Akihiko Oshita

Identification and characterization of a novel Dvl‐binding protein that suppresses Wnt signalling pathway

Background:   Dvl is a cytoplasmic protein to regulate the stability of β‐catenin in the Wnt signalling pathway. However, the molecular mechanism by which Dvl regulates the Wnt signalling pathway is not fully understood.

Splenectomy in Chronic Hepatic Disorders: Portal Vein Thrombosis and Improvement of Liver Function

Background: Splenectomy is gaining increasing importance for cirrhotic patients with hypersplenism. However, its safety and efficacy for patients with chronic liver disease remain unclear. Methods: We retrospectively examined the medical records of 38 consecutive cirrhotic patients who underwent splenectomy or simultaneous hepatectomy and splenectomy for hepatocellular carcinoma. Results: White blood cell and platelet counts significantly increased 3 months after splenectomy. Serum levels of total bilirubin and prothrombin time significantly improved 1 year after splenectomy. Interferon therapy was administered to 25 patients after splenectomy. A sustained viral response was achieved in 8 patients (42%). The total incidence of portal or splenic vein thrombosis (PSVT) detected by postoperative dynamic computed tomography was 13/38 (34.2%). Multivariate analysis revealed preoperative spleen volume (SV) to be the sole independent predictor of postoperative PSVT. Receiver-operator characteristic curve analysis showed that a cut-off SV of 450 ml corresponded to a sensitivity of 85% and a specificity of 56%. Conclusions: Splenectomy improved the liver function and facilitated effective interferon therapy in cirrhotic patients with hypersplenism, although preoperative SV was frequently associated with postoperative PSVT.

Safety and feasibility of diet-treated donors with steatotic livers at the initial consultation for living-donor liver transplantation.

Background The purpose of this study was to evaluate both safety of diet-treated donors and the feasibility of their use for living-donor liver transplantation (LDLT). Methods A total of 128 living donors were enrolled in this study between April 2003 and March 2010. Of them, 41 were diagnosed with hepatic steatosis at the initial consultation. Donor selection was based on the findings of liver biopsy accompanied with normalization of liver function tests after diet treatment consisting of an 800 to 1400 kcal/day diet and a 100 to 400 kcal/day exercise without drug treatment, targeting body mass index of 22 kg/m2. Results Body mass index of diet-treated donors was significantly reduced with diet from 23.3±0.6 to 21.9±0.4 kg/m2 (P<0.0001). Liver function tests associated with fatty liver, including alanine aminotransferase, gamma-glutamyl transpeptidase, and total cholesterol levels, also improved with diet (P=0.0128, 0.0016, and 0.0004, respectively). The liver biopsy results of most of these donors showed stage 0/1 fibrosis and minimal/mild steatosis after the diet therapy. Surgical outcomes, including postoperative liver function tests, perioperative complications, and liver regeneration rates, did not significantly differ between nondiet-treated and diet-treated donors. Surgical outcomes and the overall survival did not significantly differ between recipients of grafts from nondiet-treated and diet-treated donors. Conclusion The use of diet-treated donors for living-donor liver transplantation is feasible with respect to donor safety and the outcome of the recipient when strict selection criteria are used.

Treatment strategy for early hepatocellular carcinomas: Comparison of radiofrequency ablation with or without transcatheter arterial chemoembolization and surgical resection

The preferred choice between surgical treatment and radiofrequency ablation (RFA) for the treatment of small resectable hepatocelluar carcinoma (HCC) has become a subject for debate.

