Faculty Profiles - TOYOOKA Shinichi

Papers - TOYOOKA Shinichi

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小型肺癌に対する外科治療戦略肺野末梢型cT1aN0M0扁平上皮癌の予後因子

田尾裕之, 宗淳一, 藤原俊哉, 葉山牧夫, 岡崎幹生, 杉本龍士郎, 上野剛, 岡部和倫, 山下素弘, 佐野由文, 片岡和彦, 松浦求樹, 森山重治, 豊岡伸一, 三好新一郎

日本外科学会定期学術集会抄録集 116回 SY - 6 2016.4

メトホルミン服用における健常人および肺癌患者のCD8T細胞の多機能性調査

鵜殿平一郎, 豊岡伸一, 榮川伸吾

大和証券ヘルス財団研究業績集 ( 39 ) 96 - 100 2016.3

Language：Japanese Publisher：(公財)大和証券ヘルス財団

メトホルミン服用における健常人および肺癌患者のCD8T細胞の多機能性について検討した。末梢血単核球(PBMC)をメトホルミン存在下又は非存在下で培養し、メトホルミンを除去したものを、PMA/イオノマイシンで処理した細胞のCD8+ T細胞のうち、IFNγ、TNFα、IL-2を同時に産生できる細胞を検出した。がん患者のCD8T細胞はメトホルミン処理により多機能性の上昇を認める場合が多く、健常人では多機能性の上昇を認める場合は少なかった。

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Genetic alterations in lung adenocarcinoma with a micropapillary component. Reviewed International journal

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 2016.2

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

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

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

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

ACTA MEDICA OKAYAMA 70 ( 1 ) 63 - 65 2016.2

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

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放射線化学療法後に外科手術を行った局所進行非小細胞肺癌症例の長期フォローアップ解析

槇本剛, 久保寿夫, 南大輔, 大橋圭明, 堀田勝幸, 田端雅弘, 豊岡伸一, 勝井邦彰, 谷本光音, 木浦勝行

日本内科学会雑誌 105 ( Suppl. ) 192 - 192 2016.2

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

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 2016.1

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

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

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 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：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 (>= 10 mm or < 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 < 10 mm DAT group than in the >= 10 nun group (P < .001). In the crude and multivariate multilevel survival analyses, < 10 mm DAT was a significant risk factor for local progression in all models except model 5 (P = .067). In the >= 10 mm group, the technique efficacy rates were riot significantly different-between the 2 >= 10 min DAT subgroups (ICY to < 15 mm DAT vs >= 15 mm DAT).
Conclusions: DAT is an important risk factor for local progression. We recommend an electrode that is >= 10 mm larger than the tumor diameter.

DOI： 10.1016/j.jvir.2015.07.025

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

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 2016.1

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

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[Cross-sectoral Approach of a Perioperative Management Center for General Thoracic Surgery]. Reviewed

Shimoda A, Soh J, Ashiba T, Murata N, Fukuda T, Kobayashi M, Torigoe H, Maki Y, Sugimoto S, Yamane M, Toyooka S, Oto T, Miyoshi S

Kyobu geka. The Japanese journal of thoracic surgery 69 ( 1 ) 20 - 24 2016.1

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

CANCER SCIENCE 107 ( 1 ) 45 - 52 2016.1

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

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 G(1) 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.

DOI： 10.1111/cas.12845

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Path and challenges of the clinical trial network construction of the cancer drug―Through the lung cancer registry tumor specimen banking in Chugoku and Shikoku district―

Kiura Katsuyuki, Hotta Katsuyuki, Toyooka Shiinichi

Neurological Therapeutics 33 ( 5 ) S99 - S99 2016

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 Reviewed

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

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

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肺類上皮血管内皮腫の1例

田中晶平, 小田尚廣, 佐藤晃子, 宮原信明, 狩野裕久, 中西将元, 秦雄介, 槇本剛, 久保寿夫, 大橋圭明, 二宮崇, 堀田勝幸, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行, 牧佑歩, 宗淳一, 豊岡伸一, 三好新一郎

肺癌 55 ( 7 ) 1127 - 1127 2015.12

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

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 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：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 (>= 37.0 degrees C) was graded according to the common toxicity criteria of adverse events v. 4.0. Fever >= 37.0 degrees C and <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 >= 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

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DNA copy number gains in malignant pleural mesothelioma Reviewed

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 2015.11

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

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

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 2015.11

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

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[SIGNIFICANCE OF NONCODING RNA IN SURGERY: NONCODING RNA IN LUNG CANCER]. Reviewed

Yamamoto H, Toyooka S, Maki Y, Soh J, Miyoshi S

Nihon Geka Gakkai zasshi 116 ( 6 ) 374 - 377 2015.11

【ノンコーディングRNAの外科領域における意義】肺癌における意義

山本寛斉, 豊岡伸一, 牧佑歩, 宗淳一, 三好新一郎

日本外科学会雑誌 116 ( 6 ) 374 - 377 2015.11

Language：Japanese Publisher：(一社)日本外科学会

ノンコーディングRNA(non-coding RNA,ncRNA)はタンパク質へ翻訳されずに機能するRNAの総称であるが,近年ノンコーディングRNAの癌における異常が報告されている.特にマイクロRNA(micro-RNA,miRNA)と長鎖ノンコーディングRNA(longnon-coding RNA,lncRNA)はバイオマーカーとしての可能性が示唆されており,肺癌においてもmiRNA-21(miR-21),miR-34,miR-200などのmiRNAやMALAT1,HOTAIR,BANCRなどのlncRNAの発現異常が報告されている.そのため,ncRNAは肺癌の早期診断・予後予測・化学療法や放射線療法の感受性判定に使用されるバイオマーカーや,新規の治療標的として臨床応用することが期待されている.外科医の肺癌治療における役割は,確かな外科手技を手術適応のある肺癌患者に提供することであるが,肺癌治療成績の向上に更に大きく貢献するためには,より鋭敏なスクリーニングテストを用いて肺癌根治手術症例を増やすこと,肺癌手術症例において再発リスクの高い患者を漏らさず濃厚に観察することで再発症例を早期に確実に検出することが必要である.血液検体や肺癌切除検体においてncRNAの解析を行い,新たなバイオマーカーを探究することは一つの方法である.外科医は臨床検体へのアプローチが容易であることから,検体提供のみならず主体的な立場で研究を進めることが望まれる.(著者抄録)

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

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 2015.10

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

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Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model Reviewed

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 2015.10

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

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