Hepatocellular carcinoma outcomes and potential implications for surveillance in elderly patients.

International liver societies recommend hepatocellular carcinoma (HCC) surveillance for those at high-risk of developing HCC. While previous studies have shown the benefits of surveillance for middle-aged patients, but its necessity for elderly patients is unclear. This study aimed to assess the benefits of HCC surveillance in the elderly by comparing diagnosis mode of HCC. Consecutive, elderly patients aged 75 years or older who were newly diagnosed with HCC were screened at our institution between January 2009 and December 2021. Patients were grouped into those who were diagnosed with HCC during surveillance (n = 235, surveillance group) and those who were diagnosed with HCC due to symptoms (n = 184, symptomatic group). The study outcome was overall survival. It was compared in the overall cohort and a propensity score (PS)-matched cohort. Early-stage diagnosis was more frequent in the surveillance group than in the symptomatic group (mUICC stage I/II: 72.3% vs. 39.1%, p < 0.001). The overall survival rate was better in the surveillance group than in the symptomatic group (median 4.4 vs. 2.1 years, log-rank p < 0.001). In multivariable-adjusted models, the hazard ratio (HR) of mortality of the surveillance group compared to the symptomatic group was 0.64 (95% confidence interval (CI): 0.47-0.87). However, further adjustment for the tumor stage markedly attenuated this association, which was no longer statistically significant (adjusted HR = 0.75; 95% CI: 0.54-1.02). In the PS-matched cohort analysis, outcomes were similar when the PS matching variables included the tumor stage. In contrast, when PS matching variables did not include the tumor stage, outcomes were better for the surveillance group. The surveillance group of elderly patients showed better survival than the symptomatic group, which was largely explained by earlier tumor stage at diagnosis. This suggests that the overall outcome of elderly HCC patients could be improved by increasing surveillance-detected cases compared to symptom-driven cases.

Analysis of Factors Predicting the Real-World Efficacy of Atezolizumab and Bevacizumab in Patients with Advanced Hepatocellular Carcinoma.

Background/Aims: Atezolizumab and bevacizumab have shown promising results for the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials. In this study, the real-world efficacy and safety of atezolizumab and bevacizumab in treating advanced HCC were evaluated. Methods: In this retrospective study of patients at a Korean tertiary cancer center, 111 patients with Barcelona Clinic Liver Cancer stage B or C HCC received atezolizumab and bevacizumab as first-line therapy from May 2022 to June 2023. We assessed the progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and adverse events. Results: Patients with Barcelona Clinic Liver Cancer stage C HCC and Child-Pugh class A liver function were included in the study. The median PFS was 6.5 months, with an ORR of 27% and a DCR of 63%. Several factors, including the albumin-bilirubin grade, age, C-reactive protein and α-fetoprotein in immunotherapy score, macrovascular invasion, lung metastases, and combined radiotherapy, were found to significantly influence PFS (p<0.05). Patients with peritoneal seeding showed an higher ORR. The safety profile was consistent with that observed in clinical trials. Conclusions: Atezolizumab and bevacizumab demonstrated real-world efficacy in the treatment of advanced HCC, with ORRs and DCRs aligning with those observed in clinical trials. Variations in PFS and ORR based on specific risk factors highlight the potential of atezolizumab and bevacizumab in precision medicine for advanced HCC.

Role of transarterial chemoembolization for hepatocellular carcinoma with extrahepatic metastases in the era of advancing systemic therapy.

Background/Aims: Systemic therapy is the current standard treatment for hepatocellular carcinoma (HCC) with extrahepatic metastases (EHM). However, some patients with HCC and EHM undergo transarterial chemoembolization (TACE) to manage intrahepatic tumors. Herein, we aimed to explore the appropriateness of TACE in patients with HCC and EHM in an era of advanced systemic therapy. Methods: This study analyzed 248 consecutive patients with HCC and EHM (median age 58.5 years, 83.5% male, and 88.7% Child-Pugh A) who received TACE or systemic therapy (83 sorafenib, 49 lenvatinib, 28 immunotherapy-based) between January 2018 and January 2021. Results: Among the patients, 196 deaths were recorded during a median follow-up of 8.9 months. Patients who received systemic therapy had a higher albumin-bilirubin grade, elevated tumor markers, an increased number of intrahepatic tumors, larger-sized tumors, and more frequent portal vein invasion than those who underwent TACE. TACE was associated with longer median overall survival (OS) than sorafenib (15.1 vs. 4.7 months; 95% confidence interval [CI]: 11.1-22.2 vs. 3.7-7.3; hazard ratio [HR] 1.97, P<0.001). After adjustment for potential confounders, TACE was associated with statistically similar survival outcomes to those of lenvatinib (median OS: 8.0 months; 95% CI: 6.5-11.0; HR 1.21, P=0.411) and immunotherapies (median OS: 14.3 months; 95% CI: 9.5-27.0; HR 1.01, P=0.973), demonstrating survival benefits equivalent to these treatments. Conclusion: In patients with HCC and EHM, TACE can provide a survival benefit comparable to that of newer systemic therapies. Accordingly, TACE remains a valuable option in this era of new systemic therapies.

