Global burden of vaccine-associated hepatobiliary and gastrointestinal adverse drug reactions, 1967-2023: A comprehensive analysis of the international pharmacovigilance database.

Although previous studies have focused on hepatobiliary and gastrointestinal adverse drug reactions (ADRs) associated with COVID-19 vaccines, literature on such ADRs with other vaccines is limited, particularly on a global scale. Therefore, we aimed to investigate the global burden of vaccine-associated hepatobiliary and gastrointestinal ADRs and identify the vaccines implicated in these occurrences. This study utilized data from the World Health Organization (WHO) international pharmacovigilance database to extract reports of vaccine-associated hepatobiliary and gastrointestinal ADRs from 1967 to 2023 (total reports = 131 255 418). Through global reporting counts, reported odds ratios (ROR) with 95% confidence interval (CI), and information components (IC) with IC0.25, the study examined the association between 16 vaccines and the incidence of hepatobiliary and gastrointestinal ADRs across 156 countries. Of the 6 842 303 reports in the vaccine-associated ADRs, 10 786 reports of liver injury, 927 870 reports of gastrointestinal symptoms, 2978 reports of pancreas and bile duct injury, and 96 reports of intra-abdominal hemorrhage between 1967 and 2023 were identified. Most hepatobiliary and gastrointestinal ADRs surged after 2020, with the majority of reports attributed to COVID-19 messenger RNA (mRNA) vaccines. Hepatitis A vaccines exhibited the highest association with liver injury (ROR [95% CI]: 10.30 [9.65-10.99]; IC [IC0.25]: 3.33 [3.22]), followed by hepatitis B, typhoid, and rotavirus. Specifically, ischemic hepatitis had a significant association with both Ad5-vectored and mRNA COVID-19 vaccines. Gastrointestinal symptoms were associated with all vaccines except for tuberculosis vaccines, particularly with rotavirus (11.62 [11.45-11.80]; 3.05 [3.03]) and typhoid (11.02 [10.66-11.39]; 3.00 [2.96]). Pancreas and bile duct injury were associated with COVID-19 mRNA (1.99 [1.89-2.09]; 0.90 [0.83]), MMR (measles, mumps, and rubella), and papillomavirus vaccines. For intra-abdominal hemorrhage, inactivated whole-virus COVID-19 vaccines (3.93 [1.86-8.27]; 1.71 [0.41]) had the highest association, followed by COVID-19 mRNA (1.81 [1.42-2.29]; 0.77 [0.39]). Most of these ADRs had a short time to onset, within 1 day, and low mortality rate. Through a global scale database, the majority of ADRs occurred within 1 day, emphasizing the importance of healthcare workers' vigilant monitoring and timely management.

Five-year on-treatment variables-based PPACS model predicts subsequent hepatocellular carcinoma in entecavir/tenofovir-treated patients.

Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term potent antiviral therapy, models predicting HCC after 5 years of therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4-fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore, Platelet counts and Prothrombin time at 5 years, Age at baseline and Sex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time-dependent area under the curve of 0.80 (95% confidence interval, 0.75-0.85) at 8-year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (https://ppacs.shinyapps.io/shiny_app_up/).

Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study.

BACKGROUND/AIMS: Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS: This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS: A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS: During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.

Changes in general and central fatness are associated with hepatocellular carcinoma: A Korean nationwide longitudinal study.

We investigated the impact of short-term changes in general and central fatness on the risk of hepatocellular carcinoma (HCC) in a large, population-based cohort. We screened 7 221 479 subjects who underwent health examinations provided by the National Health Insurance Service of South Korea in 2009 and 2011. In total, 6 789 472 subjects were included in the final analysis. General fatness was defined as a body mass index (BMI) ≥25 kg/m2 , and central fatness was defined as a waist circumference (WC) ≥90 cm in men and ≥85 cm in women. Subjects were classified according to the change in body fatness between 2009 and 2011, as follows: (a) persistent no fatness as no fatness in both 2009 and 2011, (b) reversed fatness as fatness in 2009, but no fatness in 2011, (c) incident fatness as no fatness in 2009, but fatness in 2011 or (d) persistent fatness as fatness in both 2009 and 2011. During a median 6.4-year follow-up, we documented 9952 HCC cases. Compared to subjects with a persistent no general fatness, the risk of HCC significantly increased in those with incident (adjusted hazard ratio [aHR] = 1.10, 95% confidence interval [CI] = 1.01-1.20) and persistent (aHR = 1.28, 95% CI = 1.23-1.34) general fatness. Compared to subjects with persistent no central fatness, those with incident and persistent central fatness showed a significantly increased risk of HCC (aHR = 1.19, 95% CI = 1.11-1.27 and aHR = 1.33, 95% CI = 1.26-1.40, respectively). Taken together, these findings indicate the importance of strategies for preventing and reversing body fatness to reduce the incidence of HCC.

Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma.

BACKGROUND AND AIMS: Sirtuin 1 (SIRT1) is a complex NAD+ -dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA). APPROACH AND RESULTS: A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD -producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1-overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α-tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma-associated oncogene 1, phosphorylated extracellular signal-regulated kinase, and IL-6) expression. CONCLUSIONS: In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

Gamma-glutamyl transpeptidase dynamics as a biomarker for advanced fibrosis in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: It is unclear whether changes in lipid profile and liver biochemistry are associated with advanced fibrosis. METHODS: Patients diagnosed with non-alcoholic fatty liver disease (NAFLD) between 2009 and 2017 were included. The changes in blood tests were calculated as follows: [(value at 6 months - value at baseline)/value at baseline] × 100. The endpoint was advanced fibrosis determined by the NAFLD fibrosis score, calculated every year from diagnosis until 2019. Cox proportional hazards models were used to identify factors predicting advanced fibrosis. RESULTS: After a median follow-up of 31.7 (19.4-50.8) months, advanced fibrosis occurred in 64 (6.3%) of 1021 patients. Gamma-glutamyl transpeptidase (GGT) levels (72.9 vs 51.1 IU/L; P = 0.23) and ΔGGT (+6.0% vs -6.9%; P = 0.06) were higher in the advanced fibrosis group. ΔGGT (hazard ratio [HR] 1.03; P < 0.001) was significantly associated with advanced fibrosis after adjusting for age and platelet count. The positive ΔGGT group showed a higher incidence of advanced fibrosis and the 1-standard deviation increment in ΔGGT showed a significant association with advanced fibrosis both in statin users (HR, 1.35) and in non-users (HR, 1.31; Ps < 0.05). The restricted cubic spline model identified a positive correlation between ΔGGT and the NAFLD fibrosis scores (P < 0.001). ΔGGT showed sensitivity of 64.2%, specificity of 52.6%, and negative predictive value of 98.3% in predicting advanced fibrosis. CONCLUSIONS: ΔGGT calculated at 6 months following NAFLD diagnosis is associated with advanced fibrosis.

High body mass index hinders fibrosis improvement in patients receiving long-term tenofovir therapy in hepatitis B virus-related cirrhosis.

Long-term suppression of hepatitis B virus with tenofovir (TDF) induces fibrosis regression, and repeated liver stiffness (LS) measurement can indicate the improvement of fibrosis. We aimed to investigate predictors for LS improvement assessed by changes in patients receiving long-term TDF therapy in chronic hepatitis B (CHB) with liver cirrhosis. CHB patients with histologically proven liver cirrhosis who received TDF as the first-line therapy from 2012 to 2015 were recruited. LS and controlled attenuation parameter (CAP) measurements were repeated at baseline and 3 years after therapy. Liver stiffness improvement was defined as a drop of LS value ≥30% from the baseline. A total of 131 patients were enrolled (mean age 51.4% and male 64.9%). After 3 years of TDF therapy, the mean LS value significantly improved (from 14.7 to 8.6 kPa, P < .001), and 96 (73.3%) patients have achieved LS improvement. Predictors associated with improvement of LS were low body mass index (BMI), HBeAg positivity, and low CAP value at baseline. In multivariate analysis, low BMI was a single factor independently associated with LS improvement (odds ratio 0.680, 95% CI 0.560-0.825, P < .001). Patients with BMI < 23.5, had a 1.96 times more chance of achieving LS improvement compared to those with BMI ≥ 23.5 (90.1% vs. 46.0%, P = .001). High BMI was a single significant factor hindering the fibrosis improvement in patients receiving long-term TDF therapy in CHB with liver cirrhosis. Life style modification and BMI reduction should be encouraged to enhance fibrosis improvement.

Validation and reappraisal of the assessment for retreatment with transarterial chemoembolization score for unresectable non-metastatic hepatocellular carcinoma in a hepatitis b virus-endemic region.

