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Okayama-shi, Japan

Kubo T.,Okayama University of Science | Toyooka S.,Okayama University of Science | Tsukuda K.,Okayama University of Science | Sakaguchi M.,Okayama University of Science | And 12 more authors.
Clinical 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. ©2011 AACR. Source

Takigawa N.,Kawasaki Medical School | Kiura K.,Okayama University | Kishimoto T.,Okayama Rosai Hospital
Current Oncology Reports

In the present report, we review the current standard and investigational treatments of malignant pleural mesothelioma (MPM). Several studies have reported the use of gemcitabine and cisplatin as an induction chemotherapy in combination with extrapleural pneumonectomy (EPP) and thoracic radiation in a combined-modality approach for resectable MPM. Since the combination of cisplatin with pemetrexed was applied as the standard first-line regimen for unresectable MPM, the combination as an induction chemotherapy regimen has been proven effective in phase 2 trials. In addition, intensity-modulated radiation therapy and proton therapy have been introduced as new radiation methods into the combined modality. Hyperthermic intraoperative chemotherapy following EPP appears effective with acceptable toxicity. In addition, clinical studies that include molecular targeting agents, immunotherapy, and gene therapy have all been conducted. Thus, although there are numerous hopeful treatments for MPM, the benefits of these regimens remain to be proven in a randomized clinical setting. © 2011 Springer Science+Business Media, LLC. Source

Fujimoto N.,Okayama Rosai Hospital

Background: The clinical features of asbestos-related diffuse pleural thickening (DPT) remain unclear. Objectives: To clarify the association between radiological findings of DPT and respiratory function. Methods: Medical data from patients with asbestos-related DPT were collected, including their history of occupational or neighborhood asbestos exposure, initial symptoms, modified Medical Research Council dyspnea grade, smoking history, radiological findings, and respiratory function test results. Results: There were 106 DPT patients between 2005 and 2010 [i.e. 103 men (97.2%) and 3 women (2.8%)]. The median age at diagnosis was 69 years (range 46-88). Patient occupations related to asbestos exposure included: asbestos product manufacturing (n = 17); the shipbuilding industry (n = 14); the construction industry (n = 13); heat insulation work (n = 12); plumbing, asbestos spraying, and electrical work (n = 7 each), and transportation and demolition work (n = 4 each). The median duration of asbestos exposure was 25 years (range 2-54), and the median latency period before the onset of DPT was 46 years (range 25-66). Involvement of the costophrenic angle (CPA) was also negatively correlated with the percent vital capacity (%VC; r = -0.448, p < 0.01). Pleural thickness and the craniocaudal and horizontal extension of pleural thickening, as determined by chest computed tomography (CT), were also negatively correlated with %VC (r = -0.226, p < 0.05; r = -0.409, p < 0.01, and r = -0.408, p < 0.01, respectively). Conclusions: DPT develops after a long latency period following occupational asbestos exposure and causes marked respiratory dysfunction. The extension of DPT should be evaluated by chest CT, and chest X-ray would be important for the evaluation of the involvement of the CPA. © 2014 S. Karger AG, Basel. Source

Hirayama S.,University of Toronto | Sato M.,University of Toronto | Sato M.,Kyoto University | Loisel-Meyer S.,Ontario Cancer Institute | And 10 more authors.
American Journal of Transplantation

The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation. Lentivirus-mediated trans-airway IL-10 gene therapy attenuates the Th17 response and histological acute rejection in an orthotopic mouse lung transplantation. © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons. Source

Ishizaki M.,Okayama Rosai Hospital | Aibara Y.,Shikoku Central Hospital | Furuya K.,Ehime Prefectural Central Hospital
International Journal of Surgery Case Reports

INTRODUCTION Primary malignant melanoma of the gastrointestinal tract is very rare, especially in the stomach. We report an extremely rare case of primary malignant melanoma of the esophagogastric junction mainly situated in the stomach. PRESENTATION OF CASE The patient was a 72-year-old woman who complained of shortness of breath due to severe anemia. Upper endoscopy revealed a soft easy-bleeding polypoid tumor just adjacent to the esophagogastric junction in the stomach. Biopsy of the tumor did not indicate a definite result, except malignant tumor. We performed total gastrectomy with splenectomy, and histological and immunohistological examination revealed malignant melanoma of the esophagogastric junction. She had no remote metastasis or lymphnodal metastasis at the point of surgery; however, she died of multiple metastases 11 months after the operation. DISCUSSION A definite preoperative diagnosis of primary malignant melanoma was very difficult to make from the preoperative biopsy specimen. This present case was first misinterpreted as undifferentiated carcinoma, or malignant lymphoma. Following the diagnosis of malignant melanoma, the question arose as to whether this was primary or metastatic (as malignant melanoma from other sites is known to metastasize to the stomach). Finally this tumor was diagnosed as a primary one due to the pathologic characteristics such as the existence of junctional activities. CONCLUSION We report an extremely rare case of primary malignant melanoma of the esophagogastric junction present in the stomach. © 2013 Surgical Associates Ltd. Source

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