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Ito T.,Hyogo College of Medicine | Yamamura M.,Kawasaki Medical School | Hirai T.,Kawasaki Medical School | Ishikawa T.,Niigata University | And 6 more authors.
International Journal of Clinical and Experimental Pathology | Year: 2014

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the human gut. Most sporadic GISTs have somatic gain-of-function mutations of the c-kit gene. The mutations are frequently found at exon 11, sometimes at exon 9 and rarely at exon 13 or 17. Recently, exon 8 c-kit gene mutations were reported in very minor proportion of sporadic GISTs. We also found 3 GISTs with exon 8 c-kit gene mutations in approximately 1,000 sporadic GISTs examined. In the present report, we showed the clinicopathological data of those GISTs. One case had a deletion of codon 419 of aspartate, and 2 cases had a substitution of 3 amino acids of codon 417 to codon 419 to tyrosine. The former was the same mutation recently reported in 2 GIST cases, but the latter has not been reported in any GISTs. All three cases occurred at extragastric sites and two of three showed distant metastasis. Since the remaining case was regarded as high risk for recurrence, imatinib adjuvant treatment has been done without evidence of metastasis. Our results confirmed the idea that exon 8 mutations are minor but actually existing abnormalities in sporadic GISTs, and suggested that such GISTs have a feature of extragastric development and a metastasis-prone nature. Since the exon 8 mutations appeared to be really sensitive to imatinib as shown in the present case study, accurate genotyping including exon 8 of the c-kit gene is necessary in GISTs to predict response to imatinib in both the unresectable/metastatic and adjuvant settings.

Ichikawa H.,National Cancer Center Research Institute | Ichikawa H.,Niigata University | Yoshida A.,Clinical Pathology Laboratories | Kanda T.,Sanjo General Hospital | And 9 more authors.
Cancer Science | Year: 2015

Prognostic markers are urgently needed to optimize the postoperative treatment strategies for gastrointestinal stromal tumors (GIST). GIST of the small intestine (I-GIST) show more aggressive behavior than those of the stomach (S-GIST), and the molecular background of the malignancy in I-GIST may include potential prognostic biomarkers. We conducted integrated proteomic and transcriptomic analysis to identify genes showing differential expressions according to the tumor site. We generated protein expression profiles for four cases each of surgically resected I-GIST and S-GIST using label-free proteomic analysis. For proteins showing differential expressions, global mRNA expression was compared between 9 I-GIST and 23 S-GIST. Among the 2555 genes analyzed, we found that promyelocytic leukemia (PML), a tumor suppressor gene, was significantly downregulated in I-GIST at both the protein and mRNA levels (P < 0.01; fold difference ≥2.0). Immunohistochemistry of 254 additional cases from multiple clinical facilities showed that PML-negative cases were significantly frequent in the I-GIST group (P < 0.001). The 5-year recurrence-free survival rate was significantly lower in the PML-negative than in the PML-positive cases (60.1% vs 91.7%; P < 0.001). Multivariate analysis revealed that downregulation of PML was an independent unfavorable prognostic factor (hazard ratio = 2.739; P = 0.001). Our study indicated that prognostication based on PML expression may have potential for optimizing the treatment strategy for GIST patients. Further validation studies of PML for clinical application, and investigation for the mechanistic significance of PML to clarify the molecular backgrounds of malignancy in GIST are warranted. GISTs of the small intestine shows more aggressive behavior than those of the stomach. Integrated proteomic and transcriptomic analysis identified PML, a tumor suppressor gene, was down-regulated in GISTs of the small intestine. Immunohistochemical study revealed the prognostic utility of PML in the cases of GIST from multiple clinical facilities. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Isosaka M.,Sapporo Medical University | Niinuma T.,Sapporo Medical University | Nojima M.,Tokyo Medical University | Kai M.,Sapporo Medical University | And 11 more authors.
PLoS ONE | Year: 2015