OBJECTIVES: To validate and reappraise the Assessment for Retreatment with Transarterial chemoembolization (ART) score comprising three parameters (>25 % increase in aspartate aminotransferase [AST], increase in Child-Pugh score and tumour response), determined prior to subsequent transarterial chemoembolization (TACE). METHODS: Enrolled patients were diagnosed with unresectable non-metastatic hepatocellular carcinoma and underwent multiple TACEs between June 2006 and December 2007 (N = 153). Subgroupings were classified according to the established cut-off (≤1.5 vs. ≥2.5). Survival analysis using the Kaplan-Meier curve was performed. RESULTS: The original ART score dichotomized patients according to their overall survival (P = 0.004). We found several patients who actually survived longer than others were assigned to a poor prognostic group due to the AST component. Parameter estimates for AST obtained from our analysis were much lower than the original version (0.5 vs. 2.1). We adjusted the component according to the value of our parameter estimates, and patients with >25 % AST increase received 1.0 point. After this modification, patients assigned to the favourable prognostic group were more likely to have a better survival outcome (median 23.9 vs. 12.2 months, P < 0.001). CONCLUSIONS: In hepatitis B virus-endemic regions, the ART score is valid and can better predict post-TACE survival after the AST component is modified. KEY POINTS: • The ART score was validated in a HBV-endemic region. • The modified ART score improved prognostic performance by reappraising the AST component. • The modified ART score helps physicians make decisions for further TACE.

Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance.

BACKGROUND & AIMS: Little is known about whether surveillance for hepatocellular carcinoma (HCC) is worthwhile in chronic hepatitis B virus (HBV)-infected patients who have achieved HBsAg seroclearance. METHODS: A retrospective analysis of 829 patients (mean age: 52.3 years; 575 males; 98 with cirrhosis) achieving HBsAg seroclearance was performed at a tertiary hospital in Korea between 1997 and 2012. We evaluated incidence rates of HCC, and validated CU-HCC score based on data at the time of HBsAg seroclearance. RESULTS: During a follow-up of 3464 patient-years, 19 patients developed HCC (annual rate: 0.55%). Liver cirrhosis (hazard ratio [HR]: 10.80; 95% confidence interval [CI]: 4.25-27.43), male gender (HR: 8.96; 95% CI: 1.17-68.80), and age ⩾50 years at the time of HBsAg seroclearance (HR: 12.14; 95% CI: 1.61-91.68) were independently associated with HCC. The estimated annual incidence of HCC was 2.85% and 0.29% in patients with and without cirrhosis, respectively. Among the non-cirrhotic patients, the annual rate of HCC was higher in the male patients than in the females (0.40% vs. 0%, respectively), and all the HCCs developed after age 50. The time-dependent area under the receiver operating characteristic curves for the CU-HCC score for 5 year and 10 year HCC prediction were 0.85 and 0.74, respectively. CONCLUSIONS: HCC surveillance should be considered for cirrhotic patients and non-cirrhotic male patients over age 50, even after HBsAg seroclearance, especially those infected with HBV genotype C. HBsAg seroclearance at age ⩾50years was also an independent predictor for HCC.

Nomograms for Predicting Outcomes after Chemoembolization in Patients with Nonmetastatic Hepatocellular Carcinoma.

PURPOSE: To construct prognostic nomograms capable of estimating individual probabilities of tumor progression and overall survival (OS) at specific time points during serial transarterial chemoembolization for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The study included 1,181 consecutive patients with nonmetastatic HCC undergoing repeated transarterial chemoembolization at a single tertiary referral center. Patients were assigned to 2 cohorts according to the first transarterial chemoembolization date: derivation (2004-2006; n = 854) and validation (2007; n = 327) sets. Multivariate Cox proportional hazards models were developed based on covariates derived before transarterial chemoembolization and assessed for their association with 5-year OS and 3-year progression-free survival (PFS). The accuracy of the models was internally and externally validated. RESULTS: The 5-year OS of the derivation set was 25.4%, and 3-year PFS was 20.8%. Nomograms for OS and PFS were built into the derivation set incorporating the following factors: log [tumor volume] calculated as 4/3 × 3.14 × (maximum radius of tumor in cm(3)); tumor number; tumor type (nodular or infiltrative); Child-Pugh class (A or B); (model for end-stage liver disease score/10)(-2); log [α-fetoprotein]; and portal vein invasion. The models had good discrimination and calibration abilities with C-indexes of 0.80 (5-y survival) and 0.77 (3-y progression). The results of external validation confirmed that these models performed well in terms of discrimination and goodness-of-fit (C-indexes 0.77 for 5-y survival and 0.73 for 3-y progression). CONCLUSION: Nomograms quantifying the survival and progression outcomes in patients treated with transarterial chemoembolization are useful clinical aids in providing personalized care.

