Immune checkpoint inhibitors (ICIs) with nivolumab and pembrolizumab are promising agents for advanced hepatocellular carcinoma (HCC) but lack of effective biomarkers. We aimed to investigate the potential predictors of response and factors associated with overall survival (OS) for ICI treatment in unresectable HCC patients. Ninety-five patients who received nivolumab or pembrolizumab for unresectable HCC were enrolled for analyses. Radiologic evaluation was based on RECIST v1.1. Factors associated with outcomes were analyzed. Of 90 patients with evaluable images, the objective response rate (ORR) was 24.4%. Patients at Child–Pugh A or received combination treatment had higher ORR. Early alpha-fetoprotein (AFP) >10% reduction (within 4 weeks) was the only independent predictor of best objective response (odds ratio: 7.259, p = 0.001). For patients with baseline AFP ≥10 ng/mL, significantly higher ORR (63.6% vs. 10.2%, p < 0.001) and disease control rate (81.8% vs. 14.3%, p < 0.001) were observed in those with early AFP reduction than those without. In addition, early AFP reduction and albumin-bilirubin (ALBI) grade or Child–Pugh class were independent factors associated with OS in different models. In conclusion, a 10-10 rule of early AFP response can predict objective response and survival to ICI treatment in unresectable HCC. ALBI grade and Child–Pugh class determines survival by ICI treatment.

Background and Aims: For patients with intermediate-stage hepatocellular carcinoma (HCC), the definition of high tumor burden remains controversial. This study aimed to compare the prognostic value of different criteria of tumor burden in patients with intermediate-stage HCC undergoing transarterial chemoembolization (TACE). Methods: From 2007 to 2019, 632 treatment-naive patients with intermediate-stage HCC undergoing TACE were retrospectively enrolled. We compared different criteria of tumor burden in discriminating radiologic response and survival, including up-to-7, up-to-11, 5–7, 7 lesions criteria, and newly proposed 7–11 criteria. Results: The proportions of patients classified as high tumor burden were varied by different criteria. Among the 5 criteria, 7–11 criteria have the best performance to discriminate complete response (CR) and overall survival (OS) after TACE. In patients with low, intermediate, and high tumor burden classified by 7–11 criteria, the CR rate was 21, 12, and 2.5%, respectively (p < 0.001), and the median OS was 33.1, 22.3, and 11.9 months, respectively (p < 0.001). By multivariate analysis, 7–11 criteria were significantly associated with CR (intermediate vs. high burden, odds ratio = 4.617, p = 0.002; low vs. high burden, odds ratio = 8.675, p < 0.001) and OS (intermediate vs. high burden, hazard ratio = 0.650, p < 0.001; low vs. high burden, hazard ratio = 0.520, p < 0.001). Seven to 11 criteria also had the lowest corrected Akaike information criteria, highest homogeneity value, and highest area under the receiver operating characteristic curve in predicting 1-, 2-, and 3-year mortality among all criteria. Conclusion: Conventional definitions of tumor burden were not optimal for patients with intermediate HCC. The new 7–11 criteria had the best discriminative power in predicting radiologic response and survival in patients with intermediate-stage HCC undergoing TACE.

Immune checkpoint inhibitors (ICIs) can restore exhausted T cell immunity not only for cancer treatment but also potentially for curing chronic hepatitis B (CHB). The impact of ICIs on Hepatitis B surface antigen (HBsAg) seroclearance in cancer patients was unclear. Consecutive cancer patients from 2016 to 2020 (Cohort 1, n=118), and hepatocellular carcinoma (HCC) patients from 2020 to 2022 (Cohort 2, n=44, as validation) receiving ICIs and positive for HBsAg were retrospectively recruited. An additional hepatitis B virus (HBV)-HCC cohort (Cohort 3, n=85) without ICI served as a control group. Factors associated with HBsAg loss or combining HBsAg decline >1 log were analyzed. With median follow-up of 17.5 months, 8 (6.8%) in cohort 1 and 4 (9.1%) in cohort 2 achieved HBsAg seroclearance, and additional 4 in cohort 1 and 1 in cohort 2 had HBsAg decline >1 log. In multivariate analysis, HBsAg <100 IU/mL was associated with HBsAg seroclearance (HR=6.274, p=0.028). In the validation cohort, the cumulative incidence of HBsAg loss at months 12 and 24 was 13.0% and 38.4% for baseline HBsAg 1 log, 16 (94.1%) had nucleos(t)ide analogs treatment. The median time to HBsAg loss or HBsAg decline was 16.5 months (ranged 9.6 to 27.5). ICIs may accelerate HBsAg seroclearance in cancer patients with baseline HBsAg <100 IU/ml. This finding provides important information for the design of future ICI trials to achieve functional cure in patients with CHB.

