2021/07/12 更新

写真a

トヨオカ シンイチ
豊岡 伸一
TOYOOKA Shinichi
所属
医歯薬学域 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 岡山大学 )

 

論文

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

    Shunsaku Miyauchi, Junichi Soh, Kazuhiko Shien, Masato Tanaka, Hiromasa Yamamoto, Toshifumi Ozaki, Shinichi Toyooka

    General thoracic and cardiovascular surgery   68 ( 3 )   298 - 301   2020年3月

     詳細を見る

    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

    PubMed

    researchmap

  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. 査読 国際誌

    Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-Ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

    Oncology research   27 ( 8 )   945 - 956   2019年8月

     詳細を見る

    記述言語:英語  

    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

    DOI: 10.3727/096504019X15555408784978

    PubMed

    researchmap

  • Impact of chronic lung allograft dysfunction, especially restrictive allograft syndrome, on the survival after living-donor lobar lung transplantation compared with cadaveric lung transplantation in adults: a single-center experience. 査読

    Seiichiro Sugimoto, Haruchika Yamamoto, Takeshi Kurosaki, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka, Takahiro Oto

    Surgery today   49 ( 8 )   686 - 693   2019年8月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT. METHODS: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT. RESULTS: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083). CONCLUSION: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

    DOI: 10.1007/s00595-019-01782-0

    PubMed

    researchmap

  • Acquired resistance mechanisms to afatinib in HER2-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

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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

    PubMed

    researchmap

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

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   145 ( 2 )   569 - 575   2019年7月

     詳細を見る

    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

    PubMed

    researchmap

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

    Ken Suzawa, Junichi Soh, Yuta Takahashi, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    Surgery today   49 ( 7 )   601 - 609   2019年7月

     詳細を見る

    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

    PubMed

    researchmap

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

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

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

     詳細を見る

    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

    PubMed

    researchmap

  • 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

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, I Made Winarsa Ruma, Rie Kinoshita, Eisaku Kondo, Yusuke Inoue, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Ming Liu, Junichiro Futami, Kaori Sasai, Hiroshi Katayama, Miyoko Kubo, Endy Widya Putranto, Toshihiko Hibino, Bei Sun, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer letters   452   178 - 190   2019年6月

     詳細を見る

    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

    PubMed

    researchmap

  • Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. 査読 国際誌

    Hitoshi Takamatsu, Ken-Ichi Yamamoto, Nahoko Tomonobu, Hitoshi Murata, Yusuke Inoue, Akira Yamauchi, I Wayan Sumardika, Youyi Chen, Rie Kinoshita, Masahiro Yamamura, Hideyo Fujiwara, Yosuke Mitsui, Kota Araki, Junichiro Futami, Ken Saito, Hidekazu Iioka, I Made Winarsa Ruma, Endy Widya Putranto, Masahiro Nishibori, Eisaku Kondo, Yasuhiko Yamamoto, Shinichi Toyooka, Masakiyo Sakaguchi

    Oncology research   27 ( 6 )   713 - 727   2019年6月

     詳細を見る

    記述言語:英語  

    The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

    DOI: 10.3727/096504018X15433161908259

    PubMed

    researchmap

  • 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

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   144 ( 12 )   3138 - 3145   2019年6月

     詳細を見る

    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

    PubMed

    researchmap

  • 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6月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3892/ijo.2019.4768

    PubMed

    researchmap

  • 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6月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/mc.22987

    PubMed

    researchmap

  • SOCS3 overexpression in T cells ameliorates chronic airway obstruction in a murine heterotopic tracheal transplantation model. 査読

    Kumi Mesaki, Masaomi Yamane, Seiichiro Sugimoto, Masayoshi Fujisawa, Teizo Yoshimura, Takeshi Kurosaki, Shinji Otani, Shinichiro Miyoshi, Takahiro Oto, Akihiro Matsukawa, Shinichi Toyooka

    Surgery today   49 ( 5 )   443 - 450   2019年5月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Suppressor of cytokine signaling-3 (SOCS3) is a negative feedback inhibitor of cytokine signaling with T-cell-mediated immunosuppressive effects on obliterative bronchiolitis (OB). In this study, we aimed to investigate the impact of T-cell-specific overexpression of SOCS3 using a murine heterotopic tracheal transplantation (HTT) model. METHODS: Tracheal allografts from BALB/c mice were subcutaneously transplanted into wild-type C57BL/6J (B6; WT) mice and SOCS3 transgenic B6 (SOCS3TG) mice. Tracheal allografts were analyzed by immunohistochemistry and quantitative polymerase chain reaction assays at days 7 and 21. RESULTS: At day 21, allografts in SOCS3TG mice showed significant amelioration of airway obstruction and epithelial loss compared with allografts in WT mice. The intragraft expression of IFN-γ and CXCL10 was suppressed, while that of IL-4 was enhanced in SOCS3TG mice at day 7. The T-bet levels were lower in SOCS3TG allografts than in WT allografts at day 7. CONCLUSION: We revealed that the overexpression of SOCS3 in T cells effectively ameliorates OB development in a murine HTT model by inhibiting the Th1 phenotype in the early phase. Our results suggest that the regulation of the T-cell response, through the modulation of SOCS expression, has potential as a new therapeutic strategy for chronic lung allograft dysfunction.

    DOI: 10.1007/s00595-018-1753-5

    PubMed

    researchmap

  • A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY). 査読

    Ninomiya K, Hata T, Yoshioka H, Ohashi K, Bessho A, Hosokawa S, Ishikawa N, Yamasaki M, Shibayama T, Aoe K, Kozuki T, Harita S, Ueda Y, Murakami T, Fujimoto N, Yanai H, Toyooka S, Takata M, Hotta K, Kiura K, HER2-CS Network

    Chest   2019年5月

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

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

    Anticancer research   39 ( 4 )   1767 - 1775   2019年4月

     詳細を見る

    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

    PubMed

    researchmap

  • Risk assessments for broncho-pleural fistula and respiratory failure after lung cancer surgery by National Clinical Database Japan. 査読

    Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Yoshihisa Shimada, Masami Sato, Shinichi Toyooka, Yoshinori Okada, Yukio Sato, Ichiro Yoshino, Morihito Okada, Meinoshin Okumura, Masayuki Chida, Eriko Fukuchi, Hiroaki Miyata

    General thoracic and cardiovascular surgery   67 ( 3 )   297 - 305   2019年3月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Broncho-pleural fistula (BPF) and respiratory failure (RF) are life-threatening complications after lung cancer surgery and can result in long-term hospitalization and decreased quality of life. Risk assessments for BPF and RF in addition to mortality and major morbidities are indispensable in surgical decision-making and perioperative care. METHODS: The characteristics and operative data of 80,095 patients who had undergone lung cancer surgery were derived from the 2014 and 2015 National Clinical Database (NCD) of Japan datasets. After excluding 1501 patients, risk models were developed from these data and validated by another dataset for 42,352 patients derived from the 2016 NCD dataset. Receiver operating characteristic curves were generated for postoperative BPF and RF development. The concordance-index was used to assess the discriminatory ability and validity of the model. RESULTS: BPF and RF occurred in 259 (0.3%) and 420 patients (0.5%), respectively, in the model development dataset and in 129 (0.3%) and 198 patients (0.5%), respectively, in the model validation dataset. Characteristic variables including types of surgery and comorbidities were identified as risk factors for BPF and RF, respectively. The concordance indexes of assessments for BPF and RF were 0.847 (p < 0.001) and 0.848 (p < 0.001), respectively, for the development dataset and 0.850 (p < 0.001) and 0.844 (p < 0.001), respectively, for the validation dataset. CONCLUSIONS: These models are satisfactory for predicting BPF and RF after lung cancer surgery in Japan and could guide preoperative assessment and optimal measures for preventing BPF and RF.

    DOI: 10.1007/s11748-018-1022-y

    PubMed

    researchmap

  • A single-nucleotide polymorphism in a gene modulating glucocorticoid sensitivity is associated with the decline in total lung capacity after lung transplantation. 査読

    Haruchika Yamamoto, Seiichiro Sugimoto, Shin Tanaka, Takeshi Kurosaki, Shinji Otani, Masaomi Yamane, Naruto Taira, Takahiro Oto, Shinichi Toyooka

    Surgery today   49 ( 3 )   268 - 274   2019年3月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Glucocorticoids are used to prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). Our study was aimed at assessing the association between the glucocorticoid-induced transcript 1 gene (GLCCI1) variant, which modulates glucocorticoid sensitivity, and the postoperative lung function and development of CLAD after LT. METHODS: A total of 71 recipients of LT were genotyped for the GLCCI1 variant (rs37972) and divided into three groups: the homozygous mutant allele (TT) group, the heterozygous mutant allele (CT) group, and the wild-type allele (CC) group. The results of pulmonary function tests were compared with the postoperative baseline values. RESULTS: The total lung capacity (TLC) in the TT group was significantly lower than that in the CC group at 3 years after LT (P = 0.029). In the recipients of cadaveric LT, the TLC and forced expiratory volume in 1 s in the TT group were significantly lower than those in the CC groups, resulting in a significant worse CLAD-free survival at 3 years after LT (P = 0.016). CONCLUSION: The GLCCI1 variant was associated with a significant decrease of the TLC at 3 years after LT and the development of CLAD at 3 years, especially in patients undergoing cadaveric LT.

    DOI: 10.1007/s00595-018-1717-9

    PubMed

    researchmap

  • Lung transplant candidates with idiopathic pulmonary fibrosis and long-term pirfenidone therapy: Treatment feasibility influences waitlist survival. 査読 国際誌

    Shin Tanaka, Kentaroh Miyoshi, Hisao Higo, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Shinichi Toyooka, Takahiro Oto

    Respiratory investigation   57 ( 2 )   165 - 171   2019年3月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive lung disease with exceptionally poor prognosis. While lung transplantation (LTx) is considered the last-resort therapeutic option, dismal waitlist mortality still hampers the salvage of patients with IPF. Pirfenidone, originally designed for IPF treatment, has increasingly been utilized. This study aimed to evaluate whether Pirfenidone could influence outcomes of patients with IPF on the Japanese LTx waitlist. METHODS: This retrospective single-center cohort study included 25 consecutive patients with IPF who were registered as LTx candidates at our institution between July 1999 and August 2016. Patients with a history of pretransplant Pirfenidone therapy (Pirfenidone group) were compared with those with no history (non-Pirfenidone group). RESULTS: In total, 6 (24%) patients received Pirfenidone as pretransplant therapy for 45.2 (range, 18.6-66.8) months. During the treatment period, the Pirfenidone group achieved a significant reduction in the decline rate of the forced vital capacity (-6.2% vs. -0.3%, p = 0.04) and a lower lung allocation score (31 vs. 41, p = 0.013) compared with the non-Pirfenidone group. The Pirfenidone group exhibited 100% waitlist survival three years after registration that was comparable to other indications, and 66% of the patients were still alive at the time of organ availability. No patient in the Pirfenidone group developed Pirfenidone-related surgical complications postoperatively. CONCLUSIONS: Patients with IPF successfully managed with long-term Pirfenidone therapy achieved favorable outcomes after LTx registration, comparable to other patients with LTx indications. The tolerability to antifibrotic therapy can be a predictor of waitlist survival.

    DOI: 10.1016/j.resinv.2018.12.002

    PubMed

    researchmap

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

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

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

     詳細を見る

    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

    PubMed

    researchmap

  • Feasibility of lung transplantation from donors mechanically ventilated for prolonged periods. 査読

    Seiichiro Sugimoto, Takeshi Kurosaki, Shinji Otani, Shin Tanaka, Yukiko Hikasa, Masaomi Yamane, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

    Surgery today   49 ( 3 )   254 - 260   2019年3月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: When patients are mechanically ventilated for more than 5 days, they are usually declined as donors for lung transplantation (LTx); thus, the long-term outcomes of LTx from such donors remain unclear. We investigated the feasibility of LTx from donors that had been mechanically ventilated for prolonged periods. METHODS: The subjects of this retrospective comparative investigation were 31 recipients of LTx from donors who had been mechanically ventilated for < 5 days (short-term group) and 50 recipients of LTx from donors who had been mechanically ventilated for ≥ 5 days (long-term group). RESULTS: The median duration of donor mechanical ventilation was 3 days in the short-term group and 8.5 days in the long-term group. However, other than the difference in the duration of donor ventilation, there were no significant differences in the clinical characteristics of the donors or recipients between the groups. The overall survival rate after LTx was comparable between the long-term group and short-term group (5-year survival rate, 66.6% vs. 75.2%). CONCLUSION: The potential inclusion of donors who have been on mechanical ventilation for more than 5 days could be a feasible strategy to alleviate donor organ shortage.

    DOI: 10.1007/s00595-018-1730-z

    PubMed

    researchmap

  • 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

     詳細を見る

    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

    PubMed

    researchmap

  • 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 : MCR   17 ( 2 )   499 - 507   2019年2月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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

    PubMed

    researchmap

  • Demographics, Safety and Quality, and Prognostic Information in Both the Seventh and Eighth Editions of the TNM Classification in 18,973 Surgical Cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010. 査読

    Okami J, Shintani Y, Okumura M, Ito H, Ohtsuka T, Toyooka S, Mori T, Watanabe SI, Date H, Yokoi K, Asamura H, Nagayasu T, Miyaoka E, Yoshino I, Japanese Join, Committee of Lung, Cancer Registry

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   14 ( 2 )   212 - 222   2019年2月

  • SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. 査読

    Masanori Okada, Masaomi Yamane, Sumiharu Yamamoto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi

    Surgery today   48 ( 12 )   1089 - 1095   2018年12月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.

    DOI: 10.1007/s00595-018-1696-x

    PubMed

    researchmap

  • 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

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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.

    DOI: 10.1111/cas.13797

    PubMed

    researchmap

  • Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors. 査読

    Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, Fujiwara T, Udono H, Kiura K

    Clinical lung cancer   19 ( 6 )   e861 - e864   2018年11月

  • Donor-derived cell-free DNA is associated with acute rejection and decreased oxygenation in primary graft dysfunction after living donor-lobar lung transplantation. 査読 国際誌

    Shin Tanaka, Seiichiro Sugimoto, Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Ken Suzawa, Shinsuke Hashida, Masaomi Yamane, Takahiro Oto, Shinichi Toyooka

    Scientific reports   8 ( 1 )   15366 - 15366   2018年10月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors. However, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. Our study was aimed at examining the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection early after living-donor lobar LT. Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p = 0.022) and at 72 hours (p = 0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with acute rejection (median, 12.0%) than in those with infection (median, 4.2%) (p = 0.028) or in a stable condition (median, 1.1%) (p = 0.001). Thus, measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of acute rejection after LT.

    DOI: 10.1038/s41598-018-33848-3

    PubMed

    researchmap

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

    Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 10 )   3183 - 3196   2018年10月

     詳細を見る

    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

    PubMed

    researchmap

  • Dose-Volume Parameters Predict Radiation Pneumonitis after Surgery with Induction Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. 査読

    Ogata T, Katsui K, Yoshio K, Ihara H, Katayama N, Soh J, Kuroda M, Kiura K, Maeda Y, Toyooka S, Kanazawa S

    Acta medica Okayama   72 ( 5 )   507 - 513   2018年10月

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

    Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K

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

  • Low-risk donor lungs optimize the post-lung transplant outcome for high lung allocation score patients. 査読

    Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Kentaro Imanishi, Seiichiro Sugimoto, Masaomi Yamane, Motomu Kobayashi, Shinichi Toyooka, Takahiro Oto

    Surgery today   48 ( 10 )   928 - 935   2018年10月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: The lung allocation score (LAS) has been generally recognized as a contributor to the overall survival in lung transplant candidates. However, donor-related risks have never been taken into consideration in previous research that validated the LAS. This study aimed to determine whether or not the role of the LAS as a predictor of the posttransplant outcome is influenced by the quality of the donor lungs. METHODS: We retrospectively reviewed 108 patients who underwent lung transplantation at Okayama University Hospital since 1998. The cohort was divided into two groups based on the lung donor score (DS; ≤ 4/> 4). Correlations between the LAS and posttransplant outcomes were investigated in both groups. RESULTS: In the high-DS group, an elevated LAS was strongly associated with posttransplant PaO2/FiO2 (p = 0.018). However, in the low-DS group, no correlation was found between them. There was no significant difference in the long-term survival according to the LAS in the low-DS group. The LAS effectively predicted the posttransplant outcome only when lungs with DS > 4 were transplanted; the LAS was not reliable if high-quality lungs were transplanted. CONCLUSION: Lung transplantation can be feasible and provides a survival benefit even for high-LAS patients if lungs from a low-risk donor are transplanted.

    DOI: 10.1007/s00595-018-1670-7

    PubMed

    researchmap

  • Myoepithelioma occurring in the posterior mediastinum harboring EWSR1 rearrangement: a case report. 査読 国際誌

    Tomohiro Habu, Junichi Soh, Tomohiro Toji, Kazuhiko Shien, Eito Niman, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

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

     詳細を見る

    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

    PubMed

    researchmap

  • Airway complications have a greater impact on the outcomes of living-donor lobar lung transplantation recipients than cadaveric lung transplantation recipients. 査読

    Seiichiro Sugimoto, Masaomi Yamane, Shinji Otani, Takeshi Kurosaki, Shuji Okahara, Yukiko Hikasa, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

    Surgery today   48 ( 9 )   848 - 855   2018年9月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Airway complications (ACs) after living-donor lobar lung transplantation (LDLLT) could have different features from those after cadaveric lung transplantation (CLT). We conducted this study to compare the characteristics of ACs after LDLLT vs. those after CLT and investigate their impact on outcomes. METHODS: We reviewed, retrospectively, data on 163 recipients of lung transplantation, including 83 recipients of LDLLT and 80 recipients of CLT. RESULTS: The incidence of ACs did not differ between LDLLT and CLT. The initial type of AC after LDLLT was limited to stenosis in all eight patients, whereas that after CLT consisted of stenosis in three patients and necrosis in ten patients (p = 0.0034). ACs after LDLLT necessitated significantly earlier initiation of treatment than those after CLT (p = 0.032). The overall survival rate of LDLLT recipients with an AC was significantly lower than that of those without an AC (p = 0.030), whereas the overall survival rate was comparable between CLT recipients with and those without ACs (p = 0.25). CONCLUSION: ACs after LDLLT, limited to bronchial stenosis, require significantly earlier treatment and have a greater adverse impact on survival than ACs after CLT.

    DOI: 10.1007/s00595-018-1663-6

    PubMed

    researchmap

  • Inherited lung cancer syndromes targeting never smokers. 査読

    Yamamoto H, Yatabe Y, Toyooka S

    Translational lung cancer research   7 ( 4 )   498 - 504   2018年8月

  • Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. 査読 国際誌

    I Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi, Hiroki Sato, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

    Cancers   10 ( 7 )   2018年7月

     詳細を見る

    記述言語:英語  

    Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin's roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid- and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.

    DOI: 10.3390/cancers10070239

    PubMed

    researchmap

  • Is Surgery after Chemoradiotherapy Feasible in Lung Cancer Patients with Superior Vena Cava Invasion? 査読

    Sato H, Soh J, Hotta K, Katsui K, Kanazawa S, Kiura K, Toyooka S

    Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia   24 ( 3 )   131 - 138   2018年6月

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

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

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

     詳細を見る

    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

    PubMed

    researchmap

  • Preoperative short hookwire placement for small pulmonary lesions: evaluation of technical success and risk factors for initial placement failure 査読

    Toshihiro Iguchi, Takao Hiraki, Yusuke Matsui, Hiroyasu Fujiwara, Yoshihisa Masaoka, Takashi Tanaka, Takuya Sato, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

    European Radiology   28 ( 5 )   2194 - 2202   2018年5月

     詳細を見る

    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 Verlag  

    Objectives: To retrospectively evaluate the technical success of computed tomography fluoroscopy-guided short hookwire placement before video-assisted thoracoscopic surgery and to identify the risk factors for initial placement failure. Methods: In total, 401 short hookwire placements for 401 lesions (mean diameter 9.3 mm) were reviewed. Technical success was defined as correct positioning of the hookwire. Possible risk factors for initial placement failure (i.e., requirement for placement of an additional hookwire or to abort the attempt) were evaluated using logistic regression analysis for all procedures, and for procedures performed via the conventional route separately. Results: Of the 401 initial placements, 383 were successful and 18 failed. Short hookwires were finally placed for 399 of 401 lesions (99.5%). Univariate logistic regression analyses revealed that in all 401 procedures only the transfissural approach was a significant independent predictor of initial placement failure (odds ratio, OR, 15.326
    95% confidence interval, CI, 5.429–43.267
    p &lt
    0.001) and for the 374 procedures performed via the conventional route only lesion size was a significant independent predictor of failure (OR 0.793, 95% CI 0.631–0.996
    p = 0.046). Conclusions: The technical success of preoperative short hookwire placement was extremely high. The transfissural approach was a predictor initial placement failure for all procedures and small lesion size was a predictor of initial placement failure for procedures performed via the conventional route. Key points: • Technical success of preoperative short hookwire placement was extremely high. • The transfissural approach was a significant independent predictor of initial placement failure for all procedures. • Small lesion size was a significant independent predictor of initial placement failure for procedures performed via the conventional route.

