誌   26 ( 3 )   O08 - 05   2012年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • Ectopic cervical thymoma: a case report with 18F-fluorodeoxyglucose positron emission tomography findings. 査読

    Shien K, Shien T, Soh J, Ikeda H, Nogami T, Taira N, Doihara H, Miyoshi S

    Acta medica Okayama   66 ( 4 )   357 - 61   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:OKAYAMA UNIV MED SCHOOL  

    Ectopic thymoma is considered to arise from ectopic thymus tissue deposited as a result of the abnormal mislocalization of thymus tissue during the embryonic stage. An 86-year-old man visited our hospital with chief complaints of hoarseness and a mass in his anterior neck. A preoperative needle biopsy of the mass did not yield a definitive diagnosis. A positron emission tomography (PET) study revealed heterogeneous accumulation of (18)F-fluorodeoxyglucose (FDG) in the tumor. The tumor, affecting the left sternocleidomastoid muscle, the recurrent laryngeal nerve, the internal carotid vein, and the brachiocephalic vein, was resected using a combination of a collar incision in the neck and a median incision in the sternum. Immunohistochemically, the tumor was diagnosed as an ectopic thymoma of the neck. To date, only a few cases of ectopic thymoma presenting with FDG accumulation have been reported. Our experience indicates that ectopic thymoma should be kept in mind during the differential diagnosis of neck tumors with FDG accumulation appearing on PET images.

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  • Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 査読 国際誌

    Ohashi, K., Sequist, L. V., Arcila, M. E., Moran, T., Chmielecki, J., Lin, Y. L., Pan, Y., Wang, L., de Stanchina, E., Shien, K., Aoe, K., Toyooka, S., Kiura, K., Fernandez-Cuesta, L., Fidias, P., Yang, J. C., Miller, V. A., Riely, G. J., Kris, M. G., Engelman, J. A., Vnencak-Jones, C. L., Dias-Santagata, D., Ladanyi, M., Pao, W.

    Proc Natl Acad Sci U S A   109 ( 31 )   E2127-33 - E2133   2012年

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

    Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

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  • Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer 査読 国際誌

    Tanaka, N., Toyooka, S., Soh, J., Kubo, T., Yamamoto, H., Maki, Y., Muraoka, T., Shien, K., Furukawa, M., Ueno, T., Asano, H., Tsukuda, K., Aoe, K., Miyoshi, S.

    Lung Cancer   76 ( 1 )   32 - 8   2012年

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

    Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p<0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC.

    DOI: 10.1016/j.lungcan.2011.10.002

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  • Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer 査読 国際誌

    Ueno, T., Tsukuda, K., Toyooka, S., Ando, M., Takaoka, M., Soh, J., Asano, H., Maki, Y., Muraoka, T., Tanaka, N., Shien, K., Furukawa, M., Yamatsuji, T., Kiura, K., Naomoto, Y., Miyoshi, S.

    Lung Cancer   76 ( 1 )   26 - 31   2012年

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

    The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24,100 nM) than the NSCLC cells (p=0.015). There was significant depletion of both the total and phosphorylated client proteins--EGFR, MET, HER2 and AKT--at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G0-G1 cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC.

    DOI: 10.1016/j.lungcan.2011.09.011

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  • Knockdown of the epidermal growth factor receptor gene to investigate its therapeutic potential for the treatment of non-small-cell lung cancers 査読 国際誌

    Shien, K., Ueno, T., Tsukuda, K., Soh, J., Suda, K., Kubo, T., Furukawa, M., Muraoka, T., Maki, Y., Tanaka, N., Yamamoto, H., Kiura, K., Mitsudomi, T., Toyooka, S., Miyoshi, S.

    Clin Lung Cancer   13 ( 6 )   488 - 93   2012年

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

    BACKGROUND: Epidermal growth factor receptor (EGFR) is often overexpressed in non-small-cell lung cancer (NSCLC). Anti-EGFR agents, including EGFR-tyrosine kinase inhibitors are considered to be effective when a drug-sensitive EGFR mutation is present. However, inherent and acquired resistances are major problems of EGFR-targeting therapies. In this study, we performed EGFR knockdown by using small interfering RNAs in NSCLC cell lines to examine the significance of targeting EGFR for NSCLC therapy. METHODS: We treated 13 NSCLC cell lines, including 8 EGFR mutant and 5 EGFR wild type by using gefitinib or small interfering RNAs against EGFR (siEGFR). Three cell lines (PC-9-GR1, RPC-9, and HCC827-ER) were experimentally established with acquired resistance to EGFR-tyrosine kinase inhibitors. The antitumor effect was determined by using an 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt (MTS) or colony formation assay. The protein expression was evaluated by using Western blotting. RESULTS: All 13 cell lines expressed EGFR protein, and siEGFR downregulated EGFR protein expression in all. The cell viability was suppressed by siEGFR in 6 of 8 EGFR-mutant cell lines (suppressed 57%-92% of control cells), including PC-9-GR1 and RPC-9. The NCI-H1650 and HCC827-ER harbored EGFR mutations but were not suppressed. Of note, PTEN (phosphatase and tensin homolog) was deleted in NCI-H1650, and c-MET was amplified in HCC827-ER. It was not suppressed in any of the EGFR wild-type cells except in the NCI-H411, in which EGFR is phosphorylated, which indicates its activation. CONCLUSIONS: Analysis of the results indicated that EGFR can be a therapeutic target in NSCLCs with EGFR activation. In contrast, targeting EGFR is not appropriate for tumors in which EGFR is not activated, even if EGFR is expressed.

    DOI: 10.1016/j.cllc.2012.02.003

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  • Induction chemoradiotherapy followed by surgical resection for clinical T3 or T4 locally advanced non-small cell lung cancer 査読 国際誌

    Shien, K., Toyooka, S., Kiura, K., Matsuo, K., Soh, J., Yamane, M., Oto, T., Takemoto, M., Date, H., Miyoshi, S.

    Ann Surg Oncol   19 ( 8 )   2685 - 92   2012年

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

    PURPOSE: To examine the usefulness of trimodality therapy in patients with clinical T3 or T4 (cT3-4) locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Between 1997 and 2009, a total of 76 LA-NSCLC patients with cT3-4 underwent surgery. Among them, 36 patients underwent induction chemoradiotherapy with docetaxel and cisplatin plus concurrent radiation followed by surgery (IC group). The other 40 patients initially underwent surgery (IS group). The outcomes of the IC and IS groups were then investigated. To minimize possible biases caused by confounding treatment indications, we performed a retrospective cohort analysis by applying a propensity score (PS). Patients were divided into three groups according to PS tertiles, and comparisons between the IC and IS groups were made by PS tertile-stratified Cox proportional hazard models. RESULTS: For the entire cohort, which had a median follow-up duration of 48 months, the 3- and 5-year overall survival rates were 83.8 and 78.9%, respectively, in the IC group, versus 66.8 and 56.5%, respectively, in the IS group (P = 0.0092). After adjustments for potentially confounding variables, the IC group continued to have a significantly longer overall survival than the IS group (P = 0.0045). In addition, when the analysis was limited to 52 patients with cT3-4N0 or N1 disease, the IC group had a significantly longer overall survival than the IS group after adjustments for confounding variables (P = 0.019). CONCLUSIONS: Our study indicates that trimodality therapy is highly effective in patients with cT3-4 LA-NSCLC.

