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Background and Aims: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) progresses with a highly multicentric occurrence (MO) even after radical hepatectomy. Despite several efforts to clarify the pathogenesis of MO, the underlying molecular mechanism remains elusive. The aim of this study was to evaluate alterations in DNA methylation in noncancerous liver tissues in the MO of HCC. Methods: A total of 203 patients with HCV-related HCC who underwent radical hepatectomy at our hospital between January 2008 and January 2012 were recruited. We defined a group of nonearly recurrence of HCC (NR) for ≥3 years after radical hepatectomy and a group of early recurrence of HCC (ER) with MO within 2 years after radical hepatectomy. Results: Three patients each were selected in the NR and ER groups in the first set, and 13 patients in the NR group and 17 patients in the ER group were selected in the second set. Genome-wide DNA methylation profiles were obtained from noncancerous liver tissues using a Human Methylation 450 BeadChip, and the differences between the groups were analyzed for each set. After excluding single nucleotide polymorphism-associated methylation sites and low-call sites, 401,282 sites were assessed using a generalized linear model without any adjustments. Nine gene regions, APBB1P, CLSTN3, DLG5, IRX5, OAS1, SOX12, SNX19, TENM2, and TRIM54, exhibiting a significant difference (P < .001) in DNA methylation levels were identified in the common direction between the 2 analysis sets. Conclusion: Alterations in DNA methylation of 9 genes in noncancerous liver tissues appear to be involved in MO after radical hepatectomy for HCV-related HCC.

Objective: Although sorafenib, a molecular targeted agent, has survival benefits for advanced hepatocellular carcinoma (HCC) patients, its disease control rate remains limited. To explore the potential for augmenting its antitumor effect, we assessed the preclinical and clinical efficacy and tolerability of S-1 metronomic chemotherapy (MC) plus sorafenib. Methods: Antitumor effects and toxicity of this combination were tested with HAK-1B xenograft and spontaneous HCC mouse models, and a prospective pilot study was performed to compare therapeutic effects and safety between sorafenib plus MC S-1 for 12 advanced HCC cases and the historical control of 363 sorafenib-treated advanced HCC patients at our hospital from July 2011 to June 2015. Results: In mice, the combination chemotherapy enhanced anti-angiogenic effects, resulting in a stronger tumor hypoxic environment and increased tumor cell apoptosis. Clinically, the objective response rate of the combination chemotherapy was higher than that of sorafenib mono therapy (16.7%; 2/12 vs 5.2%; 19/363, p