    DOI: 10.1007/s00330-017-5176-2

    Scopus

    PubMed

    researchmap

  • Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations 査読

    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

     詳細を見る

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

    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.

    DOI: 10.1111/cas.13571

    Scopus

    PubMed

    researchmap

  • A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer. 査読 国際誌

    Toyooka S, Okumura N, Nakamura H, Nakata M, Yamashita M, Tada H, Kajiwara S, Watanabe N, Okada M, Sakamoto J, Aoe M, Soh J, Miyoshi S, Hotta K, Matsuo K, Date H

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   13 ( 5 )   699 - 706   2018年5月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jtho.2018.02.015

    PubMed

    researchmap

  • β-1,3-Galactosyl-<i>O</i>-Glycosyl-Glycoprotein β-1,6-<i>N</i>-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

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3727/096504017X15031557924123

    PubMed

    researchmap

  • Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer 査読

    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

     詳細を見る

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

    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

    Scopus

    PubMed

    researchmap

  • What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection? 査読

    Masahiro Miyajima, Atsushi Watanabe, Toshihiko Sato, Satoshi Teramukai, Masahito Ebina, Kazuma Kishi, Yukihiko Sugiyama, Haruhiko Kondo, Satoru Kobayashi, Yutaka Takahashi, Hiroyuki Ito, Ryoji Yamamoto, Shigeki Sawada, Hideki Fujimori, Kazunori Okabe, Jun Arikura, Yasushi Shintani, Hiroshige Nakamura, Shinichi Toyooka, Tohru Hasumi, Takehiro Watanabe, Yoshinobu Hata, Hisashi Iwata, Minoru Aoki, Kazuhito Funai, Shuhei Inoue, Osamu Kawashima, Tomohiko Iida, Hiroshi Date

    Surgery today   48 ( 4 )   404 - 415   2018年4月

     詳細を見る

    記述言語:英語  

    PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP.

    DOI: 10.1007/s00595-017-1605-8

    PubMed

    researchmap

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

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

    Japanese Journal of Clinical Oncology   48 ( 3 )   287 - 290   2018年3月

     詳細を見る

    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 University Press  

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

    DOI: 10.1093/jjco/hyy003

    Scopus

    PubMed

    researchmap

  • Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E 査読

    Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G. Kris, Bob T. Li, Marc Ladanyi

    Oncologist   23 ( 2 )   150 - 154   2018年2月

     詳細を見る

    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  

    We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors’ institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors’, revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. Key Points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling. Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations. In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

    DOI: 10.1634/theoncologist.2017-0345

    Scopus

    PubMed

    researchmap

  • A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer 査読

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

    Journal of Thoracic Oncology   13 ( 2 )   273 - 279   2018年2月

     詳細を見る

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

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

    DOI: 10.1016/j.jtho.2017.10.032

    Scopus

    PubMed

    researchmap

  • Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma 査読

    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   2018年1月

     詳細を見る

    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  

    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

    Scopus

    PubMed

    researchmap

  • Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. 査読 国際誌

    Kazufumi Nakamura, Masakiyo Sakaguchi, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Kaoru Akazawa, Megumi Kondo, Koji Nakagawa, Masashi Yoshida, Toru Miyoshi, Takeshi Ogo, Takahiro Oto, Shinichi Toyooka, Yuichiro Higashimoto, Kei Fukami, Hiroshi Ito

    PloS one   13 ( 9 )   e0203046   2018年

     詳細を見る

    記述言語:英語  

    BACKGROUND: Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. METHODS AND RESULTS: PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). CONCLUSIONS: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

    DOI: 10.1371/journal.pone.0203046

    PubMed

    researchmap

  • Model of lung cancer surgery risk derived from a Japanese nationwide web-based database of 78 594 patients during 2014-2015. 査読

    Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H, Yokoi K, Chida M, Sato M, Toyooka S, Yoshida K, Okada Y, Sato Y, Okada M, Okumura M, Chihara K, Fukuchi E, Miyata H

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery   52 ( 6 )   1182 - 1189   2017年12月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/ejcts/ezx190

    Web of Science

    PubMed

    researchmap

  • Restrictive ventilatory impairment is associated with poor outcome in patients with cT1aN0M0 peripheral squamous cell carcinoma of the lung 査読

    Hiroyuki Tao, Junichi Soh, Hiromasa Yamamoto, Toshiya Fujiwara, Tsuyoshi Ueno, Makio Hayama, Mikio Okazaki, Ryujiro Sugimoto, Motohiro Yamashita, Yoshifumi Sano, Kazunori Okabe, Motoki Matsuura, Kazuhiko Kataoka, Shigeharu Moriyama, Shinichi Toyooka, Shinichiro Miyoshi

    JOURNAL OF THORACIC DISEASE   9 ( 11 )   4325 - 4335   2017年11月

     詳細を見る

    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: Patients with squamous cell carcinoma (SqCC) of the lung sometimes have a comorbid pulmonary disease such as pulmonary emphysema or an interstitial lung disease (ILD), both of which negatively affect patient outcome. The aim of this study was to determine the outcome of patients in a multicenter database who underwent surgery for cT1aN0M0 peripheral SqCC lung cancer.
    Methods: The medical records of a total of 228 eligible patients from seven institutions were reviewed to evaluate the impact of concomitant impaired pulmonary function and other clinicopathological factors on overall survival (OS) and relapse-free survival (RFS).
    Results: Six patients with positive or unclear tumor margins were excluded. Of the 222 remaining study patients, 42 (18.9%) and 97 (43.7%) patients were found to have coexisting restrictive or obstructive ventilatory impairment, respectively. Over a median follow-up period of 30.6 months, the 5-year OS and RFS were 69.0% and 62.6%, respectively. By multivariate analysis, ILDs identified on high-resolution computed tomography (HRCT), pulmonary function test results indicating a restrictive ventilatory impairment, and wedge resection were found to be independent risk factors for poor OS. An increased level of serum squamous cell carcinoma antigen (SCC-Ag) (&gt; 1.5 ng/mL) and the same risk factors for poor OS were independent risk factors for recurrence. Among patients who underwent anatomical lung resection (lobectomy and segmentectomy, n=173), a restrictive ventilatory impairment was an independent risk factor for poor OS, and increased serum SCC-Ag level, ILDs on HRCT, and restrictive ventilatory impairment were independent risk factors for poor RFS by multivariate analysis. Factors such as visceral pleural invasion, and lymphatic or vascular invasion were not significantly associated with outcome.
    Conclusions: A restrictive ventilatory impairment negatively affects the outcome of patients with cT1aN0M0 peripheral SqCC lung cancer.

    DOI: 10.21037/jtd.2017.10.70

    Web of Science

    PubMed

    researchmap

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

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

    ONCOLOGY LETTERS   14 ( 4 )   4349 - 4354   2017年10月

     詳細を見る

    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 docetaxelresis-tant 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.

    DOI: 10.3892/ol.2017.6678

    Web of Science

    PubMed

    researchmap

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

    Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Carmen Behrens, Li Shen, Neda Kalhor, Juhee Song, J. Jack Lee, Jing Wang, Ximing Tang, Roy S. Herbst, Shinichi Toyooka, Luc Girard, John D. Minna, Jonathan M. Kurie, Ignacio I. Wistuba, Julie G. Izzo

    MOLECULAR CANCER THERAPEUTICS   16 ( 10 )   2234 - 2245   2017年10月

     詳細を見る

    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 crosstalk 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. (C) 2017 AACR.

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

    Web of Science

    PubMed

    researchmap

  • Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization 査読

    Takehiro Matsubara, Shuta Tomida, Junichi Soh, Takahiro Uwabo, Yoshiko Mori, Mizuki Morita, Yasutomo Nasu, Susumu Kanazawa, Shinichi Toyooka

    BIOPRESERVATION AND BIOBANKING   15 ( 5 )   484 - 486   2017年10月

     詳細を見る

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

    DOI: 10.1089/bio.2017.0076

    Web of Science

    PubMed

    researchmap

  • Postoperative pyoderma gangrenosum exacerbated by granulocyte-colony stimulating factor after lung cancer surgery 査読

    Haruchika Yamamoto, Seiichiro Sugimoto, Shinji Otani, Shinichi Toyooka

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   47 ( 10 )   991 - 992   2017年10月

     詳細を見る

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

    DOI: 10.1093/jjco/hyx121

    Web of Science

    PubMed

    researchmap

  • Estimation of age-related DNA degradation from formalin-fixed and paraffin-embedded tissue according to the extraction methods 査読

    Mototsugu Watanabe, Shinsuke Hashida, Hiromasa Yamamoto, Takehiro Matsubara, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi

    EXPERIMENTAL AND THERAPEUTIC MEDICINE   14 ( 3 )   2683 - 2688   2017年9月

     詳細を見る

    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  

    Techniques for the extraction and use of nucleic acids from formalin-fixed and paraffin-embedded (FFPE) tissues, preserved over long time periods in libraries, have been developed. However, DNA extracted from FFPE tissues is generally damaged, and long-term storage may affect DNA quality. Therefore, it is important to elucidate the effect of long-term storage on FFPE tissues and evaluate the techniques used to extract DNA from them. In the present study, the yield, purity, and integrity of DNA in FFPE tissue samples was evaluated. Two DNA extraction techniques were used: A silica-binding DNA collection method using QIAamp DNA FFPE Tissue kit (QIA) and a total tissue DNA collection method using a WaxFree DNA extraction kit (WAX). A total of 25 FFPE tissues from lung adenocarcinomas were studied, which had been surgically resected and fixed at Okayama University Hospital prior to examination and subsequent storage at room temperature for 0.5, 3, 6, 9 and 12 years. Extracted DNA was quantified using ultraviolet absorbance, fluorescent dye, and quantitative polymerase chain reaction (qPCR). The quality of the DNA was defined by the absorbance ratio of 260 to 280 nm (A260/280) and Q-score, which is the quantitative value of qPCR product size ratio. The results demonstrated that the yield of total DNA extracted using WAX was significantly greater than when QIA was used (P&lt;0.01); however, DNA extracted using WAX included more contaminants and was significantly more fragmented compared with DNA extracted using QIA (P&lt;0.01). Aging had no significant effect on absolute DNA yield or DNA purity, although it did significantly contribute to increased DNA degradation for both QIA and WAX extraction (QIA P=0.02, WAX P=0.03; 0.5 years vs. 3 years, QIA P&lt;0.01, WAX P=0.03; 9 years vs. 12 years). Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required. However, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.

    DOI: 10.3892/etm.2017.4797

    Web of Science

    PubMed

    researchmap

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

    Hidejiro Torigoe, Junichi Soh, Shuta Tomida, Kei Namba, Hiroki Sato, Kuniaki Katsui, Katsuyuki Hotta, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC DISEASE   9 ( 9 )   3076 - 3086   2017年9月

     詳細を見る

    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 nonDD 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.

    DOI: 10.21037/jtd.2017.08.87

    Web of Science

    PubMed

    researchmap

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

    Hiroki Sato, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Kazuhiko Shien, Hiromasa Yamamoto, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   104 ( 3 )   971 - 978   2017年9月

     詳細を見る

    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. (C) 2017 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2017.03.045

    Web of Science

    PubMed

    researchmap

  • 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

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

  • Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system 査読

    Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY REPORTS   37 ( 5 )   3100 - 3106   2017年5月

     詳細を見る

    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  

    Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

    DOI: 10.3892/or.2017.5567

    Web of Science

    PubMed

    researchmap

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

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Shinichiro Miyoshi

    JOURNAL OF THORACIC DISEASE   9 ( 5 )   E489 - E491   2017年5月

     詳細を見る

    記述言語:英語   出版者・発行元:PIONEER BIOSCIENCE PUBL CO  

    DOI: 10.21037/jtd.2017.03.183

    Web of Science

    PubMed

    researchmap

  • Early postoperative complications after middle lobe-preserving surgery for secondary lung cancer 査読

    Yuho Maki, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    SURGERY TODAY   47 ( 5 )   601 - 605   2017年5月

     詳細を見る

    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 Preservation of the middle lobe during lung surgery is traditionally avoided, because its presence in the hemithoracic cavity is considered a cause of complications. We report a series of lung cancer patients who underwent a secondary pulmonary resection with the preservation of the middle lobe to explore the complications and feasibility of these procedures.
    Methods We reviewed the clinical courses of six patients who underwent surgery for metachronous lung cancers. Five patients underwent right upper lobectomy, including one sleeve lobectomy, after having undergone prior right lower lobectomy. The remaining patient underwent a right lower lobectomy after having undergone a prior right upper lobectomy.
    Results There were no treatment-related deaths. One patient was readmitted for surgery to treat delayed air leakage progressing to pyothorax. One patient was treated for persistent air leakage. Two patients required intermittent drainage of pulmonary effusion, because of middle lobe atelectasis. The postoperative forced vital capacity and forced expiratory volume in 1 s were greater than the values predicted post-pneumonectomy in four evaluable patients.
    Conclusions While postoperative complications after middle lobe-preserving surgery are manageable, their high incidence should be considered when performing this surgery.

    DOI: 10.1007/s00595-016-1413-6

    Web of Science

    PubMed

    researchmap

  • Diagnostic Value of Dual-time-point F-18 FDG PET/CT and Chest CT for the Prediction of Thymic Epithelial Neoplasms 査読

    Takayoshi Shinya, Takashi Tanaka, Junichi Soh, Toshi Matsushita, Shuhei Sato, Shinichi Toyooka, Tadashi Yoshino, Shinichiro Miyoshi, Susumu Kanazawa

    ACTA MEDICA OKAYAMA   71 ( 2 )   105 - 112   2017年4月

     詳細を見る

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

    We retrospectively assessed the dual-time-point (DTP) F-18 FDG PET/CT findings of thymic epithelial neoplasms (TENs) and investigated the diagnostic capacity of PET/CT compared to that of CT for predicting carcinoma. We calculated the ratio of the standardized uptake value of the tumor and that of the aortic arch (T/M ratio) for both the 90-min early scan and the 2-h delayed scan in 56 TEN patients. We used a multivariate logistic regression (MLR) analysis to estimate the CT features of carcinoma. We compared the diagnostic capacities of PET/CT and chest CT using receiver operating characteristic (ROC) analyses. The ROC curve revealed that the appropriate cut-off T/M ratio value for the highest accuracy was 2.39 with 75.0% accuracy. The area under the curve (AUC) was 0.855. The statistical analyses for DTP scans of 35 TEN patients demonstrated 74.3% accuracy and 0.838 AUC for the early scan versus 82.9% and 0.825 for the delayed scan. The MLR analysis indicated that mediastinal fat infiltration was a predictor of carcinoma. The ROC curve obtained for the model yielded an AUC of 0.853. Delayed scanning could improve the diagnostic capacity for carcinoma. The T/M ratio and mediastinal fat infiltration are predictive of carcinoma with moderate diagnostic accuracy.

    DOI: 10.18926/AMO/54978

    Web of Science

    PubMed

    researchmap

  • Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001 査読

    Norihito Okumura, Makoto Sonobe, Kazunori Okabe, Hiroshige Nakamura, Masafumi Kataoka, Motohiro Yamashita, Masao Nakata, Kazuhiko Kataoka, Yoshinori Yamashita, Junichi Soh, Hiroshige Yoshioka, Katsuyuki Hotta, Keitaro Matsuo, Junichi Sakamoto, Shinichi Toyooka, Hiroshi Date

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   22 ( 2 )   274 - 282   2017年4月

     詳細を見る

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

    This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC).
    Patients received four cycles of S-1 (80 mg/m(2)/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m(2)/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was 50%.
    Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%.
    We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC.
    UMIN000005041.

    DOI: 10.1007/s10147-016-1067-9

    Web of Science

    PubMed

    researchmap

  • Radiofrequency ablation of pulmonary metastases from sarcoma: single-center retrospective evaluation of 46 patients 査読

    Takuya Sato, Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Jun Sakurai, Yusuke Matsui, Toshiharu Mitsuhashi, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa

    JAPANESE JOURNAL OF RADIOLOGY   35 ( 2 )   61 - 67   2017年2月

     詳細を見る

    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  

    This retrospective, single-center study evaluated radiofrequency (RF) ablation for pulmonary metastases of sarcoma.
    Forty-six patients with sarcoma (144 pulmonary metastases) underwent 88 RF ablation sessions. Data regarding local tumor progression, efficacy, procedural adverse events (AEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), overall survival (OS), and OS-associated prognostic factors were retrospectively evaluated using univariate analyses.
    Local progression occurred in 22 of 144 tumors (15.3%). Primary and secondary efficacy rates were 83.5 and 90.0% at 1 year and 76.3 and 81.4% at 2 years, respectively. Seventy-three grade 1 AEs, 33 grade 2 AEs, and no grade &gt;= 3 AEs were observed. Twenty-eight patients (60.9%) remained alive and 18 died, yielding 1-, 2-, and 3-year OS rates of 80.6, 70.1, and 47.1% (median survival time, 31.7 months). Univariate analysis revealed extrapulmonary metastasis (P = 0.005), noncurative RF ablation (P = 0.009), and a post-RF ablation disease-free interval of &lt;= 12 months (P = 0.015) as significant negative prognostic factors.
    RF ablation is safe, offers good local control, and may be a viable treatment option for pulmonary metastasis of sarcoma.

    DOI: 10.1007/s11604-016-0601-z

    Web of Science

    PubMed

    researchmap

  • Feasibility of Pulmonary Resection for Lung Cancer in Patients With Coronary Artery Disease or Atrial Fibrillation. 査読 国際誌

    Yoshitaka Kitamura, Kenji Suzuki, Satoshi Teramukai, Makoto Sonobe, Shinichi Toyooka, Yoshihisa Nakagawa, Hiroyasu Yokomise, Hiroshi Date

    The Annals of thoracic surgery   103 ( 2 )   432 - 440   2017年2月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The aim of this study was to clarify the outcomes of lung resection for lung cancer in patients with cardiac disease, especially coronary artery disease, in a large-scale multi-institutional cohort. METHODS: We retrospectively analyzed the data on 1,254 patients who underwent major lung resection for lung cancer and had been diagnosed with coronary stenosis, atrial fibrillation, or both, in 58 institutions in Japan between January 2009 and December 2011. The primary outcome was 90-day postoperative mortality or in-hospital death. RESULTS: Among the 1,254 patients, 902 (71.9%) and 452 patients (36.0%) were preoperatively diagnosed with coronary stenosis and atrial fibrillation, respectively, and 951 patients (75.8%) received antiplatelet therapy. Among the patients with coronary stents (n = 532; 42.4%), 204 (16.3%) received drug-eluting stents. The 90-mortality or in-hospital death rate was 2.6% (n = 32), including stent thrombosis (n = 1), thromboembolic events without stent thrombosis (n = 2), and bleeding events (n = 2). In the multivariate analyses, blood transfusion, history of cerebrovascular disease, amount of bleeding, and history of congestive heart failure were associated with a higher independent risk of 90-day mortality or in-hospital death (odds ratio, 9.400, 3.574, 2.827, and 2.945, respectively). Preoperative discontinuation of antiplatelet therapy was not associated with an independent risk of 90-day mortality or in-hospital death on univariate analysis. CONCLUSIONS: Major lung resection for lung cancer in patients with coronary artery disease is feasible. Our study suggests that discontinuation of antiplatelet therapy may not increase postoperative complications in patients with coronary artery disease.