Prevalence and predictors of multidrug-resistant bacteremia in liver cirrhosis.

BACKGROUND/AIMS: Improved knowledge of local epidemiology and predicting risk factors of multidrug-resistant (MDR) bacteria are required to optimize the management of infections. This study examined local epidemiology and antibiotic resistance patterns of liver cirrhosis (LC) patients and evaluated the predictors of MDR bacteremia in Korea. METHODS: This was a retrospective study including 140 LC patients diagnosed with bacteremia between January 2017 and December 2022. Local epidemiology and antibiotic resistance patterns and the determinants of MDR bacteremia were analyzed using logistic regression analysis. RESULTS: The most frequently isolated bacteria, from the bloodstream, were Escherichia coli (n = 45, 31.7%) and Klebsiella spp. (n = 35, 24.6%). Thirty-four isolates (23.9%) were MDR, and extended-spectrum beta-lactamase E. coli (52.9%) and methicillin-resistant Staphylococcus aureus (17.6%) were the most commonly isolated MDR bacteria. When Enterococcus spp. were cultured, the majority were MDR (MDR 83.3% vs. 16.7%, p = 0.003), particularly vancomycin-susceptible Enterococcus faecium. Antibiotics administration within 30 days and/or nosocomial infection was a significant predictor of MDR bacteremia (OR: 3.40, 95% CI: 1.24-9.27, p = 0.02). MDR bacteremia was not predicted by sepsis predictors, such as positive systemic inflammatory response syndrome (SIRS) or quick Sequential Organ Failure Assessment (qSOFA). CONCLUSION: More than 70% of strains that can be treated with a third-generation cephalosporin have been cultured. In cirrhotic patients, antibiotic administration within 30 days and/or nosocomial infection are predictors of MDR bacteremia; therefore, empirical administration of broad-spectrum antibiotics should be considered when these risk factors are present.

Impact of Intrahepatic External Beam Radiotherapy in Advanced Hepatocellular Carcinoma Patients Treated with Tyrosine Kinase Inhibitors.

Introduction: We aimed to investigate whether concurrent use of intrahepatic external beam radiotherapy (EBRT) is a viable option for patients with advanced hepatocellular carcinoma (HCC) undergoing tyrosine kinase inhibitor (TKI) therapy. Methods: A total of 453 patients with Barcelona Clinic Liver Cancer stage C (BCLC C) HCC, who started first-line treatment with TKI with intrahepatic EBRT (TKI + RT, n = 97) or TKI without intrahepatic EBRT (TKI, n = 356) were analyzed. The overall survival (OS) and progression-free survival (PFS) were compared in the overall cohort, patients who received at least 8 weeks of TKI treatment and a propensity score-matched cohort. Results: OS and PFS were better in those treated with TKI + RT than TKI (8.6 vs. 4.4 months and 4.5 vs. 2.3 months, respectively, with p < 0.001). Of note, the TKI + RT group demonstrated significantly longer time to intrahepatic tumor progression. In subgroup analysis, TKI + RT led to better OS than TKI in all subgroups and PFS was significantly improved in patients without extrahepatic metastasis and those with portal vein invasion. There was no significant difference in treatment discontinuation due to adverse events between the TKI + RT and TKI groups (32.0% vs. 37.9%, p = 0.34). Furthermore, patients treated with TKI + RT showed better liver function preservation over time compared to TKI without intrahepatic EBRT. Comparable treatment outcomes were observed between patients who received at least 8 weeks of TKI treatment and the propensity score-matched cohort. Conclusion: Concurrent intrahepatic EBRT targeting the liver and/or macrovascular invasion can be a viable option to improve outcomes of BCLC stage C patients receiving TKI therapy with an aim to control intrahepatic progression and preserving the liver function.

