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Background and Aim: Serum interleukin‐6 (IL‐6) before the administration of atezolizumab plus bevacizumab (Atez + Bev) is a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with Atez + Bev. We previously revealed that the neutrophil‐to‐lymphocyte ratio and serum chemokine levels during treatment with Atez + Bev were more useful as prognostic biomarkers. Therefore, we examined the predictive ability of serum IL‐6 for the efficacy of Atez + Bev in patients with HCC. Methods: We enrolled 94 patients with HCC who received treatment with Atez + Bev. Initial responses were assessed through dynamic computed tomography or magnetic resonance imaging. The levels of IL‐6 in serum were measured before and at the initiation of the second course of Atez + Bev. Subsequently, the relationship of IL‐6 levels with treatment efficacy was evaluated. Results: IL‐6 levels at the initiation of the second course tended to be higher in patients with progressive disease versus those with non‐progressive disease in the initial evaluation (P = 0.054). Moreover, the cutoff value (7.4 pg/mL) was useful in stratifying patients by overall survival (i.e. low vs high: not reached vs 21.4 months, respectively, P = 0.001) and progression‐free survival (low vs high: 11.9 vs 5.2 months, respectively, P = 0.004). This result was reproduced in patients with HCC who received Atez + Bev as first‐line therapy. In the multivariate analyses, IL‐6 levels at the initiation of the second course were independent predictive factors for progression‐free and overall survival. Conclusions: Serum levels of IL‐6 at the initiation of the second course of treatment may predict Atez + Bev efficacy and prognosis in HCC. [ABSTRACT FROM AUTHOR]