    DOI: 10.1016/j.athoracsur.2016.08.077

    PubMed

    researchmap

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

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

    ANTICANCER RESEARCH   37 ( 1 )   301 - 307   2017年1月

     詳細を見る

    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.

    DOI: 10.21873/anticanres.11321

    Web of Science

    PubMed

    researchmap

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

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

    SCIENTIFIC REPORTS   7   40847   2017年1月

     詳細を見る

    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.

    DOI: 10.1038/srep40847

    Web of Science

    PubMed

    researchmap

  • Trastuzumab Emtansine in HER2+Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol 査読

    Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura

    CLINICAL LUNG CANCER   18 ( 1 )   92 - 95   2017年1月

     詳細を見る

    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  

    The treatment outcome has been unsatisfactory for patients with non small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patientg with HER2+ lung cancers. The major eligibility criteria are as follows: age &gt;= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. (C) 2016 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.cllc.2016.06.014

    Web of Science

    PubMed

    researchmap

  • Reconstruction of Anterior Chest Wall with Polypropylene Mesh: Two Primary Sternal Chondrosarcoma Cases 査読

    Shinichi Kawana, Hiromasa Yamamoto, Yuho Maki, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   71 ( 3 )   259 - 262   2017年

     詳細を見る

    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  

    Primary sternal chondrosarcoma is a rare malignant tumor that is refractory to chemotherapy and radiation. Effective therapy is radical resection of the tumor. We present two patients with primary sternal chondrosarcoma who underwent a radical resection of the lower half of the sternum and bilateral ribs, followed by reconstruction with 2 sheets of polypropylene mesh layered orthogonally. The patients have maintained almost the same pulmonary function as preoperative values, with stability of the chest wall. Although there are various ways to reconstruct the anterior chest wall, reconstruction with polypropylene mesh layered orthogonally is an easy-to-use and sufficient method.

    DOI: 10.18926/AMO/55210

    Web of Science

    PubMed

    researchmap

  • Unique circulating microRNAs in relation to EGFR mutation status in Japanese smoker male with lung adenocarcinoma 査読

    Sachio Ito, Yoshihiro Kamoto, Akiko Sakai, Kaori Sasai, Tatsuro Hayashi, Shinichi Toyooka, Hiroshi Katayama

    Oncotarget   8 ( 70 )   114685 - 114697   2017年

     詳細を見る

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

    The incidence of lung adenocarcinoma has been increasing recently in smokers. The molecular target therapy has been developed for lung adenocarcinoma patients harboring EGFR gene mutation. However, the treatment modalities for patients without mutation are currently limited. Thus, analysis of EGFR gene mutation status at early stage is important strategy to classify the patients for improving treatments and prognosis efficiently. This study aimed to identify microRNA (miRNA) signature in relation to mutation status in EGFR gene in early stage of lung adenocarcinoma male patients with smoking history. MiRNA profiles were assessed by microarray in paired plasma and tissue pooled from 10 EGFR wild type (EGFR-wt) and 10 EGFR mutated (EGFR-mut) patients. Expressions of selected miRNAs were verified further by real-time qRT-PCR in 83 plasma samples consisting of 55 EGFR-wt patients and 28 EGFR-mut patients and their correlation with clinicopathological parameters and EGFR gene mutation status were evaluated. We found that seven miRNAs (miR-16-5p, miR-23a-3p, miR-103a-3p, miR122-5p, miR-223-3p, miR-346 and miR-451a) were differentially expressed in stage I and stage I+II. Especially, miR-23a-3p was only miRNA shown higher expression in EGFR-wt patients than EGFR-mut patients. Thus, our findings could be useful non-invasive biomarkers to differentiate mutation status in EGFR gene in smoker lung adenocarcinoma male patients.

    DOI: 10.18632/oncotarget.21425

    Scopus

    PubMed

    researchmap

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

    Takeda T, Yamamoto H, Kanzaki H, Suzawa K, Yoshioka T, Tomida S, Cui X, Murali R, Namba K, Sato H, Torigoe H, Watanabe M, Shien K, Soh J, Asano H, Tsukuda K, Kitamura Y, Miyoshi S, Sendo T, Toyooka S

    PloS one   12 ( 2 )   e0171356   2017年

  • Role of surgery in N2 NSCLC: pros 査読

    Kazuhiko Shien, Shinichi Toyooka

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   46 ( 12 )   1168 - 1173   2016年12月

     詳細を見る

    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.

    DOI: 10.1093/jjco/hyw125

    Web of Science

    PubMed

    researchmap

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

    Tomoaki Ohtsuka, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Katsuyoshi Takata, Kazuhiko Shien, Shinsuke Hashida, Tomoko Miyata-Takata, Mototsugu Watanabe, Ken Suzawa, Junichi Soh, Chen Youyi, Hiroki Sato, Kei Namba, Hidejiro Torigoe, Kazunori Tsukuda, Tadashi Yoshino, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   6   39557   2016年12月

     詳細を見る

    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.

    DOI: 10.1038/srep39557

    Web of Science

    PubMed

    researchmap

  • Usefulness of Thoracoscopic Debridement for Chronic Empyema after an Extrapleural Pneumonectomy 査読

    Hidejiro Torigoe, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   70 ( 6 )   507 - 510   2016年12月

     詳細を見る

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

    We present the case of a 65-year-old Japanese man diagnosed with chronic empyema (without a bronchopleural fistula) that occurred 7 months after he underwent an extrapleural pneumonectomy for right malignant pleural mesothelioma (MPM). Following thoracic drainage and irrigation for 1 month, we performed surgery by a thoracoscopic approach, in light of his general condition. We performed debridement and removal of the Gore-Tex polytetralluoroethylene (PTFE) patch that had been used for the reconstruction of the diaphragm and the pericardium. The empyema had not relapsed when he died from recurrence of the MPM at 4 months after the thoracoscopic surgery. This patient's case suggests that thoracoscopic debridement and patch removal can be a therapeutic option for not only early-stage (exudative or fibrinopurulent) empyema but also late-stage (organized and chronic) empyema without a bronchopleural fistula, particularly for patients in poor general condition.

    DOI: 10.18926/AMO/54816

    Web of Science

    PubMed

    researchmap

  • Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. 査読 国際誌

    Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Yoshihiko Sakaguchi, Ken Saito, Hidekazu Iioka, Nam-Ho Huh, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer microenvironment : official journal of the International Cancer Microenvironment Society   9 ( 2-3 )   93 - 105   2016年12月

     詳細を見る

    記述言語:英語  

    S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

    DOI: 10.1007/s12307-016-0185-2

    PubMed

    researchmap

  • Development of an annually updated Japanese national clinical database for chest surgery in 2014 査読

    Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Kohei Yokoi, Masayuki Chida, Masami Sato, Shinichi Toyooka, Koichi Yoshida, Yoshinori Okada, Yukio Sato, Meinoshin Okumura, Munetaka Masuda, Koji Chihara, Hiroaki Miyata

    General Thoracic and Cardiovascular Surgery   64 ( 10 )   569 - 576   2016年10月

     詳細を見る

    記述言語:英語   出版者・発行元:Springer-Verlag Tokyo  

    Objectives: A national clinical database (NCD) adopted an “Internet-based collection” in 2011. An NCD specializing in chest surgery was launched based on the NCD system in 2014. The system was linked to the board certification as the second level in the hierarchy of the specialty of chest surgery and accreditation of educational institutions for chest surgery. Here, we report the status of the NCD for chest surgery in 2014 and clarified its registration rate and its accuracy. Methods: Chest surgeries undertaken in Japan since January 1st, 2014 until the end of the same year were registered through an Internet-based system until April 8th, 2015. The registration rate was compared with the annual survey conducted by the Japanese Association for Thoracic Surgery (JATS) from 2011 to 2014. The rate of accurate inputting was measured by an Internet-based audit in reference to 563 anonymous operative notes of patients presented by 106 chest surgeons at the time of renewal for board certification for chest surgery. Results: A total of 88,112 chest-surgical procedures were registered from 1000 chest surgery units (CSUs). Distribution of procedures by thoracic disease was almost identical to that of the annual survey conducted by JATS. However, the NCD had 4260 more registered procedures compared with the annual survey. The Internet-based audit showed that inter-rater agreement between Internet-based data and operative notes in any item was &gt
    94 %. Conclusions: The NCD system can sustainably provide important and up-to-date information relating to preoperative status, oncology, and best practice for chest surgery in Japan.

    DOI: 10.1007/s11748-016-0697-1

    Scopus

    PubMed

    researchmap

  • The Feasibility of Median Sternotomy With or Without Thoracotomy for Locally Advanced Non-Small Cell Lung Cancer Treated With Induction Chemoradiotherapy 査読

    Hiroki Sato, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Hiromasa Yamamoto, Seiichiro Sugimoto, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   102 ( 3 )   985 - 992   2016年9月

     詳細を見る

    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. This study aimed to compare the morbidity and mortality of a median sternotomy approach and a lateral thoracotomy and to investigate the feasibility of a median sternotomy for locally advanced non-small cell lung cancer (NSCLC) after induction chemoradiotherapy.
    Methods. The medical records of patients with locally advanced NSCLC who underwent induction chemoradiotherapy followed by surgery at our institution between January 1999 and September 2014 were reviewed. We compared the morbidity and mortality of a median sternotomy approach and a lateral thoracotomy.
    Results. A total of 102 NSCLC patients were the subjects of this study. Among them, 31 patients underwent surgery with a median sternotomy approach and 71 patients underwent surgery with a lateral thoracotomy. Patients in the median sternotomy group had a significantly higher rate of postoperative arrhythmia than those in the lateral thoracotomy group (p = 0.0028). However, all the complications were manageable, and no treatment-related deaths occurred in the median sternotomy group. Regarding the prognosis, the 5-year overall survival rate was 72.7%, and the 2-year recurrence-free survival rate was 66.5% in the entire population. No significant differences in overall survival or recurrence-free survival were observed between the 2 approaches.
    Conclusions. Whereas the lateral thoracotomy approach is a standard procedure, our experience suggests that a median sternotomy approach for locally advanced NSCLC after induction chemoradiotherapy is a feasible procedure and can be a surgical option. (C) 2016 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2016.03.092

    Web of Science

    PubMed

    researchmap

  • Long-Term Survival after Radiofrequency Ablation of Lung Oligometastases from Five Types of Primary Lesions: A Retrospective Evaluation 査読

    Kenichi Omae, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Takeshi Nagasaka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   27 ( 9 )   1362 - 1370   2016年9月

     詳細を見る

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

    Purpose: To conduct a retrospective evaluation of long-term survival after radiofrequency (RF) ablation for lung oligometastases from 5 types of primary lesions.
    Materials and Methods: The study population consisted of 123 patients with lung oligometastases from colorectal cancer (CRC), non small-cell lung cancer, hepatocellular carcinoma, esophageal cancer, and renal-cell carcinoma treated with RF ablation. Lung oligometastases were defined as 1-5 Metastases confined to the lung while the primary cancer and other metastases were eradicated. Overall survival (OS) and recurrence-free survival (RFS) were estimated for-the overall study population and for patients with each type of primary lesion. The OS and RFS rates were compared with those of the patients with any of the other four primary lesion types. Finally, various variables were analyzed to determine what factors influenced OS and RFS.
    Results: The Median follow-up was 45.7 months; and the 5-year-OS and RFS rates for all 123 patients Were 62% and 25%, respectively, The OS :time for patients with metastases from. CRC was significantly longer (P = .042); it was significantly shorter (P = .022) in patients with metastases from esophageal cancer. Longer disease-free interval was significantly (P = .015) associated with better OS. There was no variable significantly associated with OS and RFS on multivariate analyses.
    Conclusions: Data from this single-center study appear promising in terms of long-term survival after RF ablation of lung oligometastases from 5 primary lesions.

    DOI: 10.1016/j.jvir.2016.05.017

    Web of Science

    PubMed

    researchmap

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

    Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

    ACTA MEDICA OKAYAMA   70 ( 4 )   327 - 330   2016年8月

     詳細を見る

    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.

    DOI: 10.18926/AMO/54514

    Web of Science

    PubMed

    researchmap

  • Randomized feasibility study of S-1 for adjuvant chemotherapy in completely resected Stage IA non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 0701 査読

    Junichi Soh, Norihito Okumura, Masao Nakata, Hiroshige Nakamura, Minoru Fukuda, Masafumi Kataoka, Shinsuke Kajiwara, Yoshifumi Sano, Motoi Aoe, Kazuhiko Kataoka, Katsuyuki Hotta, Keitaro Matsuo, Shinichi Toyooka, Hiroshi Date

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   46 ( 8 )   741 - 747   2016年8月

     詳細を見る

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

    Objective: The aim of this multicenter study was to determine the appropriate administration schedule for S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological-Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.
    Methods: Patients were randomly assigned to receive adjuvant chemotherapy consisting of either the 4-week oral administration of S-1 ( 80-120 mg/body/day) followed by a 2-week rest ( Group A), or the 2-week oral administration of S-1 ( 80-120mg/body/day) followed by a 1-week rest ( Group B). The duration of adjuvant chemotherapy was 1 year in both arms. The primary endpoint was compliance, namely drug discontinuation-free survival, which was calculated using the Kaplan-Meier method with log-rank test.
    Results: Eighty patients were enrolled in this study, and 76 patients actually received S-1 treatment. The drug discontinuation-free survival rates at 1 year were 49.1% in Group A and 52.7% in Group B ( P = 0.373). The means of the relative dose intensities were 55.3% in Group A and 64.6% in Group B ( P = 0.237). There were no treatment-related deaths. Patients with grade 3/ 4 toxicities were significantly more frequent in Group A ( 40.5%) than in Group B ( 15.4%, P = 0.021). The 2-year relapse-free survival rates were 97.5% in Group A and 92.5% in Group B, and the 2-year overall survival rates were 100% in both groups.
    Conclusions: The feasibility showed no significant difference between the two groups among patients with completely resected Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.

    DOI: 10.1093/jjco/hyw062

    Web of Science

    PubMed

    researchmap

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

    Yuho Maki, Yasumitsu Nishimura, Shinichi Toyooka, Junichi Soh, Kazunori Tsukuda, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoka, Tsuyoshi Ueno, Norimitsu Tanaka, Hiromasa Yamamoto, Hiroaki Asano, Megumi Maeda, Naoko Kumagai-Takei, Suni Lee, Hidenori Matsuzaki, Takemi Otsuki, Shinichiro Miyoshi

    Oncology letters   11 ( 5 )   3308 - 3316   2016年5月

     詳細を見る

    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.

    DOI: 10.3892/ol.2016.4412

    PubMed

    researchmap

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

    Masashi Furukawa, Shinichi Toyooka, Kouichi Ichimura, Hiromasa Yamamoto, Junichi Soh, Shinsuke Hashida, Mamoru Ouchida, Kazuhiko Shien, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

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

     詳細を見る

    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.

    DOI: 10.3892/mco.2015.690

    PubMed

    researchmap

  • Induction S-1+Concurrent Radiotherapy Followed by Surgical Resection of Locally Advanced Non-small-cell Lung Cancer in an Elderly Patient 査読

    Hidejiro Torigoe, Shinichi Toyooka, Kuniaki Katsui, Junichi Soh, Yuho Maki, Katsuyuki Kiura, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   70 ( 1 )   63 - 65   2016年2月

     詳細を見る

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

    We present the case of a 77 year-old Japanese man diagnosed with lung squamous cell carcinoma with mediastinal lymph node metastasis. He was treated with induction chemoradiotherapy for T1bN2M0 stage IIIA disease. Considering his age, we selected S-1 as the chemotherapeutic drug. Observing an objective response with no severe adverse events, we performed a left upper lobectomy with sleeve resection of the pulmonary artery. No residual tumor cells were found in the resected specimens, and no critical complication was observed in the clinical course. This case suggests that induction chemoradiotherapy using S-1 combined with concurrent radiation followed by surgery can he a therapeutic option for elderly patients with locally advanced non-small-cell lung cancer.

    DOI: 10.18926/AMO/54007

    Web of Science

    PubMed

    researchmap

  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations 査読

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    Cancer Science   107 ( 1 )   45 - 52   2016年1月

     詳細を見る

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

    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. In this study, we demonstrated the antitumor effect of afatinib, as a HER2-targeted therapy, in lung cancers harboring HER2 alterations in vitro and in vivo. Our results strongly suggest that afatinib is a promising therapeutic option for NSCLC patients with HER2-amplification or mutations.

    DOI: 10.1111/cas.12845

    Scopus

    PubMed

    researchmap

  • Radiofrequency Ablation of Lung Tumors Using a Multitined Expandable Electrode: Impact of the Electrode Array Diameter on Local Tumor Progression 査読

    Hiroki Ihara, Hideo Gobara, Takao Hiraki, Toshiharu Mitsuhashi, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   27 ( 1 )   87 - 95   2016年1月

     詳細を見る

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

    Purpose: To retrospectively investigate the impact of the electrode array diameter on local tumor progression after lung radiofrequency ablation.
    Materials and Methods: This study included 651 lung tumors treated using multitined expandable electrodes and followed for 6 months. The mean long-axis tumor diameter was 12 mm +/- 7 (range, 2-42 mm). The difference between electrode array diameter and tumor diameter (DAT) was used to investigate the impact of the electrode array diameter. All tumors were classified into 2 groups according to various variables including DAT (&gt;= 10 mm or &lt; 10 mm). The primary technique efficacy rates were calculated using Kaplan-Meier analysis and compared between the 2 groups of each variable using the log-rank test. In addition, crude and multivariate multilevel survival analyses were performed by sequentially including DAT and the other variables in 5 models.
    Results: The median DAT for 651 tumors was 12 mm (range, 15 to 24 mm). The technique efficacy rate was significantly lower in the &lt; 10 mm DAT group than in the &gt;= 10 nun group (P &lt; .001). In the crude and multivariate multilevel survival analyses, &lt; 10 mm DAT was a significant risk factor for local progression in all models except model 5 (P = .067). In the &gt;= 10 mm group, the technique efficacy rates were riot significantly different-between the 2 &gt;= 10 min DAT subgroups (ICY to &lt; 15 mm DAT vs &gt;= 15 mm DAT).
    Conclusions: DAT is an important risk factor for local progression. We recommend an electrode that is &gt;= 10 mm larger than the tumor diameter.

    DOI: 10.1016/j.jvir.2015.07.025

    Web of Science

    PubMed

    researchmap

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

    Ken Suzawa, Hiromasa Yamamoto, Tomoyuki Murakami, Hideki Katayama, Masashi Furukawa, Kazuhiko Shien, Shinsuke Hashida, Kazunori Okabe, Keisuke Aoe, Junichi Soh, Hiroaki Asan, Kazunori Tsukuda, Yusuke Mimura, Shinichi Toyooka, Shinichiro Miyoshi

    ONCOLOGY LETTERS   11 ( 1 )   705 - 712   2016年1月

     詳細を見る

    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.