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  • Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy 査読 国際誌

    Shien, K., Toyooka, S., Ichimura, K., Soh, J., Furukawa, M., Maki, Y., Muraoka, T., Tanaka, N., Ueno, T., Asano, H., Tsukuda, K., Yamane, M., Oto, T., Kiura, K., Miyoshi, S.

    Lung Cancer   77 ( 1 )   162 - 7   2012年

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

    The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (44.9% vs. 90.0%, respectively; P = 0.042). In a multivariate analysis, CD133 and ALDH1 negativity (P = 0.047) and cN2-3 single station metastasis (P = 0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy.

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  • MicroRNA miR-34b/c enhances cellular radiosensitivity of malignant pleural mesothelioma cells 査読 国際誌

    Maki, Y., Asano, H., Toyooka, S., Soh, J., Kubo, T., Katsui, K., Ueno, T., Shien, K., Muraoka, T., Tanaka, N., Yamamoto, H., Tsukuda, K., Kishimoto, T., Kanazawa, S., Miyoshi, S.

    Anticancer Res   32 ( 11 )   4871 - 5   2012年

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

    BACKGROUND: We previously reported that epigenetic silencing of microRNA-34b/c (miR-34b/c) plays an important role in the pathogenesis of malignant pleural mesothelioma (MPM). We examined the impact of miR-34b/c restoration on the radiosensitivity of MPM cells. MATERIALS AND METHODS: We established stable miR-34b/c and scramble transfectants of two MPM cell lines, H2052 and H28. We examined these transfectants by clonogenic survival assay, phosphorylated histone H2AX (γH2AX) foci assay, cell-cycle analysis, and western blotting. RESULTS: The clonogenic survival assay revealed that miR-34b/c radiosensitized MPM cells. γH2AX foci assay showed that DNA double-strand break repair was delayed in miR-34b/c transfectants. The proportion of sub-G(1) phase cells was increased in miR-34b/c transfectants after irradiation. miR-34b/c inhibited expression of cyclin-D1, cyclin-dependent kinase 4/6, B-cell lymphoma-2 (BCL-2) and increased cleaved poly (ADP-ribose) polymerase (cPARP) and cleaved caspase-3 after irradiation. CONCLUSION: Our results indicate that miR-34b/c enhances radiosensitivity by promoting radiation-induced apoptosis and suggested that miR-34b/c might be a useful therapeutic molecule to enhance radiotherapy in MPM.

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  • Induction chemoradiotherapy is superior to induction chemotherapy for the survival of non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis 査読 国際誌

    Toyooka, S., Kiura, K., Shien, K., Katsui, K., Hotta, K., Kanazawa, S., Date, H., Miyoshi, S.

    Interact Cardiovasc Thorac Surg   15 ( 6 )   954 - 60   2012年

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

    OBJECTIVES: The purpose of this study was to compare the clinical outcomes of induction chemoradiotherapy and chemotherapy and to identify the prognostic factors for non-small-cell lung cancer patients with mediastinal lymph node metastasis who were treated with induction therapy. METHODS: Between August 1995 and December 2010, 50 non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis were scheduled to receive induction therapy followed by surgery. Irinotecan plus cisplatin was used for induction chemotherapy from June 1995 to April 1999, and docetaxel plus cisplatin with concurrent radiation at a dose of 40-46 Gy has been used for induction chemoradiotherapy since May 1999. RESULTS: Thirty-five patients were treated with induction chemoradiotherapy and 15 were treated with induction chemotherapy. For the entire population, the 3-year and 5-year overall survival rates were 64.1 and 53.9%, respectively, and the 1-year and 2-year disease-free survival rates were 70.0 and 53.1%, respectively. Among the clinicopathological factors, the chemoradiotherapy group exhibited longer overall survival and disease-free survival than the chemotherapy group (overall survival, P = 0.0020; disease-free survival, P = 0.015). Pathological downstaging was also significantly associated with favorable overall survival (P = 0.0042) and disease-free survival (P = 0.021). A multivariate analysis showed that chemoradiotherapy (P = 0.0099) and pathological downstaging (P = 0.039) were independent prognostic factors. CONCLUSIONS: Our results indicated that induction chemoradiotherapy was superior to induction chemotherapy with regard to the outcome of non-small-cell lung cancer patients with mediastinal lymph node metastasis.

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  • 胸腺癌切除後の再発症例における治療成績の検討

    重松 久之, 安藤 陽夫, 枝園 和彦, 井野川 英利, 前田 宏也, 末久 弘, 澤田 茂樹, 山下 素弘, 岡崎 幹生, 佐野 由文, 山本 寛斉, 岡部 和倫, 三好 新一郎

    肺癌   51 ( 5 )   506 - 506   2011年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Primary lung cancer surgery after curative chemoradiotherapy for esophageal cancer patients 査読 国際誌

    Shien, K., Yamashita, M., Okazaki, M., Suehisa, H., Sawada, S., Miyoshi, S.

    Interact Cardiovasc Thorac Surg   12 ( 6 )   1002 - 6   2011年

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

    The safety and perioperative problems of primary lung cancer surgery after curative chemoradiotherapy (CRT) for thoracic esophageal cancer (EC) are controversial. We retrospectively evaluated six patients who had received curative CRT for EC from 2003 to 2009, in whom the lung nodule was identified as a primary lung cancer and who subsequently underwent pulmonary resection. The treatment for EC consisted of chemotherapy with cisplatin and 5-fluorouracil with concurrent curative thoracic radiotherapy (60 Gy). The median age at the surgery was 75 years (range 69-80 years). The median time from radiation to pulmonary resection was 26 months (range 7-70 months). All patients had a predicted postoperative forced expiratory volume in 1 s (FEV(1))% of >40% before lung surgery. The surgical difficulty involves mediastinal lymph node dissection following tissue fibrotic changes after thoracic radiation. Postoperative complications occurred in two patients, and included arrhythmia and empyema. The patient who developed empyema had a massive pericardial effusion after CRT and underwent pericardial fenestration at the time of pulmonary resection. There was no operative mortality. Lung cancer surgery after curative CRT for EC is feasible in carefully evaluated and selected patients.

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  • Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer. 査読 国際誌

    Ikeda, H., Taira, N., Nogami, T., Shien, K., Okada, M., Shien, T., Doihara, H., Miyoshi, S.

    Cancer Sci   102 ( 11 )   2038 - 42   2011年

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

    Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.

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  • Pulmonary mucosa-associated lymphoid tissue lymphoma with a pulmonary arteriovenous fistula 査読

    Shien, K., Yamashita, M., Okazaki, M., Suehisa, H., Sawada, S., Kurita, A.

    Gen Thorac Cardiovasc Surg   59 ( 5 )   371 - 5   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:5  

    We report an extremely rare case of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma with a pulmonary arteriovenous fistula (PAVF). A 60-year-old woman with vulvar carcinoma was admitted to our hospital for further examination of an abnormal shadow on chest computed tomography (CT). She showed hypoxemia in the arterial blood gas analysis. (18)F-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed consolidations in the left lower lobe and soft-tissue density lesions in the anterior mediastinum. Each lesion showed heterogeneous FDG uptake. Although needle biopsy of these lesions was performed, a pathological diagnosis was not obtained. For the evaluation of hypoxemia, chest contrast-enhanced CT was performed, and a PAVF in the consolidation of the left lower lobe was revealed. For diagnostic and therapeutic purposes, we performed left lower lobectomy under video-assisted thoracoscopic surgery. In the surgical specimen the PAVF measured 3 cm, and histopathological examination revealed pulmonary MALT lymphoma adjacent to the PAVF.

