Takafumi Ichida

Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey

Advances in the diagnosis and surgical treatment of hepatocellular carcinoma (HCC) have improved the prognosis for patients with HCC who undergo liver resection. The objective of this study was to evaluate prognostic predictors for patients with HCC who underwent liver resection in a Japanese nationwide data base.

Genome-wide Association Study Identifies TNFSF15 and POU2AF1 as Susceptibility Loci for Primary Biliary Cirrhosis in the Japanese Population

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84xa0× 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38xa0× 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined pxa0= 3.66xa0× 10(-8), 3.66xa0× 10(-9), and 3.04xa0× 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11xa0× 10(-6) and 1.42xa0× 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Comparison of resection and ablation for hepatocellular carcinoma: A cohort study based on a Japanese nationwide survey

BACKGROUND & AIMSnThe treatment of choice for early or moderately advanced hepatocellular carcinoma (HCC) with good liver function remains controversial. We evaluated the therapeutic impacts of surgical resection (SR), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) on long-term outcomes in patients with HCC.nnnMETHODSnA database constructed on the basis of a Japanese nationwide survey of 28,510 patients with HCC treated by SR, PEI, or RFA between 2000 and 2005 was used to identify 12,968 patients who had no more than 3 tumors (≤ 3 cm) and liver damage of class A or B. The patients were divided into SR (n=5361), RFA (n=5548), and PEI groups (n=2059). Overall survival and time to recurrence were compared among them.nnnRESULTSnMedian follow-up was 2.16 years. Overall survival at 3 and 5 years was respectively 85.3%/71.1% in the SR group, 81.0%/61.1% in the RFA, and 78.9%/56.3% in the PEI. Time to recurrence at 3 and 5 years was 43.3%/63.8%, 57.2%/71.7%, and 64.3%/76.9%, respectively. On multivariate analysis, the hazard ratio for death was significantly lower in the SR group than in the RFA (SR vs. RFA:0.84, 95% confidence interval, 0.74-0.95; p=0.006) and PEI groups (SR vs. PEI:0.75, 0.64-0.86; p=0.0001). The hazard ratios for recurrence were also lower in the SR group than in the RFA (SR vs. RFA:0.74, 0.68-0.79; p=0.0001) and PEI groups (SR vs. PEI:0.59, 0.54-0.65; p=0.0001).nnnCONCLUSIONSnOur findings suggest that surgical resection results in longer overall survival and time to recurrence than either RFA or PEIin patients with HCC [corrected].

Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma

Aim:u2002 Intra‐arterial cisplatin appears to have high therapeutic efficacy, but this has not been studied in detail. Accordingly, we developed a fine‐powder cisplatin formulation and tested it in advanced hepatocellular carcinoma (HCC) patients in an open‐label, uncontrolled study in which 27 institutions participated.

A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. In addition to hepatitis viral infections, several cohort studies have shown that diabetes mellitus is a risk factor of HCC, making the incidence alarming high. However, it has not been demonstrated directly how diabetes develops to HCC, because of its difficulty to follow changes of liver histology in diabetic populations. Here, we report that non-alcoholic steatohepatitis (NASH) is pivotal to link diabetes with HCC by establishing a novel, reproducible NASH–HCC model in mice. Neonatal male mice exposed to low-dose streptozotocin (STZ) developed liver steatosis with diabetes 1xa0week after feeding high-fat diet (HFD). Continuous HFD decreased hepatic fat deposit whilst increased lobular inflammation with foam cell-like macrophages, showing NASH pathology. In parallel with decreased phagocytosis of macrophages, fibroblasts accumulated to form “chicken-wired” fibrosis. All mice developed multiple HCC later. Female mice treated with STZ–HFD and male mice treated with STZ alone showed diabetes but never developed HCC by the absence of NASH-based fibrosis. Thus, the present study provides the evidence in novel mouse model that NASH-based fibrosis is an essential histological process for diabetic populations to accelerate the development of HCC.

The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study

Aim:u2002 Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis.

Asian consensus workshop report: expert consensus guideline for the management of intermediate and advanced hepatocellular carcinoma in Asia.