    DOI: 10.3892/ol.2015.3955

    Web of Science

    PubMed

    researchmap

  • Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection 査読

    Hideaki Kinugasa, Fusao Ikeda, Kouichi Takaguchi, Chizuru Mori, Takehiro Matsubara, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Shinichi Toyooka, Kazuhide Yamamoto

    ANTIVIRAL THERAPY   21 ( 1 )   37 - 44   2016年

     詳細を見る

    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 MEDICAL PRESS LTD  

    Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
    Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
    Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
    Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

    DOI: 10.3851/IMP2976

    Web of Science

    PubMed

    researchmap

  • Fever after lung radiofrequency ablation: Prospective evaluation of its incidence and associated factors 査読

    Yoshihisa Masaoka, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Junichi Soh, Katsuyuki Kiura, Susumu Kanazawa

    EUROPEAN JOURNAL OF RADIOLOGY   84 ( 11 )   2202 - 2209   2015年11月

     詳細を見る

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

    Purpose: To prospectively investigate the incidence of post-lung radiofrequency (RF) ablation fever as well as its associated factors, according to the grade of fever.
    Materials and Methods: A total of 56 patients who underwent 67 lung RF sessions were analyzed. Postablation fever (&gt;= 37.0 degrees C) was graded according to the common toxicity criteria of adverse events v. 4.0. Fever &gt;= 37.0 degrees C and &lt;38.0 C was defined as grade 0 fever. The 67 RF sessions were divided into two groups according to the presence of post-ablation fever, and the factors associated with fever were determined using univariate and multivariate analyses. Subsequently, the RF sessions accompanied by post-ablation fever were further divided into two groups according to the grade of fever (grade 0 vs. grade &gt;= 1), and the factors associated with the grade of fever were determined.
    Results: Grade 0, 1, and 2 fever accompanied 36 (54%), 11(16%), and 2 (3%) sessions, respectively. Post-ablation fever was significantly associated with larger ablated parenchymal volume (P=0.001) and development of pulmonary infiltration (P=0.004). Additionally, development of pulmonary infiltration (P=0.048) was also significantly and independently associated with higher grade of fever in the multivariate analysis.
    Conclusions: The incidences of grade 0, 1, and 2 post-ablation fever were 54%, 16%, and 3%, respectively. Larger ablated parenchymal volume and development of pulmonary infiltration were found to be associated with the development of post-ablation fever, with the latter being an independent factor associated with higher grade of fever. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.ejrad.2015.07.009

    Web of Science

    PubMed

    researchmap

  • DNA copy number gains in malignant pleural mesothelioma 査読

    Masashi Furukawa, Shinichi Toyooka, Tatsuro Hayashi, Hiromasa Yamamoto, Nobukazu Fujimoto, Junichi Soh, Shinsuke Hashida, Kazuhiko Shien, Hiroaki Asano, Keisuke Aoe, Kazunori Okabe, Harvey I. Pass, Kazunori Tsukuda, Takumi Kishimoto, Shinichiro Miyoshi

    Oncology Letters   10 ( 5 )   3274 - 3278   2015年11月

     詳細を見る

    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.

    DOI: 10.3892/ol.2015.3652

    Web of Science

    PubMed

    researchmap

  • Predicting pleural invasion using HRCT and F-18-FDG PET/CT in lung adenocarcinoma with pleural contact 査読

    Takashi Tanaka, Takayoshi Shinya, Shuhei Sato, Toshiharu Mitsuhashi, Koichi Ichimura, Junichi Soh, Shinichi Toyooka, Mitsumasa Kaji, Shinichiro Miyoshi, Susumu Kanazawa

    ANNALS OF NUCLEAR MEDICINE   29 ( 9 )   757 - 765   2015年11月

     詳細を見る

    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  

    To evaluate the relevance of high-resolution computed tomography (HRCT) findings and fluorine-18-fluorodeoxyglucose (F-18-FDG) uptake for risk stratification of visceral pleural invasion by lung adenocarcinoma.
    The HRCT findings and F-18-FDG uptake for lung adenocarcinomas with pleural contact on CT were retrospectively analyzed in 208 consecutive patients (94 females and 114 males; median age, 69.0 years) between January 2009 and December 2013, with institutional review board approval. The HRCT findings and maximum standardized uptake value (SUVmax) were recorded for each patient. Multivariate logistic regression was used for statistical analysis, and subgroup analysis stratified for whole tumor size a parts per thousand currency sign3 cm was also performed.
    Multivariate analysis showed that SUVmax [odds ratio (OR) 1.09, 95 % confidence interval (CI) 1.02-1.16, P = 0.014] and obtuse angle (OR 4.14, 95 % CI 1.97-8.74, P &lt; 0.001) were significant independent predictors for visceral pleural invasion. Receiver operating characteristic (ROC) analysis showed that, compared with the multivariate models [area under the curve (Az) 0.819-0.829], SUVmax alone (Az 0.815) was useful in predicting visceral pleural invasion. In the subgroup analysis, multivariate analysis showed that SUVmax (OR 1.29, 95 % CI 1.12-1.50, P = 0.001) and contact length with the pleura (OR 1.13, 95 % CI 1.05-1.22, P = 0.001) were significant independent predictors for visceral pleural invasion. ROC analysis showed that SUVmax alone (Az 0.844) showed similar diagnostic performance to the multivariate models (Az 0.845-0.857).
    SUVmax alone and multivariate models including SUVmax are useful for the prediction of visceral pleural invasion by lung adenocarcinoma.

    DOI: 10.1007/s12149-015-0999-x

    Web of Science

    PubMed

    researchmap

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

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

    CANCER SCIENCE   106 ( 10 )   1377 - 1384   2015年10月

     詳細を見る

    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.

    DOI: 10.1111/cas.12749

    Web of Science

    PubMed

    researchmap

  • Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model 査読

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

    CANCER SCIENCE   106 ( 10 )   1296 - 1302   2015年10月

     詳細を見る

    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  

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

    DOI: 10.1111/cas.12752

    Web of Science

    PubMed

    researchmap

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

    Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Masaomi Yamane, Shigeru Hattori, Kazuhiko Shien, Kentaroh Miyoshi, Seiichiro Sugimoto, Takahiro Oto, Shinichiro Miyoshi

    SURGERY TODAY   45 ( 9 )   1121 - 1126   2015年9月

     詳細を見る

    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  

    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.
    The medical records of patients who underwent a surgery for NSCLC after ChRT were reviewed.
    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.
    Our experience suggests that an extended sleeve lobectomy after induction ChRT is feasible, but careful patient selection and perioperative management are mandatory.

    DOI: 10.1007/s00595-014-1025-y

    Web of Science

    PubMed

    researchmap

  • Primary pulmonary melanoma: a report of two cases 査読

    Mototsugu Watanabe, Hiromasa Yamamoto, Shinsuke Hashida, Junichi Soh, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

    WORLD JOURNAL OF SURGICAL ONCOLOGY   13   274   2015年9月

     詳細を見る

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

    Malignant melanoma is a refractory malignancy with a dismal prognosis. It generally arises from the skin in most cases, and cases of primary pulmonary malignant melanoma are rare and often behave aggressively. We have treated two cases of localized primary pulmonary malignant melanoma using surgical resection. Pulmonary malignant melanomas often metastasize to the brain and liver; one of our cases exhibited metastasis to the cecum at about 8 months after surgery. Because cutaneous melanomas often carry activating mutations in the BRAF gene (V600E), we performed a BRAF mutational analysis using direct sequencing for both of these tumors arising from the lung. However, no BRAF mutations were detected. We detected a p53 mutation, which was thought to be a potential somatic mutation, in one of the two cases using a sequencing panel targeting 20 lung cancer-related genes. Although we also checked the expression of programmed death ligand 1 (PD-L1) on the surface of the tumor cells by immunohistochemical testing, neither of our two cases expressed PD-L1. Further molecular analyses may uncover the characteristics of primary pulmonary malignant melanomas.

    DOI: 10.1186/s12957-015-0695-2

    Web of Science

    PubMed

    researchmap

  • Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma 査読

    Junichi Soh, Shinichi Toyooka, Keitaro Matsuo, Hiromasa Yamamoto, Ignacio I. Wistuba, Stephen Lam, Kwun M. Fong, Adi F. Gazdar, Shinichiro Miyoshi

    ONCOLOGY LETTERS   10 ( 3 )   1775 - 1782   2015年9月

     詳細を見る

    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  

    Mutations or copy number gains (CNGs) of the EGFR and KRAS genes are representative alterations in lung adenocarcinomas that are individually associated with patient characteristics such as ethnicity, smoking status and gender. However, the effects of combinations of these genetic alterations have not been statistically examined. The present study analyzed previously examined lung adenocarcinoma cases in Asian (n=166) and non-Asian (n=136) individuals in whom all four EGFR and KRAS alterations had been studied. The polynomial logistic regression models were used following adjustment for gender and smoking status, and using patients without any type of EGFR/KRAS alterations as a reference. Between the two ethnic groups, EGFR CNGs (gEGFR) occurred more frequently than EGFR mutations (mEGFR) (46 vs. 38% in Asians; 21 vs. 10% in non-Asians), whereas KRAS mutations (mKRAS) were more frequent than KRAS CNGs (gKRAS) (13 vs. 7% and 35 vs. 4%, respectively). Additionally, gEGFR and gKRAS occurred significantly more frequently in respective mutant cases, and all EGFR alterations were almost exclusive of all KRAS alterations. The polynomial logistic regression models confirmed that all types of EGFR alterations were significantly more frequent among Asian individuals than among non-Asian individuals, independent of gender and smoking status (odds ratios, 2.36-6.67). KRAS alterations occurred less frequently among Asian individuals than among non-Asian individuals, although a significant difference was not detected. The present study results indicated that the EGFR and KRAS profiles, including mutations and CNGs, differ between Asian and non-Asian individuals with lung adenocarcinoma, suggesting that ethnicity strongly affects the molecular characteristics of lung adenocarcinoma.

    DOI: 10.3892/ol.2015.3414

    Web of Science

    PubMed

    researchmap

  • Simultaneous Multiple Preoperative Localizations of Small Pulmonary Lesions Using a Short Hook Wire and Suture System 査読

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   38 ( 4 )   971 - 976   2015年8月

     詳細を見る

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

    The aim of the study was to retrospectively evaluate simultaneous multiple hook wire placement outcomes before video-assisted thoracoscopic surgery (VATS).
    Thirty-eight procedures were performed on 35 patients (13 men and 22 women; mean age, 59.9 years) with 80 lung lesions (mean diameter 7.9 mm) who underwent simultaneous multiple hook wire placements for preoperative localizations. The primary endpoints were technical success, complications, procedure duration, and VATS outcome; secondary endpoints included comparisons between technical success rates, complication rates, and procedure durations of the 238 single-placement procedures performed. Complications were also evaluated.
    In 35 procedures including 74 lesions, multiple hook wire placements were technically successful; in the remaining three procedures, the second target placement was aborted because of massive pneumothorax after the first placement. Although complications occurred in 34 procedures, no grade 3 or above adverse event was observed. The mean procedure duration was 36.4 +/- A 11.8 min. Three hook wires dislodged during patient transport to the surgical suite. Seventy-four successfully marked lesions were resected. Six lesions without hook wires were successfully resected after detection by palpation with an additional mini-thoracotomy or using subtle pleural changes as a guide. The complication rates and procedure durations of multiple-placement procedures were significantly higher (P = 0.04) and longer (P &lt; 0.001) than those in the single-placement group, respectively, while the technical success rate was not significantly different (P = 0.051).
    Simultaneous multiple hook wire placements before VATS were clinically feasible, but increased the complication rate and lengthened the procedure time.

    DOI: 10.1007/s00270-014-1028-5

    Web of Science

    PubMed

    researchmap

  • TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells 査読

    Hiroki Otani, Hiromasa Yamamoto, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

    PLOS ONE   10 ( 6 )   e0129838   2015年6月

     詳細を見る

    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  

    TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The antitumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

    DOI: 10.1371/journal.pone.0129838

    Web of Science

    PubMed

    researchmap

  • Kissing-stents technique after living-donor lobar lung transplantation 査読

    Seiichiro Sugimoto, Takahiro Oto, Shinichi Toyooka, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   47 ( 6 )   1105 - 1106   2015年6月

     詳細を見る

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

    Stent placement has become common practice for bronchial stenosis (BS) after lung transplantation (LT). Especially, segmental BS after lobar LT requires a complex stenting technique. We describe a case of multiple segmental bronchial stenoses treated by the kissing-stents technique using balloon-expandable metallic stents after living-donor lobar LT. Based on the vascular kissing-stents technique, we simultaneously placed two stents, side by side, in the superior segmental bronchus and the basal segmental bronchus of the right transplanted lobar lung. This technique may represent a valuable option for complex segmental BS after lobar LT.

    DOI: 10.1093/ejcts/ezu314

    Web of Science

    PubMed

    researchmap

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

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Jiro Okami, Masahiko Higashiyama, Yoshihisa Kadota, Hajime Maeda, Makio Hayama, Masayuki Chida, Soichiro Funaki, Meinoshin Okumura, Shinichiro Miyoshi

    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY   20 ( 6 )   791 - 797   2015年6月

     詳細を見る

    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.

    DOI: 10.1093/icvts/ivv062

    Web of Science

    PubMed

    researchmap

  • Radiofrequency Ablation of Lung Metastases from Adenoid Cystic Carcinoma of the Head and Neck: Retrospective Evaluation of Nine Patients 査読

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Kazunori Nishizaki, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   26 ( 5 )   703 - 708   2015年5月

     詳細を見る

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

    Purpose: To retrospectively evaluate the outcomes of radiofrequency (RF) ablation of lung metastases from head and neck adenoid cystic carcinoma (ACC).
    Materials and Methods: Nine patients (two men and seven women; mean age, 61.6 y) with 45 lung metastases (mean diameter, 1.1 cm; range, 0.4-2.7 cm) from head and neck ACC underwent RF ablation in 30 sessions. Primary endpoints were technical success, technique effectiveness, and procedural complications. Secondary endpoints included overall survival (OS).
    Results: RF ablation was technically successful for all 45 metastases. The median tumor follow-up period was 37.1 months (range, 12.9-128.3 mo). Local progression occurred in six tumors, two of which were treated again and subsequently showed complete response. Major complications (pneumothorax requiring chest tube placement) occurred in five sessions (16.7%). The median patient follow-up period was 61.6 months (range, 20.5-134.5 mo). Two patients died of disease progression at 38.9 and 61.6 months after RF ablation, respectively, whereas the other seven remained alive at the end of the study. OS rates from the initial RF ablation were 100% at 3 years and 83.3% at 5 years (mean survival time, 106.4 mo). OS rates from the treatment of the primary site were 100% at 5 years and 62.5% at 10 years (mean survival time, 210.1 mo).
    Conclusions: Radiofrequency ablation is an acceptable and effective local treatment for lung metastases from head and neck ACC. However, further study is needed to evaluate its effect on patient survival.

    DOI: 10.1016/j.jvir.2014.11.040

    Web of Science

    PubMed

    researchmap

  • 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

    Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Hiroshi Date, Shinichiro Miyoshi

    Molecular and clinical oncology   3 ( 3 )   706 - 712   2015年5月

     詳細を見る

    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.

    DOI: 10.3892/mco.2015.509

    PubMed

    researchmap

  • Percutaneous Radiofrequency Ablation of Lung Cancer Presenting as Ground-Glass Opacity 査読

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Junichi Soh, Shinichi Toyooka, Katsuyuki Kiura, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   38 ( 2 )   409 - 415   2015年4月

     詳細を見る

    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  

    We retrospectively evaluated the outcomes of lung cancer patients presenting with ground-glass opacity (GGO) who received radiofrequency ablation (RFA).
    Sixteen patients (5 men and 11 women; mean age, 72.6 years) with 17 lung cancer lesions showing GGO (mean long axis diameter, 1.6 cm) underwent a total of 20 percutaneous computed tomography (CT) fluoroscopy-guided RFA sessions, including three repeated sessions for local progression. Lung cancer with GGO was defined as a histologically confirmed malignant pulmonary lesion with a GGO component accounting for &gt; 50 % of the lesion on high-resolution CT. Procedure outcomes were evaluated.
    There were no major complications. Pneumothorax occurred in 15 of 20 treatment sessions: 14 were asymptomatic, and 1 required chest tube placement but resolved satisfactorily within 48 h. Minor pulmonary hemorrhage occurred in two and mild pneumonitis in one. The median tumor follow-up period was 61.5 (range 6.1-96.6) months. The effectiveness rates of the primary and secondary techniques were 100 and 100 % at 1 year, 93.3 and 100 % at 2 years, and 78.3 and 92.3 % at 3 years, respectively. The median patient follow-up period was 65.6 (range 6.1-96.6) months. One patient died owing to recurrent other cancer 11.7 months after RFA, whereas the other 15 remained alive. Overall survival and disease-specific survival rates were 93.3 and 100 % at 1 year and 93.3 and 100 % at 5 years, respectively.
    RFA for lung cancer with GGO was safe and effective, and resulted in promising survival rates.

    DOI: 10.1007/s00270-014-0926-x

    Web of Science

    PubMed

    researchmap

  • EGFR Mutation Testing Practices within the Asia Pacific Region Results of a Multicenter Diagnostic Survey 査読

    Yasushi Yatabe, Keith M. Kerr, Ahmad Utomo, Pathmanathan Rajadurai, Van Khanh Tran, Xiang Du, Teh-Ying Chou, Ma. Luisa D. Enriquez, Geon Kook Lee, Jabed Iqbal, Shanop Shuangshoti, Jin-Haeng Chung, Koichi Hagiwara, Zhiyong Liang, Nicola Normanno, Keunchil Park, Shinichi Toyooka, Chun-Ming Tsai, Paul Waring, Li Zhang, Rose McCormack, Marianne Ratcliffe, Yohji Itoh, Masatoshi Sugeno, Tony Mok

    JOURNAL OF THORACIC ONCOLOGY   10 ( 3 )   438 - 445   2015年3月

     詳細を見る

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

    Introduction: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods.
    Methods: A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site.
    Results: Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%-32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme.
    Conclusions: In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.

    DOI: 10.1097/JTO.0000000000000422

    Web of Science

    PubMed

    researchmap

  • Pneumocephalus and Chylothorax Complicating Vertebrectomy for Lung Cancer 査読

    Seiichiro Sugimoto, Masato Tanaka, Ken Suzawa, Hitoshi Nishikawa, Shinichi Toyooka, Takahiro Oto, Toshifumi Ozaki, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   99 ( 4 )   1425 - 1428   2015年3月

     詳細を見る

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

    Pneumocephalus is a rare, but potentially fatal complication of thoracic surgery. We describe a case of successful management of pneumocephalus complicated by persistent chylothorax developing after en bloc partial vertebrectomy performed after induction chemoradiotherapy for lung cancer invading the spine. Surgical treatment should be considered for pneumocephalus complicated by any condition requiring persistent chest drainage. (C) 2015 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2014.05.098

    Web of Science

    PubMed

    researchmap

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

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

    ONCOLOGY REPORTS   33 ( 3 )   1499 - 1504   2015年3月

     詳細を見る

    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 G(2)/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 G(2)/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.

    DOI: 10.3892/or.2015.3735

    Web of Science

    PubMed

    researchmap

  • Long-Term Survival following Percutaneous Radiofrequency Ablation of Colorectal Lung Metastases 査読

    Yusuke Matsui, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Takeshi Nagasaka, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   26 ( 3 )   303 - 310   2015年3月

     詳細を見る

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

    Purpose: To retrospectively evaluate long-term survival outcomes of radiofrequency (RF) ablation of colorectal lung metastases and evaluate factors associated with improved survival.
    Materials and Methods: Eighty-four patients (46 male and 38 female; median age, 65 y) with 172 colorectal lung metastases (median size, 1.2 cm) underwent 113 RF ablation sessions. Thirteen patients had viable extrapulmonary recurrences at the time of RF ablation. The primary endpoint was patient survival. Prognostic factors associated with survival were determined by univariate and multivariate analyses. Secondary endpoints were local tumor progression and adverse events (per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).
    Results: During follow-up (median duration, 37.5 mo), 36 patients (42.9%) died. The estimated overall survival (OS) rates were 95.2%, 65.0%, and 51.6% at 1, 3, and 5 years, respectively (median OS time, 67.0 mo). Multivariate analysis revealed that a carcinoembryonic antigen (CEA) level of at least 5 ng/mL before RE ablation (P = .03) and the presence of viable extrapulmonary recurrences at the time of RF ablation (P = .001) were independent negative prognostic factors. The local tumor progression rate was 14.0% (24 of 172 tumors). Grade 3 adverse events were observed after two sessions (1.8%), and grade 415 adverse events were not observed.
    Conclusions: RF ablation of colorectal lung metastases provided favorable long-term survival With a low incidence of severe adverse events. Independent prognostic factors were a high CEA level before RF ablation and the presence of viable extrapulmonary recurrences at the time of RF ablation.

