Faculty Profiles - TOYOOKA Shinichi

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

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 2014.7

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

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

DOI： 10.3892/or.2014.3197

アスベスト問題予防・診断・治療を科学する悪性胸膜中皮腫におけるマイクロRNA異常

小児がん治療のUp to Date AYA世代のがんをどう治療するか? 稀少がん肉腫の新治療戦略水平分業型治療連携とパゾパニブ血管新生阻害剤による分子標的治療

高橋克仁, 山村倫子, 冨田裕彦, 矢嶋淳, 寺岡慧, 波多江亮, 大野烈士, 宗淳一, 山本寛斉, 豊岡伸一, 小池幸宏, 烏野隆博, 小山隆文, 楢原啓之, 大山優

日本癌治療学会誌 49 ( 3 ) 764 - 764 2014.6

豊岡伸一, 宗淳一, 橋田真輔, 山本寛斉, 牧祐歩, 三好新一郎

日本衛生学雑誌 69 ( Suppl. ) S115 - S115 2014.5

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

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 2014.4

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

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

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

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 37 ( 2 ) 548 - 551 2014.4

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

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 2014.4

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

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

Hiromasa Yamamoto, Shinichi Toyooka, Shinichiro Miyoshi

THORACIC AND CARDIOVASCULAR SURGEON 62 ( 2 ) 181 - 183 2014.3

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

Asymptomatic but Functional Paraganglioma of the Posterior Mediastinum Reviewed

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

ANNALS OF THORACIC SURGERY 97 ( 3 ) 1077 - 1080 2014.3

Language：English Publisher：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

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

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 2014.3

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

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

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 2014.3

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

気管支鏡検査で診断し外科的切除を行った肺原発悪性黒色腫の1例

萱谷紘枝, 南大輔, 渡邉元嗣, 山本寛斉, 宗淳一, 久保寿夫, 堀田勝幸, 田端雅弘, 豊岡伸一, 三好新一郎, 谷本光音, 木浦勝行

気管支学 36 ( 2 ) 208 - 208 2014.3

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

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 2014.2

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

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

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 2014.2

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