Nomogram for predicting overall survival in patients with large (>5 cm) hepatocellular carcinoma based on real-world practice.

BACKGROUND/AIM: Patients with large (>5 cm) hepatocellular carcinoma (HCC) have limited treatment options, thus necessitating the identification of prognostic factors and the development of predictive tools. This study aimed to identify prognostic factors and to construct a nomogram to predict survival outcomes in patients with large HCC. METHODS: A cohort of 438 patients, who were diagnosed with large HCC at a tertiary hospital between 2015 and 2018, was analyzed. Cox proportional hazards models were used to identify key prognosticators of overall survival (OS), and an independent set of prognostic factors was used to develop a nomogram. The discrimination and calibration abilities of the nomogram were assessed and internal validation was performed using cross-validation and bootstrapping methods. RESULTS: During a median follow-up of 9.3 months, the median OS was 9.9 months, and the 1-year OS rate was 43.9%. Multivariable Cox regression analysis revealed that performance status, modified albumin-bilirubin grade, tumor size, extent of portal vein tumor thrombosis, and initial treatment significantly affected OS. The newly developed nomogram incorporating these variables demonstrated favorable accuracy (Harrell's concordance index, 0.807). CONCLUSIONS: The newly developed nomogram facilitated the estimation of individual survival outcomes in patients with large HCC, providing an acceptable level of accuracy.

Metabolic dysfunction-associated fatty liver disease and the risk of hepatocellular carcinoma.

Background & Aims: The metabolic dysfunction-associated fatty liver disease (MAFLD) is a new inclusive term proposed to replace non-alcoholic fatty liver disease (NAFLD). We analysed whether hepatocellular carcinoma (HCC) risk differs by MAFLD or NAFLD status in a large sample of asymptomatic adults. Methods: A cohort comprising 73,691 adults were followed up for the development of HCC. NAFLD was diagnosed among participants without other liver diseases (n = 65,992). Results: Participants with MAFLD showed higher incidence of HCC than those without MAFLD (0.37 and 0.24 per 1,000 person-years, respectively; p = 0.006). However, MAFLD was not an independent factor associated with HCC in multivariable adjusted analysis (hazard ratio [HR] 1.21; 95% CI 0.92-1.60). When stratified according to presence of other liver diseases, MAFLD was not associated with HCC in participants with other liver diseases. In participants without other liver diseases, both MAFLD (adjusted HR 1.84; 95% CI 1.09-3.11) and NAFLD (adjusted HR 1.71; 95% CI 1.01-2.90) were independent factors associated with HCC. When stratified according to NAFLD and MAFLD status, there was no HCC development among participants with NAFLD only during 8,936 person-years of follow-up, but this NAFLD-only group comprised 3.4%, and the majority of participants with hepatic steatosis fulfilled both NAFLD and MAFLD criteria. Conclusions: In patients with other chronic liver diseases, the presence of MAFLD is not independently associated with an increased risk of HCC. For those without other chronic liver diseases, MAFLD largely overlaps with NAFLD and is associated with an increased risk of HCC. Impact and Implications: This study investigated the usefulness of newly proposed nomenclature, metabolic dysfunction-associated fatty liver disease (MAFLD), over non-alcoholic fatty liver disease (NAFLD), in terms of predicting hepatocellular carcinoma. In patients with other chronic liver diseases, the presence of MAFLD is not independently associated with an increased risk of HCC. However, for those without chronic liver disease, MAFLD largely overlaps with NAFLD and is associated with an increased risk of HCC.

Radiotherapy trend in elderly hepatocellular carcinoma: retrospective analysis of patients diagnosed between 2005 and 2017.