    DOI: 10.1016/j.jvir.2014.11.013

    Web of Science

    PubMed

    researchmap

  • Transfissural Route Used for Preoperative Localization of Small Pulmonary Lesions with a Short Hook Wire and Suture System 査読

    Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   38 ( 1 )   222 - 226   2015年2月

     詳細を見る

    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  

    We retrospectively evaluated the results of the transfissural route for preoperative localization with a short hook wire and suture system for video-assisted thoracoscopic surgery (VATS).
    Eleven patients with 11 tumors underwent CT-guided transfissural placement of a hook wire before VATS. This route was selected for all patients, because the distance between the tumor and interlobar fissure was much shorter than the required distance traversed using the conventional approach. Complications were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
    The hook wire was successfully placed using the transfissural route in all but one case. Of these ten successful placements, two tumors needed a second puncture for optimal placement, because the CT scan showed that the first hook wire was not properly placed in the lung. In one patient, we did not attempt replacement after the first placement was incorrect. In ten successful procedures, the mean distance traversed in the parenchyma of the unaffected lung lobe was 27.9 mm. The distance between the pleura and placed hook wire was significantly shorter than the estimated distance between the pleura and hook wire using the conventional route (mean 16.3 vs. 40.9 mm; P = 0.0002). Grade 1 adverse events occurred (11 pneumothoraxes and 4 pulmonary hemorrhages). No grade 2 or higher adverse event was observed.
    The transfissural route used for preoperative localization before VATS is useful for selected patients because this route may allow for more limited lung parenchyma resection.

    DOI: 10.1007/s00270-014-0862-9

    Web of Science

    PubMed

    researchmap

  • 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

    Shinichiro Miyoshi, Kazuhiko Shien, Shinichi Toyooka, Kentaroh Miyoshi, Hiromasa Yamamoto, Seiichiro Sugimoto, Junichi Soh, Makio Hayama, Masaomi Yamane, Takahiro Oto

    SURGERY TODAY   44 ( 11 )   2028 - 2036   2014年11月

     詳細を見る

    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.

    DOI: 10.1007/s00595-013-0772-5

    Web of Science

    PubMed

    researchmap

  • A New Human Lung Adenocarcinoma Cell Line Harboring the EML4-ALK Fusion Gene 査読

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

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   44 ( 10 )   963 - 968   2014年10月

     詳細を見る

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

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

    DOI: 10.1093/jjco/hyu110

    Web of Science

    PubMed

    researchmap

  • Percutaneous Radiofrequency Ablation for Pulmonary Metastases from Esophageal Cancer: Retrospective Evaluation of 21 Patients 査読

    Yusuke Matsui, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Toshihiro Iguchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   25 ( 10 )   1566 - 1572   2014年10月

     詳細を見る

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

    Purpose: To evaluate retrospectively Outcomes after radiofrequency (RF) ablation for pulmonary Metastases from esophageal cancer.
    Materials and Methods: This study included 21 consecutive patients who met inclusion. criteria (all men; mean age, 66.0 y) and had pulmonary metastases from esophageal cancer. There were 31 tumors (mean size, 1.7 cm) that Were treated with 27 planned ablation sessions. At the initial RF ablation sessions, 3 patients had viable extrapulmonary recurrences, and 18 patients had Viable recurrences confined to the lung. Primary study endpoints included patient survival and the determination of prognostic factors. Secondary endpoints included local efficacy and safety of the treatment. The log-rank test was used to identify prognostic factors. Adverse events Were evaluated according to,the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
    Results: Median follow-up duration after the initial RF ablation was 22.4 months (range, 6.2-76.1 mo). Estimated overall survival rates were 85.7% at 1 year, 54.8% at 2 years, and 38.4% at 3 years after the initial RF ablation session. The presence of viable extrapulmonary recurrences at the initial RF ablation session was an unfavorable prognostic factor (P &lt; .001). Local tumor progression was observed in 25.8% (8 of 31) of tumors and occurred 2.6-10.0 months (median, 4.8 mo) after RP ablation. Grade 3 adverse events occurred in 7.4% (2 of 27) of sessions, including pleural effusion requiring chest tube placement and pneumoderma requiring surgical intervention. No grade 4 or greater adverse events occurred.
    Conclusions: RF ablation is a promising treatment option for patients with pulmonary metastases from esophageal cancer.

    DOI: 10.1016/j.jvir.2014.06.030

    Web of Science

    PubMed

    researchmap

  • Drug Resistance to EGFR Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer 査読

    Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Shinichiro Miyoshi, Shinichi Toyooka

    ACTA MEDICA OKAYAMA   68 ( 4 )   191 - 200   2014年8月

     詳細を見る

    記述言語:英語   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.

    DOI: 10.18926/AMO/52785

    Web of Science

    PubMed

    researchmap

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

    Shinsuke Hashida, Junichi Soh, Shinichi Toyooka, Tomoaki Tanaka, Masashi Furukawa, Kazuhiko Shien, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Koichi Hagiwara, Shinichiro Miyoshi

    ONCOLOGY REPORTS   32 ( 1 )   145 - 152   2014年7月

     詳細を見る

    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 &lt;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.

    DOI: 10.3892/or.2014.3197

    Web of Science

    PubMed

    researchmap

  • A case of carcinoma showing thymus-like differentiation with a rapidly lethal course 査読

    Tomohiro Nogami, Naruto Taira, Shinichi Toyooka, Takehiro Tanaka, Taeko Mizoo, Takayuki Iwamoto, Tadahiko Shien, Junichi Soh, Shinichiro Miyoshi, Hiroyoshi Doihara

    Case Reports in Oncology   7 ( 3 )   840 - 844   2014年4月

     詳細を見る

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

    A 55-year-old woman underwent a total thyroidectomy for carcinoma showing thymus-like differentiation (CASTLE). The patient was referred to our hospital after the tumor was found to have directly invaded the cervical esophagus and the entire circumference of the trachea. A total thyroidectomy was performed, followed by end-to-end anastomosis of the trachea, suprahyoid release and dissection of bilateral pulmonary ligaments. No major complications, including anastomotic dehiscence or stenosis, were observed. The patient experienced some swallowing disturbances and hoarseness during the perioperative period but fully recovered. Radiotherapy to the neck was performed as an adjuvant therapy. Eleven months after surgery, lower back pain and right leg numbness developed and led to gait inability. Multiple lung and bone recurrences were observed, but no local recurrence. Palliative radiotherapy to the bone metastasis was performed. The patient died of pleural metastasis 14 months after the initial diagnosis of CASTLE.

    DOI: 10.1159/000370306

    Scopus

    PubMed

    researchmap

  • Massive Subcutaneous and Mediastinal Emphysema with Little Pneumothorax Treated by Surgery after Pulmonary Radiofrequency Ablation 査読

    Yusuke Konishi, Hiromasa Yamamoto, Takao Hiraki, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa, Shinichiro Miyoshi

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   37 ( 2 )   548 - 551   2014年4月

     詳細を見る

    記述言語:英語   出版者・発行元:SPRINGER  

    DOI: 10.1007/s00270-013-0753-5

    Web of Science

    PubMed

    researchmap

  • Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations 査読

    Adi Gazdar, Linda Robinson, Dwight Oliver, Chao Xing, William D. Travis, Junichi Soh, Shinichi Toyooka, Lori Watumull, Yang Xie, Kemp Kernstine, Joan H. Schiller

    JOURNAL OF THORACIC ONCOLOGY   9 ( 4 )   456 - 463   2014年4月

     詳細を見る

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

    Introduction: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance.
    Methods: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals).
    Results: T790M germline mutations occurred in approximately 1% of non-small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06).
    Conclusion: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.

    DOI: 10.1097/JTO.0000000000000130

    Web of Science

    PubMed

    researchmap

  • Wedge Resection of the Bronchial Corner at the Bifurcation of the Lobar Bronchi for a Low-Grade Bronchial Tumor 査読

    Hiromasa Yamamoto, Shinichi Toyooka, Shinichiro Miyoshi

    THORACIC AND CARDIOVASCULAR SURGEON   62 ( 2 )   181 - 183   2014年3月

     詳細を見る

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

    We experienced a case of wedge resection of the bronchus for a bronchial carcinoid of the left upper bronchus located near the bifurcation of the upper and lower lobar bronchi. Bronchial resection was performed longitudinally including the bronchial corner of the upper and lower lobar bronchi, and the length of resected bronchus from the bronchial corner to distant sites was made nearly equal. The presented procedure is useful as a parenchyma-preserving bronchial resection.

    DOI: 10.1055/s-0032-1330924

    Web of Science

    PubMed

    researchmap

  • Asymptomatic but Functional Paraganglioma of the Posterior Mediastinum 査読

    Ken Suzawa, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   97 ( 3 )   1077 - 1080   2014年3月

     詳細を見る

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

    A 72-year-old woman was referred to our hospital because of a posterior mediastinal tumor. On the basis of detailed imaging tests, including I-123-metaiodobenzylguanidine single photon emission computed tomography-computed tomography, and elevated values of catecholamines in the plasma and urine, the tumor was diagnosed as a functional mediastinal paraganglioma even in the absence of symptoms. After preoperative blood pressure control, surgical resection was performed. During the operation, the systemic blood pressure increased transiently as a result of surgical manipulation of the tumor. Soon after the tumor was removed, the patient conversely experienced hypotension. The postoperative course was uneventful, and pathologic diagnosis revealed a paraganglioma. (C) 2014 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2013.06.100

    Web of Science

    PubMed

    researchmap

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

    Seiichiro Sugimoto, Shinichi Toyooka, Norichika Iga, Masashi Furukawa, Ryujiro Sugimoto, Kazuhiko Shien, Hitoshi Nishikawa, Junichi Soh, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    SURGERY TODAY   44 ( 3 )   540 - 545   2014年3月

     詳細を見る

    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  

    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.
    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.
    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.
    Our study suggests that the LigaSure system may be superior to conventional electrocautery, indicating its clinical usefulness for non-anatomic pulmonary resection.

    DOI: 10.1007/s00595-013-0545-1

    Web of Science

    PubMed

    researchmap

  • Detection of airway ischaemic damage after lung transplantation by using autofluorescence imaging bronchoscopy 査読

    Norichika Iga, Takahiro Oto, Masanori Okada, Masaaki Harada, Hitoshi Nishikawa, Kentaroh Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   45 ( 3 )   509 - 513   2014年3月

     詳細を見る

    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: Airway complications related to ischaemia are a major cause of morbidity after lung transplantation. Early detection of airway ischaemia and optimal management of the anastomotic site could reduce the risk of airway complications. Autofluorescence imaging (AFI) bronchoscopy has been increasingly recognized as an effective technique for detecting abnormal mucosal thickening. The aim of this study was to investigate whether AFI bronchoscopy can facilitate the detection of airway ischaemic damage in lung transplant patients.
    METHODS: Twenty Landrace pigs were used to create a tracheal autotransplantation model. A four-ring length of trachea was excised and implanted orthotopically. The tracheal autograft was observed on postoperative days 0, 2, 4 and 7 with AFI bronchoscopy. The extent and origin of graft autofluorescence were examined using histology and measured according to fluorescence intensity.
    RESULTS: The lesions on the tracheal autografts appeared as bright green fluorescence on AFI bronchoscopy. On confocal fluorescence microscopy, high-intensity green fluorescence was observed in the elastin fibre layer of the submucosa. The fluorescence intensity of elastin was significantly higher in the graft showing fluorescence than the graft that did not show fluorescence and that at the control site.
    CONCLUSIONS: Bright green fluorescence was seen in an elastin fibre layer in the submucosa, which was likely a result of epithelial sloughing. There is a close relationship between the bright green fluorescence pattern observed using AFI bronchoscopy and airway ischaemic damage. We conclude that AFI bronchoscopy may detect airway ischaemic damage after lung transplantation.

    DOI: 10.1093/ejcts/ezt437

    Web of Science

    PubMed

    researchmap

  • Preclinical Evaluation of MicroRNA-34b/c Delivery for Malignant Pleural Mesothelioma 査読

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

    ACTA MEDICA OKAYAMA   68 ( 1 )   23 - 26   2014年2月

     詳細を見る

    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.

    DOI: 10.18926/AMO/52140

    Web of Science

    PubMed

    researchmap

  • Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer 査読

    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, Shinichi Toyooka

    PLOS ONE   9 ( 2 )   e87900   2014年2月

     詳細を見る

    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 nonmalignant 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.

    DOI: 10.1371/journal.pone.0087900

    Web of Science

    PubMed

    researchmap

  • Novel Germline Mutation in the Transmembrane Domain of HER2 in Familial Lung Adenocarcinomas 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, Shinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

    JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE   106 ( 1 )   djt338   2014年1月

     詳細を見る

    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.

    DOI: 10.1093/jnci/djt338

    Web of Science

    PubMed

    researchmap

  • Surgical Resection of a Massive Primary Mediastinal Liposarcoma Using Clamshell Incision Combined with Lower Median Sternotomy: Report of a Case 査読

    Yutaka Hirano, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20   606 - 608   2014年

     詳細を見る

    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  

    We experienced a case of massive mediastinal liposarcoma expanding to the bilateral pleural cavities. Preoperative positron emission tomography-computed tomography scan showed that the uptake of F-18-fluorodeoxyglucose (FDG) into the tumor was slight for its size. Clamshell incision together with lower median sternotomy provided the excellent visualization and the complete resection of the tumor. The surgical resection should be performed even for a massive liposarcoma, especially if the uptake of F-FDG into the tumor is low, as complete surgical resection is the only definitive treatment for liposarcoma.

    DOI: 10.5761/atcs.cr.13.02263

    Web of Science

    PubMed

    researchmap

  • 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

    Hiroyuki Tao, Kazuhiko Shien, Junichi Soh, Eisuke Matsuda, Shinichi Toyooka, Kazunori Okabe, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20 ( 6 )   980 - 986   2014年

     詳細を見る

    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 sub-populations 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.

    DOI: 10.5761/atcs.oa.13-00237

    Web of Science

    PubMed

    researchmap

  • Thoracoscopic Lobectomy as Salvage Surgery for Local Recurrence of Non-Small Cell Lung Cancer after Carbon Ion Radiotherapy in an Initially Operable Patient 査読

    Seiichiro Sugimoto, Shinichi Toyooka, Ken Suzawa, Kouichi Ichimura, Osamu Fujii, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20   501 - 504   2014年

     詳細を見る

    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  

    Carbon ion radiotherapy (CIRT) for patients with early-stage non-small cell lung cancer (NSCLC) has recently provided favorable local control with very few toxic reactions. Because CIRT for NSCLC has been mostly performed for elderly or inoperable patients, salvage surgery for NSCLC after CIRT has rarely been reported. We describe a case of complete thoracoscopic right upper lobectomy with mediastinal lymphadenectomy performed as salvage surgery for local recurrence of stage IA NSCLC after CIRT in an initially operable patient who had refused surgery 27 months previously. Pleural adhesions caused by CIRT were localized to the pulmonary apex and the central pulmonary structures were intact at the time of the salvage surgery, which allowed us to successfully perform thoracoscopic lobectomy without any complications. Thus, salvage surgery for NSCLC after CIRT may be feasible in an initially operable patient, as CIRT appears to be unlikely to cause any difficulties in the salvage surgery.

    DOI: 10.5761/atcs.cr.13-00223

    Web of Science

    PubMed

    researchmap

  • Adult Mesenchymal Hamartoma of the Chest Wall: Report of a Case 査読

    Hiromasa Yamamoto, Junichi Soh, Koichi Ichimura, Yusuke Konishi, Shinichi Toyooka, Takayuki Nojima, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   20   663 - 665   2014年

     詳細を見る

    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  

    We present an adult case of the chest wall tumor, which was accidentally pointed out by a medical checkup. Surgical resection was performed for the tumor, as preoperative biopsy of the tumor suggested the possibility of malignancy. Postoperative pathological examination revealed the diagnosis of mesenchymal hamartoma of the chest wall, which usually occurs in early infancy and childhood. Immunohistochemical staining for Sox9 was positive for chondrocytes and partially positive for spindle tumor cells. It is considered that the present case was not pointed out until the patient became an adult, because the tumor was relatively small and thus asymptomatic.

    DOI: 10.5761/atcs.cr.13-00225

    Web of Science

    PubMed

    researchmap

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

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

    LUNG CANCER   82 ( 3 )   485 - 490   2013年12月

     詳細を見る

    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 degrees 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 &lt; 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2013.09.017

    Web of Science

    PubMed

    researchmap

  • Bleeding into a pulmonary cyst caused by pulmonary radiofrequency ablation 査読

    Ryotaro Kishi, Hidefumi Mimura, Takao Hiraki, Hideo Gobara, Mayu Uka, Shinichi Toyooka, Susumu Kanazawa

    Journal of Vascular and Interventional Radiology   24 ( 7 )   1069 - 1071   2013年7月

     詳細を見る

  • Different sizes of centrilobular ground-glass opacities in chest high-resolution computed tomography of patients with pulmonary veno-occlusive disease and patients with pulmonary capillary hemangiomatosis 査読

    Aya Miura, Satoshi Akagi, Kazufumi Nakamura, Keiko Ohta-Ogo, Katsushi Hashimoto, Satoshi Nagase, Kunihisa Kohno, Kengo Kusano, Aiko Ogawa, Hiromi Matsubara, Shinichi Toyooka, Takahiro Oto, Aiji Ohtsuka, Tohru Ohe, Hiroshi Ito

    CARDIOVASCULAR PATHOLOGY   22 ( 4 )   287 - 293   2013年7月

     詳細を見る

    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: Centrilobular ground-glass opacity (GGO) is one of the characteristic findings in chest high-resolution computed tomography (HRCT) of patients with pulmonary veno-occlusive disease (PVOD) and patients with pulmonary capillary hemangiomatosis (PCH). However, clinical differential diagnosis of these two diseases is difficult and has not been established. In order to clarify their differences, we compared the sizes of GGOs in chest HRCT and the sizes of capillary assemblies in pulmonary vascular casts between patients diagnosed pathologically with PVOD and PCH.
    Methods: We evaluated chest HRCT images for four patients with idiopathic pulmonary arterial hypertension (IPAH), three patients with PVOD and three patients with PCH, and we evaluated pulmonary vascular casts of lung tissues obtained from those patients at lung transplantation or autopsy.
    Results: Centrilobular GGOs in chest HRCT were observed in patients with PVOD and patients with PCH but not in patients with IPAH. We measured the longest diameter of the GGOs. The size of centrilobular GGOs was significantly larger in patients with PCH than in patients with PVOD (5.60 +/- 1.43 mm versus 2.51 +/- 0.79 mm, P&lt;.01). We succeeded in visualization of the 3-dimensional structures of pulmonary capillary vessels obtained from the same patients with PVOD and PCH undergoing lung transplantation or autopsy and measured the diameters of capillary assemblies. The longest diameter of capillary assemblies was also significantly larger in patients with PCH than in patients with PVOD (5.44 +/- 1.71 mm versus 3.07 +/- 1.07 mm, P&lt;.01).
    Conclusion: Measurement of the sizes of centrilobular GGOs in HRCT is a simple and useful method for clinical differential diagnosis of PVOD and PCH. (C) 2013 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.carpath.2012.12.002

    Web of Science

    PubMed

    researchmap

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

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

    ONCOLOGY REPORTS   29 ( 6 )   2169 - 2174   2013年6月

     詳細を見る

    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.

    DOI: 10.3892/or.2013.2351

    Web of Science

    PubMed

    researchmap

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

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

    CANCER RESEARCH   73 ( 10 )   3051 - 3061   2013年5月

     詳細を見る

    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. Cancer Res; 73(10); 3051-61. (C) 2013 AACR.

    DOI: 10.1158/0008-5472.CAN-12-4136

    Web of Science

    PubMed

    researchmap

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

    Shinichi Toyooka, Junichi Soh, Kazuhiko Shien, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Hiroshi Date, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   43 ( 3 )   568 - 572   2013年3月

     詳細を見る

    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  

    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.
    The medical records of NSCLC patients who underwent surgery after receiving CRT were reviewed. The relationships between anastomotic complications and clinicopathological factors were examined.
    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).
    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.

