Hisashi Takayama

Neonatal sunburn and melanoma in mice.

Retrospective epidemiological data have indicated that cutaneous malignant melanoma may arise as a consequence of intense, intermittent exposure of the skin to ultraviolet radiation, particularly in children, rather than from the cumulative lifetime exposure that is associated with other forms of skin cancer. Here we use a genetically engineered mouse model to show that a single dose of burning ultraviolet radiation to neonates, but not adults, is necessary and sufficient to induce tumours with high penetrance which are reminiscent of human melanoma. Our results provide experimental support for epidemiological evidence that childhood sunburn poses a significant risk of developing this potentially fatal disease.

Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.

Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, but it is not clear whether HGF stimulates or inhibits hepatocarcinogenesis. We previously reported that HGF transgenic mice under the metallothionein gene promoter developed benign and malignant liver tumors spontaneously after 17 months of age. To elucidate the role of HGF in hepatocarcinogenesis, diethylnitrosamine (DEN) was administered to HGF transgenic mice. HGF overexpression accelerated DEN-induced hepatocarcinogenesis, often accompanied by abnormal blood vessel formation. In this study, 59% of transgenic males (versus 20% of wild-type males) and 39% of transgenic females (versus 2% of wild-type females) developed either benign or malignant liver tumors by 48 weeks (P<0.005, P<0.001, respectively). Moreover, 33% of males and 23% of female transgenic mice developed hepatocellular carcinoma (HCC), while none of the wild-type mice developed HCC (P<0.001, P<0.005, respectively). Enhanced kinase activity of the HGF receptor, Met, was detected in most of these tumors. Expression of vascular endothelial growth factor (VEGF) was up-regulated in parallel with HGF transgene expression. Taken together, our results suggest that HGF promotes hepatocarcinogenesis through the autocrine activation of the HGF-Met signaling pathway in association with stimulation of angiogenesis by HGF itself and/or indirectly through VEGF.

Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis

Patients with chronic hepatitis C virus (HCV) infection often develop liver cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection. Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at random into two groups. Forty-four patients were treated with alpha-tocopherol (Vit E group) while the other 39 were followed as controls. The clinical background (gender, age, and laboratory data) was similar in the two groups. Serum levels of alpha-tocopherol, albumin, alanine aminotransferase (ALT), and total cholesterol and platelet count were measured serially over a period of five years. The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment. Platelet count, serum albumin, ALT, and total cholesterol were not different between the two groups during the five-year period. Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls, albeit statistically insignificant. The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV. Although the administration of alpha-tocopherol normalized the level one month later, it could neither improve liver function, suppress hepatocarcinogenesis, nor improve cumulative survival. Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant.

Safety and efficacy of balloon‐occluded transcatheter arterial chemoembolization using miriplatin for hepatocellular carcinoma

Balloon‐occluded transcatheter arterial chemoembolization (B‐TACE) using a microballoon catheter was performed to administrate miriplatin, and the early therapeutic efficacy and safety of the procedure were evaluated.

Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine.

To examine the potentially chemopreventive effects of alpha-tocopherol on hepatocarcinogenesis, we fed the transgenic mice line MT42, which overexpresses transforming growth factor-alpha (TGF-alpha) and which has been established as having a high incidence of liver tumor, with different concentrations of alpha-tocopherol and examined the hepatic tumorigenesis of these mice. At 3 weeks of age, MT42 male mice received a single intraperitoneal injection of diethylnitrosamine (DEN), 5 mg/kg body weight, to initiate the formation of liver tumors. The mice were divided into three groups: group A, control diet (20 mg/kg of alpha-tocopherylacetate); group B, deficient diet (less than 1 mg/kg); group C, supplemented diet (500 mg/kg). Neoplastic change was determined at 40 weeks of age. The incidence of adenomas (p < 0.05), the maximum tumor size (p < 0.01), the mean relative liver weight (p < 0.01), and the proliferating cell nuclear antigen (PCNA) labeling indices of the non-tumor sites (p < 0.01) of group B were significantly higher than those of group C. No toxic effects of alpha-tocopherol were found. Alpha-tocopherol-deficient diet accelerated the hepatocarcinogenesis of TGF-alpha transgenic mice treated with DEN. At best, these data demonstrate that alpha-tocopherol-deficiency is not beneficial for prevention of hepatocarcinogenesis in this model. Alpha-tocopherol may be useful for the chemoprevention for liver cancer.

