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.

Proton Beam Radiotherapy as a Curative Alternative to Radiofrequency Ablation for Newly Diagnosed Hepatocellular Carcinoma.

BACKGROUND/AIM: This study aimed to compare the oncological outcomes of proton beam radiotherapy (PBT) with those of radiofrequency ablation (RFA) for newly diagnosed hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study included 323 patients who underwent PBT (n=40) or RFA (n=283) as a curative treatment for previously untreated HCC between October 2016 and June 2021. The primary endpoints were local progression and toxicity. RESULTS: The median follow-up was 3.4 years (range=1.1-5.7 years). In terms of portal vein tumor thrombosis, tumor size, alpha-fetoprotein, and prothrombin-induced by vitamin K absence-II, the PBT group had significantly more severe tumor burdens than those of the RFA group (p<0.0001, p<0.0001, p=0.0004, and p<0.0001, respectively). No significant difference was observed in cumulative local progression rate (10.4% in PBT vs. 7.8% in RFA at 3-years, p=0.895). Grade 3 or higher toxicity was reported in only one patient (0.4%) after RFA. Multivariable analysis demonstrated that treatment modality was not a significant prognostic factor for local progression (hazard ratio=1.05; 95% confidence interval=0.32-3.48; p=0.934). CONCLUSION: PBT demonstrated comparable local control with acceptable toxicity to RFA in newly diagnosed HCC. Therefore, PBT may be a valid alternative.

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.

External validation of subclassification system and progression pattern analysis in hepatocelluar carcinoma with macroscopic vascular invasion.

BACKGROUND AND PURPOSE: The present study aimed to validate the performance of a previously proposed subclassification model to predict prognosis after combined transarterial chemoembolization (TACE) and external beam radiotherapy (RT) for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) in an independent cohort that received the same first-line treatment for the patients with the similar disease extent characteristics, and analyzed the progression patterns as well as progression-free survival (PFS). MATERIALS AND METHODS: This study was conducted using prospectively collected data from the XXXXX HCC registry for newly diagnosed, previously untreated HCC between 2005 and 2018. Finally, 417 patients who satisfied the eligibility criteria were included and analyzed. RESULTS: The median PFS and overall survival (OS) were 5.2 and 13.9 months, respectively. Similar to a previous study, subclassification of patients into very low-, low-, intermediate-, and high-risk groups showed a median OS of 98.4, 18.3, 9.7, and 5.8 months, respectively (P < 0.001). Additionally, subclassification of patients into the very low-, low-, intermediate-, and high-risk groups showed median PFS of 18.7, 6.7, 3.3, and 2.3 months, respectively (p < 0.001). Overall, intrahepatic progression was the most common pattern of progression; however, extrahepatic progression was more common in the intermediate- and high-risk groups. CONCLUSION: The previously proposed subclassification model was successfully validated in an independent cohort. Treatment modification should be considered in the intermediate- and high-risk patient groups because of their frequent extrahepatic as well as intrahepatic progressions after combined TACE and RT.

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.

Clinical practice guideline and real-life practice in hepatocellular carcinoma: A Korean perspective.

Hepatocellular carcinoma (HCC) is a major cause of death in many countries, including South Korea. To provide useful and sensible advice for clinical management of patients with HCC, the Korean Liver Cancer Association and National Cancer Center Korea Practice Guideline Revision Committee have recently revised the practice guidelines for HCC management. However, there are some differences between practice guidelines and real-life clinical practice. In this review, we describe some key recommendations of the 2022 version of practice guidelines and the real-life clinical situation in South Korea, together with discussion about efforts needed to reduce the difference between guidelines and real-life clinical practice.

Trends in radiotherapy administration in the management of hepatocellular carcinoma: Analysis of a Korean tertiary hospital registry of hepatocellular carcinoma patients diagnosed between 2005 and 2017.

Purpose: To present the trends in radiotherapy for the management of hepatocellular carcinoma (HCC) at a single tertiary referral hospital in South Korea. Materials and Methods: We retrospectively reviewed prospectively collected registry data of patients newly diagnosed with HCC between January 2005 and December 2017 at the Samsung Medical Center. Trends in radiotherapy, delivery techniques, tumor stage, and age were evaluated. Results: During the study period, 9,132 patients were newly diagnosed with HCC at our institution. Of these, 2,445 patients (26.8%) received radiotherapy for all lesions, including extrahepatic metastases; 1,865 patients (20.4%) received radiotherapy for intrahepatic lesions alone, and 469 patients (5.1%) received radiotherapy as initial management. Although the proportion of patients receiving radiotherapy increased slightly over the study period (24.2% vs. 26.6%), the proportions of patients receiving radiotherapy for intrahepatic lesions (16.8% vs. 21.9%) and as initial management (0.1% vs. 12.5%) increased dramatically. The majority of patients treated between 2005 and 2008 received three-dimensional conformal radiotherapy (56.3%), whereas the majority of patients treated between 2018 and 2021 received proton beam therapy (43.6%). With the technical developments, the overall survival (OS) of patients who received radiotherapy as initial management increased significantly (5-year OS: from 5.4% to 30.1%), and the OS difference between patients who did and did not receive radiotherapy as initial management significantly decreased (ratio of restricted mean survival time: from 0.383 to 0.544). Conclusion: This registry-based, retrospective study indicated an increasing trend in the utilization of radiotherapy, adoption of advanced radiotherapy techniques, and OS improvements in patients with 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.