Intimate association of visceral obesity with non-alcoholic fatty liver disease in healthy Asians: A case-control study.

BACKGROUND AND AIM: To identify factors associated with non-alcoholic fatty liver disease (NAFLD) in healthy Asian subjects. METHODS: A propensity score-matched case-control study was designed. To investigate the effects of demographic and clinical factors on the presence of NAFLD, a baseline-category logit model was used. Potential living liver donors with no hepatic steatosis (< 5%: n = 1353, group 1) were considered the baseline category, and subjects with mild (5-33%: n = 724, group 2) and moderate/severe (> 33%: n = 116, group 3) hepatic steatosis were defined as cases. Age and gender were matched between cases and controls, which resulted in 83 matched subjects in each of the three groups. The area of abdominal (visceral and subcutaneous) fat was directly measured in all subjects by unenhanced computed tomography. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase (ALT), gamma-glutamyltranspeptidase, total cholesterol and triglyceride levels, and visceral fat amount were directly correlated with the grade of hepatic steatosis, and high-density lipoprotein cholesterol levels were inversely correlated with it (all P values < 0.05). In a multivariate model, visceral fat amount was significantly correlated with both mild (group 2) and moderate to severe (group 3) NAFLD, with respective odds ratios (ORs) of 1.03 relative to group 1 (Ps < 0.05). Body mass index (BMI), ALT, and subcutaneous fat were significant predictors of only moderate to severe NAFLD (ORs of 0.54, 1.20, and 1.02, respectively, for group 3 vs group 1; Ps < 0.05). CONCLUSIONS: Our results indicate that visceral adiposity makes non-obese subjects more susceptible to NAFLD, compared with subcutaneous fat and BMI.

Clinical appraisal of the recently proposed Barcelona Clinic Liver Cancer stage B subclassification by survival analysis.

BACKGROUND AND AIM: To evaluate the usefulness of Barcelona Clinic Liver Cancer B subclassification (B1-B4) proposed by Bolondi et al. in subjects with hepatocellular carcinoma treated with transarterial chemoembolization according to the current Barcelona Clinic Liver Cancer policy. METHODS: A total of 466 Barcelona Clinic Liver Cancer B patients initially treated with transarterial chemoembolization were included. The subclassification system was tested and modified on the basis of correlation with survival outcomes, which were examined by Kaplan-Meier method and log-rank test. RESULTS: There were 101 (21.7%), 232 (49.8%), 35 (7.5%), and 98 (21.0%) patients in B1, B2, B3, and B4, respectively. There was a significant difference in median survival time between B1 and B2 (41.0 vs 22.1 months, P ≤ 0.001), and B2 and B3 (22.1 vs 14.1 months, P = 0.004), but not between B3 and B4 (14.1 vs 17.2 months, P = 0.48). We, therefore, developed a modified subclassification, in which B3 subclass was merged with B4 as BIII, and BI and BII corresponded to B1 and B2. The median survival times differed between all three modified subclasses (41.0 vs 22.1 vs 16.6 months, P ≤ 0.001), and multivariate Cox analysis revealed that the modified Barcelona Clinic Liver Cancer B subclasses independently predicted overall survival (hazard ratios, 1.92 and 2.78 for BII and BIII vs BI; P < 0.001 for each). CONCLUSIONS: The modified subclassification, which divides the Barcelona Clinic Liver Cancer B stage into three substages, would be an effective tool for stratifying this heterogeneous population and facilitating per-subclass-based treatment options.

Extrahepatic Malignancies Are the Leading Cause of Death in Patients with Chronic Hepatitis B without Cirrhosis: A Large Population-Based Cohort Study.

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis.

Sorafenib vs. Lenvatinib in advanced hepatocellular carcinoma after Atezolizumab/Bevacizumab Failure: A real-world study.

