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Shizuoka-shi, Japan

Tsuchiya A.,University of Edinburgh | Tsuchiya A.,Niigata University | Lu W.-Y.,University of Edinburgh | Weinhold B.,Hannover Medical School | And 12 more authors.
Hepatology | Year: 2014

In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2+/-4+/-, and St8sia2-/-4-/-). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2+/-4+/- and St8sia2-/-4-/- mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM+ cells. Subsequent to injury, NCAM+ cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma. Conclusion: PolySia modification of NCAM+ ductules weakens cell-cell and cell-matrix interactions, allowing DRs/HPCs to migrate for normal development and regeneration. Modulation of polySia levels may provide a therapeutic option in liver regeneration. © 2014 by the American Association for the Study of Liver Diseases. Source


Shimizu A.,Juntendo Shizuoka Hospital | Komuro Y.,Juntendo Urayasu Hospital | Miyajima M.,Juntendo University | Arai H.,Juntendo University
Journal of Neurosurgery: Pediatrics | Year: 2012

An otherwise healthy, developmentally normal 3-week-old male infant presented with complex multisuture craniosynostosis involving the metopic suture and bilateral coronal sutures with frontal prominence and hypotelorism. Frontal craniectomy and bilateral frontoorbital advancement remodeling were performed at the age of 5 months. The postoperative course was uneventful. The child's development was normal up to 8 months after the operation. His father and grandfather had similar specific deformities of the cranium, but no anomaly of the extremities was found, and conversation suggested that their intelligence was normal, excluding the possibility of syndromic craniosynostosis. A DNA analysis revealed large-scale copy number polymorphism of chromosome 4 in the patient and his family, which may include the phenotype of the cranium. Neither FGFR mutation nor absence of a TWIST1 mutation in the sequence from 291 to 1087, which includes DNA binding, Helix1, Loop, and Helix2, was identified. The patient apparently had a rare case of familial nonsyndromic craniosynostosis. The authors plan further genomic analysis of this family and long-term observation of the craniofacial deformity of this patient. Source


Utsunomiya T.,Tokushima University | Shimada M.,Tokushima University | Kudo M.,Kinki University | Ichida T.,Juntendo Shizuoka Hospital | And 8 more authors.
Annals of Surgery | Year: 2014

OBJECTIVE:: To examine the prognostic factors and outcomes after several types of treatments in patients with hepatocellular carcinoma (HCC) negative for hepatitis B surface antigen and hepatitis C antibody, so-called "non-B non-C HCC" using the data of a nationwide survey. BACKGROUND:: The proportion of non-B non-C HCC is rapidly increasing in Japan. METHODS:: A total of 4741 patients with non-B non-C HCC, who underwent hepatic resection (HR, n = 2872), radiofrequency ablation (RFA, n = 432), and transcatheter arterial chemoembolization (TACE, n = 1437) as the initial treatment, were enrolled in this study. The exclusion criteria included extrahepatic metastases and/or Child-Pugh C. Significant prognostic variables determined by a univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. RESULTS:: The degree of liver damage in the HR group was significantly lower than that in the RFA and TACE groups. The HR and TACE groups had significantly more advanced HCC than the RFA group. The 5-year survival rates after HR, RFA, and TACE were 66%, 49%, and 32%, respectively. Stratifying the survival rates, according to the TNM stage and the Japan Integrated Staging (JIS) score, showed the HR group to have a significantly better prognosis than the RFA group in the stage II and in the JIS scores "1" and "2." The multivariate analysis showed 12 independent prognostic factors. HR offers significant prognostic advantages over TACE and RFA. CONCLUSIONS:: The findings of this large prospective cohort study indicated that HR may be recommended, especially in patients with TNM stage II and JIS scores "1" and "2" of non-B non-C HCC. © 2013 by Lippincott Williams and Wilkins. Source


Utsunomiya T.,Tokushima University | Shimada M.,Tokushima University | Kudo M.,Kinki University | Ichida T.,Juntendo Shizuoka Hospital | And 8 more authors.
Annals of Surgery | Year: 2015

Objective: To compare the prognostic factors and outcomes after hepatic resection among patients with hepatitis B virus (HBV)-positive, hepatitis C virus (HCV)-positive, and negative for hepatitisBsurface antigen and hepatitis Cantibody, so-called "NBNC"-hepatocellular carcinoma (HCC) using the data from a nationwide survey. Background: The incidence of NBNC-HCC is rapidly increasing in Japan. Methods: A total of 11,950 patients with HBV-HCC (n = 2194), HCV-HCC (n = 7018), or NBNC-HCC (n = 2738) who underwent a curative hepatic resection were enrolled in this study. The clinicopathological features were compared among the groups. The significant prognostic variables determined by univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. Results: Liver function in the HCV-HCC group was significantly worse than that in the HBV-HCC and NBNC-HCC groups. The NBNC-HCC group had significantly more advanced HCC than the HCV-HCC group. The 5-year overall survival rates after hepatectomy in the HBV-HCC, HCV-HCC, and NBNCHCC groups were 65%, 59%, and 68%, respectively. The 5-year recurrencefree survival (RFS) rates in these 3 groups were 41%, 31%, and 47%, respectively. Stratifying the RFS rates according to the TNM stage showed that the NBNC-HCC group had a significantly better prognosis than the HBVHCC group in stages II, III, and IVA, and a significantly better prognosis than the HCV-HCC group in stages I and II. Multivariate analysis revealed a significantly better RFS rate in the NBNC-HCC group. Conclusions: The findings of this nationwide survey indicated that patients with NBNC-HCC had a significantly lower risk of HCC recurrence than those with HBV-HCC and HCV-HCC. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved. Source


Takayasu K.,National Cancer Center Hospital | Arii S.,Tokyo Medical and Dental University | Kudo M.,Kinki University | Ichida T.,Juntendo Shizuoka Hospital | And 8 more authors.
Journal of Hepatology | Year: 2012

Background & Aims: Transcatheter arterial chemoembolization with lipiodol (TACE) is widely performed in patients with hepatocellular carcinoma (HCC) unsuitable for curative treatment. It has recently been recommended for patients with 2 or 3 tumors >3 cm or ≥4 tumors in a treatment algorithm proposed by Japanese guidelines. However, the best indication and appropriateness of the algorithm for TACE are still unclear. Methods: In 4966 HCC patients who underwent TACE, survival was evaluated based on tumor number, size and liver function; and the adequacy of the algorithm for TACE was validated. Exclusion criteria were: vascular invasion, extrahepatic metastasis, and prior treatment. The mean follow up period was 1.6 years. Results: The overall median and 5-year survivals were 3.3 years and 34%, respectively. Multivariate analysis revealed that Child-Pugh class, tumor number, size, alpha-fetoprotein, and des-gamma carboxy-prothrombin were independent predictors. The survival rate decreased as the tumor number (p = 0.0001) and size increased (p = 0.04 to p = 0.0001) in all but one subgroup in both Child-Pugh-A and -B. The stratification of these patients to four treatments in the algorithm showed potential ability to discriminate survivals of the resection and ablation (non-TACE) groups from those of the TACE group in Child-Pugh-B and partially in A. Conclusions: TACE showed higher survival rates in patients with fewer tumor numbers, smaller tumor size, and better liver function. The treatment algorithm proposed by the Japanese guidelines might be appropriate to discriminate the survival of patients with non-TACE from TACE therapy. © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Source

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