Purpose: Modified gemcitabine and S-1 (GS) is an active regimen for patients with advanced biliary tract cancer (ABTC) in our previous study. Herein, we report the results of a single-arm phase II of nivolumab plus modified GS (NGS) as first-line treatment in ABTC. Patients and Methods: Patients received nivolumab 240 mg and 800 mg/m2 gemcitabine on day 1 plus daily 80/100/120 mg of S-1 (based on body surface area) on days 1 to 10, in a 2-week cycle. The primary endpoint was the objective response rate (ORR). The correlation between therapeutic efficacy and genetic alterations with signatures identified by targeted next-generation sequencing panels was explored. Results: Between December 2019 and December 2020, 48 eligible patients were enrolled. After a median of 17.6 months of follow-up, the ORR was 45.9% [95% confidence interval (CI), 31.4%–60.8%]. The median progression-free survival (PFS) and overall survival (OS) was 9.1 (95% CI, 5.8–9.6) and 19.2 (95% CI, 11.6–not reached) months, respectively. All grade 3/4 treatment-related adverse events (AE) were less than 10%, except fatigue (14.6%) and skin rash (10.4%). Eighteen patients (35.4%) experienced immune-related AEs without treatment-related death. High tumor mutational burden (TMB-H; top 20%; ≥7.1 mut/Mb) only predicted prolonged median PFS but not OS. Up to 28.9% of patients who harbored loss-of-function mutations in chromatin remodeling genes demonstrated significantly longer median PFS and OS than those without alterations. Conclusions: NGS is a safe and promising regimen in ABTC. Impaired functions of chromatin remodeling genes may be a potential surrogate biomarker with predictive value in this study.

Background and Aims: Gut microbiota could modulate the outcome of cancer immunotherapy, including HCC. Although metabolic dysfunction–associated steatotic liver disease-related HCC (MASLD-HCC) and viral hepatitis-related HCC (V-HCC) exhibit different tumor microenvironments and gut microbiome composition, both respond to combination immunotherapy. This study aimed to investigate whether distinct microbiota/metabolomic signatures are associated with outcomes of combination immunotherapy in MASLD-HCC and V-HCC, separately. Approach and Results: Between January 2021 and April 2024, 77 V-HCC patients and 25 with MASLD-HCC initiating first-line combination immunotherapy were prospectively enrolled. Pre-treatment fecal microbiota/metabolites and serum cytokines/chemokines were analyzed in association with durable tumor response, overall survival (OS) and progression-free survival (PFS). MASLD-HCC patients showed predominant fecal Bacteroides ovatus, Kluyvera georgiana, Klebsiella oxytoca, and Enterococcus faecium, with lower levels of short-chain fatty acids (SCFAs) and ursodeoxycholic acid (UDCA) compared to V-HCC. Durable responders (DRs) of MASLD-HCC had enriched Mediterraneibacter gnavus ATCC 29149 and significantly higher SCFAs (acetate, propionate, butyrate, and isobutyrate) and UDCA. In contrast, V-HCC-DRs were characterized by predominant Bifidobacterium and similarly enriched SCFAs. In both MASLD-HCC and V-HCC, fecal acetate level was a common significant predictor of DR, PFS, and OS. Patients with higher acetate levels had significantly longer OS (median: 25.2 vs. 11.3 mo; p<0.001) and PFS (median: 15.3 vs. 4.2 mo; p<0.001). Conclusions: Distinct gut microbiota, but shared beneficial metabolites, particularly fecal acetate, are associated with durable response to combination immunotherapy and improved survival in both MASLD-HCC and V-HCC. Fecal acetate may serve as a potential biomarker and therapeutic target for optimizing HCC treatment.

Introduction: Outcomes of transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) are diverse because of the heterogeneity of tumor burden. Radiologic pattern is one criterion for determining whether TACE is unsuitable. However, additional evidence is required. This study determined the influence of radiologic morphology on the outcomes of initial and subsequent TACE. Methods: From January 2007 to September 2021, 633 treatment-naive patients with HCC with intermediate-stage HCC undergoing TACE were retrospectively enrolled. Of these patients, 386 patients received repeated TACE. The radiological features of HCC were evaluated by two radiologists and classified into encapsulated nodular type, simple nodular type with extranodular growth, confluent multinodular type, and infiltrative type. The objective response rate (ORR) and survival rate after initial and subsequent TACE among various radiologic morphologies were compared. Results: After initial TACE, encapsulated nodular type HCC had the highest ORR (58%), followed by extranodular type (45.8%), confluent multinodular type (29%), and infiltrative type (19.5%). Notably, radiologic pattern was highly associated with tumor burden. Tumor burden and radiologic morphology were significantly associated with ORR and overall survival (OS) in the multivariate analysis. In 386 patients with subsequent TACE, encapsulated nodular type HCC had the highest ORR (48.7%), followed by extranodular type (37.3%), confluent multinodular type (26.2%), and infiltrative type (10%). In the multivariate analysis, radiologic features were significant independent predictors of ORR and OS after receiving subsequent TACE. Conclusion: Radiologic patterns determine the outcomes of initial and subsequent TACE. Systemic therapy should be considered for patients with intermediate-stage HCC with unfavorable radiologic patterns.