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  • 術前補助療法 進行非小細胞肺癌に対する導入化学放射線療法

    枝園 和彦, 豊岡 伸一, 武本 充広, 宗 淳一, 山根 正修, 大藤 剛宏, 堀田 勝幸, 頼 冠名, 瀧川 奈義夫, 田端 雅弘, 木浦 勝行, 三好 新一郎

    肺癌   50 ( 5 )   472 - 472   2010年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 肺癌pN2症例におけるFDG-PETによるN因子診断能と予後予測能

    岡崎 幹生, 山下 素弘, 枝園 和彦, 末久 弘, 澤田 茂樹

    日本呼吸器外科学会雑誌   24 ( 3 )   640 - 640   2010年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 肺動静脈瘻に辺縁帯B細胞リンパ腫(BALToma)を合併した1例

    枝園 和彦, 山下 素弘, 岡崎 幹生, 末久 弘, 澤田 茂樹

    日本呼吸器外科学会雑誌   24 ( 3 )   527 - 527   2010年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • すりガラス状陰影(GGO)を伴う小型肺野病変の画像所見および病理所見に関する検討

    枝園 和彦, 山下 素弘, 岡崎 幹生, 末久 弘, 澤田 茂樹

    日本呼吸器外科学会雑誌   24 ( 3 )   583 - 583   2010年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 肺癌術後follow-upの有用性の検討

    沢田 茂樹, 末久 弘, 枝園 和彦, 岡崎 幹生, 山下 素弘

    日本呼吸器外科学会雑誌   24 ( 3 )   515 - 515   2010年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • Two case reports of esophageal schwannoma and literature review of case reports 査読

    Kazuhiko Shien, Isao Nozaki, Takaya Kobatake, Kouzi Ohta, Yoshiro Kubo, Minoru Tanada, Akira Kurita

    Japanese Journal of Gastroenterological Surgery   43 ( 11 )   1106 - 1111   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:Japanese Society of Gastroenterological Surgery  

    We report two cases of esophageal schwannoma. A 66-year-old woman (case 1) and a 56-year-old man (case 2) were admitted for abnormal shadows pointed out in barium esophagography. In case 1, an esophageal sub-mucosal tumor was resected by transthoracic esophagectomy with gastric tube reconstruction. In case 2, esophageal tumor was enucleated by thoracoscopic surgery. To remove the tumor from the muscular layer, a Sangstaken-Blakemore tube (S-B tube) was used intraoperatively inserted into the esophagus preoperatively. Both tumors consisted histopathologically of spindle-shaped cell bundles and S-100 protein expression was im-munohistochemically confirmed in both tumors. The definitive diagnose was benign esophageal schwannoma in both cases. Esophageal schwannoma is extremely rare, and we review 26 cases from the Japanese literature. © 2010 The Japanese Society of Gastroenterological Surgery.

    DOI: 10.5833/jjgs.43.1106

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  • 呼吸器周術期の上室性不整脈に対するランジオロール塩酸塩の使用経験

    沢田 茂樹, 末久 弘, 岡崎 幹生, 枝園 和彦, 小森 栄作, 山下 素弘

    Progress in Medicine   29 ( 12 )   3143 - 3145   2009年12月

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    記述言語:日本語   出版者・発行元:(株)ライフ・サイエンス  

    呼吸器術後に発生した上室性不整脈に対するランジオロール塩酸塩の使用経験を報告した。症例は56歳男で、検診の胸部X線写真で異常を指摘された。気管支カメラの生検で扁平上皮癌と診断され、手術を施行した。#10、11リンパ節が腫大し転移が疑われたので、予定どおり左肺全摘を行った。術後8時間より心房組動を発症した。ジギタリスを使用したが効果なく、ランジオロール塩酸塩を0.01mg/kg/minで開始し、漸増し、0.04mg/kg/minで洞調律に戻ったため中止した。中止約2時間後、再度心房細動あり、ランジオロール塩酸塩投与を再開し、洞調律に戻った。その他3例のランジオロール塩酸塩の使用を経験し、ランジオロール塩酸塩にて、血圧低下なく心拍数をコントロールできた。また、投与前後で酸素飽和度の変化はなく、呼吸状態に対し影響はないようであった。

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  • 肺腫瘍に対する定位放射線治療後、局所再発に対してsalvage手術を行った6例

    多田 龍平, 山下 素弘, 枝園 和彦, 岡崎 幹生, 末久 弘, 沢田 茂樹, 濱本 泰, 片岡 正明

    肺癌   49 ( 5 )   650 - 650   2009年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Nissen手術を要した食道裂孔ヘルニア合併肺癌に対する肺切除例の検討

    岡崎 幹生, 豊岡 伸一, 岡田 真典, 枝園 和彦, 田尾 裕之, 山根 正修, 大藤 剛宏, 佐野 由文

    日本呼吸器外科学会雑誌   23 ( 3 )   481 - 481   2009年4月

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  • 術前治療後肺切除時の有茎大網被覆術に伴う消化器合併症の検討

    枝園 和彦, 豊岡 伸一, 岡崎 幹生, 山根 正修, 羽藤 慎二, 伊野 英男, 大藤 剛宏, 内藤 稔, 土井原 博義, 佐野 由文

    日本臨床外科学会雑誌   69 ( 増刊 )   663 - 663   2008年10月

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    記述言語:日本語   出版者・発行元:日本臨床外科学会  

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  • 【肺癌のUp-To-Date】肺癌手術の実際

    山根 正修, 岡崎 幹生, 枝園 和彦, 大藤 剛宏, 佐野 由文, 豊岡 伸一

    THE LUNG-perspectives   16 ( 4 )   469 - 473   2008年10月

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    記述言語:日本語   出版者・発行元:(株)メディカルレビュー社  

    肺癌、特に早期の非小細胞肺癌に対する治療において外科的切除は重要な位置を占める。医学の進歩により胸腔鏡を用いた手術、また、非浸潤肺癌に対する積極的縮小手術、術前導入療法、術後補助療法の付加など手術を取り巻く環境も次第に変化している。本稿では岡山大学で行っている肺癌手術を中心とした肺癌への取り組みについて述べる。(著者抄録)

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  • 縦隔巨大軟骨肉腫に対して外科的切除を施行し得た1例

    平野 豊, 枝園 和彦, 古川 公之, 野上 智弘, 山本 寛斉, 岡崎 幹生, 山根 正修, 豊岡 伸一, 大藤 剛宏, 佐野 由文

    岡山医学会雑誌   120 ( 2 )   246 - 246   2008年8月

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    記述言語:日本語   出版者・発行元:岡山医学会  

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  • 左肺全摘、大網充填術後に胃の通過障害を来した1例

    枝園 和彦, 豊岡 伸一, 岡崎 幹生, 山根 正修, 羽藤 慎二, 大藤 剛宏, 内藤 稔, 土井原 博義, 佐野 由文

    岡山医学会雑誌   120 ( 2 )   249 - 249   2008年8月

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    記述言語:日本語   出版者・発行元:岡山医学会  

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  • A case of metachronous brain metastases from gastric cancer with no recurrence 査読

    Masatoshi Kubo, Kazuhiko Shien, Yusuke Konishi, Naohisa Waki, Makio Hayama, Katsuya Miyatani, Tetsunobu Udaka, Minoru Mizuta, Kazutoyo Shirakawa