Spleen stiffness correlates with the presence of ascites but not esophageal varices in chronic hepatitis C patients.

Although spleen stiffness has recently been identified as potential surrogate marker for portal hypertension, the relationship between spleen stiffness and portal hypertension has not been fully elucidated. We attempted to determine the relationship between the liver or spleen stiffness and the presence of ascites or esophageal varices by acoustic radiation force impulse (ARFI) imaging. A total of 33 chronic hepatitis C (CHC) patients (median age 68; range 51–84) were enrolled. We evaluated the relationship between the liver or spleen stiffness and indicators of portal hypertension as well as clinical and biochemical parameters. Fourteen healthy volunteers were used for validating the accuracy of AFRI imaging. The liver and spleen stiffness increased significantly with progression of liver disease. A significant positive correlation was observed between the liver and spleen stiffness. However, spleen stiffness, but not liver stiffness, was significantly associated with the presence of ascites (P < 0.05), while there was no significant association between the spleen stiffness and spleen index/presence of esophageal varices in CHC patients. The area under the receiver operating characteristic curve based on the spleen stiffness was 0.80. In conclusion, spleen stiffness significantly correlates with the presence of ascites but not esophageal varices in CHC patients.

Prediction of Effect of Interferon on Chronic Hepatitis C

Clinical, pathological, and virological analysisincluding hypervariable region-1 of hepatitis C virus(HCV) was performed to predict the effect of interferon(IFN) on 41 patients with chronic hepatitis type C. The low virus load, low frequency ofthe mutation in the hypervariable region-1 as the changeof amino acid and high level of serum aminotransferasemake one estimate the good effect of IFN on patients with HCV. Mutation in the hypervariableregion-1 of HCV measured by fast assay fluorescencesingle-stranded conformational polymorphism was morefrequent in nonresponders to IFN than responders. Themost frequently mutated position was amino acidnumber 406. This indicates that the specific mutationsite might affect the response of IFN.

Respiratory effects of balloon occluded retrograde transvenous obliteration of gastric varices: a prospective controlled study.

Background and Aim:u2002 We evaluated the respiratory effects of balloon‐occluded retrograde transvenous obliteration (BRTO) performed for the treatment of gastric varices complicating liver cirrhosis.

Transileocolic Vein Obliteration for Bleeding Rectal Varices with Portal Thrombus

We report a case of rectal varices treated successfully with transileocolic vein obliteration (TIO). A 70-year-old man was admitted to our hospital for evaluation of fresh bloody stools in January 2011. Emergent colonoscopy revealed fresh blood in the rectum and tortuous rectal varices. Three-dimensional computed tomography was used as a non-invasive method for the identification of rectal varices and thrombus in the extrahepatic portal vein. Angiography demonstrated that rectal varices were supplied with backward blood flow by the inferior mesenteric vein. Transileocolic variceal obliteration was performed using coils and 5% ethanolamine oleate with iopamidol. Complete hemostasis was achieved without complications. We conclude that TIO is a safe and effective hemostatic measure for ruptured rectal varices with portal thrombus.

Factors predicting the overall response and overall survival in hepatocellular carcinoma patients undergoing balloon-occluded transcatheter arterial chemoembolization (B-TACE): A retrospective cohort study

This study aimed to investigate the factors predicting overall response and overall survival in hepatocellular carcinoma patients undergoing balloon‐occluded transcatheter arterial chemoembolization (B‐TACE).