PURPOSE: To report the trends of radiotherapy in the management of elderly patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We retrospectively reviewed patients who entered HCC registry of Samsung Medical Center between 2005 and 2017. Patients who were 75 years or older at the time of registration were defined as elderly. They were categorized into three groups based on the year of registration. Radiotherapy characteristics were compared between the groups to observe differences by age groups and period of registration. RESULTS: Out of 9,132 HCC registry patients, elderly comprised 6.2% (566 patients) of the registry, and the proportion increased throughout the study period (from 3.1% to 11.4%). Radiotherapy was administered to 107 patients (18.9%) in elderly group. Radiotherapy utilization in the early treatment process (within 1 year after registration) has rapidly increased from 6.1% to 15.3%. All treatments before 2008 were delivered with two-dimensional or three-dimensional conformal radiotherapy, while more than two-thirds of treatments after 2017 were delivered with advanced techniques such as intensity-modulated radiotherapy, stereotactic body radiotherapy, or proton beam therapy. Overall survival (OS) of elderly was significantly worse than younger patients. However, for patients who received radiotherapy during the initial management (within one month after registration), there was no statistically significant difference in OS between age groups. CONCLUSION: The proportion of elderly HCC is increasing. Radiotherapy utilization and adoption of advanced radiotherapy technique showed a consistently increasing trend for the group of patients, indicating that the role of radiotherapy in the management of elderly HCC is expanding.

Validation of non-invasive diagnosis of CSPH in patients with compensated advanced chronic liver disease according to Baveno VII.

BACKGROUND AND AIMS: Baveno VII consensus introduced the non-invasive criteria of clinically significant portal hypertension (CSPH) using liver stiffness measurement (LSM). We evaluated the usefulness of the Baveno VII criteria to predict the risk of decompensation in patients with compensated advanced chronic liver disease (cACLD). METHODS: We conducted a retrospective cohort study of 1966 patients with cACLD. Patients were categorized into four groups (CSPH excluded (n = 619), grey zone (low risk of CSPH (n = 699), high risk of CSPH (n = 207)), and CSPH included (n = 441)) according to Baveno VII consensus. The risk of events was estimated using a Fine and Gray competing risk regression analysis, with liver transplantation and death as competing events. We calculated standardized hazard ratios (sHR) to assess the relative risk of decompensation. RESULTS: Among 1966 patients, 178 developed decompensations over a median follow-up of 3.06 (IQR: 1.03-6.00) years. Patients with CSPH had the highest decompensation risk, followed by the grey zone high-risk group, grey zone low-risk group, and those without CSPH with 3-year cumulative risks of 22%, 12%, 3.3%, and 1.4% respectively (p < .001). Compared to CSPH excluded group, CSPH included group (sHR: 8.00, 95% CI: 4.00-16.0), grey zone high-risk group (sHR: 6.57, 95% CI: 3.16-13.6), grey zone low-risk group (sHR: 2.15, 95% CI: 1.04-4.41) had significantly higher risk of decompensation (Gray's test p < .01). CONCLUSION: Non-invasive diagnosis of CSPH according to the Baveno VII criteria can stratify the risk of decompensation.

Improved on-treatment fibrosis-4 during antiviral therapy and lower hepatocellular carcinoma risk in cirrhotic patients with hepatitis B.

Normalization of serum alanine aminotransferase (ALT) levels is one of the goals of hepatitis B treatment. However, ALT levels in cirrhosis patients might be normal or mildly elevated regardless of ongoing inflammation. Therefore, we examined whether on-treatment ALT and other potential on-treatment indicators could be clinical surrogates of antiviral therapy in HBV-related cirrhosis. A total of 911 patients with HBV-related liver cirrhosis who started treatment with entecavir or tenofovir were analyzed. At 1 year of antiviral therapy, we evaluated 'ALT normalization', 'undetectable serum HBV DNA', 'fibrosis-4 (FIB-4) index improvement', and 'serum HBeAg loss' as potential biomarkers for HCC development. During 6.6 (3.8-10.2) years of follow-up, 222 patients (24.3%) newly developed HCC. Undetectable HBV DNA levels at 1 year were observed in 667 patients (73.2%), and the HCC incidence was significantly lower in this population (adjusted hazard ratio (HR) 0.66, 95% CI 0.50-0.87). Improvement of the FIB-4 index (< 3.25) was associated with a lower risk of HCC in 478 patients with an elevated FIB-4 index (adjusted HR 0.59, 95% CI 0.55-0.82). However, there was no significant difference in HCC risk between those with and without normalization of ALT levels (p = 0.39) among those with elevated ALT levels or between those with and without HBeAg seroconversion (p = 0.55) among HBeAg-positive patients. Therefore, on-treatment FIB-4 levels at 1 year are clinically useful surrogates of antiviral therapy for HBV-related cirrhosis patients.

Clinical Outcomes and Validation of Ursodeoxycholic Acid Response Scores in Patients with Korean Primary Biliary Cholangitis: A Multicenter Cohort Study.

