Background and aims: The underlying molecular mechanisms of hepatocellular carcinoma (HCC) remain poorly understood due to its complex development process. The human T cell-specific transcription factor sex-determining region Y-related high-mobility group (HMG) box 4 ( SOX4 ) has been linked to development and tumorigenesis. In this study, we characterized the roles of SOX4 in regulation of the p53 transcription activity and evaluated the expression patterns and prognostic value of the transcription factor SOX4 in HCC. Methods: The expression levels of human SOX4 were examined in HCC samples obtained from 58 patients having curative partial hepatectomy. The interaction and effects of SOX4 on the p53 pathway were assessed in HCC cell lines. Luciferase reporter assay to examine p53-mediated transcription of target genes was performed. The association of SOX4 expression level with tumor recurrence and overall survival was evaluated. Results: We showed that the HMG box domain of SOX4 interacted with p53, resulting in the inhibition of p53-mediated transcription by the Bax promoter. More importantly, SOX4 overexpression led to a significant repression of p53-induced Bax expression and subsequent repression of p53-mediated apoptosis induced by γ-irradiation. In clinicopathological analysis, nuclear overexpression of SOX4 was observed in 37 out of 58 (63.8%) HCC samples, and this correlated with diminished risk of recurrence ( P = 0.014) and improved overall survival time ( P = 0.045) in HCC patients. Conclusion: These results suggest that SOX4 contributes to hepatocarcinogenesis by inhibiting p53-mediated apoptosis and that its overexpression might be a useful prognostic marker for survival after surgical resection.

Background: There are no convincing data supporting the routine use of pre-emptive therapy against HBV reactivation in various loco-regional therapies for hepatocellular carcinoma (HCC). This study investigated the incidence, severity and risk factors of HBV reactivation during loco-regional therapies. Methods: A total of 205 prospectively enrolled patients were classified in order of increasing intensity of loco-regional therapies: local ablation therapy (LAT; 43 patients), transarterial chemotherapy using adriamycin (TAC-ADR; 93 patients) or combined epirubicin-cisplatin (TAC-EC; 26 patients), and combined chemo-radiotherapy (TAC-EC+RT; 43 patients). Results: During the follow-up, 62 (30.2%) patients developed HBV reactivation. Multivariate analysis identified HBV DNA levels >10 ⁴ copies/ml ( P=0.041) and treatment option ( P=0.001) to be independent predictors of HBV reactivation. There was a significant trend for increasing risk of reactivation with increasing intensity of therapy, with hazard ratios of 1.0 for LAT, 2.45 for TAC-ADR, 4.19 for TAC-EC and 10.17 for TAC-EC+RT. The severity of reactivated disease was also increased with increasing treatment intensity ( P-value for trend <0.05). Only one of the patients with low-level viraemia receiving LAT alone developed reactivation, whereas a substantial number of patients with high-level viraemia eventually developed reactivation. Conclusions: High-level viraemia and high-level treatment intensity are the major risk factors for HBV reactivation during loco-regional therapy. Trends are evident for the increased risk and severity of reactivation with the aggressiveness of treatment. Pre-emptive antiviral therapy should be recommended for all patients with high-level viraemia irrespective of treatment option, or those undergoing any intensive therapy.

Lipiodol transcatheter arterial chemoembolization (TACE) is widely used to treat hepatocellular carcinoma (HCC). Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. The purpose of this study was to compare the efficacy and safety of intra-arterial injection of DEB loaded with doxorubicin versus conventional, Lipiodol-based TACE regimens in Asian patients with HCC. The study was designed as a case-control, single-institution clinical trial. Twenty patients with HCC who received DEB loaded with 50 mg doxorubicin ('cases') were matched with 20 patients who had undergone conventional TACE ('controls'). The primary efficacy endpoint was tumor response at 1 month according to modified Response Evaluation Criteria in Solid Tumors. The primary safety endpoint was liver toxicity. The rate of objective response by modified Response Evaluation Criteria in Solid Tumors was 85% (17 of 20 patients) in the DEB arm versus 30% (six of 20 patients) in the conventional TACE arm (P=0.001). Subgroup analyses conducted in patients with large (>5 cm) or multinodular tumor confirmed significantly higher objective response rates in patients receiving DEB as compared with those treated with conventional TACE (P=0.003 and P=0.005, respectively). At the dose of 50 mg doxorubicin, there was no statistically significant difference in liver toxicity between DEB and conventional TACE (P>0.05). In Asian patients with HCC, transcatheter treatment with DEB loaded with doxorubicin offers a distinct advantage in objective tumor response rate as compared with conventional, Lipiodol-based TACE regimens.

Transarterial chemoembolization (TACE) has long been used as a palliative therapy for unresectable hepatocellular carcinoma (HCC). High-dose hepatic arterial infusion chemotherapy (HAIC) has showed favorable outcomes in patients with intractable, advanced HCC. The aim of this study was to compare the effectiveness and safety of high-dose HAIC and conventional TACE using doxorubicin for advanced HCC. The high-dose HAIC group comprised 36 patients who were enrolled prospectively from six institutions. The enrollment criteria were good liver function, main portal vein invasion (including vascular shunt), infiltrative type, bilobar involvement, and/or refractory to prior conventional treatment (TACE, radiofrequency ablation, or percutaneous ethanol injection), and documented progressive disease. Patients received 5-fluorouracil (500 mg/m(2) on days 1~3) and cisplatin (60 mg/m(2) on day 2 every 4 weeks) via an implantable port system. In the TACE group, 31 patients with characteristics similar to those in the high-dose HAIC group were recruited retrospectively from a single center. Patients underwent a transarterial infusion of doxorubicin every 4~8 weeks. Overall, 6 patients (8.9%) achieved a partial response and 20 patients (29.8%) had stable disease. The objective response rate (complete response+partial response) was significantly better in the high-dose HAIC group than in the TACE group (16.7% vs. 0%, P=0.030). Overall survival was longer in the high-dose HAIC group than in the TACE group (median survival, 193 vs. 119 days; P=0.026). There were no serious adverse effects in the high-dose HAIC group, while hepatic complications occurred more often in the TACE group. High-dose HAIC appears to improve the tumor response and survival outcome compared to conventional TACE using doxorubicin in patients with intractable, advanced HCC.