    Japanese Journal of Gastroenterological Surgery   41 ( 11 )   1921 - 1926   2008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 Society of Gastroenterological Surgery  

    A 75-year-old man with acute myeloid leukemia brought to complete remission by systemic chemotherapy was diagnosed by gastrointestinal endoscopy with advanced gastric cancer of the upper stomach during examination for severe anemia. He underwent total gastrectomy with D2 lymphadenectomy. One year and 5 months later, he underwent magnetic resonance imaging (MRI) of the brain due to changes in personality and vomiting. MRI showed three cerebral metastases, but computed tomography (CT) of the chest and abdomen and ultrasound imaging of the abdomen found no other metastasis. Tumor markers were within normal limits. The brain tumor was biopsied because acute myeloid leukemia recurrence could not be ruled out, and histopathological examination showed moderately differentiated adenocarcinoma consistent with gastric cancer, yielding a definitive diagnosis of brain metastases from gastric cancer. He underwent cyberknife radiosurgery to lessen clinical symptoms and was discharged. Although a second cyberknife radiosurgery was required for two brain metastases 5 months after initial radiosurgery, he is doing well without evidence of metastases to the brain, chest, or abdomen, one year after the diagnosis of brain metastasis. ©2008 The Japanese Society of Gastroenterological Surgery.

    DOI: 10.5833/jjgs.41.1921

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▼全件表示

MISC

  • 災害ボランティア活動に参加した喘息患者の血痰精査中に発見された右胸部異常陰影の一例

    鹿谷 芳伸, 黒崎 毅史, 大谷 真二, 中田 憲太郎, 難波 圭, 諏澤 憲, 枝園 和彦, 久保 寿夫, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    岡山医学会雑誌   131 ( 2 )   113 - 113   2019年8月

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    記述言語:日本語   出版者・発行元:岡山医学会  

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  • 呼吸器外科医によるトランスレーショナルリサーチ トランスレーショナル研究の経験

    豊岡 伸一, 枝園 和彦, 山本 寛斉, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏

    日本外科学会定期学術集会抄録集   119回   WS - 8   2019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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  • 生体肺移植後慢性拒絶反応と血中Irisin濃度の関係

    塩谷 俊雄, 杉本 誠一郎, 山本 治慎, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 岡崎 幹生, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   RO11 - 1   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 術前放射線同時併用化学療法後手術を行った局所進行肺癌の術後再発に対する治療戦略 局所治療の有用性

    諏澤 憲, 宗 淳一, 枝園 和彦, 黒崎 毅史, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   RO12 - 2   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • ラジオ波焼灼療法を契機に発症した肺膿瘍と膿胸に対する段階的手術の経験

    中田 憲太郎, 杉本 誠一郎, 鹿谷 芳伸, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   RO8 - 4   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • MET exon 14スキッピング変異肺癌に対する治療戦略 薬剤耐性克服を目指して

    諏澤 憲, 枝園 和彦, 山本 寛斉, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, ソムワー・ロメル, ラダニー・マーク, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   RO2 - 4   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 呼吸器感染症の外科治療 感染性肺疾患に対する肺移植の長期成績

    杉本 誠一郎, 黒崎 毅史, 大谷 真二, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏

    日本呼吸器外科学会雑誌   33 ( 3 )   WS4 - 5   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 呼吸器以外の併存疾患を有する症例および高齢者肺癌の周術期管理 高齢者肺癌に対する多職種連携周術期管理による術後合併症減少の試み

    三浦 章博, 宗 淳一, 宮内 俊策, 荒木 恒太, 中田 憲太郎, 塩谷 俊雄, 高橋 優太, 黒崎 毅史, 諏澤 憲, 枝園 和彦, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   PD3 - 7   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 局所進行悪性胸部腫瘍に対する拡大手術 中枢進行型肺癌における自家肺移植(the Oto procedure)の長期成績

    塩谷 俊雄, 大谷 真二, 田中 真, 黒崎 毅史, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏

    日本呼吸器外科学会雑誌   33 ( 3 )   PD2 - 8   2019年4月

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  • 肺移植へのゲノム医療の応用

    杉本 誠一郎, 山本 治慎, 田中 真, 諏澤 憲, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 岡崎 幹生, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本外科学会定期学術集会抄録集   119回   SF - 036   2019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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  • 保険診療に向けた肺癌に対するロボット支援手術の導入

    岡崎 幹生, 枝園 和彦, 黒崎 毅史, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   P17 - 7   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 手掌多汗症に対する胸腔鏡下胸部交感神経交通枝切離術の手術成績

    黒崎 毅史, 森山 重治, 葉山 牧夫, 枝園 和彦, 大谷 真二, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   RV6 - 5   2019年4月

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  • 肉腫多発肺転移に対する肺切除術

    山本 寛斉, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   RO20 - 1   2019年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • EGFR遺伝子検索が診断・治療の一助となった両側同時多発肺腺癌の1例

    梅田 将志, 山本 寛斉, 中田 憲太郎, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   59 ( 1 )   99 - 99   2019年2月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 左上葉切除術後6日目に診断しえた左上肺静脈断端血栓の1例

    本田 貴裕, 杉本 誠一郎, 鹿谷 芳伸, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 宗 淳一, 山根 正修, 豊岡 伸一, 黒崎 毅史, 大谷 真二, 大藤 剛宏

    肺癌   59 ( 1 )   107 - 108   2019年2月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 縦隔炎合併前縦隔腫瘍の1例

    三浦 章博, 枝園 和彦, 黒崎 毅史, 大谷 真二, 山本 寛斉, 岡崎 幹夫, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    岡山医学会雑誌   130 ( 3 )   185 - 185   2018年12月

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    記述言語:日本語   出版者・発行元:岡山医学会  

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  • 局所進行非小細胞肺癌に対する導入療法後肺切除術の晩期肺障害を考える

    宗 淳一, 杉本 誠一郎, 枝園 和彦, 山本 寛斉, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 山根 正修, 勝井 邦彰, 大藤 剛宏, 木浦 勝行, 金澤 右, 豊岡 伸一

    肺癌   58 ( 6 )   567 - 567   2018年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 免疫療法の新展開 悪性胸膜中皮腫に対するREIC/Dkk-3遺伝子治療

    山本 寛斉, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 岡崎 幹生, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   58 ( 6 )   441 - 441   2018年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 肺移植後に発見された肺癌の検討

    大谷 真二, 黒崎 毅史, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 杉本 誠一郎, 宗 淳一, 豊岡 伸一, 大藤 剛宏

    肺癌   58 ( 6 )   526 - 526   2018年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 右上葉スリーブ切除を施行した気管支原発粘液腫の1例

    二萬 英斗, 三好 健太郎, 黒崎 毅史, 枝園 和彦, 大谷 真二, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   58 ( 6 )   619 - 619   2018年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 導入化学放射線療法後手術を施行した局所進行非小細胞肺癌患者に発症した肺アスペルギルス症

    杉本 誠一郎, 宗 淳一, 枝園 和彦, 黒崎 毅史, 大谷 真二, 山本 寛斉, 岡崎 幹生, 山根 正修, 大藤 剛宏, 木浦 勝行, 金澤 右, 豊岡 伸一

    肺癌   58 ( 6 )   569 - 569   2018年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 乳がんにおけるネラチニブ耐性化の機序解析(Analyses of the mechanisms of the resistance to neratinib in breast cancer)

