Aim The predictors for the development of hepatocellular carcinoma (HCC) after direct‐acting antiviral (DAA) treatment were investigated. Methods A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed. Results During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre‐ and post‐treatment factors identified the Fibrosis‐4 (FIB‐4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021–1.178; P = 0.011) and post‐treatment α‐fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054–1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high‐score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1‐ and 2‐year cumulative incidence rates of HCC were 6.1% and 14.4%. Conclusions A high FIB‐4 index and a high post‐treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed.

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Dendritic cells (DCs) are increasingly used as adjuvants for vaccination strategies; however, there has been very little development in DC vaccines for patients with hepatocellular carcinoma (HCC). In this study, we assessed the safety, feasibility and efficacy of a multiple tumor-associated antigen (TAA)-pulsed DC vaccine in 5 patients with advanced HCC. DCs were generated by culturing blood monocytes in the presence of granulocyte macrophage-colony stimulating factor and interleukin-4 for 5 days. The DC vaccine was prepared by pulsing DCs with cytoplasmic transduction peptide-attached α-fetoprotein, glypican-3 and MAGE-1 recombinant fusion proteins and cultivating them in the presence of maturation cocktail. DCs were injected subcutaneously near the inguinal lymph nodes, followed by topical application of toll-like receptor-7 agonist around the injection site. We showed that our DC vaccine was safe and well-tolerated over 6 vaccinations in 5 patients. All 5 patients showed T cell responses against TAAs. Clinical benefit was observed in one of the 5 patients. In conclusion, the feasibility, safety and immune activity of DCs pulsed with TAAs were confirmed in HCC patients. However, clinical response was detected only in one patient. Future trials may consider applying this therapy in a less advanced stage to obtain better clinical responses.

Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell‐activating factor (BAFF) in the induction of insulin resistance. We investigated BAFF levels in the sera and VAT of obese mice. In obese mice, the BAFF levels were preferentially increased in VAT and sera compared to these levels in normal control mice. Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate‐1 in adipocytes. We propose that autocrine or paracrine BAFF and BAFF‐receptor (BAFF‐R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.

À mice fed a high-fat diet (HFD). Furthermore, the effect of BAFF on lipid metabolism in hepatocytes was analyzed in vitro. BAFF-R À / À mice showed improvements in HFD-induced obesity and insulin resistance. In addition, the number of B cells, levels of serum IgG, and inflammation of visceral fat were reduced in these mice. However, the expression of steatogenic genes and fatty acid deposition in the liver was higher in these mice than in control mice. BAFF was also found to downregulate the expression of steatogenesis genes and enhance steatosis in hepatocytes through BAFF-R. Collectively, these data indicated that, in addition to its known functions in inflammation and glucose metabolism, BAFF has a protective role in hepatic steatosis by regulating lipid metabolism in the liver.