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Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early‐stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced‐stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, the effect of direct‐acting antiviral (DAA)‐induced sustained virologic response (SVR) on HCC progression remains uninvestigated. We conducted a retrospective cohort study of patients with hepatitis C virus‐related HCC with BCLC stage 0/A diagnosed for the first time and treated by curative resection or ablation. Using a time‐varying method, we estimated the risk of tumour progression (defined as progression to BCLC stage B‐D) and liver‐related death and the characteristics of repeated recurrence. Overall, 165 patients were enrolled. Following curative HCC treatment, 72 patients received DAA therapy (DAA‐treated group), whereas 93 did not (untreated group). Approximately 75% of the recurrences were at an early stage and expected to be disease‐free by retreatment. We recorded 56 tumour progressions, of which 60.7% were observed after second recurrence. Multivariate adjusted time‐varying Cox regression analysis showed that the DAA‐induced SVR significantly reduced the risk of tumour progression (hazard ratio [HR] 0.28; p =.001) and liver‐related death (HR 0.12; p <.001). The annual incidence of HCC treatment until tumour progression was 82.8% and 23.9% in the untreated and DAA‐treated groups, respectively (HR 0.30; p <.001). DAA‐induced SVR significantly reduced the risk for tumour progression and liver‐related death and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A. [ABSTRACT FROM AUTHOR]

Introduction: Lenvatinib has been approved as a systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). We recently experienced lenvatinib-induced tumor-related hemorrhage in patients with HCC. The full details of tumor-related hemorrhage as a lenvatinib-related adverse event have not been elucidated. Methods: This was a retrospective single-center study that enrolled consecutive patients treated with lenvatinib for unresectable HCC from April 2018 to February 2020. Results: Sixty-eight consecutive patients were enrolled in this study. Among them, 5 cases developed intraperitoneal or intratumoral hemorrhages. The patients with hemorrhage had larger tumors (maximum tumor size, 97.5 ± 46.4 and 38.2 ± 28.8 mm, respectively; p = 0.009) than the patients without hemorrhage. The dosing period of lenvatinib (median, 3 and 93 days, respectively; p < 0.001) and the survival time from initial administration of lenvatinib (median, 77 and 495 days, respectively; p < 0.001) of the patients with hemorrhage were shorter than those of the patients without hemorrhage. Especially, in 4 cases with large HCCs (maximum tumor diameter was >90 mm), tumor hemorrhage with vascular lake-like phenomenon was evident, although most tumor blood flow was suppressed. Discussion/Conclusion: It becomes clear that lenvatinib treatment brings about tumor-related hemorrhages despite rapid suppression of tumor blood flow. We speculate that lenvatinib quickly blocks the feeding circulation, resulting in tumor hemorrhage by necrosis. Clinicians should pay careful attention to the development of life-threatening hemorrhages when treating large HCCs with lenvatinib. [ABSTRACT FROM AUTHOR]

Background and Aims: It remains unclear whether there is an association between single‐nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog‐naïve patients with chronic hepatitis B virus infection. We investigated the risk factors for HCC, especially host factors, during ETV treatment. Methods: A total of 127 Japanese patients undergoing ETV treatment were enrolled in this study. Univariate and multivariate analyses for clinical factors, hepatic fibrosis markers, and SNPs associated with HCC development were analyzed. Results: A total of 10 patients developed HCC during the follow‐up period (median duration, 3.3 years). The 3‐, 5‐, and 7‐year cumulative rates of HCC development were 4.8%, 10.6%, and 13.6%, respectively. Liver fibrosis (cirrhosis; P = 0.0005), age (≥ 49 years; P = 0.0048), platelet count (≤ 115 × 10/mm3; P = 0.0007), α‐fetoprotein (≥ 8.0 ng/mL; P = 0.030), type IV collagen (≥ 200 ng/mL; P = 0.043), fibrosis‐4 index (≥ 4.14; P = 0.0006), and human leukocyte antigen (HLA)‐DQA1/DRB1‐SNP (AA genotype; P = 0.0092) were significantly associated with HCC development according to the log‐rank test. In multivariate analysis, AA genotype in the HLA‐DQA1/DRB1 gene (P = 0.013; hazard ratio 4.907; 95% confidence interval 1.407–17.113) and cirrhosis (P = 0.019; hazard ratio 4.789; 95% confidence interval 1.296–17.689) were significantly associated with HCC development. Conclusions: Our findings suggested that patients with AA genotype in the HLA‐DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment. [ABSTRACT FROM AUTHOR]