Background/Aims: The ursodeoxycholic acid (UDCA) response score (URS) was developed to identify poor responders to UDCA before treatment, in order to offer timely and proactive intervention. However, validation of the URS in Asian population is warranted. Methods: A total of 173 Asian patients diagnosed with primary biliary cholangitis (PBC) between 2007 and 2016 at seven academic institutions in Korea who started UDCA treatment were analyzed to validate the performance of URS. UDCA response was defined as an alkaline phosphatase level less than 1.67 times the upper limit of normal after 1-year of UDCA treatment. In addition, prognostic performance of URS for liver-related events, defined as newly developed hepatic decompensation or hepatocellular carcinoma was evaluated. Results: After 1 year of UDCA treatment, 133 patients (76.9%) achieved UDCA response. UDCA response rate was 98.7% for those with URS ≥1.41 (n=76) and 58.8% for those with URS <1.41 (n=97). The area under the receiver operating characteristic curve of URS in predicting UDCA response was 0.84 (95% confidence interval, 0.78 to 0.88). During a median follow-up of 6.5 years, liver-related events developed in 18 patients (10.4%). Among 117 patients with PBC stage I-III by histological evaluation, the 5-year liver-related event-free survival rate differed according to the URS; 100% for URS ≥1.41 and 86.5% for URS <1.41 (p=0.005). Conclusions: URS demonstrated good performance in predicting a UDCA treatment response in Asian PBC patients. In addition, the risk of liver-related events differed according to the URS for the PBC stage. Thus, URS can be used to predict the response and clinical outcome in patients with PBC.

Pretransplant Functional Status Predicts Postoperative Morbidity and Mortality after Liver Transplantation in Patients with Cirrhosis.

Background/Aims: This study aimed to investigate whether pretransplant frailty can predict postoperative morbidity and mortality after liver transplantation (LT) in patients with cirrhosis. Methods: We retrospectively reviewed 242 patients who underwent LT between 2018 and 2020 at a tertiary hospital in Korea. Results: Among them, 189 patients (78.1%) received LT from a living donor. Physical frailty at baseline was assessed by the Short Physical Performance Battery (SPPB), by which patients were categorized into two groups: frail (SPPB <10) and non-frail (SPPB ≥10). Among the whole cohort (age, 55.0±9.2 years; male, 165 [68.2%]), 182 patients were classified as non-frail and 60 patients were classified as frail. Posttransplant survival was shorter in the frail group than the non-frail group (9.3 months vs 11.6 months). Postoperative intensive care unit stay was longer in the frail group than in the non-frail group (median, 6 days vs 4 days), and the 30-day complication rate was higher in the frail group than in the non-frail group (78.3% vs 59.3%). Frailty was an independent risk factor for posttransplant mortality (adjusted hazard ratio, 2.38; 95% confidence interval, 1.02 to 5.57). In subgroup analysis, frail patients showed lower posttransplant survival regardless of history of hepatocellular carcinoma and donor type. Conclusions: Assessment of pretransplant frailty, as measured by SPPB, provides important prognostic information for clinical outcomes in cirrhotic patients undergoing LT.

Impact of nationwide hepatocellular carcinoma surveillance on the prognosis in patients with chronic liver disease.

BACKGROUND/AIMS: This study aimed to investigate the effect of hepatocellular carcinoma (HCC) surveillance using the Korea National Liver Cancer Screening Program on the receipt of curative treatment for HCC and mortality in patients with chronic liver disease. METHODS: This population-based cohort study from the Korean National Health Insurance Service included 2003 to 2015 claims data collected from 1,209,825 patients aged ≥40 years with chronic hepatitis B, chronic hepatitis C, and liver cirrhosis. Patients were divided according to HCC surveillance using ultrasonography and serum alpha-fetoprotein every 6-12 months. The study outcomes were the receipt of curative treatment (surgical resection, radiofrequency ablation, or liver transplantation) and all-cause mortality. RESULTS: The study population consisted of 1,209,825 patients with chronic hepatitis B, chronic hepatitis C, and liver cirrhosis (median age, 52.0 years; interquartile range, 46-55 years; 683,902 men [56.5%]). The proportion of participants who underwent HCC surveillance was 52.7% (n=657,889). During 10,522,940 person-years of follow-up, 74,433 HCC cases developed, including 36,006 patients who underwent curative treatment. The surveillance group had a significantly higher proportion of curative treatment for HCC than the non-surveillance group after adjusting for confounding factors (adjusted hazard ratio [HR], 5.64; 95% confidence interval [CI], 5.48-5.81). The surveillance group had a significantly lower mortality rate than the non-surveillance group (adjusted HR, 0.56; 95% CI, 0.55-0.56). CONCLUSION: HCC surveillance using the national screening program in patients with chronic viral hepatitis or liver cirrhosis provides better opportunity for curative treatment for HCC and improves overall survival.