    DOI: 10.1093/ejcts/ezs323

    Web of Science

    PubMed

    researchmap

  • Silenced Expression of NFKBIA in Lung Adenocarcinoma Patients with a Never-smoking History 査読

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

    ACTA MEDICA OKAYAMA   67 ( 1 )   19 - 24   2013年2月

     詳細を見る

    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 kappa-light polypeptide gene enhancer in B cells inhibitor alpha (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.

    DOI: 10.18926/AMO/49253

    Web of Science

    PubMed

    researchmap

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

    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 - 140   2013年1月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3892/or.2012.2087

    Web of Science

    PubMed

    researchmap

  • Contralateral pneumothorax in bullous lung after pneumonectomy: report of two cases. 査読

    Masashi Furukawa, Takahiro Oto, Shinichi Toyooka, Junichi Soh, Masaomi Yamane, Shinichiro Miyoshi

    General thoracic and cardiovascular surgery   61 ( 1 )   35 - 7   2013年1月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Contralateral pneumothorax after pneumonectomy is potentially fatal. We experienced two cases of right pneumothorax after left pneumonectomy in which the patients had multiple bullae in the right lung. Case 1 involved a 49-year-old man with non-small-cell lung cancer (NSCLC) who underwent left pneumonectomy after induction chemoradiotherapy. Eleven months after surgery, he had pneumothorax and was treated with chest tube drainage and pleurodesis. He was discharged but died of recurrent pneumothorax 1 month later. Case 2 involved a 57-year-old man with NSCLC who had left pneumonectomy. Five months after surgery, he had pneumothorax and was treated with chest tube drainage. Because of prolonged air leak, ligation of the ruptured bulla was performed with a percutaneous cardiopulmonary support system on standby. No pneumothorax recurrence occurred for 2 years. Although management of pneumothorax after pneumonectomy is challenging, surgical intervention may be useful and necessary especially when there is high risk of recurrent pneumothorax.

    DOI: 10.1007/s11748-012-0112-5

    PubMed

    researchmap

  • The impact of prolonged cold preservation on the graft function and gene expression levels in an experimental lung transplantation model 査読

    Osamu Yoshida, Masaomi Yamane, Sumiharu Yamamoto, Mikio Okazaki, Shinichi Toyooka, Takahiro Oto, Yoshifumi Sano, Shinichiro Miyoshi

    SURGERY TODAY   43 ( 1 )   81 - 87   2013年1月

     詳細を見る

    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  

    Ischemia reperfusion injury (IRI) remains a significant cause of morbidity and mortality after lung transplantation. Early growth response-1 (EGR1) drives the expression of inflammatory mediators and has an important role in IRI. We hypothesized that the severe IRI caused by a long preservation induces a specific expression pattern of EGR1 and its target genes which would correlate with the lung graft function.
    SD rat lungs were preserved at 4 A degrees C for 3 or 18 h, then transplanted and reperfused. Pulmonary grafts were evaluated for the blood gas oxygenation and pathological findings. The intra-graft mRNA levels of EGR1 and its downstream target genes were measured by real-time PCR. A Western blotting analysis of the EGR1 expression was used to validate the changes in the protein level.
    There was upregulation of EGR1, MIP-2 and PAI-1 when there was prolonged hypothermic preservation. The expression levels of MIP-2 and PAI-1 were observed to increase for up to 4 h in the 18 h preserved lungs. There were no differences in the expression levels of IL-1 beta and ICAM-1 between the lungs subjected to short and long periods of ischemia.
    Our data showed that prolonged hypothermic graft preservation deteriorates the pulmonary graft function, which was associated with the induction of EGR1 and its downstream target genes, which may aggravate IRI following lung transplantation.

    DOI: 10.1007/s00595-012-0234-5

    Web of Science

    PubMed

    researchmap

  • Retraction: DNA methylation profiles of lymphoid and hematopoietic malignancies. 査読

    Takahashi T, Shivapurkar N, Reddy J, Shigematsu H, Miyajima K, Suzuki M, Toyooka S, Zöchbauer-Müller S, Drach J, Parikh G, Zheng Y, Feng Z, Kroft SH, Timmons C, McKenna RW, Gazdar AF

    Clinical cancer research : an official journal of the American Association for Cancer Research   19 ( 1 )   307   2013年1月

  • Bronchoplasty to adjust mismatches in the proximal and distal bronchial stumps during bronchial sleeve resection of the left lower lobe and lingular division. 査読

    Toyooka S, Soh J, Oto T, Miyoshi S

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery   43 ( 1 )   182 - 183   2013年1月

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

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

    Molecular and clinical oncology   1 ( 1 )   185 - 189   2013年1月

     詳細を見る

    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

    PubMed

    researchmap

  • 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

    Shinichi Toyooka, Katsuyuki Kiura, Kazuhiko Shien, Kuniaki Katsui, Katsuyuki Hotta, Susumu Kanazawa, Hiroshi Date, Shinichiro Miyoshi

    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY   15 ( 6 )   954 - 960   2012年12月

     詳細を見る

    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.

    DOI: 10.1093/icvts/ivs412

    Web of Science

    PubMed

    researchmap

  • Impact of age on epidermal growth factor receptor mutation in lung cancer 査読

    Tsuyoshi Ueno, Shinichi Toyooka, Kenichi Suda, Junichi Soh, Yasushi Yatabe, Shinichiro Miyoshi, Keitaro Matsuo, Tetsuya Mitsudomi

    LUNG CANCER   78 ( 3 )   207 - 211   2012年12月

     詳細を見る

    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  

    Aging is one of the best, but rarely referred, risk factors for various types of cancer including lung cancer, because age could be a surrogate for accumulation of genetic events in cancers. Smoking inversely associates with the presence of epidermal growth factor receptor (EGFR) mutation in lung cancer, but its strong confounding with age and sex makes it difficult to evaluate sole impact of age. To clarify an impact of age on EGFR mutation, we conducted a cross-sectional study based on data of 1262 lung cancer patients. The associations between EGFR mutation and age, considering sex, smoking and histology, were evaluated using logistic regression models. In multivariate analysis, we found a significant increase of EGFR mutation prevalence by increase of age (p-trend = 0.0004). Consistent trend was observed among never-smoking females (p-trend = 0.011) and never-smoking males also showed similar trend although not significant. These were consistently observed when we limit the subject to those with adenocarcinoma. In conclusion, age independently associates with EGFR mutation among lung cancer. Positive association between EGFR mutation and age among never-smokers regardless of sex might indicate that EGFR mutation occurs cumulatively by unidentified internal/external factors other than smoking. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2012.09.006

    Web of Science

    PubMed

    researchmap

  • MicroRNA miR-34b/c Enhances Cellular Radiosensitivity of Malignant Pleural Mesothelioma Cells 査読

    Yuho Maki, Hiroaki Asano, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Kuniaki Katsui, Tsuyoshi Ueno, Kazuhiko Shien, Takayuk Muraoka, Norimitsu Tanaka, Hiromasa Yamamoto, Kazunori Tsukuda, Takumi Kishimoto, Susumu Kanazawa, Shinichiro Miyoshi

    ANTICANCER RESEARCH   32 ( 11 )   4871 - 4875   2012年11月

     詳細を見る

    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-34b1c (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 his-tone H2AX (gamma H2AX) foci assay, cell-cycle analysis, and western blotting. Results: The clonogenic survival assay revealed that miR-34b/c radiosensitized MPM cells. gamma H2AX 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 416, 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.

    Web of Science

    PubMed

    researchmap

  • Knockdown of the Epidermal Growth Factor Receptor Gene to Investigate Its Therapeutic Potential for the Treatment of Non-Small-Cell Lung Cancers 査読

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

    CLINICAL LUNG CANCER   13 ( 6 )   488 - 493   2012年11月

     詳細を見る

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

    Epidermal growth factor receptor (EGFR) can be a therapeutic target in non-small-cell lung cancer with EGFR activation, even if EGFR mutation is not present. By contrast, EGFR cannot be a target when EGFR is not activated, even if EGFR protein is expressed. For acquired resistant cells to EGFR-tyrosine kinase inhibitors, EGFR can be a target if those cells depend on EGFR and are not driven by other oncogenes.
    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

    Web of Science

    PubMed

    researchmap

  • Basal segmental auto-transplantation after pneumonectomy for advanced central lung cancer 査読

    Takahiro Oto, Katsuyuki Kiura, Shinichi Toyooka, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   42 ( 3 )   579 - 581   2012年9月

     詳細を見る

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

    In patients with central lung cancer that extensively involves the bronchus/pulmonary artery, a double-sleeve lobectomy is often difficult to perform. We describe a case of post-pneumonectomy basal segmental auto-transplantation using a lung preservation technique that uses cold low-potassium dextran glucose solution to protect the lung graft from ischaemia-reperfusion injury during the ex situ division of the segmental graft and the pathological investigations for the clearance of the surgical margins. A right basal segmental auto-transplantation procedure was performed in a patient with stage-IIIA squamous cell lung cancer. This technique could allow extensive pulmonary resection while minimizing the loss of pulmonary reserve.

    DOI: 10.1093/ejcts/ezs224

    Web of Science

    PubMed

    researchmap

  • Intrathoracic irrigation with arbekacin for methicillin-resistant Staphylococcus aureus empyema following lung resection 査読

    Tsuyoshi Ueno, Shinichi Toyooka, Junichi Soh, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY   15 ( 3 )   437 - 441   2012年9月

     詳細を見る

    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: Empyema is a well-known complication following lung resection. In particular, empyema caused by methicillin-resistant Staphylococcus aureus (MRSA) is difficult to treat. Here, we present our experience of MRSA empyema treated with local irrigation using arbekacin.
    METHODS: Six patients consisted of 4 males and 2 females with an average age of 65.7 years. They developed MRSA empyema following lung resection and were treated at our institution between 2007 and 2011. Cases comprised four primary and one metastatic lung cancer, and 1 patient was a living lung transplantation donor. The surgical procedure consisted of four lobectomies, one segmentectomy and one wedge resection. After diagnosis of MRSA empyema, anti-MRSA drugs were administered intravenously in all cases. In addition, arbekacin irrigation at a dose of 100 mg dissolved in saline was performed after irrigation with saline only.
    RESULTS: The average number of postoperative days for the diagnosis of MRSA empyema was 13 (range 4-19). The period of irrigation ranged from 6 to 46 days. Arbekacin irrigation did not induce nephrotoxicity or other complications, and no bacteria resistant to arbekacin was detected in the thoracic cavity. We re-operated on 1 case because he had pulmonary fistula and severe wound infection. At the time of removing the thoracic catheter, MRSA in the pleural effusion disappeared completely in 3 patients. The period until MRSA concentration in the pleural effusion became negative after starting arbekacin irrigation ranged from 4 to 9 days. In the remaining cases, in which MRSA did not disappear, the catheter was removed because of no inflammatory reaction after stopping irrigation and clamping the catheters. All patients were discharged from our institution without thoracic catheterization and no patients had relapsed during the follow-up period ranging from 6 to 44 months.
    CONCLUSIONS: Irrigation of the thoracic cavity with arbekacin proved to be an effective, safe and readily available method for treating MRSA empyema following lung resection.

    DOI: 10.1093/icvts/ivs285

    Web of Science

    PubMed

    researchmap

  • Takotsubo cardiomyopathy associated with pulmonary resections after induction chemoradiotherapy for non-small cell lung cancer. 査読

    Shinichi Toyooka, Satoshi Akagi, Masashi Furukawa, Kazufumi Nakamura, Junichi Soh, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

    General thoracic and cardiovascular surgery   60 ( 9 )   599 - 602   2012年9月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Takotsubo cardiomyopathy (TTC), also known as transient left ventricular (LV) apical ballooning syndrome, is characterized by transient LV dysfunction. We present the case of a 72-year-old man who was diagnosed as having TTC after surgery for two lung tumors. The patient was treated with induction chemoradiotherapy (CRT) followed by pulmonary resections for double primary non-small cell lung cancers (NSCLC): cT4N1M0 disease in the right lung and cT2N0M0 in the left lung. Induction CRT was performed. A right upper lobectomy was initially performed, and a left upper divisionectomy was subsequently performed. At 3 days after the second surgery, he developed dyspnea and general fatigue accompanied by a T-wave inversion on electrocardiography (ECG). An echocardiogram revealed akinesis at the apex with a 30 % ejection fraction. He was diagnosed as having TTC and recovered with supportive care. This case is the first report of TTC occurring after tri-modality therapy for NSCLC.

    DOI: 10.1007/s11748-012-0058-7

    PubMed

    researchmap

  • Resection of the entire first rib for fibrous dysplasia using a combined posterior-transmanubrial approach 査読

    Masashi Furukawa, Junichi Soh, Shinichi Toyooka, Toshifumi Ozaki, Shinichiro Miyoshi

    General Thoracic and Cardiovascular Surgery   60 ( 9 )   584 - 586   2012年9月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 27-year-old woman presented with pain of the left anterior chest of 2-year duration. Chest X-ray revealed a mass in the upper-left lung field and chest computed tomography (CT) a 6-cm first-rib tumor. CT-guided biopsy was performed and the tumor diagnosed as fibrous dysplasia. Because of continued pain, surgery was deemed necessary. Surgery began with the use of the posterior approach in the prone position to expose the first thoracic vertebra and detach the first rib at the costotransverse joint. After transitioning to the spine position, the transmanubrial approach was used to resect the tumor en bloc with the left first rib. Histological examination revealed the tumor to be fibrous dysplasia. Postoperative recovery was uneventful. The outcomes of this case suggest that the combined posterior-transmanubrial approach described here is a safe, successful approach for first-rib resection of a space-occupying tumor that yields good cosmetic results. © The Japanese Association for Thoracic Surgery 2012.

    DOI: 10.1007/s11748-012-0044-0

    Scopus

    PubMed

    researchmap

  • Influence of Radiofrequency Ablation of Lung Cancer on Pulmonary Function 査読

    Akihiro Tada, Takao Hiraki, Toshihiro Iguchi, Hideo Gobara, Hidefumi Mimura, Shinichi Toyooka, Katsuyuki Kiura, Toshihide Tsuda, Toshiharu Mitsuhashi, Susumu Kanazawa

    CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY   35 ( 4 )   860 - 867   2012年8月

     詳細を見る

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

    The purpose of this study was to evaluate altered pulmonary function retrospectively after RFA.
    This retrospective study comprised 41 ablation sessions for 39 patients (22 men and 17 women; mean age, 64.8 years). Vital capacity (VC) and forced expiratory volume in 1 s (FEV1) at 1 and 3 months after RFA were compared with the baseline (i.e., values before RFA). To evaluate the factors that influenced impaired pulmonary function, univariate analysis was performed by using multiple variables. If two or more variables were indicated as statistically significant by univariate analysis, these variables were subjected to multivariate analysis to identify independent factors.
    The mean VC and FEV1 before RFA and 1 and 3 months after RFA were 3.04 and 2.24 l, 2.79 and 2.11 l, and 2.85 and 2.13 l, respectively. The values at 1 and 3 months were significantly lower than the baseline. Severe pleuritis after RFA was identified as the independent factor influencing impaired VC at 1 month (P = 0.003). For impaired FEV1 at 1 month, only severe pleuritis (P = 0.01) was statistically significant by univariate analysis. At 3 months, severe pleuritis (VC, P = 0.019; FEV1, P = 0.003) and an ablated parenchymal volume a parts per thousand yen20 cm(3) (VC, P = 0.047; FEV1, P = 0.038) were independent factors for impaired VC and FEV1.
    Pulmonary function decreased after RFA. RFA-induced severe pleuritis and ablation of a large volume of marginal parenchyma were associated with impaired pulmonary function.

    DOI: 10.1007/s00270-011-0221-z

    Web of Science

    PubMed

    researchmap

  • Induction Chemoradiotherapy Followed by Surgical Resection for Clinical T3 or T4 Locally Advanced Non-Small Cell Lung Cancer 査読

    Kazuhiko Shien, Shinichi Toyooka, Katsuyuki Kiura, Keitaro Matsuo, Junichi Soh, Masaomi Yamane, Takahiro Oto, Mitsuhiro Takemoto, Hiroshi Date, Shinichiro Miyoshi

    ANNALS OF SURGICAL ONCOLOGY   19 ( 8 )   2685 - 2692   2012年8月

     詳細を見る

    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  

    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).
    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.
    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).
    Our study indicates that trimodality therapy is highly effective in patients with cT3-4 LA-NSCLC.

    DOI: 10.1245/s10434-012-2302-x

    Web of Science

    PubMed

    researchmap

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

    Kadoaki Ohashi, Lecia V. Sequist, Maria E. Arcila, Teresa Moran, Juliann Chmielecki, Ya-Lun Lin, Yumei Pan, Lu Wang, Elisa de Stanchina, Kazuhiko Shien, Keisuke Aoe, Shinichi Toyooka, Katsuyuki Kiura, Lynnette Fernandez-Cuesta, Panos Fidias, James Chih-Hsin Yang, Vincent A. Miller, Gregory J. Riely, Mark G. Kris, Jeffrey A. Engelman, Cindy L. Vnencak-Jones, Dora Dias-Santagata, Marc Ladanyi, William Pao

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   109 ( 31 )   E2127 - E2133   2012年7月

     詳細を見る

    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.

    DOI: 10.1073/pnas.1203530109

    Web of Science

    PubMed

    researchmap

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

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

    LUNG CANCER   77 ( 1 )   162 - 167   2012年7月

     詳細を見る

    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 (449% 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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2012.02.006

    Web of Science

    PubMed

    researchmap

  • A Case of Delayed Massive Hemothorax Caused by the Rupture of a Pulmonary Artery Pseudoaneurysm after Radiofrequency Ablation of Lung Tumors 査読

    Junichi Soh, Shinichi Toyooka, Hideo Gobara, Takao Hiraki, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Shinichiro Miyoshi

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   42 ( 7 )   646 - 649   2012年7月

     詳細を見る

    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  

    Radiofrequency ablation has been applied as a minimally invasive therapy for the local control of lung tumors, including primary and metastatic neoplasms. Hemorrhagic complications after radiofrequency ablation can usually be treated conservatively, but such complications can be massive and fatal in some cases. In this paper, we report the rare case of delayed massive hemothrax caused by the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation that was treated using transcatheter coil embolization followed by a left lower lobectomy. A 75-year-old woman underwent radiofrequency ablation for the treatment of a metastatic lung tumor in the left lower lobe arising from a colorectal carcinoma located close to a branch of the pulmonary artery. Thirty-six hours later, hemothorax and hemorrhagic shock occurred as a result of a ruptured pulmonary artery pseudoaneurysm and radiofrequency ablation-induced damage to the interlobular pleura. After transcatheter coil embolization of the pulmonary artery pseudoaneurysm, she recovered from a state of shock and a left lower lobectomy was performed. Histological findings revealed the presence of residual tumor cells in the ablated lung tumor. The postoperative course was uneventful, and no evidence of recurrence of the primary disease was seen at 1 year after the surgery. Although hemothorax secondary to the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation is a rare complication, it should be recognized as a serious potential complication of lung radiofrequency ablation for a tumor located close to the pulmonary artery branch.

    DOI: 10.1093/jjco/hys068

    Web of Science

    PubMed

    researchmap

  • Phrenic Nerve Injury after Radiofrequency Ablation of Lung Tumors: Retrospective Evaluation of the Incidence and Risk Factors 査読

    Yusuke Matsui, Takao Hiraki, Hideo Gobara, Mayu Uka, Yoshihisa Masaoka, Akihiro Tada, Shinichi Toyooka, Toshiharu Mitsuhashi, Hidefumi Mimura, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   23 ( 6 )   780 - 785   2012年6月

     詳細を見る

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

    Purpose: To retrospectively investigate the incidence of and risk factors for phrenic nerve injury after radiofrequency (RF) ablation of lung tumors.
    Materials and Methods: The study included 814 RF ablation procedures of lung tumors. To evaluate the development of phrenic nerve injury, chest radiographs obtained before and after the procedure were examined. Phrenic nerve injury was assumed to have developed if the diaphragmatic level was elevated after the procedure. To identify risk factors for phrenic nerve injury, multiple variables were compared between cases of phrenic nerve injury and randomly selected controls by using univariate analyses. Multivariate analysis was then performed to identify independent risk factors.
    Results: Evaluation of phrenic nerve injury from chest radiographs was possible after 786 procedures. Evidence of phrenic nerve injury developed after 10 cases (1.3%). Univariate analysis revealed that larger tumor size &gt;= 20 mm; P = .014), proximity of the phrenic nerve to the tumor (&lt; 10 mm; P &lt; .001), the use of larger electrodes (array diameter or noninsulated tip length &gt;= 3 cm; P = .001), and higher maximum power applied during ablation (&gt;= 100 W; P &lt; .001) were significantly associated with the development of phrenic nerve injury. Multivariate analysis demonstrated that the proximity of the phrenic nerve to the tumor (&lt; 10 mm; P &lt; .001) was a significant independent risk factor.
    Conclusions: The incidence of phrenic nerve injury after RF ablation was 1.3%. The proximity of the phrenic nerve to the tumor was an independent risk factor for phrenic nerve injury.

