Faculty Profiles - TOYOOKA Shinichi

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

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 2012.2

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

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 Reviewed

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 2012.2

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

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

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 2012.2

Language：English

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

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

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 2012.2

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

肺癌切除後に発症し治療に難渋した肺アスペルギルス症の1例

三好雄一郎, 山根正修, 牧佑歩, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

肺癌 52 ( 1 ) 109 - 109 2012.2

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung Reviewed

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 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：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 <1 cm, 1-2 cm, and >= 2 cm in diameter, respectively, were analyzed. Of the 24 tumors <= 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 < 0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p = 0.017). In the tumors <= 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

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

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

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 23 ( 1 ) 126 - 130 2012.1

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

Spontaneous Regression of Primary Lung Cancer Arising from an Emphysematous Bulla Reviewed

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

ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 17 ( 6 ) 577 - 579 2011.12

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

Diaphragmatic Hernia after Percutaneous Radiofrequency Ablation of Lung Tumor Reviewed

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

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 22 ( 12 ) 1777 - 1778 2011.12

Ileal perforation induced by acute radiation injury under gefitinib treatment Reviewed

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 2011.12

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

Activations of mitogen-activated protein kinases and regulation of their downstream molecules after rat lung transplantation from donors after cardiac death Reviewed

S. Yamamoto, M. Yamane, O. Yoshida, M. Okazaki, N. Waki, S. Toyooka, T. Oto, S. Miyoshi

Transplantation Proceedings 43 ( 10 ) 3628 - 3633 2011.12

Language：English Publishing type：Research paper (international conference proceedings)

Accepting organs donated after cardiac death (DCD) is an effective approach to the donor shortage. However, lung transplantations from DCD donors show severe rapid pulmonary graft dysfunction (PGD) followed by warm ischemiareperfusion injury (IRI). This study sought to clarify the molecular mediators in warm IRI, including activation of mitogen-activated protein kinase (MAPK) and the downstream cascades. We performed single left lung transplantation using organs from male Sprague-Dawley rats after 0 (CIT group), 30 (30WIT group), or 180 (180WIT group) minutes of warm ischemia time. Pulmonary graft functions were estimated by blood gas analysis. At 1 hour after reperfusion, the phosphorylation status of MAPKs (ERK, p38, and JNK) and the gene expression levels of transcription factors (Egr-1 and ATF-3) and immune mediators (MCP-1, MIP-2, PAI-1, ICAM-1, TNF-α, IL-1β, IL-6, and COX-2) in the grafts were examined using Western blotting and real-time polymerase chain reaction assays. Severe PGD was observed in the 180WIT group compared with transplanted lungs in the other groups, which exhibited good pulmonary graft function. ERK and JNK activations, as well as mRNA levels of transcription factors (Egr-1 and ATF3) significantly increased with greater warm ischemic times. The pattern of JNK activation correlated with the severity of PGD. MCP-1, ICAM-1, IL-1β, IL-6, and COX-2 were also up-regulated among the 180WIT group, although MIP-2 and PAI-1 showed no significant differences among the groups. We suggest that the ERK and JNK pathways may play important roles to induce the injury caused by prolonged warm ischemia followed by reperfusion in the setting of lung transplantation from DCD donors. © 2011 Published by Elsevier Inc.

DOI： 10.1016/j.transproceed.2011.09.075

Scopus

Methylation Profiling of Lung Cancer: A Decade of Progress Reviewed

Shinichi Toyooka, Adi F. Gazdar

MOLECULAR CANCER THERAPEUTICS 10 ( 11 ) 2020 - 2020 2011.11

Elevation of Antidonor Immunoglobulin M Levels Precedes Acute Lung Transplant Rejection Reviewed

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

ANNALS OF THORACIC SURGERY 92 ( 4 ) 1233 - 1238 2011.10

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

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

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 2011.10

Language：English Publisher：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

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

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 2011.10

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