Introduction: Our previous studies showed that serum angiopoietin-2 (Ang-2) and C-X-C motif chemokine ligand 10 (CXCL10) levels predicted improvement in liver fibrosis following sustained virological response (SVR) of hepatitis C virus (HCV) obtained with administration of with direct-acting antiviral agents (DAAs). These levels were evaluated retrospectively as predictive indicators of hepatocellular carcinoma (HCC) development following SVR. Methods: We enrolled individuals from a historical cohort of 89 chronic HCV patients without history of HCC at baseline and with SVR following DAA therapy and had baseline serum levels of Mac-2 binding protein glycosylation isomer ≥2.0 cut-off index (C.O.I.). Results: Multivariate analyses revealed that only the Ang-2 level at 24 weeks following the end of treatment (EOT24W) was significantly related to HCC development (hazard ratio 2.27; p = 0.003). This result was reproduced in individuals without history of HCC and with advanced liver fibrosis (M2BPGi level ≥3.3 C.O.I. at baseline). Time-dependent receiver operating characteristic curve analyses for the future risk of developing HCC within 5 years of follow-up (5y-HCC) showed the best cut-off Ang-2 level at the EOT24W was 2,780 pg/mL, and significantly stratified the cumulative incidence of HCC (≥2,780 vs. < 2,780 pg/mL, 5y-HCC: 45.5 vs. 8.2%, p < 0.001). Conclusions: At the EOT24W, serum Ang-2 level predicts the likelihood of developing HCC following SVR to DAA therapy. Plain Language Summary: Our previous studies showed that serum angiopoietin-2 (Ang-2) and C-X-C motif chemokine ligand 10 (CXCL10) levels predicted improvement in liver fibrosis following sustained virological response (SVR) of hepatitis C virus (HCV) obtained with administration of with direct-acting antiviral agents (DAAs). These levels were evaluated retrospectively as predictive indicators of hepatocellular carcinoma (HCC) development following SVR. We enrolled individuals from a historical cohort of 89 chronic HCV patients without history of HCC at baseline with SVR following DAA therapy and had baseline serum levels of Mac-2 binding protein glycosylation isomer ≥2.0 C.O.I. Multivariate analyses of patients revealed that only the Ang-2 level at 24 weeks following the end of treatment (EOT24W) was significantly related to HCC development (hazard ratio 2.27; p = 0.003). This result was reproduced in individuals with advanced liver fibrosis (M2BPGi level ≥3.3 C.O.I. at baseline). Time-dependent receiver operating characteristic curve analyses for the future risk of developing HCC within 5 years of follow-up (5y-HCC) showed the best cut-off Ang-2 level at EOT24W was 2,780 pg/mL, and significantly stratified the cumulative incidence of HCC (≥2,780 vs. < 2,780 pg/mL, 5y-HCC: 45.5 vs. 8.2%, p < 0.001). The serum Ang-2 level at EOT24W is a feasible predictor of HCC development after achieving SVR to DAAs therapy. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)‐targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization. Methods: Twenty‐two patients were randomized 1:1 to receive VEGFR‐targeted peptides or placebo. The primary end‐point was the safety assessment of the immunization. The secondary end‐points were evaluation of immunological responses and clinical outcomes. Results: No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1‐specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2‐specific CTL response was induced in 10 (83.3%). The median progression‐free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response. Conclusions: Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide‐specific CTLs in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Aim: It is desirable to identify predictors of regression of liver fibrosis after achieving sustained virological response by anti‐hepatitis C virus (anti‐HCV) therapy. We retrospectively investigated the serum interferon‐γ inducible protein 10 kDa (IP‐10) level as a predictive indicator of regression of liver fibrosis after successful hepatitis C virus eradication by direct‐acting antiviral agents (DAAs) therapy. Methods: The study participants were recruited from a historical cohort of 116 chronically hepatitis C virus‐infected patients who had achieved sustained virological response by DAAs therapy and whose serum Mac‐2 binding protein glycosylation isomer (M2BPGi) levels at baseline (before DAAs therapy) were ≥2.0 cut‐off index. We defined patients with M2BPGi levels <1.76 and ≥1.76 cut‐off index at 2 years after the end of treatment (EOT) as the regression (n = 71) and non‐regression (n = 45) groups, respectively. Results: Multivariate analyses revealed that the albumin‐bilirubin score at baseline, and albumin‐bilirubin score, Fibrosis‐4 index at 24 weeks after the EOT, and serum IP‐10 change from baseline to 24 weeks after the EOT (IP‐10 change) were significantly associated with regression of M2BPGi‐based liver fibrosis. In addition, IP‐10 change was significantly associated with regression of M2BPGi‐based liver fibrosis by a multivariate analysis, even when the serum M2BPGi levels were aligned by propensity score matching and in patients with advanced M2BPGi‐based liver fibrosis: M2BPGi levels ≥3.3 cut‐off index at baseline. Conclusions: Serum IP‐10 change from baseline to 24 weeks after the EOT is a feasible predictor of regression of M2BPGi‐based liver fibrosis after achieving sustained virological response with DAA therapy. [ABSTRACT FROM AUTHOR]

A study published in Hepatology Research explores the relationship between the ribonuclease RNase-L and hepatitis B virus (HBV) infection. The researchers found a positive correlation between RNase-L levels and HBV viral titers in patients with chronic HBV infection. Higher levels of RNase-L were identified as a potential risk factor for cirrhosis. The study suggests that serum RNase-L levels could serve as a biomarker to stratify the stage of chronic hepatitis B disease, although further investigation is needed to fully understand the relationship between RNase-L and HBV. [Extracted from the article]

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high‐throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule‐1 (VCAM1), and α‐fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression‐free survival. In addition, "NR‐index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN‐resistant HepG2 cells (HepG2‐SR) and found that sCLU significantly increased in HepG2‐SR cells compared with normal HepG2 cells, and confirmed that HepG2‐SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient‐related transcription factor, sterol regulatory element binding protein 1c (SREBP‐1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2‐SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU‐related NR‐index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU‐overexpressing HCC might be susceptible to mTOR inhibition. [ABSTRACT FROM AUTHOR]