    武田 達明, 山本 寛斉, 冨田 秀太, 高橋 優太, 栗原 英祐, 大越 祐介, 枝園 和彦, 宗 淳一, 北村 佳久, 千堂 年昭, 豊岡 伸一

    日本癌学会総会記事   77回   839 - 839   2018年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 骨髄異形成症候群を合併した若年者自然気胸に対する再発予防手術の適応

    塩谷 俊雄, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本気胸・嚢胞性肺疾患学会雑誌   18 ( 2 )   109 - 109   2018年7月

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    記述言語:日本語   出版者・発行元:日本気胸・嚢胞性肺疾患学会  

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  • 上縦隔に発生した肺葉外肺分画症の1例

    三浦 章博, 大谷 真二, 林 直宏, 荒木 恒太, 宮内 俊策, 塩谷 俊雄, 黒崎 毅史, 枝園 和彦, 山本 寛斉, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本臨床外科学会雑誌   79 ( 6 )   1340 - 1340   2018年6月

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  • 脳死両側肺葉移植後に胸骨ワイヤーの皮下への迷入を認めた1例

    林 直宏, 三浦 章博, 山本 治慎, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏

    日本臨床外科学会雑誌   79 ( 6 )   1340 - 1340   2018年6月

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    記述言語:日本語   出版者・発行元:日本臨床外科学会  

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  • cN1非小細胞肺癌に対する術前化学放射線療法後手術の可能性

    高橋 優太, 宗 淳一, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   32 ( 3 )   O6 - 2   2018年4月

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  • Superior sulcus tumorに対するtransmanubrial approachとVATSを組み合わせた仰臥位での左肺上葉切除

    塩谷 俊雄, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   32 ( 3 )   V15 - 2   2018年4月

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  • 肺移植後気管支合併症は脳死肺移植より生体肺移植の予後に大きな影響を与える

    杉本 誠一郎, 山根 正修, 黒崎 毅史, 大谷 真二, 枝園 和彦, 山本 寛斉, 宗 淳一, 豊岡 伸一, 大藤 剛宏

    日本呼吸器外科学会雑誌   32 ( 3 )   RO17 - 6   2018年4月

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  • cN2非小細胞肺癌に対する術前導入療法後手術の治療成績の検討 治療後再発因子に注目して

    三浦 章博, 宗 淳一, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   32 ( 3 )   RO11 - 4   2018年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 異なる癌腫におけるHER2膜貫通領域の遺伝子変異の同定と最適化治療

    山本 寛斉, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本外科学会定期学術集会抄録集   118回   2157 - 2157   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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  • 局所進行非小細胞肺癌に対する化学放射線療法後の心大血管合併切除手術

    宗 淳一, 佐藤 博紀, 難波 圭, 鳥越 英次郎, 黒崎 毅史, 枝園 和彦, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本外科学会定期学術集会抄録集   118回   348 - 348   2018年4月

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  • 妊婦に合併した縦隔成熟奇形腫に対して手術を行った1例

    宮内 俊策, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    日本呼吸器外科学会雑誌   32 ( 3 )   P64 - 4   2018年4月

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  • 診断および周術期管理に苦慮した縦隔炎合併胸腺嚢胞の1例

    高橋 洋祐, 枝園 和彦, 宗 淳一, 栗原 英祐, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 豊岡 伸一

    肺癌   57 ( 7 )   907 - 907   2017年12月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 肉腫多発肺転移に対する肺切除術の検討

    山本寛斉, 難波圭, 枝園和彦, 宗淳一, 大谷真二, 杉本誠一郎, 大藤剛宏, 豊岡伸一

    日本臨床外科学会雑誌   78 ( 増刊 )   412 - 412   2017年10月

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    記述言語:日本語   出版者・発行元:日本臨床外科学会  

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  • G-CSF投与による増悪が示唆された肺癌術後壊疽性膿皮症の1例

    山本 治慎, 杉本 誠一郎, 大谷 真二, 黒崎 毅史, 枝園 和彦, 山本 寛斉, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏

    肺癌   57 ( 5 )   497 - 497   2017年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 肉腫多発肺転移に対する肺切除術の検討

    山本 寛斉, 豊岡 伸一, 枝園 和彦, 宗 淳一, 黒崎 毅史, 大谷 真二, 杉本 誠一郎, 山根 正修, 大藤 剛宏

    肺癌   57 ( 5 )   485 - 485   2017年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • G-CSF投与による増悪が示唆された肺癌術後壊疽性膿皮症の1例

    山本 治慎, 杉本 誠一郎, 大谷 真二, 黒崎 毅史, 枝園 和彦, 三好 健太郎, 山本 寛斉, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏, 三好 新一郎

    岡山医学会雑誌   129 ( 1 )   70 - 70   2017年4月

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    記述言語:日本語   出版者・発行元:岡山医学会  

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  • 線維性縦隔炎の一例

    大越 祐介, 山本 寛斉, 牧 佑歩, 枝園 和彦, 黒崎 毅史, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 宗 淳一, 山根 正修, 豊岡 伸一, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   31 ( 3 )   P47 - 6   2017年4月

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  • 術前化学放射線療法が奏効し完全切除し得た左房浸潤を伴う局所進行肺癌の1例

    高橋 優太, 枝園 和彦, 宗 淳一, 豊岡 伸一, 黒崎 毅史, 三好 健太郎, 大谷 真二, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大塚 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   31 ( 3 )   P10 - 2   2017年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 局所進行非小細胞肺癌の術前化学放射線療法後手術後の術後再発に対する局所治療は有効か?

    宗 淳一, 諏澤 憲, 豊岡 伸一, 枝園 和彦, 山本 寛斉, 黒崎 毅史, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   31 ( 3 )   RO11 - 6   2017年4月

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  • 外科における分子標的治療の役割

    山本 寛斉, 枝園 和彦, 宗 淳一, 諏澤 憲, 渡邉 元嗣, 佐藤 博紀, 鳥越 英次郎, 難波 圭, 黒崎 毅史, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎, 豊岡 伸一

    日本呼吸器外科学会雑誌   31 ( 3 )   RO9 - 4   2017年4月

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  • 肉腫多発肺転移に対する肺切除術

    難波 圭, 豊岡 伸一, 枝園 和彦, 山本 寛斉, 宗 淳一, 黒崎 毅史, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   31 ( 3 )   RO6 - 6   2017年4月

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  • 左肺下葉切除後に冠状動脈損傷をきたした一例

    栗原 英祐, 山本 寛斉, 豊岡 伸一, 小谷 恭弘, 大越 祐介, 枝園 和彦, 黒崎 毅史, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   31 ( 3 )   P102 - 1   2017年4月

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  • 肺移植患者における胸骨横切開術後胸骨合併症の検討

    山本 治慎, 杉本 誠一郎, 大谷 真二, 黒崎 毅史, 枝園 和彦, 三好 健太郎, 山本 寛斉, 宗 淳一, 山根 正修, 豊岡 伸一, 三好 新一郎, 大藤 剛宏

    日本呼吸器外科学会雑誌   31 ( 3 )   P99 - 6   2017年4月

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  • 悪性・良性疾患に対する気道外科手術 気道再建術の要点 局所進行肺癌に対する術前化学放射線療法後手術を中心に