Background: Atezolizumab plus bevacizumab (ATE+BEV) therapy has become the recommended first-line therapy for patients with unresectable hepatocellular carcinoma (HCC) because of favorable treatment responses. However, there is a lack of data on sequential regimens after ATE+BEV treatment failure. We aimed to investigate the clinical outcomes of patients with advanced HCC who received subsequent systemic therapy for disease progression after ATE+BEV. Methods: This multicenter, retrospective study included patients who started second-line systemic treatment with sorafenib or lenvatinib after HCC progressed on ATE+BEV between August 2019 and December 2022. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). Clinical features of the two groups were balanced through propensity score (PS) matching. Results: This study enrolled 126 patients, 40 (31.7%) in the lenvatinib group, and 86 (68.3%) in the sorafenib group. The median age was 63 years, and males were predominant (88.1%). In PS-matched cohorts (36 patients in each group), the objective response rate was similar between the lenvatinib- and sorafenib-treated groups (5.6% vs. 8.3%; p=0.643), but the disease control rate was superior in the lenvatinib group (66.7% vs. 22.2%; p<0.001). Despite the superior progression-free survival (PFS) in the lenvatinib group (3.5 vs. 1.8 months, p=0.001), the overall survival (OS, 10.3 vs. 7.5 months, p=0.353) did not differ between the two PS-matched treatment groups. Conclusion: In second-line therapy for unresectable HCC after ATE+BEV failure, lenvatinib showed better PFS and comparable OS to sorafenib in a real-world setting. Future studies with larger sample sizes and longer follow-ups are needed to optimize second-line treatment.

Predictive biomarkers of survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab treatment.

BACKGROUND: Since atezolizumab plus bevacizumab (ATE+BEV) regimen for patients with unresectable hepatocellular carcinoma (HCC) was released quite recently, real-world data are lacking. We evaluated efficacy, safety, and predictive biomarkers for survival in patients receiving ATE+BEV. METHODS: Between 2020 and 2021, HCC patients receiving ATE+BEV at academic teaching hospitals were recruited. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). RESULTS: Among 121 patients enrolled, the median age was 63 years, with male predominance (82.6%). Complete response, partial response, stable disease, and progressive disease were identified in 2.5%, 26.4%, 54.5%, and 16.6%, respectively. Patients with alpha-fetoprotein and des-gamma-carboxy prothrombin (DCP) response, defined as ≥30% and ≥50% decreases, respectively, at the first response evaluation relative to baseline, and those with neutrophil-to-lymphocyte ratio (NLR) <2.5, had significantly higher objective response rates (42.6% vs. 21.5%, 50.0% vs. 26.2%, and 39.0% vs. 19.4%, respectively; all p < 0.05). During follow-up, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 5.7 months. Multivariable analyses showed that macrovascular invasion (adjusted hazard ratio [aHR] 2.541; p = 0.017), DCP ≥186 mAU/ml (aHR 5.102; p < 0.001), NLR ≥2.5 (aHR 3.584; p = 0.001), and an NLR decrease ≥10% at the first response (aHR 0.305; p = 0.002) were independent predictors of OS, and DCP ≥186 mAU (aHR 2.311; p = 0.002) and NLR ≥2.5 (aHR 1.938; p = 0.012) were independent predictors of PFS. Grade ≥3 treatment-related adverse events (AEs) occurred in 33 (27.3%) patients. CONCLUSION: ATE+BEV showed favorable efficacy and safety. Baseline high DCP and NLR may be useful prognostic predictors for OS and PFS.

Atezolizumab plus bevacizumab in patients with child-Pugh B advanced hepatocellular carcinoma.