Rho inhibitor prevents ischemia–reperfusion injury in rat steatotic liver

BACKGROUND & AIMS Hepatic stellate cells are thought to play a role in modulating intrahepatic vascular resistance based on their capacity to contract via Rho signaling. We investigated the effect of a Rho-kinase inhibitor on ischemia-reperfusion injury in the steatotic liver. METHODS Steatotic livers, induced by a choline-deficient diet in rats, were subjected to ischemia-reperfusion injury. Hepatic stellate cells isolated from steatotic livers were analyzed for contractility and Rho signaling activity. The portal pressure of the perfused rat liver and the survival rate after ischemia-reperfusion were also investigated. RESULTS Hepatic stellate cells from steatotic livers showed increased contractility and upregulation of Rho-kinase 2 compared with those from normal livers. Furthermore, endothelin-1 significantly enhanced the contractility and phosphorylation level of myosin light chain and cofilin in hepatic stellate cells isolated from steatotic livers. A specific Rho-kinase inhibitor, fasudil, significantly suppressed the contractility and decreased the phosphorylation levels of myosin light chain and cofilin. Serum levels of endothelin-1 were markedly increased after IR in rats with steatotic livers, whereas fasudil significantly decreased endothelin-1 serum levels. Rats with steatotic livers showed a significant increase in portal perfusion pressure after ischemia-reperfusion and a significant decrease in survival rate; fasudil treatment significantly reduced these effects. CONCLUSIONS Activation of Rho/Rho-kinase signaling in hepatic stellate cells isolated from steatotic livers is associated with an increased susceptibility to ischemia-reperfusion injury. A Rho-kinase inhibitor attenuated the activation of hepatic stellate cells isolated from steatotic livers and improved ischemia-reperfusion injury in steatotic rats.

Significance of platelet count in the outcomes of hepatectomized patients with hepatocellular carcinoma exceeding the Milan criteria.

BackgroundThe appropriate treatment strategy for advanced hepatocellular carcinoma (HCC) that does not meet the Milan criteria (MC) is unclear. The aim of this study was to determine the significance of surgical treatment for such patients.Study designFrom January 1990 to December 2007, 151 patients with HCC exceeding MC who underwent curative surgical treatment were enrolled. Survival and recurrence data and clinicopathological factors were examined. Prognostic factors were analyzed to identify those that contributed to improved surgical outcomes retrospectively.ResultsAfter the initial hepatectomy, the overall 3-, 5-, and 10-year survival rates were 73%, 55%, and 33%, respectively, for the 151 patients in this study; the corresponding disease-free survival rates were 36%, 30%, and 17%, respectively. A platelet count under 105/mm3, multiple tumors, and liver cirrhosis of noncancerous tissue were adverse survival and disease-free survival factors by univariate analysis. Platelet count was an independent prognostic factor by multivariate analysis. The 3-, 5-, and 10-year overall survival rates of HCC exceeding MC in patients whose platelet count was 105/mm3 or greater reached 76%, 65%, and 44%, respectively, and were comparable with those that met MC (86%, 68%, and 37%, respectively).ConclusionsHepatectomy for patients with advanced HCC exceeding MC improves survival, especially for patients with a sufficiently high platelet count, although recurrence rates after initial hepatectomy are high.

Attenuation of portal hypertension by continuous portal infusion of PGE1 and immunologic impact in adult-to-adult living-donor liver transplantation.

Background Small-for-size syndrome remains the greatest limiting factor of expanding segmental liver transplantation from living donors. Portal hyperperfusion is considered to substantially contribute to small-for-size syndrome. We investigated the impact of continuous portal infusion of prostaglandin E1 (PGE1) on small-for-size grafts (SFSGs) in adult-to-adult living-donor liver transplantation (LDLT). Methods From July 2003 to December 2009, LDLT was performed in 122 patients. We introduced continuous portal infusion of PGE1 to five SFSG patients (PG group) from November 2007 to December 2009 and retrospectively compared them with a historical control group of eight relevant SFSG patients without PGE1 infusion (non-PG group) from July 2003 to October 2007 to determine the safety and efficacy of continuous PGE1 portal infusion for SFSGs. Splenectomy cases were excluded from analysis. Results The PG group demonstrated significantly lower postoperative portal pressure than the non-PG group. Moreover, the PG group demonstrated significantly improved liver function in the early posttransplantation period and significantly better recovery from hyperammonemia at 1 week after transplantation and from hyperbilirubinemia in the late posttransplantation period. Overall survival was significantly better in the PG group than in the non-PG group. Three patients in the non-PG group died of rejection-related reasons. Interestingly, immunomonitoring assay revealed that antidonor immune responses were significantly accelerated in the non-PG group compared with the PG group after LDLT. In contrast, the PG group showed well-suppressed antidonor immune responses. Conclusion Continuous portal infusion of PGE1 for SFSG attenuated portal hypertension, improved graft function, and suppressed antidonor immune responses, resulting in better survival.