    豊岡 伸一, 佐藤 博紀, 枝園 和彦, 宗 淳一, 山本 寛斉, 黒崎 毅史, 三好 健太郎, 大谷 真二, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎

    日本呼吸器外科学会雑誌   31 ( 3 )   PD2 - 5   2017年4月

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  • Clinical Outcomes of Induction Chemoradiotherapy with High Dose Chest Radiation for Locally Advanced Non-Small Cell Lung Cancer Patients

    Hidejiro Torigoe, Shinichi Toyooka, Kazuhiko Shien, Junichi Soh, Hiromasa Yamamoto, Kentaro Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Kuniaki Katsui, Katsuyuki Hotta, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S851 - S851   2017年1月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Impact of Preoperative Serum Anti-60S Ribosomal Protein L29 Levels on Prognosis in Patients Who Underwent Surgery for Non-Small Cell Lung Cancer

    Hiromasa Yamamoto, Akinobu Takaki, Tatsuro Hayashi, Masashi Furukawa, Hiroyuki Tao, Kazuhiko Shien, Junichi Soh, Kazunori Okabe, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S804 - S804   2017年1月

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  • Detection of Multiple Low-Frequency Mutations by Molecular-Barcode Sequencing

    Kei Namba, Shuta Tomida, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S531 - S531   2017年1月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Impact of Prognostic Nutrition Index for Induction Chemoradiotherapy Followed by Surgery in Locally Advanced Non-Small Lung Cancers

    Junichi Soh, Shinichi Toyooka, Kazuhiko Shien, Hiromasa Yamamoto, Tsuyoshi Kurosaki, Kentaro Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S880 - S881   2017年1月

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  • The Advantage of Induction Chemoradiotherapy in Bronchoplastic Procedure for Non-Small Cell Lung Cancer Accompanied with Central Disease Region

    Hiroki Sato, Shinichi Toyooka, Takeshi Kurosaki, Kazuhiko Shien, Kentaro Miyoshi, Shinji Ohtani, Hiromasa Yamamoto, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S868 - S869   2017年1月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Targeting miR-200c/LIN28B Axis in Acquired EGFR-TKI Resistance Non-Small Cell Lung Cancer Cells Harboring EMT Features

    Kazuhiko Shien, Hiroki Sato, Ken Suzawa, Shuta Tomida, Shinsuke Hashida, Hiromasa Yamamoto, Junichi Soh, Hidejiro Torigoe, Kei Namba, Mototsugu Watanabe, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S1267 - S1267   2017年1月

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  • 陽型肺腺癌の1切除例

    清水大, 三好健太郎, 目崎久美, 枝園和彦, 杉本誠一郎, 山本寛斉, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

    日本肺癌学会総会号   57th   682   2016年11月

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  • 導入療法後肺切除時の大網被覆により術後胃排出障害を生じた2例

    土生智大, 枝園和彦, 豊岡伸一, 宗淳一, 二萬英斗, 山本寛斉, 黒崎毅史, 三好健太郎, 大谷真二, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

    日本肺癌学会総会号   57th ( 6 )   851 - 851   2016年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • FDGの高集積を伴う巨大前縦隔腫瘍を呈したCastleman病の1切除例

    大谷真二, 杉本誠一郎, 田中顕之, 鹿谷芳伸, 黒崎毅史, 枝園和彦, 三好健太郎, 山本寛斉, 宗淳一, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

    日本肺癌学会総会号   57th ( 6 )   595 - 595   2016年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 右残肺全摘後の気管支断端瘻に対し,ヒストアクリルによる閉鎖術が有効であった1例

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    日本肺癌学会総会号   57th ( 6 )   643 - 643   2016年11月

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  • 肺癌に対する左上葉切除後に発症した食道アカラシアの1例

    二萬 英斗, 宗 淳一, 枝園 和彦, 豊岡 伸一, 黒崎 毅史, 大谷 真二, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎

    肺癌   56 ( 6 )   749 - 749   2016年11月

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  • 肉腫肺転移に対して区域切除以上の肺切除を施行した患者における術前予後予測因子の検討

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    肺癌   56 ( 6 )   534 - 534   2016年11月

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  • 高線量照射による術前化学放射線療法後手術症例の検討

    鳥越 英次郎, 豊岡 伸一, 枝園 和彦, 三好 健太郎, 山本 寛斉, 杉本 誠一郎, 宗 淳一, 山根 正修, 大藤 剛宏, 三好 新一郎

    肺癌   56 ( 6 )   525 - 525   2016年11月

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  • 非小細胞肺癌切除症例における術前血漿中抗RPL29抗体価と予後

    山本 寛斉, 高木 章乃夫, 林 達朗, 古川 公之, 田尾 裕之, 枝園 和彦, 宗 淳一, 大谷 真二, 三好 健太郎, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 岡部 和倫, 三好 新一郎, 豊岡 伸一

    肺癌   56 ( 6 )   518 - 518   2016年11月

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  • 局所進行非小細胞肺癌の術前化学放射線療法後手術における予後栄養指数(PNI)の治療効果への影響

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    肺癌   56 ( 6 )   782 - 782   2016年11月

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  • Detection of a novel ALK fusion variant in lung adenocarcinoma using a comprehensive genomic analysis

    Kazuhiko Shien, Dennis Ruder, Ecaterina E. Ileana, Vassiliki A. Papadimitrakopoulou, Garrett M. Frampton, Carmen Behrens, Neda Kalhor, J. Jack Lee, Ximing Tang, Roy S. Herbst, Ignacio I. Wistuba, Julie G. Izzo

    CANCER RESEARCH   76   2016年7月

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  • がんのバイオマーカーと分子標的治療 胸部悪性腫瘍に対するREIC遺伝子治療

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    日本外科学会定期学術集会抄録集   116回   PD - 10   2016年4月

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  • 悪性胸膜中皮腫に対するREIC/Dkk-3遺伝子治療

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    肺癌   55 ( 5 )   502 - 502   2015年10月

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  • Effect of Hsp90 inhibitor NVP-AUY922 with radiation on lung adenocarcinoma cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors

    Yuho Maki, Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Tomoaki Ohtsuka, Ken Suzawa, Masashi Furukawa, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Susumu Kanazawa, Shinichi Toyooka

    CANCER RESEARCH   75   2015年8月

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  • Oncostatin M receptor activation leads to molecular targeted therapy resistance in non-small cell lung cancer

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    CANCER RESEARCH   75   2015年8月

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  • Rictor alterations elicit non-canonical signaling mechanisms contributing to tumorigenicity and therapeutic resistance in non-small cell lung cancer (NSCLC)

    Dennis Ruder, Vassiliki Papadimitrakopoulou, Kazuhiko Shien, Neda Kalhor, J. Jack Lee, Waun K. Hong, Ximing Tang, Luc Girard, John D. Minna, Lixia Diao, Jing Wang, Nana E. Hanson, James Sun, Vincent Miller, Garrett Frampton, Roy S. Herbst, Ignacio I. Wistuba, Julie G. Izzo

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • 肺腺癌におけるHER2膜貫通領域の遺伝子変異と機能解析

    山本寛斉, 阪口政清, 諏澤憲, 大塚智昭, 枝園和彦, 橋田真輔, 渡邉元嗣, 牧佑歩, 宗淳一, 岡田真典, 伊賀徳周, 三好健太郎, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎, 豊岡伸一

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  • 3期局所進行非小細胞肺癌に対する導入化学放射線治療後手術の治療成績