Imaging features of hepatobiliary MRI and the risk of hepatocellular carcinoma development.

OBJECTIVE: This study aimed to determine whether hepatocellular carcinoma (HCC) risk and time to HCC development differ according to hepatobiliary magnetic resonance imaging (MRI) findings among people at risk for developing HCC. MATERIALS AND METHODS: A total of 199 patients aged 40 years or older with liver cirrhosis or chronic liver disease who underwent gadoxetic acid-enhanced hepatobiliary MRI between 2011 and 2015 were analyzed. An independent radiologist retrospectively reviewed MRI findings, blinded to clinical information, and categorized them into low-risk features, high-risk features and high-risk nodules. High-risk features were defined as liver cirrhosis diagnosed by imaging. High-risk nodules were defined as LR-3 or LR-4 nodules based on LI-RADS version 2018. The primary outcome was development of HCC within 5-year of MRI evaluation. RESULTS: HCC was diagnosed in 28 patients (14.1%). HCC development was null for those with low-risk features (n = 84). The cumulative incidence rates of HCC were 0%, 2.3%, 13.4% and 22.1% at 1-, 2-, 3- and 5-year for those with high-risk features (n= 64), and were 19.1%, 31.8%, 37.3% and 46.7% at 1-, 2-, 3- and 5-year for those with high-risk nodules (n= 51). Among 28 patients developed HCC, the median time from baseline MRI to HCC diagnosis was 33.1 months (interquartile range: 25.9-46.7 months) for high-risk feature group, and 17.3 months (interquartile range: 6.2-26.5 months) for high-risk nodule group. CONCLUSIONS: HCC risk and time to HCC development differ according to baseline hepatobiliary MRI findings, indicating that hepatobiliary MRI findings can be used as biomarkers to differentiate HCC risk.

Safety and Efficacy of Liver-Directed Radiotherapy in Combination With Lenvatinib for Hepatocelluar Carcinoma With Macroscopic Tumor Thrombosis.

Background: This study aimed to compare the clinical outcomes of patients with hepatocellular carcinoma (HCC) and macroscopic tumor thrombosis who were treated with lenvatinib with or without combined liver-directed radiotherapy (LRT). Methods: From the institutional registry, we enrolled 82 patients diagnosed with HCC involving macroscopic tumor thrombosis and treated with lenvatinib monotherapy (non-LRT group, n = 54, 65.9%) or lenvatinib in combination with LRT (LRT group, n = 28, 34.1%). Patients were classified into the LRT group if LRT was performed within 8 weeks of lenvatinib initiation. Results: During the median follow-up period of 5.4 (range 1.4 to 17.5) months, there was no significant difference between the two groups in terms of overall adverse events. Although there was no statistical difference between the two groups in terms of overall response rate (32.1% vs. 20.4%, p = 0.15), a significantly higher treatment response was observed in the LRT group in terms of intrahepatic tumor response (67.9% vs. 20.4%, p < 0.001). In the LRT group, there was a slight difference in overall survival compared to the non-LRT group (64.1% in the LRT group vs. 37.7% in the non-LRT group at 12 months, hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.28-1.03; p = .06), although it did not reach a statistically significant level. However, progression-free survival (PFS, 67.2% in the LRT group vs. 35.0% in the non-LRT group at 6 months, HR 0.47; 95% CI 0.27-0.82; p = 0.008) and intrahepatic progression-free survival (IHPFS, 74.3% in the LRT group vs. 43.3% in the non-LRT group at 6 months, HR 0.45; 95% CI 0.25-0.81; p = 0.008) were significantly superior in the LRT group. This result was also reproduced in the multivariate analysis adjusted for α-fetoprotein, another significant prognostic factor in this study, and the well-known prognostic factors, namely the presence of main portal vein tumor thrombosis and albumin-bilirubin grade. Conclusions: The combination of lenvatinib and LRT is relatively safe and effective in increasing the intrahepatic tumor response and improving PFS and IHPFS in patients with HCC and macroscopic tumor thrombosis.