The Significance of Systemic Inflammation Markers in Intrahepatic Recurrence of Early-Stage Hepatocellular Carcinoma after Curative Treatment.

Systemic inflammatory markers (SIMs) are known to be associated with carcinogenesis and prognosis of hepatocellular carcinoma (HCC). We evaluated the significance of SIMs in intrahepatic recurrence (IHR) of early-stage HCC after curative treatment. This study was performed using prospectively collected registry data of newly diagnosed, previously untreated HCC between 2005 and 2017 at a single institution. Inclusion criteria were patients with Barcelona Clinic Liver Cancer stage 0 or A, who underwent curative treatment. Pre-treatment and post-treatment values of platelet, neutrophil, lymphocyte, monocyte, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) were analyzed with previously well-known risk factors of HCC to identify factors associated with IHR-free survival (IHRFS), early IHR, and late IHR. Of 4076 patients, 2142 patients (52.6%) experienced IHR, with early IHR in 1018 patients (25.0%) and late IHR in 1124 patients (27.6%). Pre-treatment platelet count and PLR and post-treatment worsening of NLR, PLR, and LMR were independently associated with IHRFS. Pre-treatment platelet count and post-treatment worsening of NLR, PLR, and LMR were significantly related to both early and late IHR. Pre-treatment values and post-treatment changes in SIMs were significant factors of IHR in early-stage HCC, independent of previously well-known risk factors of HCC.

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.

Laparoscopic Hepatic Resection Versus Laparoscopic Radiofrequency Ablation for Subcapsular Hepatocellular Carcinomas Smaller Than 3 cm: Analysis of Treatment Outcomes Using Propensity Score Matching.

OBJECTIVE: To compare the therapeutic outcomes of laparoscopic hepatic resection (LHR) and laparoscopic radiofrequency ablation (LRFA) for single subcapsular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We screened 244 consecutive patients who had received either LHR or LRFA between January 2014 and December 2016. The feasibility of LRFA in patients who underwent LHR was retrospectively assessed by two interventional radiologists. Finally, 60 LRFA-feasible patients who had received LHR and 29 patients who had received LRFA as the first treatment for a solitary subcapsular HCC between 1 cm and 3 cm were finally included. We compared the therapeutic outcomes, including local tumor progression (LTP), recurrence-free survival (RFS), and overall survival (OS) between the two groups before and after propensity score (PS) matching. Multivariable Cox proportional hazard regression was also used to evaluate the difference in OS and RFS between the two groups for all 89 patients. RESULTS: PS matching yielded 23 patients in each group. The cumulative LTP and OS rates were not significantly different between the LHR and LRFA groups after PS matching (p = 0.900 and 0.003, respectively). The 5-year LTP rates were 4.6% and 4.4%, respectively, and OS rates were 100% and 90.7%, respectively. The RFS rate was higher in LHR group without statistical significance (p = 0.070), with 5-year rates of 78.3% and 45.3%, respectively. OS was not significantly different between the LHR (reference) and LRFA groups in multivariable analyses, with a hazard ratio (HR) of 1.33 (95% confidence interval, 0.12-1.54) (p = 0.818). RFS was higher in LHR (reference) than in LRFA without statistical significance in multivariable analysis, with an HR of 2.01 (0.87-4.66) (p = 0.102). CONCLUSION: There was no significant difference in therapeutic outcomes between LHR and LRFA for single subcapsular HCCs measuring 1-3 cm. The difference in RFS should be further evaluated in a larger study.

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).

Outcomes of patients presenting with elevated tumor marker levels but negative gadoxetic acid-enhanced liver MRI after a complete response to hepatocellular carcinoma treatment.

PURPOSE: Hepatocellular carcinoma (HCC) patients usually achieve a complete response after treatment. This study was aimed to assess the clinical outcome of HCC patients who had achieved a complete response but later presented with elevated tumor marker levels without an identifiable recurrent tumor on gadoxetic acid-enhanced magnetic resonance imaging (MRI). METHODS: We retrospectively reviewed the clinical outcome of 58 HCC treated patients who had achieved a complete response but later was referred to our institution's multidisciplinary tumor board for a clinically suspected hidden HCC recurrence based on elevated tumor marker levels but negative gadoxetic acid-enhanced MRI. The imaging studies, tumor markers, and clinical information were reviewed. The total follow-up period was at least 15 months after the initial negative gadoxetic acid-enhanced MRI. RESULTS: Follow-up imaging studies detected an HCC lesion in 89.7% (n = 52/58) of the patients within the study period, and approximately half of the tumors (46.2%, n = 24/52) developed within 3 months. The most frequent site of recurrence was the liver (86.5%; n = 45/52), but extra-hepatic metastasis was also common (19.2%; n = 10/52). In 5.8% (n = 3/52), HCC reoccurred in the combined form of intra-hepatic and extra-hepatic recurrence. Extra-hepatic metastasis alone occurred in 13.5% (n = 7/52) of patients. CONCLUSIONS: HCC frequently recurred within a short interval in patients who achieved a complete response to treatment in the presence of increased tumor marker levels, even if gadoxetic acid-enhanced MRI was negative. Under such circumstances, we suggest a short-term follow-up including, but not limited to, gadoxetic acid-enhanced MRI along with systemic evaluation.

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.