Faculty Profiles - TOYOOKA Shinichi

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

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 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：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'-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

頸部及び剣状突起下アプローチで同時切除した縦隔内甲状腺腫合併胸腺癌の1例

三浦章博, 宗淳一, 木村紘爾, 山根正修, 豊岡伸一, 大藤剛宏, 土井原博義, 三好新一郎

肺癌 51 ( 4 ) 314 - 314 2011.8

ラジオ波焼灼術後に生じた仮性肺動脈瘤へのコイル塞栓が気管支に穿通した1例

木村紘爾, 宗淳一, 古川公之, 林達朗, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎, 金澤右

肺癌 51 ( 4 ) 317 - 317 2011.8

両側肺腺癌に対する術前放射線化学療法後両側の肺切除を行い、その後"たこつぼ心筋症"を発症した1例

林達朗, 豊岡伸一, 宗淳一, 古川公之, 山根正修, 大藤剛宏, 三好新一郎, 木浦勝行

肺癌 51 ( 4 ) 312 - 312 2011.8

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

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

JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 142 ( 1 ) 24 - 30 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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 < 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 < 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 < 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

Less maintenance immunosuppression in lung transplantation following hematopoietic stem cell transplantation from the same living donor Reviewed

Chen F, Yamane M, Inoue M, Shiraishi T, Oto T, Minami M, Yanagisawa J, Fujinaga T, Shoji T, Toyooka S, Okumura M, Miyoshi S, Bando T, Date H

Am J Transplant 2011 Jul;11(7):1509-16. doi: 10.1111/j.1600-6143.2011.03591.x. Epub 2011 Jun 14 2011.7

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

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 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：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

Pediatric transplantation:International consensus and future in Japan 小児肺移植における生体肺葉移植の位置づけ(Pediatric transplantation: International consensus and future in Japan Living-donor-lobar lung transplantation: A practical option for pediatric lung transplant candidates in Japan)

大藤剛宏, 山根正修, 伊達洋至, 南正人, 白石武史, 杉本誠一郎, 青景圭樹, 原田昌明, 伊賀徳周, 西川仁士, 岡田真典, 大谷真二, 三好健太郎, 脇直久, 宗淳一, 豊岡伸一, 三好新一郎

日本外科学会雑誌 112 ( 臨増1-2 ) 197 - 197 2011.5

The impact of adenoviral gene transfer of microRNA-34b/c on malignant pleural mesotheliomas Reviewed

Soh Junichi, Toyooka Shinichi, Kubo Takafumi, Fukazawa Takuya, Sakaguchi Masakiyo, Ueno Tsuyoshi, Tsukuda Kazunori, Asano Hiroaki, Yamamoto Hiromasa, Huh Nam-ho, Miyoshi Shinichiro

CANCER RESEARCH 71 2011.4

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

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 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：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

NSCLCの外科的切除におけるCTNBの病理学的陰性試料のEGFR変異の検出(Detection of EGFR mutation in pathological negative specimens of CTNB in surgically resected NSCLCs)

上野剛, 豊岡伸一, 宗淳一, 浅野博昭, 佃和憲, 田中則光, 村岡孝幸, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 25 ( 3 ) O23 - 04 2011.4

神経性食思不振症に合併した小児両側自然気胸の1例

岡田真典, 山根正修, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 25 ( 3 ) P22 - 06 2011.4

肺癌におけるmicroRNA-9sの異常メチル化と臨床病理学的特徴の相関

村岡孝幸, 豊岡伸一, 宗淳一, 牧佑歩, 上野剛, 青景圭樹, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 25 ( 3 ) O04 - 05 2011.4

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

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

CLINICAL LUNG CANCER 12 ( 1 ) 51 - 55 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：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