Background and Aims: Patients with intermediate-stage hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE) are considered to be candidates for sorafenib. The aim of this study was to evaluate the superiority of conversion of treatment to sorafenib on overall survival (OS) for cases refractory to TACE. Methods: This was a retrospective cohort study carried out on 497 patients with HCC who were treated with TACE therapy at our hospital between January 2008 and December 2013. Fifty-six patients were diagnosed as refractory to TACE during their clinical course and they were divided into two cohorts, (1) those who switched from TACE to sorafenib and (2) those who continued TACE. The overall survival (OS) after the time of being refractory to TACE was evaluated between the two groups. Results: After refractoriness to TACE therapy was confirmed, 24 patients continued with TACE (TACE-group) and 32 patients underwent treatment conversion to sorafenib (sorafenib-group). The median OS was 24.7 months in the sorafenib-group and 13.6 months in the TACE-group (p=0.002). Conclusions: Conversion to sorafenib significantly improves the OS in patients refractory to TACE therapy with intermediate-stage HCC. Administration of sorafenib is therefore recommended in such circumstances of TACE treatment failure.

Objective: To clarify the value of contrast-enhanced harmonic ultrasonography (US) with Sonazoid, a second-generation US contrast agent, in the differential diagnosis of liver tumors compared to dynamic CT. Methods: A total of 249 hepatic nodules in 214 patients were studied; these included 177 hepatocellular carcinomas (HCCs), 42 liver metastases, 20 liver hemangiomas, 6 dysplastic nodules and 4 focal nodular hyperplasias (FNHs). After the injection of Sonazoid, nodules were scanned using real-time contrast-enhanced harmonic US in the vascular phases, i.e. the early and late vascular phases, and the Kupffer phase. Results: Six enhancement patterns were identified to be significant for the differential diagnosis of hepatic tumors. In HCCs, the presence of intratumoral vessels supplied from the periphery and fast washout (sensitivity, 96.6%; specificity, 94.4%) were the most typical characteristics. In metastases, the presence of rim-like enhancement with peripheral tumor vessels (sensitivity, 88.1%; specificity, 100%) was the typical pattern. In hemangiomas, the presence of intratumoral hypoperfusion images with globular or cotton wool-like pooling, which continue to the late vascular phase (sensitivity, 90.0%; specificity, 99.6%), was typical. In dysplastic nodules, the presence of portal enhancement without arterial supply in the early vascular phase and the presence of intratumoral uptake in the Kupffer phase (sensitivity, 83.3%; specificity, 100%) were the most typical patterns. In FNHs, the presence of a spoke-wheel pattern in the early vascular phase with dense staining in the late vascular phase, and positive uptake within the nodule in the Kupffer phase (sensitivity, 100%; specificity, 100%) were the most typical patterns. Conclusion: Contrast-enhanced harmonic US with Sonazoid allowed intimate vascular and Kupffer imaging and, therefore, is useful for the differential diagnosis of hepatic tumors.

Background: Although hepatic arterial infusion chemotherapy (HAIC) using low-dose 5-fluorouracil (5-FU) and cisplatin (low-dose FP) is commonly used for advanced hepatocellular carcinoma (HCC) with vascular invasion in Japan, few reports have investigated the efficacy and safety of this approach. We investigated the efficacy and toxicity of HAIC using low-dose FP for patients with advanced HCC as a phase II trial. Methods: Low-dose FP consisted of a continuous arterial infusion of 5-FU (250–500 mg/day, 5 days/week, for the first 2 weeks) and cisplatin (10 mg/day, 5 days/week, for the first 2 weeks). Then, 5-FU (1,000 mg/body for 5 h) and cisplatin (10 mg/body) were administered once weekly. Results: In these patients treated with low-dose FP, the response rate was 38.5%, the median time to progression was 4.1 months (95% CI 2.1–6.1 months) and the median survival time was 15.9 months (95% CI 9.8–22.0 months). The most frequent adverse events were myelosuppression such as neutropenia or thrombocytopenia. Conclusions: HAIC using low-dose FP is an effective treatment option for locally advanced HCC. However, it is not well tolerated hematologically because of potent pancytopenia and poor hepatic reserve. Therefore, this regimen should be performed carefully with regular monitoring of hematological function.

Objective: The aim of this study was to investigate liver fibrosis using non-invasive Real-time Tissue Elastography® (RTE) and transient elastography (FibroScan®) methods. Methods: RTE, FibroScan and percutaneous liver biopsy were all performed on patients with chronic liver disease, particularly hepatitis C, to investigate liver fibrosis. Results: FibroScan and RTE were compared for fibrous liver staging (F stage), which was pathologically classified using liver biopsy. In FibroScan, significant differences were observed between F1/F3 and F2/F4, but no such differences were observed between F1/F2, F2/F3 and F3/F4. In RTE, significant differences were observed between F1/F2, F2/F3 and F2/F4. But for F3/F4, no significant differences were observed. Conclusion: FibroScan and RTE correlated well with F staging of the liver. In particular RTE was more successful than FibroScan in diagnosing the degree of liver fibrosis.

Chronic hepatitis C (CHC) triggers oxidative stress and contributes to the emergence of hepatocellular carcinoma (HCC). We previously reported that tumor suppressor gene (TSG) methylation is a critical factor during the early stages of hepatocarcinogenesis. In this study, we clarify the association between oxidative stress and epigenetic alterations during hepatocarcinogenesis. We examined DNA oxidation and methylation profiles in 128 liver biopsy samples from CHC patients. The DNA oxidation and methylated TSG numbers were quantified using immunohistochemical analysis of 8-hydroxydeoxyguanosine (8-OHdG) and quantitative PCR for 11 TSGs, respectively. The quantitative chromatin immunoprecipitation-PCR (ChIP-qPCR) assay in HepG2 and fetal liver Hc cells treated with H₂O₂ was used to quantify trimethyl-H3K4, acetylated-H4K16 (an active chromatin marker), trimethyl-H3K27 (a repressive chromatin marker) and 8-OHdG. We analyzed 30 promoters of 25 different TSGs by qPCR. The high levels of 8-OHdG was the only variable that was significantly associated with the increased number of methylated TSGs in CHC (p < 0.0001). The ChIP-qPCR revealed that after H₂O₂ treatment of the cell lines, the 8-OHdG-bound promoters showed a modification from an active chromatin (trimethyl-H3K4 and acetylated-H4K16 dominant) to a repressive chromatin (trimethyl-H3K27 dominant) status. We conclude that oxidative stress alters the chromatin status, which leads to abnormal methylation of TSGs, and contributes to hepatocarcinogenesis in CHC patients.