Background Dysregulation of microRNA (miRNA) has been implicated in gastrointestinal stromal tumors (GISTs) but the mechanism is not fully understood. In this study, we aimed to explore the involvement of epigenetic alteration of miRNA genes in GISTs. Methods GIST-T1 cells were treated with 5-aza-2'-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which miRNA expression profiles were analyzed using TaqMan miRNA arrays. DNA methylation was then analyzed using bisulfite pyrosequencing. The functions of miRNAs were examined using MTT assays, wound-healing assays, Boyden chamber assays and Matrigel invasion assays. Gene expression microarrays were analyzed to assess effect of ectopic miRNA expression in GIST-T1 cells. Results Of the 754 miRNAs analyzed, 61 were significantly upregulated in GIST-T1 cells treated with 5-aza-dC plus PBA. Among those, 21 miRNA genes were associated with an upstream CpG island (CGI), and the CGIs of miR-34a and miR-335 were frequently methylated in GIST-T1 cells and primary GIST specimens. Transfection of miR-34a or miR-335 mimic molecules into GIST-T1 cells suppressed cell proliferation, and miR-34a also inhibited migration and invasion by GIST-T1 cells. Moreover, miR-34a downregulated a number of predicted target genes, including PDGFRA. RNA interference-mediated knockdown of PDGFRA in GIST-T1 cells suppressed cell proliferation, suggesting the tumor suppressive effect of miR-34a is mediated, at least in part, through targeting PDGFRA. Conclusions Our results suggest that miR-34a and miR-335 are candidate tumor suppressive miRNAs in GISTs, and that they are frequent targets of epigenetic silencing in GISTs. Copyright © 2015 Isosaka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Edama M.,Niigata University of Health and Welfare | Edama M.,The Nippon Dental University | Kubo M.,Niigata University of Health and Welfare | Onishi H.,Niigata University of Health and Welfare | And 6 more authors.
Annals of Anatomy | Year: 2016

Because connections exist between the flexor hallucis longus (FHL) and flexor digitorum longus (FDL), the FHL is surmised to exert a flexion action on the lesser toes, but this has not been studied quantitatively. The objectives of this study have thus been to clarify the types of FHL and FDL connections and branching, and to deduce the toe flexion actions of the FHL. One hundred legs from 55 cadavers were used for the study, with FHLs and FDLs harvested from the plantar aspect of the foot, and connections and branches classified. Image-analysis software was then used to analyze cross-sectional areas (CSAs) of each tendon, and the proportion of FHL was calculated in relation to flexor tendons of each toe. Type I (single slip from FHL to FDL tendon) was seen in 86 legs (86%), Type II (crossed connection) in 3 legs (3%), and Type III (single slip from FDL to FHL tendon) or Type IV (no connection between muscles) in 0 legs (0%). In addition, Type V (double slip from FHL to FDL tendon) was seen in 11 legs (11%), representing a new type not recorded in previous classifications. In terms of the various flexor tendons, the proportion of FHL showing tendons to toes 2 and 3 was high, at approximately 50-70%. Consequently, considering the branching type and proportion of CSA, the FHL was conjectured to not only act to flex the hallux, but also play a significant role in the flexion of toes 2 and 3. These results offer useful information for future clarification of the functional roles of tendinous slips from the FHL. © 2015 Elsevier GmbH.

Kakuta T.,Niigata University | Kosugi S.-I.,Niigata University | Kanda T.,Sanjo General Hospital | Ishikawa T.,Niigata University | And 3 more authors.
Annals of Surgical Oncology | Year: 2014

Background: The number of patients cured of esophageal cancer after esophagectomy is gradually increasing owing to advances in surgical techniques, perioperative management, and adjuvant therapies. This study assessed the clinical course and sought to identify the prognostic factors of these patients. Methods: A series of 220 consecutive patients who underwent esophagectomy and survived for more than 5 years with no relapse were enrolled. Survival analysis was performed using 25 variables including patient characteristics and operative and perioperative factors. Potential prognostic factors were identified by univariate and multivariate analyses, and the development of other primary cancers and the causes of death were retrospectively reviewed. Results: The overall 10-, 15-, and 20-year survival rates were 71.6, 50.1, and 32.2 %, respectively, with a median survival time of 180 months (range, 61-315 months). The negative independent prognostic factors identified were age at surgery [hazard ratio (HR), 1.05; P <.01], being male (HR, 2.62; P =.02), pulmonary comorbidities (HR, 2.03; P =.02), synchronous presence of other cancers (HR, 2.35; P <.01), colonic/jejunal interposition (HR, 1.76; P =.03), perioperative blood transfusion (HR, 1.92; P =.02), development of pulmonary complications (HR, 1.71; P =.02), and adjuvant radiotherapy (HR, 2.13; P =.01). Pulmonary diseases and other primary cancers were found to be the most common causes of death. Conclusions: Careful follow-up including the surveillance of other primary cancers is required for long-term survivors of esophageal cancer after esophagectomy. © 2014 Society of Surgical Oncology.

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