Hepatocellular carcinoma (HCC) is a highly prevalent disease in many Asian countries, accounting for 80% of victims worldwide. Screening programs improve the detection of early HCC and have a positive impact on survival, but the majority of HCC patients in Asia still present with advanced stage disease. The treatment outcomes of HCC are affected by multiple variables, including liver function, performance status of the patient, and tumor stage. Therefore, it is not easy to apply a multidisciplinary therapeutic approach for optimal management. At present, limited numbers of HCC patients are eligible for curative therapies such as surgery or ablation in Asia. Therefore, most patients are eligible for only palliative treatments. For optimal management, the treatment choice is guided by staging systems and treatment guidelines. Numerous staging systems have been proposed and treatment guidelines vary by region. According to the Barcelona Clinic Liver Cancer (BCLC) guideline based on evidence from randomized clinical trials, only transarterial chemoembolization (TACE) is recommended for intermediate stage HCC and sorafenib for advanced stage HCC. However, treatment guidelines from Asian countries have adopted several other therapeutic modalities such as a surgical approach, hepatic arterial infusion chemotherapy, external radiation, and their combinations based on clinical experiences for intermediate and advanced stage HCC. Although TACE is the main therapeutic modality in the intermediate stage, overall therapeutic outcomes depend on the tumor size. In the advanced stage, the prognosis depends on the tumor status, e.g. major vessel invasion or extrahepatic spread. Thus, a new staging system representing prognoses suitable for Asian HCC patients and a corresponding optimal treatment algorithm should be further investigated using evidence-based data, which will finally bring about an Asian consensus for the management of intermediate and advanced stage HCC.

Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan : Summary of the annual nationwide survey between 2004 and 2009

To summarize the annual nationwide survey on fulminant hepatitis (FH) and late‐onset hepatic failure (LOHF) between 2004 and 2009 in Japan.

Diagnostic criteria of acute liver failure: A report by the Intractable Hepato-Biliary Diseases Study Group of Japan

The diagnostic criteria of fulminant hepatitis in Japan are different from those of acute liver failure in Europe and the United States, both in regard to the histological features in the liver and the cutoff values of the prothrombin time. Thus, the Intractable Hepato‐Biliary Disease Study Group established novel diagnostic criteria for “acute liver failure” in Japan based on the demographic and clinical features of the patients. Patients showing prothrombin time values of 40% or less of the standardized values or international normalized ratios of 1.5 or more caused by severe liver damage within 8u2003weeks of onset of the symptoms are diagnosed as having “acute liver failure”, where the liver function prior to the current onset of liver damage is estimated to be normal. Acute liver failure is classified into “acute liver failure without hepatic coma” and “acute liver failure with hepatic coma,” depending on the severity of the hepatic encephalopathy; the latter is further classified into two types, the “acute type” and the “subacute type”, in which grade II or more severe hepatic coma develops within 10u2003days and between 11 and 56u2003days, respectively, after the onset of disease symptoms. Patients without histological findings of hepatitis, such as those with liver damage caused by drug toxicity, circulatory disturbance or metabolic disease, are also included in the disease entity of “acute liver failure”, while acute‐on‐chronic liver injuries, such as liver injury caused by alcohol, are excluded. A nationwide survey of “acute liver failure” in Japan based on the novel criteria is proposed.

A modified Japan Integrated Stage score for prognostic assessment in patients with hepatocellular carcinoma

BackgroundFor patients with hepatocellular carcinoma (HCC), the selection of effective therapeutic options depends on a reliable prognostic assessment of both the tumor characteristics and liver impairment. This study sought to provide a modified Japan Integrated Stage (m-JIS) score to predict more accurately the survival of patients with HCC.MethodsWe analyzed the records of 42u2009269 patients diagnosed with HCC that were registered between 1992 and 1999 in a nationwide Japanese database. The m-JIS score was calculated from the tumor-node-metastasis stage and the grade of liver damage as defined by the Liver Cancer Study Group of Japan. The predictive accuracy for patient survival based on the m-JIS score was compared with that determined by the modified Cancer of the Liver Italian Program (m-CLIP) score using the cross-validation method.ResultsPatients were divided randomly into two groups, a training sample for construction of prediction models (n = 21u2009127 patients with 8458 deaths) and a validation sample for assessment of those prediction models (n = 21u2009142 patients with 8434 deaths). Both the m-JIS score and the m-CLIP score showed good discriminatory ability in the training sample. In the validation sample, the residuals of prediction based on the m-JIS score were smaller than those of the m-CLIP score (P < 0.0001).ConclusionsThe m-JIS scoring system had better predictive accuracy than the m-CLIP score system for survival of Japanese patients with HCC.