Synthetic Bioabsorbable Stent Material for Duct-to-Duct Biliary Reconstruction

Biliary stricture remains a significant cause of morbidity after liver transplantation. We performed duct-to-duct biliary anastomosis by using an absorbable stent tube with a diameter equal to that of pig common bile duct as an internal stent. The stent tube was constructed using a synthetic biodegradable material-a lactic glycolic acid and epsilon-caprolactone copolymer. Three pigs were alive without cholestasis for 180 d; however, 1 pig died on the 65th postoperative d, and autopsy revealed no cholestasis or biliary sledge in the biliary stent tube. The 3 pigs were euthanized for histological examinations 180 d after surgery; the biliary stent tube was completely absorbed by this time. These experimental results showed the good patency of the absorbable biliary stent tube. In the future, the absorbable biliary stent tube is expected to be clinically developed as a biliary stent for biliary anastomosis, which may protect the biliary anastomotic stricture.

Comparative study of the Japan Integrated Stage (JIS) and modified JIS score as a predictor of survival after hepatectomy for hepatocellular carcinoma

BackgroundThe purpose of the study was to compare the abilities of the JIS and modified JIS (m-JIS) scores to predict survival after hepatectomy for hepatocellular carcinoma (HCC).MethodsData for patients who underwent hepatectomy for HCC at Hiroshima University Hospital between 1986 and 2006 were included. The overall survival and disease-free survival were calculated by the Kaplan-Meier method, and differences between groups were tested by the log-rank test. The statistics of the Akaike information criterion (AIC) were used to show the more appropriate model.ResultsA total of 626 patients were included (male/female, 468/158; mean age, 63.4 ± 9.6 years; Child-Pugh class A/B, 524/102; liver damage grade A/B/C, 356/261/9). Mean survival and disease-free survival were 8.04±0.39 and 4.69 ± 0.32 years, respectively. There was a significant difference in the overall survival rate between JIS scores 1 and 2, and 2 and 3 (P < 0.05), but not between scores 0 and 1, or 3 and 4 (P > 0.05). Except between m-JIS scores 0 and 1, there was excellent discriminatory ability in overall survival rate between other consecutive groups. Concerning disease-free survival, a significant difference was found only between JIS scores 1 and 2. However, the disease-free survival rate could be well differentiated between m-JIS scores 1 and 2, and 3 and 4. The m-JIS score had a higher discriminatory ability, indicated by a linear trend analysis, and a higher homogeneity likelihood ratio, and lower AIC statistics, than the original JIS score in predicting both overall and disease-free survival.ConclusionsThe modified-JIS scoring system using liver damage grade is better than the original JIS scoring system in predicting survival after hepatectomy for HCC in Japan.

Using recipient's middle hepatic vein for drainage of the right paramedian sector in right liver graft.

Background. Congestion in the right paramedian sector of a right liver graft without a middle hepatic vein (MHV) may lead to graft dysfunction. To solve this problem, we have developed a technique for reconstructing the MHV tributaries of the right liver grafts by using the preserved recipient’s native MHV trunk. Methods. Between 2005 and 2007, among 34 right liver graft liver transplant patients with significant MHV tributaries (>5 mm in diameter), 21 patients underwent right liver graft living-donor liver transplantation: draining MHV tributaries with recipient’s native MHV trunk. We evaluated the patency of the reconstructed MHV tributaries, graft regeneration, and graft survival. Results. The 3-month patency rates of the reconstructed V8 and V5 were 92% and 76%, respectively. The 1-year survival rate and the regeneration index of the right paramedian sector 6 months after transplantation were higher in patients with reconstructed MHV tributaries than that for patients without reconstructed MHV tributaries. Conclusion. The use of the recipient’s MHV trunk for the reconstruction of the MHV tributaries of the right liver grafts is considered to be a valuable and a feasible strategy in right liver graft living-donor liver transplantation.