Background: Atezolizumab plus bevacizumab (Ate/Bev) demonstrated promising efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III IMbrave150 trial. However, patients with Child-Pugh B HCC were excluded in the abovementioned prospective trial. Therefore, we aimed to investigate the efficacy and safety of Ate/Bev in patients with Child-Pugh B HCC. Methods: This multicenter retrospective study included 36 patients with Child-Pugh B advanced HCC who received Ate/Bev at four cancer referral centers between May 2020 and August 2021. Comparative analyses were performed with an independent cohort of patients with Child-Pugh A HCC from the same registry (n = 133). Results: All patients received Ate/Bev as first-line systemic treatment for advanced HCC. The objective response and disease control rates of patients in the Child-Pugh groups B and A were 11.1% and 58.3% and 34.6% and 76.7%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.0 months [95% confidence interval (CI), 1.7-4.3) and 7.7 months (95% CI, 4.8-10.6) in the Child-Pugh B group, whereas the median PFS and OS were 9.6 months (95% CI, 5.1-14.2) and not reached (95% CI, not available) in the Child-Pugh A group, respectively. Compared to the Child-Pugh A group, grade 3-4 adverse events (AEs) were more common in the Child-Pugh B group (44.4% versus 15.8, p < 0.001), with the most frequent grade 3-4 AEs being gastrointestinal bleeding (n = 6, 16.7%), neutropenia (n = 5, 13.9%), and thrombocytopenia (n = 4, 11.1%). Conclusions: In the Child-Pugh B subgroup of patients with advanced HCC, Ate/Bev treatment showed modest clinical activity. However, due to the increased frequency of serious AEs, careful evaluation of treatment response and AE management is required in this subgroup of patients.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma.

Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Impact of anthropometric parameters on outcomes in Asians with metabolic dysfunction-associated fatty liver disease.

BACKGROUND: We examined the incidence and predictors of clinical outcomes in metabolic dysfunction-associated fatty liver disease (MAFLD), focusing on anthropometric parameters. METHODS: Adult patients with MAFLD were identified in nationwide databases and a hospital cohort. Primary endpoints were atherosclerotic cardiovascular disease (ASCVD) and advanced fibrosis. Logistic and Cox regression analyses were used to analyse the association between anthropometric parameters and endpoints. RESULTS: In total, 4407 of 15 256 (28.9%) and 6274 of 25 784 subjects (24.3%) had MAFLD in the nationwide database; of these, 403 (9.2%) and 437 (7.0%) subjects were of lean/normal weight, respectively. Compared to the overweight/obese group, the lean/normal weight group had a significantly lower muscle mass (15.0 vs. 18.9 kg) and handgrip strength (31.9 vs. 35.1 kg) and had a higher ASCVD risk (9.0% vs. 6.3% and 15.9% vs. 8.5%; Ps < 0.001). Sarcopenia (odds ratio [OR], 6.66; 95% confidence interval [CI], 1.79-24.80) and handgrip strength (OR, 0.92; 95% CI, 0.86-0.97; Ps = 0.005) were associated with the ASCVD risk in the lean/normal weight group. In a hospital cohort (n = 1363), the ASCVD risk was significantly higher in the lean/normal weight group than in the overweight/obese group (median follow-up, 39.1 months). Muscle mass was inversely correlated with the ASCVD risk (hazard ratio [HR], 0.72; 95% CI, 0.56-0.94), while visceral adiposity was associated with advanced fibrosis (HR, 1.36; 95% CI, 1.10-1.69; Ps < 0.05). CONCLUSIONS: Muscle mass/strength was significantly associated with the ASCVD risk in patients with MAFLD. Visceral adiposity was an independent predictor of advanced fibrosis.

Atezolizumab/Bevacizumab vs. Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Real-World, Multi-Center Study.

Lenvatinib (LENV) and atezolizumab/bevacizumab (ATE/BEV) have been approved as first-line regimens for the treatment of unresectable hepatocellular carcinoma (HCC). We aimed to compare their clinical efficacy and safety. Patients receiving ATE/BEV (n = 86) or LENV (n = 146) as first-line treatment were recruited from three academic hospitals in Korea. Overall survival (OS), progression-free survival (PFS), and radiological response were assessed according to the Response Evaluation Criteria in Solid Tumors. Clinical features of the two groups were balanced through propensity score (PS) matching with a 1:1 ratio and inverse probability of treatment weighting (IPTW) analyses. The median age was 62 years, with male predominance (83.6%). There was no significant difference in the objective response rate between the ATE/BEV and LENV groups (32.6% vs. 31.5%; p = 0.868). Neither median OS (not reached vs. 12.8 months; p = 0.357) nor PFS (5.7 vs. 6.0 months; p = 0.738) was different between ATE/BEV and LENV groups. PS-matched and IPTW analyses yielded comparable results in terms of OS and PFS (all p > 0.05). Grade ≥ 3 adverse events occurred in 42.8% and 21.9% of patients in the ATE/BEV and LENV groups, respectively (p = 0.141). The two first-line therapy regimens for unresectable HCC had comparable clinical efficacy and safety in real-world practice settings. Further studies with a larger sample size and longer follow-up are needed to validate these results.