    宗淳一, 豊岡伸一, 枝園和彦, 岡田真典, 伊賀徳周, 牧佑歩, 三好健太郎, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 木浦勝行, 金澤右, 伊達洋至, 三好新一郎

    日本肺癌学会総会号   55th ( 5 )   417 - 417   2014年10月

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  • MiR-200c expression and methylation status determines epithelial characteristics of NSCLC

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Shinsuke Hashida, Ken Suzawa, Tomoaki Otsuka, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    DOI: 10.1158/1538-7445.AM2014-5194

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  • The molecular characters of acquired resistant non-small cell lung cancer cells to afatinib

    Shinsuke Hashida, Shinichi Toyooka, Tomoaki Ohtsuka, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    DOI: 10.1158/1538-7445.AM2014-1834

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  • Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer

    Ken Suzawa, Shinichi Toyooka, Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon

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  • 家族性・孤発性肺腺癌におけるHER2膜貫通領域の新規遺伝子変異

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    日本呼吸器外科学会雑誌   28 ( 3 )   O17 - 4   2014年4月

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  • 術前3D-CTで気管支分岐/肺静脈還流異常を診断し、右肺低区域切除を行った多発肺線癌の1例

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    日本呼吸器外科学会雑誌   28 ( 3 )   V9 - 5   2014年4月

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  • cN2非小細胞肺癌に対する化学放射線療法後手術療法の成績

    豊岡伸一, 堀田勝幸, 勝井邦彰, 枝園和彦, 宗淳一, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 木浦勝行, 三好新一郎

    日本呼吸器学会誌   3 ( 増刊 )   57 - 57   2014年3月

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  • EGFR阻害剤に対する獲得耐性の機構

    豊岡伸一, 枝園和彦, 宗淳一, 山本寛斉, 大塚智昭, 諏澤憲, 橋田真輔, 葉山牧夫, 杉本誠一郎, 山根正修, 大藤剛宏, 木浦勝行, 三好新一郎

    日本呼吸器学会誌   3 ( 増刊 )   23 - 23   2014年3月

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  • 最適化医療時代における外科医:研究心という剪刀を携える

    豊岡伸一, 山本寛斉, 枝園和彦, 宗淳一, 葉山牧夫, 岡田真典, 三好健太郎, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

    日本外科学会雑誌   115 ( 臨増2 )   124 - 124   2014年3月

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  • SY-3-2 最適化医療時代における外科医 : 研究心という剪刀を携える(SY-3 シンポジウム(3)肺癌の個別化医療時代における外科医の役割,第114回日本外科学会定期学術集会)

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    日本外科学会雑誌   115 ( 2 )   2014年3月

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  • PERIOPERATIVE NUTRITION OF INDUCTION CHEMORADIOTHERAPY FOLLOWED BY SURGERY IN LOCALLY ADVANCED NON-SMALL LUNG CANCER PATIENTS

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  • TUMOR ARISING FROM LOWER LOBES IS A POOR PROGNOSTIC FACTOR IN NON-SMALL CELL LUNG CANCER PATIENTS WITH N2 DISEASE TREATED WITH INDUCTION CHEMORADIOTHERAPY

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  • EXTENDED SLEEVE LOBECTOMY AFTER INDUCTION CHEMORADIOTHERAPY FOR LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER

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  • 術前診断し得た後縦隔原発の無症候性かつ機能性傍神経節腫の1切除例

    諏澤憲, 山本寛斉, 岡田真典, 枝園和彦, 三好健太郎, 杉本誠一郎, 宗淳一, 葉山牧夫, 山根正修, 大藤剛宏, 豊岡伸一, 三好新一郎

    日本肺癌学会総会号   54th ( 5 )   655 - 655   2013年10月

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  • 分子標的治療と肺癌外科治療―EGFR阻害剤獲得耐性機構とその克服

    豊岡伸一, 枝園和彦, 宗淳一, 山本寛斉, 諏澤憲, 橋田真輔, 葉山牧夫, 杉本誠一郎, 山根正修, 大藤剛宏, 木浦勝行, 三好新一郎

    日本肺癌学会総会号   54th ( 5 )   397 - 397   2013年10月

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  • 導入化学放射線療法後に左下葉・舌区スリーブ切除術を施行した局所進行左下葉原発肺癌の3例

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    日本呼吸器外科学会雑誌   27 ( 3 )   P15 - 07   2013年4月

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  • PS-024-6 Micropapillary componentを有する肺腺癌の遺伝子異常(PS ポスターセッション,第113回日本外科学会定期学術集会)

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    日本外科学会雑誌   114 ( 2 )   552 - 552   2013年3月

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  • 縦隔リンパ節転移陽性Stage III期非小細胞肺癌に対する治療

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    肺癌   52 ( 5 )   505 - 505   2012年10月

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  • 局所進行肺癌に対する導入化学放射線療法後スリーブ肺葉切除術の成績と工夫

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  • FOXP3+/CD8+tumor-infiltrating T-cell ratio as a marker for pathologic response to induction therapy of non-small cell lung cancer.

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    JOURNAL OF CLINICAL ONCOLOGY   30 ( 15 )   2012年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

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  • Knockdown of EGFR to investigate its therapeutic potential for treatment of non-small cell lung cancers

    Junichi Soh, Kazuhiko Shien, Tsuyoshi Ueno, Kazunori Tsukuda, Kenichi Suda, Takafumi Kubo, Masashi Furukawa, Takayuki Muraoka, Yuho Maki, Norimitsu Tanaka, Hiromasa Yamamoto, Katsuyuki Kiura, Tetsuya Mitsudomi, Shinichi Toyooka, Shinichiro Miyoshi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-7

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  • RAS signaling pathway gene mutations and acquired resistance to EGFR tyrosine-kinase inhibitors in EGFR mutant lung cancer

    Kadoaki Ohashi, Juliann Chmielecki, Ya-Lun Lin, Helen Pan, Cindy Vnencak-Jones, Maria Arcila, Lu Wang, Lynnette Fernandez, Aoe Keisuke, Kazuhiko Shien, Hiromasa Yamamoto, Shinichi Toyooka, Katsuyuki Kiura, Roman Thomas, James Chih-Hsin Yang, Vincent Miller, Marc Ladanyi, Katerina Politi, William Pao

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-1897

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  • Down-regulation of microRNA34 induces cell proliferation and invasion of human mesothelial cells

    Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Kazunori Tsukuda, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoka, Yuho Maki, Tsuyoshi Ueno, Hiroaki Asano, Takemi Otsuki, Shinichiro Miyoshi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-187

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  • Prognostic impact of GLUT-1 and Ki-67 expressions in early-stage lung adenocarcinomas

    Yuho Maki, Shinichi Toyooka, Koichi Ichimura, Junichi Soh, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Masomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-4551

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  • Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy

    Kazuhiko Shien, Shinichi Toyooka, Kouichi Ichimura, Junichi Soh, Masashi Furukawa, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Hiromasa Yamamoto, Masaomi Yamane, Takahiro Oto, Katsuyuki Kiura, Shinichiro Miyoshi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-1717

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  • Usefulness of sensitive digital PCR assay to quantify microRNA-34b/c methylation in the circulating serum DNA of malignant mesothelioma patients

    Takayuki Muraoka, Junichi Soh, Shinichi Toyooka, Nobukazu Fujimoto, Keisuke Aoe, Hiromasa Yamamoto, Kazuhiko Shien, Masashi Furukawa, Yuho Maki, Norimitsu Tanaka, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Takumi Kishimoto, Takemi Otsuki, Shinichiro Miyoshi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-4153

