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.

Statin use and the risk of hepatocellular carcinoma among patients with chronic hepatitis B: an emulated target trial using longitudinal nationwide population cohort data.

BACKGROUND: No randomized controlled trials have been completed to see whether statin can decrease hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. We used large-scale, population-based, observational data to emulate a target trial with two groups, statin user and statin non-user. METHODS: Among 1,379,708 nonunique individuals from the Korean National Health Insurance Service data, 2,915 CHB patients with serum cholesterol level of 200 mg/dL or higher who started statin therapy and 8,525 propensity-score matched CHB patients with serum cholesterol level of 200 mg/dL or higher who did not start statin therapy were analyzed for the development of HCC. In addition, liver cancer or liver-related mortality and all-cause mortality were assessed. RESULTS: During follow-up, 207 participants developed HCC. Incidence rate of HCC was 0.2 per 1,000 person-years in the statin user group and 0.3 per 1,000 person-years in the statin non-user group. Fully adjusted hazard ratio (HR) for incident HCC comparing statin user group to statin nonuser group was 0.56 (95% confidence interval [CI]: 0.39 to 0.80). The association between statin use and decreased HCC risk was consistent in all subgroups analyzed. Fully adjusted HR comparing statin user to statin nonuser was 0.59 (95% CI: 0.35 to 0.99) for liver cancer or liver-related mortality and 0.93 (95% CI: 0.78 to 1.11) for all-cause mortality. CONCLUSIONS: Statin might have a benefit for preventing HCC in CHB patients with elevated cholesterol levels. Statin should be actively considered for CHB patients with dyslipidemia.

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.

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.

Effect of lifestyle modification on hepatocellular carcinoma incidence and mortality among patients with chronic hepatitis B.

BACKGROUND: Research exploring the influence of healthier lifestyle modification (LSM) on the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is limited. AIM: To emulate a target trial to determine the effect of LSM on HCC incidence and mortality among patients with CHB by large-scale population-based observational data. METHODS: Among the patients with CHB enrolled in the Korean National Health Insurance Service between January 1, 2009, and December 31, 2017, those aged ≥ 20 years who drank alcohol, smoked cigarettes, and were sedentary were analyzed. Exposure included at least one LSM, including alcohol abstinence, smoking cessation, and regular exercise. The primary outcome was HCC development, and the secondary outcome was liver-related mortality. We used 2:1 propensity score matching to account for covariates. RESULTS: With 48766 patients in the LSM group and 103560 in the control group, the adjusted hazard ratio (HR) for incident HCC and liver-related mortality was 0.92 [95% confidence interval (CI): 0.87-0.96] and 0.92 (95%CI: 0.86-0.99) in the LSM group, respectively, compared with the control group. Among the LSM group, the adjusted HR (95%CI) for incident HCC was 0.84 (0.76-0.94), 0.87 (0.81-0.94), and 1.08 (1.00-1.16) for alcohol abstinence, smoking cessation, and regular exercise, respectively. The adjusted HR (95%CI) for liver-related mortality was 0.92 (0.80-1.06), 0.81 (0.72-0.91), and 1.15 (1.04-1.27) for alcohol abstinence, smoking cessation, and regular exercise, respectively. CONCLUSION: LSM lowered the risk of HCC and mortality in patients with CHB. Thus, active LSM, particularly alcohol abstinence and smoking cessation, should be encouraged in patients with CHB.

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.

Associations of physical activity domains and muscle strength exercise with non-alcoholic fatty liver disease: a nation-wide cohort study.

It is unclear if various types and domains of exercise have an identical effect on non-alcoholic fatty liver disease (NAFLD). Thus, this study aimed to investigate associations of different physical activity domains and muscle strength exercise with NAFLD using a nation-wide cohort database. Adults aged 20-79 years who participated in the Korean National Health and Nutrition Examination Survey between 2014 and 2018 were analyzed. Hepatic steatosis index was used to identify NAFLD. Physical activity was assessed with the Global Physical Activity Questionnaire. Of 21,015 participants, 4942 (23.5%) had NAFLD. Participants with ≥ 150 min/week of total physical activity had a lower risk of NAFLD than those with < 150 min/week (the fully adjusted OR: 0.86, 95% CI 0.78-0.95). When the individual domain of physical activity was assessed, ≥ 150 min/week of recreation activity was associated with a reduced risk of NAFLD (OR: 0.77, 95% CI 0.67-0.88), whereas ≥ 150 min/week of travel or work activity was not. The fully adjusted OR for NAFLD comparing participants with ≥ 2/week to those with < 2/week of muscle strength exercise was 0.83 (95% CI 0.73-0.94). Muscle strength exercise ≥ 2/week showed a lower risk of NAFLD for all levels of total and each specific domains of physical activity except for ≥ 150 min/week of work activity. An increased level of physical activity and muscle strength exercise was associated with a reduced risk of NAFLD, albeit the effect varied depending on domains of physical activity. Thus, physical activity should be differentiated by domains for the management of NAFLD. Muscle strength exercise could also be a good option for individuals who could not perform moderate-to-vigorous physical activity.