    DOI: 10.1016/j.jvir.2012.02.014

    Web of Science

    PubMed

    researchmap

  • Long-term outcome of induction chemoradiotherapy with docetaxel and cisplatin followed by surgery for non-small-cell lung cancer with mediastinal lymph node metastasis 査読

    Shinichi Toyooka, Katsuyuki Kiura, Mitsuhiro Takemoto, Takahiro Oto, Nagio Takigawa, Toshiyoshi Fujiwara, Shinichiro Miyoshi, Hiroshi Date

    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY   14 ( 5 )   565 - 569   2012年5月

     詳細を見る

    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 purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40-46 Gy. The induction therapy was followed by surgery 4-6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.

    DOI: 10.1093/icvts/ivs028

    Web of Science

    PubMed

    researchmap

  • DNA methylation status of REIC/Dkk-3 gene in human malignancies 査読

    Tatsuro Hayashi, Hiroaki Asano, Shinichi Toyooka, Kazunori Tsukuda, Junichi Soh, Tadahiko Shien, Naruto Taira, Yuho Maki, Norimitsu Tanaka, Hiroyoshi Doihara, Yasutomo Nasu, Nam-ho Huh, Shinichiro Miyoshi

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   138 ( 5 )   799 - 809   2012年5月

     詳細を見る

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

    The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies.
    We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed.
    The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group.
    REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies.

    DOI: 10.1007/s00432-012-1158-6

    Web of Science

    PubMed

    researchmap

  • 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   76 ( 1 )   32 - 38   2012年4月

     詳細を見る

    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 &lt; 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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2011.10.002

    Web of Science

    PubMed

    researchmap

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

    Tsuyoshi Ueno, Kazunori Tsukuda, Shinichi Toyooka, Midori Ando, Munenori Takaoka, Junichi Soh, Hiroaki Asano, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Kazuhiko Shien, Masashi Furukawa, Tomoki Yamatsuji, Katsuyuki Kiura, Yoshio Naomoto, Shinichiro Miyoshi

    LUNG CANCER   76 ( 1 )   26 - 31   2012年4月

     詳細を見る

    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, HERZ and ART - 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-G(0)-G(1) 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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2011.09.011

    Web of Science

    PubMed

    researchmap

  • Peculiar mechanisms of graft recovery through anti-inflammatory responses after rat lung transplantation from donation after cardiac death 査読

    Sumiharu Yamamoto, Mikio Okazaki, Masaomi Yamane, Kentaro Miyoshi, Shinji Otani, Tomokazu Kakishita, Osamu Yoshida, Naohisa Waki, Shinichi Toyooka, Takahiro Oto, Yoshifumi Sano, Shinichiro Miyoshi

    TRANSPLANT IMMUNOLOGY   26 ( 2-3 )   133 - 139   2012年3月

     詳細を見る

    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 BV  

    Background: Although lung transplantation from donation after cardiac death (DCD), especially uncontrolled DCD, is limited by warm ischemic periods, the molecular mechanism of warm ischemia-reperfusion-injury (IRI) has not been well elucidated. The purpose of this study was to clarify the particular longitudinal mechanisms of molecular factors involved in warm IRI.
    Methods: Cold ischemic-time (CIT)-group lungs were retrieved and subjected to 3-h of cold preservation, whereas warm ischemic-time (WIT)-group lungs were retrieved after 3-h of warm ischemia. Orthotopic rat lung transplantation was performed and the grafts were reperfused for 1 or 4-h. The graft functions, gene expression, and activation of inflammatory molecules in the grafts were analyzed. Exhaled-carbon-monoxide-concentration (ExCO-C) was measured during reperfusion.
    Results: Only the WIT-group showed obvious primary graft dysfunction at 1-h reperfusion, but the graft function was recovered during 4-h reperfusion. Most of pro-inflammatory cytokines and stress-induced molecules showed different expression and activation patterns between CIT and WIT groups. In the WIT-group, the expressions of anti-inflammatory molecules, IL-10 and HO-1, were significantly increased at 1-h reperfusion compared to the CIT-group, and these high levels were maintained through 4-h reperfusion. Furthermore, ExCO-C levels in the WIT-group increased immediately after reperfusion compared to the CIT-group.
    Conclusions: This study indicates that warm IRI may involve a different mechanism than cold IRI and anti-inflammatory pathways may play important roles in the graft recovery after lung transplantation from uncontrolled DCD. (C) 2011 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.trim.2011.11.002

    Web of Science

    PubMed

    researchmap

  • Presence of EGFR mutation in pathologically non-malignant specimens from computed tomography-guided lung needle biopsies 査読

    Tsuyoshi Ueno, Junichi Soh, Takao Hiraki, Hiroaki Asano, Koichi Ichimura, Kentaro Shibamoto, Hideo Gobara, Susumu Kanazawa, Shinichi Toyooka, Shinichiro Miyoshi

    ONCOLOGY LETTERS   3 ( 2 )   401 - 404   2012年2月

     詳細を見る

    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  

    Activating mutations of the epidermal growth factor receptor (EGFR) gene are characteristic of non-small cell lung cancer (NSCLC). EGFR mutations were previously detected in histologically normal lung tissue around NSCLC tumors. Computed tomography-guided lung needle biopsy (CTNB) is an accurate and useful technique for the diagnosis of lung tumors. However, pathologically non-malignant cases occasionally become apparent following lung tumor resection. In this study, we determined the EGFR mutational status of lung tumors diagnosed as non-malignant in CTNB specimens, but diagnosed as NSCLC following surgical resection. Between 2000 and 2008, 1,109 CTNBs were performed at Okayama University Hospital. Among them, 15 cases were initially diagnosed as non-malignant by CTNB, but diagnosed as NSCLC following surgical resection as a result of a high likelihood of malignancy by clinical findings. Twelve paired DNAs of CTNB and corresponding resected specimens were available to examine the EGFR mutational status using a mutant-enriched PCR assay. EGFR mutations were detected in one out of 12 CTNB specimens and three of the corresponding resected tumors. This case harbored the same EGFR mutation in the CTNB specimen and resected tumor, but not in the distant corresponding nonmalignant lung tissue. Our results indicated that the detection of EGFR mutations may therefore aid the diagnosis of NSCLC in pathologically non-malignant CTNB specimens.

    DOI: 10.3892/ol.2011.471

    Web of Science

    PubMed

    researchmap

  • The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor 査読

    Naruyuki Kobayashi, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Hideaki Dote, Kensuke Kawasaki, Hiroki Otani, Takafumi Kubo, Masaru Jida, Tsuyoshi Ueno, Midori Ando, Atsuko Ogino, Katsuyuki Kiura, Shinichiro Miyoshi

    LUNG CANCER   75 ( 2 )   161 - 166   2012年2月

     詳細を見る

    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  

    Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC50 values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16 mu M while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4 mu M. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGER-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2011.04.022

    Web of Science

    PubMed

    researchmap

  • Current status of postoperative follow-up for lung cancer in Japan: Questionnaire survey by the Setouchi Lung Cancer Study Group-A0901 査読

    Shigeki Sawada, Hiroshi Suehisa, Motohiro Yamashita, Masao Nakata, Norihito Okumura, Kazunori Okabe, Hiroshige Nakamura, Hirohito Tada, Shinichi Toyooka, Hiroshi Date

    General Thoracic and Cardiovascular Surgery   60 ( 2 )   104 - 111   2012年2月

     詳細を見る

    記述言語:英語  

    Purpose: There is no recommended standard follow-up program after resection for lung cancer. Under these circumstances, each doctor establishes his or her own follow-up protocol. This questionnaire survey was conducted to grasp the current status of postoperative follow-up in Japan. Methods: The questionnaire survey was aimed at determining what examinations were performed and at what frequencies in the setting of postoperative follow-up. Based on these results, examinations performed at a frequency of &gt
    50% and the time points after resection at which they were performed were selected and presented as components of an average follow-up program. Results: Questionnaires were sent to 44 institutions, and 26 doctors responded to the questionnaire. All 26 of the doctors performed physical examinations, blood examinations, chest radiography, and computed tomography (CT) routinely, but their frequencies varied widely among the doctors. The average frequencies of the follow-up examinations as judged from this survey are as follows: Physical and blood examinations are performed three to four times a year for the first 3 years and twice a year during the next 2 years. CT is scheduled at 6 and 12 months after resection and is repeated annually thereafter. Chest radiography is performed three to four times a year for the first 3 years and once a year thereafter, between the CT examinations. Conclusion: The follow-up programs used in clinical practice vary widely among institutions and doctors in terms of the types of examination performed and the frequencies at which they are performed. © 2012 The Japanese Association for Thoracic Surgery.

    DOI: 10.1007/s11748-011-0850-9

    Scopus

    PubMed

    researchmap

  • CT fluoroscopy-guided cutting needle biopsy of focal pure ground-glass opacity lung lesions: Diagnostic yield in 83 lesions 査読

    Daisaku Inoue, Hideo Gobara, Takao Hiraki, Hidefumi Mimura, Katsuya Kato, Kentaro Shibamoto, Tatsuhiko Iishi, Yusuke Matsui, Shinichi Toyooka, Susumu Kanazawa

    EUROPEAN JOURNAL OF RADIOLOGY   81 ( 2 )   354 - 359   2012年2月

     詳細を見る

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

    Objective: The objective of our study was to retrospectively determine the diagnostic yield of CT fluoroscopy-guided cutting needle biopsy of focal pure ground-glass opacity lung lesions.
    Materials and methods: Biopsies were performed using 20-G coaxial cutting needles for 83 focal pure ground-glass opacity lung lesions (mean lesion size, 12.1 mm). After excluding the lesions for which biopsy specimens were unobtainable and final diagnoses were undetermined, the diagnostic yield, including sensitivity and specificity for a diagnosis of malignancy and accuracy, was calculated. The lesions were then divided into 2 groups: the diagnostic failure group, comprising lesions with false-negative results and for which a biopsy specimen was unobtainable; and the diagnostic success group, comprising lesions with true-negative results and true-positive results. Various variables were compared between the 2 groups by univariate analysis.
    Results: Biopsy specimens were obtained from 82 lesions, while specimens could not be obtained from 1 lesion. Final diagnosis was undetermined in 16 lesions. The sensitivity and specificity for a diagnosis of malignancy were 95% (58/61) and 100% (5/5), respectively. Diagnostic accuracy was 95% (63/66). The 4 lesions in diagnostic failure group were smaller, deeper, and more likely to be located in the lower lobe and further, for those lesions, number of specimens obtained was smaller, compared with 63 lesions in diagnostic success group. However, none of the differences were statistically significant.
    Conclusion: CT fluoroscopy-guided cutting needle biopsy provided high diagnostic yield for focal pure ground-glass opacity lung lesions. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.ejrad.2010.11.025

    Web of Science

    PubMed

    researchmap

  • STAT3 expression in activating EGFR-driven adenocarcinoma of the lung 査読

    Saburo Takata, Nagio Takigawa, Yoshihiko Segawa, Toshio Kubo, Kadoaki Ohashi, Toshiyuki Kozuki, Norihiro Teramoto, Motohiro Yamashita, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

    LUNG CANCER   75 ( 1 )   24 - 29   2012年1月

     詳細を見る

    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  

    Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors &lt;1 cm, 1-2 cm, and &gt;= 2 cm in diameter, respectively, were analyzed. Of the 24 tumors &lt;= 2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p &lt; 0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p = 0.017). In the tumors &lt;= 2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p = 0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n = 17) and 82% of the wild-type tumors (n = 33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.lungcan.2011.05.015

    Web of Science

    PubMed

    researchmap

  • Bronchiolitis Obliterans Organizing Pneumonia after Radiofrequency Ablation of Lung Cancer: Report of Three Cases 査読

    Takao Hiraki, Hideo Gobara, Katsuya Kato, Shinichi Toyooka, Hidefumi Mimura, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   23 ( 1 )   126 - 130   2012年1月

     詳細を見る

    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  

    The present report describes three cases of a bronchiolitis obliterans organizing pneumonia (BOOP)-like reactive pneumonitis following radiofrequency (RF) ablation for lung cancer. The incidence of BOOP-like reactive pneumonitis after RF ablation at the authors' institution was estimated to be approximately 0.4% (three of 840 sessions). The patients presented with nonspecific symptoms. Computed tomography images showed consolidation or ground-glass opacity in a peripheral-dominant distribution and/or patchy air-space opacities. The disease was nonresponsive to antibiotic therapy but responded favorably to pulse therapy of steroids. BOOP-like reactive pneumonitis should be recognized as a complication following lung RF ablation.

    DOI: 10.1016/j.jvir.2011.09.011

    Web of Science

    PubMed

    researchmap

  • Spontaneous Regression of Primary Lung Cancer Arising from an Emphysematous Bulla 査読

    Masashi Furukawa, Takahiro Oto, Masaomi Yamane, Shinichi Toyooka, Katsuyuki Kiura, Shinichiro Miyoshi

    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY   17 ( 6 )   577 - 579   2011年12月

     詳細を見る

    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  

    Bullous emphysema is an important risk factor for lung cancer. Here, we report the case of a 56-year-old man who underwent surgical treatment for primary lung cancer arising from the wall of a bulla. Chest computed tomography (CT) had revealed a nodule arising from the bulla wall. This nodule showed positive uptake of (18)fluorodeoxyglucose (FDG) during positron emission tomography (PET)-CT. However, repeat CT performed after 2 months showed a spontaneous decrease in the tumor size. Exploratory resection revealed non-small cell lung cancer, which was confirmed by the findings of intraoperative frozen-section analysis; therefore, right upper lobectomy and mediastinal lymph node dissection were performed. The postoperative, pathological diagnosis was squamous cell carcinoma arising from the wall of a bulla. From this case, we infer that lung cancer arising from the wall of a bulla may spontaneously regress, and FDG/PET is a useful tool to diagnose lung tumor in patients with pulmonary bullous disease.

    DOI: 10.5761/atcs.cr.10.01638

    Web of Science

    PubMed

    researchmap

  • Diaphragmatic Hernia after Percutaneous Radiofrequency Ablation of Lung Tumor 査読

    Takao Hiraki, Hideo Gobara, Yoshihisa Masaoka, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   22 ( 12 )   1777 - 1778   2011年12月

     詳細を見る

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

    DOI: 10.1016/j.jvir.2011.08.014

    Web of Science

    PubMed

    researchmap

  • Ileal perforation induced by acute radiation injury under gefitinib treatment 査読

    Takayuki Muraoka, Kazunori Tsukuda, Shinichi Toyooka, Shunsuke Kagawa, Yoshio Naomoto, Mitsuhiro Takemoto, Kuniaki Katsui, Susumu Kanazawa, Yuho Maki, Hiroko Masuda, Masaaki Harada, Hiroaki Asano, Minoru Naito, Shinichiro Miyoshi

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   16 ( 6 )   774 - 777   2011年12月

     詳細を見る

    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 TOKYO  

    Enteritis is one of the side effects of radiotherapy to the abdominal cavity. Radiation enteritis involves damage to mucous membranes in the acute phase and to stromal tissues in the late phase. Perforation of the intestine tends to occur in the late phase, and rarely in the acute phase. However, we describe here a case of intestinal perforation occurring in the acute phase after irradiation in a patient who received gefitinib treatment. Gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is widely used to treat non-small cell lung cancer (NSCLC) patients, but is simultaneously known to inhibit wound healing. We suspect that gefitinib may affect regeneration of the small intestinal mucosa injured by irradiation. A 76-year-old woman had NSCLC with metastases to the 5th lumbar, sacral, and right iliac bones. To control the pain from bone metastasis, anterior-posterior opposing portal irradiation (total 35 Gy) was started, and was completed over 22 days. On day 25 after starting radiotherapy, the patient began to take gefitinib. On day 35, she presented with acute peritonitis, and an emergency laparotomy was performed. The terminal ileum was affected by radiation enteritis and there were two pin-hole perforations. In the surgical specimen, no cancerous lesions were detected, and immunohistochemical staining of phosphorylated EGFR (pEGFR) was negative. pEGFR has an important role in mucous membrane repair after irradiation. Intestinal perforation in the acute phase of radiation enteritis may be associated with impaired mucosal repair mechanisms due to the use of an EGFR-TKI such as gefitinib, as evidenced by the absence of pEGFR.

    DOI: 10.1007/s10147-011-0249-8

    Web of Science

    PubMed

    researchmap

  • Methylation Profiling of Lung Cancer: A Decade of Progress 査読

    Shinichi Toyooka, Adi F. Gazdar

    MOLECULAR CANCER THERAPEUTICS   10 ( 11 )   2020 - 2020   2011年11月

     詳細を見る

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

    DOI: 10.1158/1535-7163.MCT-11-0768

    Web of Science

    PubMed

    researchmap

  • Elevation of Antidonor Immunoglobulin M Levels Precedes Acute Lung Transplant Rejection 査読

    Kentaroh Miyoshi, Yoshifumi Sano, Masaomi Yamane, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   92 ( 4 )   1233 - 1238   2011年10月

     詳細を見る

    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. No useful noninvasive biomarker exists for diagnosing acute rejection after lung transplantation (LTx). In this study, antidonor T-cell antibodies were monitored daily in living-donor lobar LTx recipients to determine whether they are correlated with the onset of steroid-responsive typical acute rejection.
    Methods. Ten nonsensitized patients who underwent bilateral living-donor lobar LTxs donated from 2 persons were analyzed. In 5 patients, unilateral acute rejection developed during the first 14 days after LTx and responded to subsequent pulse steroid therapies. The other patients experienced no rejection episodes during the period. Immunoreactivity against T cells from each lobe of the donors was monitored daily by detecting antidonor immunoglobulin (Ig) M and IgG using flow cytometry crossmatching for 14 days after LTx.
    Results. There was a remarkable increase in IgM levels against rejected grafts around the onset of acute rejection, but this increase was not observed against nonrejected grafts. The mean IgM levels against rejected grafts 14 days after transplantation was significantly higher than that against nonrejected grafts in the acute rejection group (p = 0.009) and the no rejection group (p = 0.010). In the acute rejection group, the IgM level against rejected grafts became significantly higher than those against nonrejected grafts 2 days before the clinical onset of acute rejection. These trends were statistically marginal or not detected for IgG levels.
    Conclusions. Significant immunoreactivity of IgM, but not IgG, preceded the clinical onset of acute rejection. Antidonor IgM monitoring can contribute to the early detection of steroid-responsive acute rejection. (Ann Thorac Surg 2011;92:1233-8) (C) 2011 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2011.04.090

    Web of Science

    PubMed

    researchmap

  • Radiofrequency Ablation of Lung Cancer at Okayama University Hospital: A Review of 10 Years of Experience 査読

    Takao Hiraki, Hideo Gobara, Hidefumi Mimura, Shinichi Toyooka, Hiroyasu Fujiwara, Kotaro Yasui, Yoshifumi Sano, Toshihiro Iguchi, Jun Sakurai, Nobuhisa Tajiri, Takashi Mukai, Yusuke Matsui, Susumu Kanazawa

    ACTA MEDICA OKAYAMA   65 ( 5 )   287 - 297   2011年10月

     詳細を見る

    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The application of radiofrequency ablation for the treatment of lung cancer by our group at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences began in June 2001, and in the present report, we review our 10-year experience with this treatment modality at Okayama University Hospital. The local efficacy of radiofrequency ablation for the treatment of lung cancer depends on tumor size and the type of electrode used, but not on tumor type. An important factor for the prevention of local failure may be the acquisition of an adequate ablative margin. The combination of embolization and radiation therapy enhances the local efficacy. Local failure may be salvaged by repeating the radiofrequency ablation, particularly in small tumors. Survival rates after radiofrequency ablation are quite promising for patients with clinical stage I non-small cell lung cancer and pulmonary metastasis from colorectal cancer, hepatocellular carcinoma, and renal cell carcinoma. The complications caused by radiofrequency ablation can be treated conservatively in the majority of cases. However, attention should be paid to rare but serious complications. This review shows that radiofrequency ablation is a promising treatment for patients with lung cancer.