Changes in the prevalence of hepatitis B and metabolic abnormalities among young men in Korea.

Changes in the prevalence of disease over time provide valuable information from a public health perspective. We used data from Korea Military Manpower Administration medical examinations for conscription between 2003 and 2019 (n = 5,355,941), which involved young men aged 19 years, to observe changes in liver disease over time at a population level. Trends in the prevalence of hepatitis B surface antigen (HBsAg), elevated alanine aminotransferase (ALT) levels, the fibrosis-4 (FIB-4) index, obesity, and hypertension were assessed. The prevalence of HBsAg steadily decreased from 3.19% for men born in 1984 to 0.18% for men born in 2000. Among HBsAg-negative subjects, the prevalence of elevated ALT levels increased from 13.15% for men born in 1986 to 16.48% for men born in 2000. The prevalence of obesity, hypertension and the proportion with high FIB-4 scores (≥ 1.45) also increased. This population-based nationwide analysis showed a decreasing trend of HBsAg and increasing trends of possible non-alcoholic fatty liver disease.

Prognostic significance of cachexia index in patients with advanced hepatocellular carcinoma treated with systemic chemotherapy.

Cancer cachexia affects quality of life, response to chemotherapy, and survival in many advanced cancer patients. The aim of this study was to evaluate the prognostic value of pretreatment cachexia index (CXI) in patients with advanced hepatocellular carcinoma (HCC) treated with systematic chemotherapy. Patients with advanced HCC treated with lenvatinib therapy between October 2018 and October 2020 were retrospectively studied. The CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil-to-lymphocyte ratio). The association with treatment response and early adverse events within the first two months of lenvatinib therapy was investigated. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method with log-rank test. Multivariable Cox regression was used to identify the predictors of survival. A total of 116 patients (median age: 60, male: 84.5% ) with calculated CXI. They divided into two groups: high CXI (≥ 53, n = 82) and low CXI (< 53, n = 34). Patients with low CXI had a significantly lower disease control rate (61.8% vs. 89.0%, p = 0.001) and a shorter median OS (8.0 [95% CI 6.2-9.8] vs. 12.3 [95% CI 10.1-14.4] months, p = 0.002) than those with high CXI. In multivariable analysis, low CXI was independently associated with shorter OS (HR: 2.07, 95% CI: 1.17-3.65, p = 0.01) and PFS (HR: 1.84, 95% CI: 1.09-3.09, p = 0.02). Of note, during the first two months of lenvatinib therapy, anorexia (41.2% vs. 22.0%, p = 0.04) developed more frequently among patients with low CXI than those with high CXI. The CXI may be a clinically useful index for predicting poor treatment response and prognosis in patients with advanced HCC undergoing lenvatinib treatment.

Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial.

BACKGROUND: A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. METHODS: Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. RESULTS: The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. CONCLUSIONS: Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment. TRIAL REGISTRATION: NCT#03163992 (first posted: May 23, 2017).

Age and fibrosis index for the prediction of hepatocellular carcinoma risk in patients with high hepatitis B virus DNA but normal alanine aminotransferase.

AIM: Chronic hepatitis B patients positive for hepatitis B e antigen (HBeAg) with high serum hepatitis B virus (HBV) DNA levels but normal alanine aminotransferase (ALT) levels may develop hepatocellular carcinoma (HCC). However, ways to risk stratify are limited. METHODS: A retrospective cohort of 651 HBeAg positive, adult patients with high serum HBV DNA levels (>7 log IU/ml) but normal or mildly elevated ALT levels (<80 U/L) were analyzed. RESULTS: Age and FIB-4 index were independent factors associated with HCC development. When stratified, 5- and 10-year cumulative HCC incidence rates were 0 and 2.0% for patients aged <40 years with FIB-4 index <1.45, and were 5.9 and 32.7% for patients aged ≥40 years with FIB-4 index ≥1.45, respectively (P < 0.001). In patients with normal ALT levels (n = 301), the 10-year HCC incidence rate was 0% for patients aged <40 years with FIB-4 index <1.45, while 5- and 10-years HCC incidence rate was 4.5 and 27.1% for patients aged ≥40 years with FIB-4 index ≥1.45, respectively (P < 0.001). CONCLUSION: In patients with high HBV DNA but normal ALT levels, age and FIB-4 index could effectively stratify HCC risk, indicating that these parameters may guide management plans for this population.