Nonalcoholic Fatty Liver Disease Without Metabolic-associated Fatty Liver Disease and the Risk of Metabolic Syndrome.

BACKGROUND & AIMS: Metabolic (dysfunction)-associated fatty liver disease (MAFLD) was proposed to replace nonalcoholic fatty liver disease (NAFLD). Some people fulfill diagnostic criteria of NAFLD but not MAFLD (NAFLD without MAFLD), but the clinical implications of NAFLD in these subjects is unknown. METHODS: We followed cohort of 12,197 men and women 20 years of age or older without metabolic dysfunction (defined by MAFLD criteria), heavy alcohol use, chronic viral hepatitis, liver cirrhosis, or malignancy for their risk of incident metabolic syndrome defined by Adult Treatment Panel III criteria. RESULTS: By design, none of the study participants had MAFLD at baseline. The prevalence of NAFLD among participants without metabolic dysfunction meeting MAFLD criteria and without significant alcohol intake was 7.6%. During 74,508 person-years of follow-up, 2179 participants developed metabolic syndrome. The fully adjusted hazard ratio for metabolic syndrome comparing participants with NAFLD to those without it was 1.61 (95% confidence interval, 1.42-1.83). The increased risk of incident metabolic syndrome associated with NAFLD persisted for all studied subgroups, and the association was stronger for those with increased waist circumference (P for interaction = .029) and those without elevated triglycerides levels (P for interaction = .047). CONCLUSION: In this large cohort, participants with NAFLD without MAFLD were at higher risk of developing metabolic syndrome compared to participants with no NAFLD and no MAFLD. Using MAFLD criteria may miss opportunities for early intervention in these subjects.

Proteome Multimarker Panel for the Early Detection of Hepatocellular Carcinoma: Multicenter Derivation, Validation, and Comparison.

Conventional methods for the surveillance of hepatocellular carcinoma (HCC) by imaging, with and without serum tumor markers, are suboptimal with regard to accuracy. We aimed to develop and validate a reliable serum biomarker panel for the early detection of HCC using a proteomic technique. This multicenter case-control study comprised 727 patients with HCC and patients with risk factors but no HCC. We developed a multiple reaction monitoring-mass spectrometry (MRM-MS) multimarker panel using 17 proteins from the sera of 398 patients. Area under the receiver operating characteristics curve (AUROC) values of this MRM-MS panel with and without α-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were compared. The combination and standalone MRM-MS panels had higher AUROC values than AFP in the training (0.940 and 0.929 vs 0.775, both P < 0.05), test (0.894 and 0.893 vs 0.593, both P < 0.05), and confirmation sets (0.961 and 0.937 vs 0.806, both P < 0.05) in detecting small single HCC. The combination and standalone MRM-MS panels had significantly higher AUROC values than the GALAD score (0.945 and 0.931 vs 0.829, both P < 0.05). Our proteome 17-protein multimarker panel distinguished HCC patients from high-risk controls and had high accuracy in the early detection of HCC.

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.

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.

Incidence and risk factors for development of hepatocellular carcinoma at young age in patients with chronic hepatitis B.