    DOI: 10.18926/AMO/47010

    Web of Science

    PubMed

    researchmap

  • Early effects of the ex vivo evaluation system on graft function after swine lung transplantation 査読

    Shinji Otani, Takahiro Oto, Tomokazu Kakishita, Kentaroh Miyoshi, Shiro Hori, Masaomi Yamane, Shinichi Toyooka, Shinichiro Miyoshi

    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY   40 ( 4 )   956 - 961   2011年10月

     詳細を見る

    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 BV  

    Objectives: Ex vivo lung evaluation (ex vivo) has been developed as a useful method by which to assess lungs from donation-after-cardiac death (DCD) donors prior to transplant. However, the safety of the ex vivo circulation itself with respect to grafts has not been fully investigated. The aim of this study is to evaluate the effects of the ex vivo circuit using a swine lung transplant model. Methods: Lungs with or without 2-h warm ischemia were used. To assess post-transplant graft function, the left lung was transplanted after 2-h ex vivo or cold preservation; blood gas analysis of the left pulmonary vein (partial pressure of oxygen, PO(2)) was performed during the 6-h post-transplant follow-up period. Data were compared between the ex vivo (+) and ex vivo (-) groups. Results: Partial pressure of oxygen/inspired oxygen fraction (PO(2)/FiO(2)) in the ex vivo (-) group was significantly greater than that in the ex vivo (+) group until 3 h after transplant. The PO(2)/FiO(2) levels in both groups then increased and became similar at 6 h after transplant, regardless of whether ischemic or non-ischemic lungs (p &lt; 0.001 and p = 0.004, respectively) were used. Conclusions: Negative effects of the ex vivo system were limited and seen only in the immediate post-transplant period. Therefore, in DCD swine lung transplantation, the ex vivo system appears to be safe. (C) 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.ejcts.2010.12.071

    Web of Science

    PubMed

    researchmap

  • Molecular oncology of lung cancer. 査読

    Shinichi Toyooka, Tetsuya Mitsudomi, Junichi Soh, Keiju Aokage, Masaomi Yamane, Takahiro Oto, Katsuyuki Kiura, Shinichiro Miyoshi

    General thoracic and cardiovascular surgery   59 ( 8 )   527 - 37   2011年8月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Progress in genetic engineering has made it possible to elucidate the molecular biological abnormalities in lung cancer. Mutations in KRAS and P53 genes, loss of specific alleles, and DNA methylation of the tumor suppressor genes were the major abnormalities investigated between 1980 and the 2000s. In 2004, mutations in the epidermal growth factor receptor (EGFR) gene that cause oncogene addiction were discovered in non-small-cell lung cancers (NSCLCs), especially in adenocarcinomas. Because they are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), a great deal of knowledge has been acquired in regard to both EGFR and other genes in the EGFR family and their downstream genes. Moreover, in 2007 the existence of the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was discovered in NSCLC; and the same as EGFR-TKIs, ALK inhibitors are being found to be highly effective in lung cancers that have this translocation. These discoveries graphically illustrate that molecular biological findings are directly linked to the development of clinical oncology and to improving the survival rates of lung cancer patients. Here, we review the remarkable progress in molecular biological knowledge acquired thus far in regard to lung cancer, especially NSCLC, and the future possibilities.

    DOI: 10.1007/s11748-010-0743-3

    PubMed

    researchmap

  • Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma 査読

    Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Masakiyo Sakaguchi, Takuya Fukazawa, Junichi Soh, Hiroaki Asano, Tsuyoshi Ueno, Takayuki Muraoka, Hiromasa Yamamoto, Yasutomo Nasu, Takumi Kishimoto, Harvey I. Pass, Hideki Matsui, Nam-ho Huh, Shinichiro Miyoshi

    CLINICAL CANCER RESEARCH   17 ( 15 )   4965 - 4974   2011年8月

     詳細を見る

    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  

    Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.
    Experimental Design: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.
    Results: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2&apos;-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.
    Conclusions: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. Clin Cancer Res; 17(15); 4965-74. (C)2011 AACR.

    DOI: 10.1158/1078-0432.CCR-10-3040

    Web of Science

    PubMed

    researchmap

  • Percutaneous radiofrequency ablation of clinical stage I non-small cell lung cancer 査読

    Takao Hiraki, Hideo Gobara, Hidefumi Mimura, Yusuke Matsui, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY   142 ( 1 )   24 - 30   2011年7月

     詳細を見る

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

    Objective: This study aimed at retrospectively evaluating the outcomes of radiofrequency ablation of clinical stage I non-small cell lung cancer.
    Methods: This study was carried out on 50 nonsurgical candidates (29 men and 21 women; mean age, 74.7 years) with clinical stage I (IA, n = 38; IB, n = 12) histologically proven non-small cell lung cancer. A total of 52 tumors were treated with 52 ablation sessions. Radiofrequency ablation was performed percutaneously under computed tomography fluoroscopic guidance. The outcomes of radiofrequency ablation were evaluated, including toxicity, local efficacy, and patient survival. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Local efficacy was evaluated by using computed tomography scan with a contrast medium. The overall, cancer-specific, and disease-free survivals were estimated with Kaplan-Meier analysis.
    Results: Grade 2 and 3 adverse events occurred after 6 (12%) and 3 (6%) of the 52 sessions, respectively. The median follow-up period was 37 months. Local progression was observed in 16 (31%) of the 52 tumors. The median survival time was 67 months. The overall, cancer-specific, and disease-free survivals were 94%, 100%, and 82% at 1 year, 86%, 93%, and 64% at 2 years, and 74%, 80%, and 53% at 3 years, respectively.
    Conclusions: Radiofrequency ablation of clinical stage I non-small cell lung cancer was minimally invasive and provided promising patient survival, although the local efficacy needs to be improved. (J Thorac Cardiovasc Surg 2011;142:24-30)

    DOI: 10.1016/j.jtcvs.2011.02.036

    Web of Science

    PubMed

    researchmap

  • Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells 査読

    Toshiaki Ohara, Munenori Takaoka, Shinichi Toyooka, Yasuko Tomono, Toshio Nishikawa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

    CANCER SCIENCE   102 ( 7 )   1344 - 1349   2011年7月

     詳細を見る

    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  

    Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of &lt; 1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0)/G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3); P &lt; 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P &lt; 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival. (Cancer Sci 2011; 102: 1344-1349)

    DOI: 10.1111/j.1349-7006.2011.01967.x

    Web of Science

    PubMed

    researchmap

  • Aberrant Methylation of p21 Gene in Lung Cancer and Malignant Pleural Mesothelioma 査読

    Hirotake Teramen, Kazunori Tsukuda, Norimitsu Tanaka, Tsuyoshi Ueno, Takafumi Kubo, Midori Ando, Junichi Soh, Hiroaki Asano, Harvery I. Pass, Shinichi Toyooka, Shinichiro Miyoshi

    ACTA MEDICA OKAYAMA   65 ( 3 )   179 - 184   2011年6月

     詳細を見る

    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  

    Suppression of p21 has been implicated in the genesis and progression of many human malignancies. DNA methylation is an important mechanism of gene silencing in human malignancies. In this study, we examined the expression status and aberrant methylaion of p21 in lung cancers and malignant pleural mesotheliomas (MPM). We used 12 small cell lung cancer (SCLC) cell lines, 13 non-small cell lung cancer (NSCLC) cell lines, 50 primary NSCLCs, 6 MPM cell lines and 10 primary MPMs. The expression and methylation of p21 was examined by reverse transcription-PCR (RT-PCR), Western blotting and methylation-specific PCR (MSP) assay. Loss of p21 protein expression was observed in 7 SCLC cell lines (58.3%), 5 NSCLC cell lines (38.5%) and 3 MPM cell lines (50%) while mRNA expression was lost in 2 SCLC cell lines (16.7%), 2 NSCLC cell lines (15.4%) and none of the MPM cell lines. Aberrant methylation of p21 was found in 8.3% of SCLC cell lines, 30.2% of NSCLCs and 6.3% of MPMs. Among primary NSCLCs, methylation in adenocarcinomas was significantly more frequent than in squamous cell carcinomas. Loss of p21 expression was frequently observed in lung cancers and MPMs and aberrant methylation was one of the mechanisms of suppression of p21, especially in NSCLCs.

    DOI: 10.18926/AMO/46629

    Web of Science

    PubMed

    researchmap

  • Technique for Creation of Artificial Pneumothorax for Pain Relief during Radiofrequency Ablation of Peripheral Lung Tumors: Report of Seven Cases 査読

    Takao Hiraki, Hideo Gobara, Kentaro Shibamoto, Hidefumi Mimura, Yuko Soda, Mayu Uka, Yoshihisa Masaoka, Shinichi Toyooka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   22 ( 4 )   503 - 506   2011年4月

     詳細を見る

    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  

    This report describes seven cases in which a pneumothorax was artificially created for relief from severe pain that occurred during radiofrequency (RF) ablation of peripheral lung tumors. In this procedure the multitined probe surrounding the legion was advanced into the chest, displaoing the tines and the peripheral tumor away from the parietal pleura and the chest wall and resulting in pain relief in one patient; in the remaining patients, an intravenous catheter was also introduced, followed by the administration of carbon dioxide (CO2) into the space between the tumor and the parietal pleura. The pain decreased-considerably-immediately after this procedure. No complication related to the creation of the artificial pneumothorax was observed. Creation of an artificial pneumothorax is a safe and effective method for pain relief.

    DOI: 10.1016/j.jvir.2010.12.018

    Web of Science

    PubMed

    researchmap

  • Role of Computed Tomography Fluoroscopy-Guided Cutting Needle Biopsy of Lung Lesions After Transbronchial Examination Resulting in Negative Diagnosis 査読

    Yusuke Matsui, Takao Hiraki, Hidefumi Mimura, Hideo Gobara, Daisaku Inoue, Tatsuhiko Iishi, Shinichi Toyooka, Susumu Kanazawa

    CLINICAL LUNG CANCER   12 ( 1 )   51 - 55   2011年1月

     詳細を見る

    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  

    Introduction: Computed tomography (CT)-guided lung biopsy is occasionally used for the lesions that were diagnosed as nonmalignant by transbronchial examination despite the fact that other clinical data suggested those as malignant. The purpose of this study is to evaluate the outcomes of CT fluoroscopy-guided cutting needle biopsy of lung lesions after transbronchial examination resulting in negative diagnosis. Patients and Methods: We retrospectively evaluated the outcomes of CT fluoroscopy-guided lung biopsy for 351 lesions (mean size, 2.8 cm) that were found to be nonmalignant by transbronchial examination. Diagnostic yield, including sensitivity and specificity for the diagnosis of malignancy, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. Various variables were analyzed to determine the factors for diagnostic failure. Results: The biopsy result was nondiagnostic, true-positive, true-negative, false-positive, or false-negative for 2, 262, 70, 0, or 17 lesions, respectively. Thus, the sensitivity, specificity, PPV, NPV, and accuracy of CT fluoroscopy-guided cutting needle biopsy was found to be 93% (262/281), 100% (70/70), 100% (262/262), 80% (70/87), and 94% (332/351), respectively. There was no significant risk factor for diagnostic failure. Conclusion: Computed tomography fluoroscopy-guided cutting needle lung biopsy is a useful technique to correct or confirm negative diagnosis by transbronchial examination.

    DOI: 10.3816/CLC.2011.n.007

    Web of Science

    PubMed

    researchmap

  • Brachial Nerve Injury Caused by Percutaneous Radiofrequency Ablation of Apical Lung Cancer: A Report of Four Cases 査読

    Takao Hiraki, Hideo Gobara, Hidefumi Mimura, Yoshifumi Sano, Shinichi Toyooka, Kentaro Shibamoto, Ryotaro Kishi, Mayu Uka, Susumu Kanazawa

    JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY   21 ( 7 )   1129 - 1133   2010年7月

     詳細を見る

    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  

    The present report describes four cases of brachial nerve injury caused by percutaneous radiofrequency (RF) ablation of lung cancer. All the tumors were located in the lung apex. The patients developed symptoms indicative of a low brachial plexus injury during RF ablation or as long as 7 days afterward. These symptoms partially receded over time. The indications of RF ablation in patients with apical lung cancer should be carefully determined because of the risk of brachial nerve injury associated with the procedure.

    DOI: 10.1016/j.jvir.2010.03.007

    Web of Science

    PubMed

    researchmap

  • Suppression of Inflammatory Cytokines During Ex Vivo Lung Perfusion With an Adsorbent Membrane 査読

    Tomokazu Kakishita, Takahiro Oto, Shiro Hori, Kentaroh Miyoshi, Shinji Otani, Sumiharu Yamamoto, Naohisa Waki, Osamu Yoshida, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka, Yoshifumi Sano, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   89 ( 6 )   1773 - 1781   2010年6月

     詳細を見る

    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. Lung grafts can be perfused ex vivo for 2 hours without edema formation; however, prolonged ex vivo lung perfusion (EVLP) eventually induces lung injury. This study evaluated the change in proinflammatory cytokines of the perfusate during EVLP and investigated the effect of cytokine removal using an adsorbent membrane.
    Methods. Porcine heart-lung blocks were harvested after electrically induced cardiac arrest and underwent 12-hour EVLP with an adsorbent membrane (membrane group: n = 5) and without an adsorbent membrane (control group: n = 6).
    Results. In the control group, both tumor necrosis factor-alpha and interleukin 8 levels were elevated in the perfusate 2 hours after perfusion. Although tumor necrosis factor-alpha and interleukin 8 levels were significantly lower in the membrane group than in the control group during the EVLP period, there was no significant difference in oxygenation, pulmonary vascular resistance, edema formation, or myeloperoxidase activity between the two groups.
    Conclusions. Tumor necrosis factor-alpha and interleukin 8 levels of the perfusate were elevated during EVLP. Although adverse effects of these inflammatory cytokines were anticipated, removal of inflammatory cytokines by the adsorbent membrane did not improve lung function during prolonged EVLP. Factors other than the cytokines may play a major role in causing lung injury during EVLP. Further research is needed to investigate the real mechanism of lung graft injury during prolonged EVLP and to establish longer EVLP duration for graft treatment. This strategy could contribute to the salvage of potentially damaged lungs, especially from cardiac death donors, and to expansion of the donor pool. (Ann Thorac Surg 2010; 89: 1773-81) (C) 2010 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2010.02.077

    Web of Science

    PubMed

    researchmap

  • Calcineurin Inhibitor-Related Cholestasis Complicating Lung Transplantation 査読

    Takahiro Oto, Mikio Okazaki, Ken Takata, Moritoki Egi, Masaomi Yamane, Shinichi Toyooka, Yoshifumi Sano, Gregory I. Snell, Keiji Goto, Shinichiro Miyoshi

    ANNALS OF THORACIC SURGERY   89 ( 5 )   1664 - 1665   2010年5月

     詳細を見る

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

    Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy. (Ann Thorac Surg 2010;89:1664-5) (C) 2010 by The Society of Thoracic Surgeons

    DOI: 10.1016/j.athoracsur.2009.09.081

    Web of Science

    PubMed

    researchmap

  • Triplet Chemotherapy with Cisplatin, Docetaxel, and Irinotecan for Patients with Recurrent or Refractory Non-small Cell Lung Cancer 査読

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

    ACTA MEDICA OKAYAMA   64 ( 1 )   33 - 37   2010年2月

     詳細を見る

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

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

    DOI: 10.18926/AMO/32866

    Web of Science

    PubMed

    researchmap

  • Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial 査読

    Tetsuya Mitsudomi, Satoshi Morita, Yasushi Yatabe, Shunichi Negoro, Isamu Okamoto, Junji Tsurutani, Takashi Seto, Miyako Satouchi, Hirohito Tada, Tomonori Hirashima, Kazuhiro Asami, Nobuyuki Katakami, Minoru Takada, Hiroshige Yoshioka, Kazuhiko Shibata, Shinzoh Kudoh, Eiji Shimizu, Hiroshi Saito, Shinichi Toyooka, Kazuhiko Nakagawa, Masahiro Fukuoka

    LANCET ONCOLOGY   11 ( 2 )   121 - 128   2010年2月

     詳細を見る

    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 Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain.
    Methods We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m(2), intravenously) plus docetaxel (60 mg/m(2), intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
    Findings Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9.2 months (95% CI 8.0-13.9) versus 6.3 months (5.8-7.8; HR 0.489, 95% CI 0.336-0.710, log-rank p&lt;0.0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2.3%), one of whom died.
    Interpretation Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel.

    DOI: 10.1016/S1470-2045(09)70364-X

    Web of Science

    PubMed

    researchmap

  • The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells 査読

    Hirokuni Ikeda, Naruto Taira, Fumikata Hara, Takeo Fujita, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka, Tomohiro Nogami, Tadahiko Shien, Hiroyoshi Doihara, Shinichiro Miyoshi

    BREAST CANCER RESEARCH   12 ( 3 )   R43   2010年

     詳細を見る

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

    Introduction: Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.
    Methods: The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT-and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.
    Results: mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-beta-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.
    Conclusions: Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT-and ER-positive breast cancer cells.

    DOI: 10.1186/bcr2598

    Web of Science

    PubMed

    researchmap

▼全件表示

 

担当授業科目

  • 再生医療学演習 (2021年度) 特別  - その他

  • 医学AIセミナー (2021年度) 特別  - その他

  • 医学AI入門 (2021年度) 特別  - その他

  • 医学AI応用特論Ⅰ (2021年度) 特別  - その他

  • 医学AI応用特論Ⅱ (2021年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学(基本臨床実習) (2021年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学I(演習・実習) (2021年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学I(講義・演習) (2021年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学II(演習・実習) (2021年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学II(講義・演習) (2021年度) 特別  - その他

  • 外科学Ⅱ (2021年度) 第4学期  - 月4

  • 外科総論 (2021年度) 特別  - その他

  • 実践地域総合外科学(演習・実習) (2021年度) 特別  - その他

  • 実践地域総合外科学(講義・演習) (2021年度) 特別  - その他

  • 臨床医歯科学概論 (2021年度) 集中  - その他

  • 選択制臨床実習(呼吸器・乳腺内分泌外科学) (2021年度) 特別  - その他

  • 選択制臨床実習(呼吸器・乳腺内分泌外科学)2 (2021年度) 特別  - その他

  • 再生医療学演習 (2020年度) 通年  - その他

  • 再生医療学総論 (2020年度) 通年  - その他

  • 呼吸器・乳腺内分泌外科学(基本臨床実習) (2020年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学I(演習・実習) (2020年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学I(講義・演習) (2020年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学II(演習・実習) (2020年度) 特別  - その他

  • 呼吸器・乳腺内分泌外科学II(講義・演習) (2020年度) 特別  - その他

  • 外科学Ⅱ (2020年度) 第4学期  - 月4

  • 外科総論 (2020年度) 特別  - その他

  • 実践地域総合外科学(演習・実習) (2020年度) 特別  - その他

  • 実践地域総合外科学(講義・演習) (2020年度) 特別  - その他

  • 臨床医歯科学概論 (2020年度) 集中  - その他

  • 選択制臨床実習(呼吸器・乳腺内分泌外科学) (2020年度) 特別  - その他

  • 選択制臨床実習(呼吸器・乳腺内分泌外科学)2 (2020年度) 特別  - その他

▼全件表示