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  • Aberrant NFKBIA expression in lung adenocarcinomas arising from never smokers

    Masashi Furukawa, Junichi Soh, Shinichi Toyooka, Kazuhiko Shien, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-3988

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  • PD-9-2 T3/4局所進行非小細胞肺癌に対する導入化学放射線治療後手術療法(PD-9 パネルディスカッション(9)局所進行肺癌に対する外科治療戦略,第112回日本外科学会定期学術集会)

    枝園 和彦, 豊岡 伸一, 木浦 勝行, 松尾 恵太郎, 宗 淳一, 山根 正修, 大藤 剛宏, 武本 充広, 伊達 洋至, 三好 新一郎

    日本外科学会雑誌   113 ( 2 )   211 - 211   2012年3月

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    記述言語:英語   出版者・発行元:一般社団法人日本外科学会  

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  • PS-156-1 非小細胞肺癌に対する根治的放射線化学療法後手術の治療成績(肺集学的治療,ポスターセッション,第112回日本外科学会定期学術集会)

    宗 淳一, 豊岡 伸一, 枝園 和彦, 三好 健太郎, 上野 剛, 杉本 誠一郎, 山根 正修, 大藤 剛宏, 三好 新一郎

    日本外科学会雑誌   113 ( 2 )   2012年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • PS-109-6 REIC/Dickkopf-3 shows anti-proliferative effect for non-small cell lung cancer cells with negative phosphorylated-Akt status

    Tanaka Norimitsu, Toyooka Shinichi, Watanabe Masami, Soh Junichi, Sakaguchi Masakiyo, Tsukuda Kazunori, Asano Hiroaki, Shien Kazuhiko, Furukawa Masashi, Maki Yuho, Muraoka Takayuki, Huh Nam-ho, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro

    日本外科学会雑誌   113 ( 2 )   710 - 710   2012年3月

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    記述言語:英語   出版者・発行元:一般社団法人日本外科学会  

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  • 「切除困難例」への化学療法後の手術―根治切除はどこまで可能か 非小細胞肺癌に対する根治的放射線化学療法後の手術

    豊岡伸一, 宗淳一, 枝園和彦, 牧佑歩, 三好健太郎, 上野剛, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

    臨床外科   67 ( 1 )   12 - 16   2012年1月

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    記述言語:日本語   出版者・発行元:(株)医学書院  

    <ポイント>◆局所進行非小細胞肺癌に対しては根治的放射線化学療法を行うことが多いが,その後,外科手術になることがある.◆根治的放射線化学療法の再発症例に対するサルベージ手術,あるいは高線量による導入放射線化学療法の有用性は確立していない.◆高線量の放射線照射後の手術はリスクが高くなることが考えられるが,手術が原病,あるいは治療による合併症を改善する症例があり,必要に応じて手術を考慮すべきである.(著者抄録)

    DOI: 10.11477/mf.1407103898

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  • 局所進行非小細胞肺癌に対する集学的治療の成績と今後の展望

    豊岡伸一, 木浦勝行, 勝井邦彰, 宗淳一, 枝園和彦, 山本寛斉, 三好健太郎, 杉本誠一郎, 久本晃子, 山根正修, 大藤剛宏, 伊達洋至, 金澤右, 三好新一郎

    日本癌治療学会学術集会(CD-ROM)   50th ( 3 )   ROMBUNNO.S03-4 - 608   2012年

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    記述言語:日本語   出版者・発行元:(一社)日本癌治療学会  

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  • 血清中microRNA34b/cメチル化同定による悪性胸膜中皮腫高感度スクリーニング法

    村岡孝幸, 宗淳一, 豊岡伸一, 枝園和彦, 古川公之, 牧佑歩, 上野剛, 山本寛斉, 青江啓介, 藤本伸一, 岸本卓巳, 大槻剛巳, 三好健太郎, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

    日本呼吸器外科学会総会(Web)   29th ( 3 )   RS06-03 (WEB ONLY) - 03   2012年

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 非喫煙者肺腺癌におけるNFKBIA遺伝子発現の検討

    古川公之, 宗淳一, 豊岡伸一, 市村浩一, 枝園和彦, 牧佑歩, 村岡孝幸, 田中則光, 上野剛, 山本寛斎, 三好健太郎, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

    日本呼吸器外科学会総会(Web)   29th ( 3 )   RS06-01 (WEB ONLY) - 01   2012年

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    記述言語:日本語   出版者・発行元:(NPO)日本呼吸器外科学会  

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  • 腫瘍原発部位はN2非小細胞肺癌に対する導入化学放射線治療後手術療法の予後因子である

    難波圭, 豊岡伸一, 枝園和彦, 宗淳一, 勝井邦彰, 山本寛斉, 三好健太郎, 杉本誠一郎, 久本晃子, 山根正修, 大藤剛宏, 金澤右, 木浦勝行, 三好新一郎

    日本癌治療学会学術集会(CD-ROM)   50th ( 3 )   ROMBUNNO.PS2-021 - 2125   2012年

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    記述言語:日本語   出版者・発行元:(一社)日本癌治療学会  

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  • 縦隔リンパ節転移陽性非小細胞肺癌に対する導入化学放射線治療後手術療法の長期成績

    豊岡伸一, 宗淳一, 枝園和彦, 上野剛, 三好健太郎, 杉本誠一郎, 山根正修, 大藤剛宏, 武本充広, 堀田勝幸, 田端雅弘, 木浦勝行, 伊達洋至, 三好新一郎

    肺癌   51 ( 5 )   361 - 361   2011年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 原発性肺癌に対する術中迅速リンパ節診断に基づく縮小リンパ節郭清の妥当性

    枝園和彦, 豊岡伸一, 宗淳一, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

    General Thoracic and Cardiovascular Surgery   59 ( Supplement )   521   2011年9月

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    記述言語:日本語  

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  • 肺実質切離時におけるVessel sealing system(LigaSure)の有用性

    杉本誠一郎, 豊岡伸一, 伊賀徳周, 古川公之, 杉本龍士郎, 田中真, 枝園和彦, 西川仁士, 三好健太郎, 上野剛, 宗淳一, 山根正修, 大藤剛宏, 三好新一郎

    Gen Thorac Cardiovasc Surg   59 ( Supplement )   590   2011年9月

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    記述言語:日本語  

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  • 導入療法後切除N2非小細胞肺癌症例における予後因子としての癌幹細胞関連マーカー

    枝園和彦, 豊岡伸一, 宗淳一, 杉本誠一郎, 山根正修, 大藤剛宏, 武本充広, 木浦勝行, 三好新一郎

    Gen Thorac Cardiovasc Surg   59 ( Supplement )   486   2011年9月

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    記述言語:日本語  

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  • WS9-3 局所進行肺非小細胞癌に対する術前放射線同時併用化学療法の検討(放射線治療の現状と展望,第49回日本肺癌学会総会号)

    枝園 和彦, 豊岡 伸一, 武本 充広, 山根 正修, 大藤 剛宏, 堀田 勝幸, 頼 冠名, 瀧川 奈義夫, 田端 雅弘, 伊達 洋至, 佐野 由文, 木浦 勝行

    肺癌   48 ( 5 )   2008年10月

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    記述言語:日本語   出版者・発行元:日本肺癌学会  

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