BACKGROUND: Some young adults with chronic hepatitis B virus (HBV) infection might be at high risk for hepatocellular carcinoma (HCC), enough to justify regular HCC surveillance despite the young age of the patients. However, ways to identify at-risk individuals who may benefit from HCC surveillance need further evaluations. METHODS: A hospital-based retrospective cohort of 2757 chronic HBV mono-infected young adults (median age: 34 years, males 66%) were analyzed. The primary outcome was young-onset HCC, defined as a diagnosis made under 40 years of age. We calculated the HCC incidence/1000 person-years in the overall cohort and pre-defined subgroups of patients assessed the independent risk factors that can be used to identify surveillance targets. RESULTS: The HCC incidence was low (2.55/1000 person-years) in the overall cohort. However, the HCC incidence varied widely according to baseline characteristics: lowest among young adults with FIB-4 ≤ 0.70 (0.17/1000 person-years) and highest in young adults with radiological cirrhosis (30.7/1000 person-years). In multivariable analysis, radiological cirrhosis, the FIB-4 index, and serum HBV DNA level were independent factors associated with HCC development at a young age. Performance for prediction of young-onset HCC in radiological cirrhotic patients showed the highest specificity but sensitivity was <70%. Combination with FIB-4 index and HBV DNA levels increased sensitivity to 90%. CONCLUSION: Risk stratification using FIB-4 index, HBV DNA levels, and either combining radiological cirrhosis or gender and AFP levels would be helpful to stratify young patients who would and would not benefit from regular HCC surveillance.

Clinical Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma Patients with Undetectable Serum HBV DNA Levels.

BACKGROUND AND AIMS: Some hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients show undetectable serum HBV DNA levels at HCC diagnosis. The risk of HBV reactivation and its impact on clinical outcomes are not well-unknown. METHODS: This retrospective cohort study included a total of 985 HBV-related HCC patients with undetectable serum HBV DNA levels (< 12 IU/mL) at HCC diagnosis (112 were antiviral treatment (AVT)-naïve; 873 were receiving AVT). Incidence and risk factors for HBV reactivation (re-detection of HBV DNA in serum) during follow-up, as well as its association to overall survival, were assessed. RESULTS: During a median of 33.4 months of follow-up (range: 0.2-124.2 months), HBV reactivation was observed in 279 patients. HBV reactivation rate was significantly lower for patients receiving AVT than AVT-naïve patients (three-year cumulative incidence rate: 27.3% versus 56.0%; P < 0.001). In multivariable-adjusted analysis, the risk of HBV reactivation was lower for those receiving AVT compared to AVT-naïve patients (adjusted hazard ratio: 0.39, 95% confidence interval: 0.29-0.54). Overall survival was significantly lower for those experiencing HBV reactivation than those who did not (71.5% and 85.7% at five-year) and was associated with higher risk of overall mortality (adjusted hazard ratio: 5.15, 95% confidence interval: 3.60-7.38). CONCLUSION: More than half of AVT-naïve patients experienced HBV reactivation within three years, which was associated with increased risk of overall mortality. The risk of HBV reactivation was lower for those receiving AVT, suggesting that prompt AVT needs to be considered for AVT naïve HBV-related HCC patients with undetectable HBV DNA levels.

Inclusive Quantification Assay of Serum Des-γ-Carboxyprothrombin Proteoforms for Hepatocellular Carcinoma Surveillance by Targeted Mass Spectrometry.

Hepatocellular carcinoma (HCC) is a malignant cancer with one of the highest mortality rates. Des-γ-carboxyprothrombin (DCP) is an HCC serologic surveillance marker that can complement the low sensitivity of alpha-fetoprotein (AFP). DCP exists in the blood as a mixture of proteoforms from an impaired carboxylation process at glutamic acid (Glu) residues within the N-terminal domain. The heterogeneity of DCP may affect the accuracy of measurements because DCP levels are commonly determined using an immunoassay that relies on antibody reactivity to an epitope in the DCP molecule. In this study, we aimed to improve the DCP measurement assay by applying a mass spectrometry (MS)-based approach for a more inclusive quantification of various DCP proteoforms. We developed a multiple-reaction monitoring-MS (MRM-MS) assay to quantify multiple noncarboxylated peptides included in the various des-carboxylation states of DCP. We performed the MRM-MS assay in 300 patients and constructed a robust diagnostic model that simultaneously monitored three noncarboxylated peptides. The MS-based quantitative assay for DCP had reliable surveillance power, which was evident from the area under the receiver operating characteristic curve (AUROC) values of 0.874 and 0.844 for the training and test sets, respectively. It was equivalent to conventional antibody-based quantification, which had AUROC values at the optimal cutoff (40 mAU/mL) of 0.743 and 0.704 for the training and test sets, respectively. The surveillance performance of the MS-based DCP assay was validated using an independent validation set consisting of 318 patients from an external cohort, resulting in an AUROC value of 0.793. Conclusion: Due to cost effectiveness and high reproducibility, the quantitative DCP assay using the MRM-MS method is superior to antibody-based quantification and has equivalent performance.