Updated Reference Intervals for Alanine Aminotransferase in a Metabolically and Histologically Normal Population.

BACKGROUND & AIMS: This study aims to reevaluate upper reference limit (URL) for alanine aminotransferase (ALT) by considering the changing epidemiology of major liver diseases. We employed histological and metabolic parameters in Asian living liver donors. METHODS: We performed a retrospective analysis of 5455 potential living liver donors from 2005 to 2019. Participants were screened for hepatitis B, C, HIV, and alcohol use. Histologically and metabolically healthy participants were assessed using the Prati criteria (body mass index <23 kg/m2, triglyceride ≤200 mg/dL, fasting glucose ≤105 mg/dL, total cholesterol ≤220 mg/dL). The updated ALT-URL was determined as the 95th percentile among participants without hepatic steatosis and who met the Prati criteria. RESULTS: The median age was 30 years, with a male predominance (66.2%). Among 5455 participants, 3162 (58.0%) showed no hepatic steatosis, with 1553 (49.1%) meeting both the criteria for no steatosis and the Prati criteria for metabolic health. The updated URL for ALT in these participants was 34 U/L for males and 22 U/L for females, which was significantly lower than conventionally accepted values. Using this revised ALT-URL, 72.8% of males with ALT levels ≥34 U/L and 55.0% of females with ALT levels ≥22 U/L showed signs of steatosis, whereas 32.7% of males and 22.2% of females met the criteria for metabolic syndrome. CONCLUSIONS: Our study provided the newly established reference intervals for ALT levels in a metabolically and histologically verified Asian population. The proposed URL for ALT are 34 U/L and 22 U/L for males and females, respectively.

Tenofovir Is Associated With a Better Prognosis Than Entecavir for Hepatitis B Virus-Related Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Whether tenofovir or entecavir has different effects on the prevention of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in secondary and tertiary preventive settings is still a matter of debate. This study aimed to compare the long-term prognosis of HCC between tenofovir and entecavir in patients with chronic hepatitis B. METHODS: Chronic hepatitis B patients diagnosed with HCC between November 2008 and December 2018 and treated with either entecavir or tenofovir at a tertiary center in Korea were included. The effect of tenofovir compared with entecavir on the prognosis of HBV-related HCC was assessed using multivariable-adjusted Cox and propensity score (PS)-matched analyses. Various predefined subgroup analyses were conducted. RESULTS: During a median follow-up period of 3.0 years, the mortality rate for entecavir-treated patients (n = 3469) was 41.2%, while tenofovir-treated patients (n = 3056) had a mortality rate of 34.6%. Overall survival (OS) was better in the tenofovir group (adjusted hazard ratio [aHR], 0.79; P < .001), which were consistently observed in the PS-matched analysis. The magnitude of the risk difference in OS was more prominent 2 years after the diagnosis of HCC (aHR, 0.50; P < .001) than 2 years before (aHR, 0.88; P = .005), and it was more pronounced in patients with earlier HCC stages. In all subgroups, except for those with shorter life expectancy, such as those with compromised liver function, tenofovir was associated with better OS compared with entecavir. CONCLUSIONS: Among patients with HBV-related HCC, those treated with tenofovir had a better prognosis than those treated with entecavir, particularly among those with prolonged survival.

Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination-deficient hepatocellular carcinoma.

BACKGROUNDS AND AIMS: We performed an in-depth examination of pathogenic germline variants (PGVs) and somatic variants in DNA damage response (DDR) genes in hepatocellular carcinoma (HCC) to explore their clinical and genomic impacts. APPROACH AND RESULTS: We used a merged whole-exome or RNA sequencing data set derived from in-house ( n = 230) and The Cancer Genome Atlas ( n = 362) databases of multiethnic HCC samples. We also evaluated synthetic lethal approaches targeting mutations in homologous recombination (HR) genes using HCC cells selected from five genomic databases of cancer cell lines. A total of 110 PGVs in DDR pathways in 96 patients were selected. Of the PGV carriers, 44 were HR-altered and found to be independently associated with poorer disease-free survival after hepatectomy. The most frequently altered HR gene in both germline and somatic tissues was POLQ , and this variant was detected in 22.7% (10/44) and 23.8% (5/21) of all the corresponding carriers, respectively. PGVs in HR were significantly associated with upregulation of proliferation and replication-related genes and familial risk of HCC. Samples harboring PGVs in HR with loss of heterozygosity were most strongly correlated with the genomic footprints of deficient HR, such as mutation burden and denovoSig2 (analogous to Catalogue of Somatic Mutations in Cancer [COSMIC] 3), and poor outcome. Pharmacologic experiments with HCC cells defective in BRCA2 or POLQ suggested that tumors with this phenotype are synthetic lethal with poly(ADP-ribose) polymerase inhibitors. CONCLUSIONS: Our findings suggest that germline HR defects in HCC tend to confer a poor prognosis and result in distinctive genomic scarring. Tests of the clinical benefits of HR-directed treatments in the affected patients are needed.

Response to atezolizumab plus bevacizumab specific for lung and lymph node metastases affects survival of patients with HCC.

BACKGROUND & AIMS: Tumour microenvironment heterogeneity among different organs can influence immunotherapy responses. Here, we evaluated the impact of differential organ-specific responses on survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). METHODS: We retrospectively analysed 366 consecutive patients with advanced-stage HCC treated with Atezo/Bev as first-line systemic treatment. Therapeutic response was assessed using RECIST v1.1. Patients were divided into an intention-to-treat (ITT) group (patients treated with ≥1 dose of Atezo/Bev) and a per-protocol (PP) analysis group (patients with at least one measurable lesion irrespective of location treated with ≥3 doses of Atezo/Bev). Overall response and organ-specific response at initial and best response were evaluated in the PP group. Responders were defined as patients achieving complete remission or partial response. Initial progressors were defined as patients with progressive disease after three doses of Atezo/Bev. RESULTS: The ITT and PP groups comprised 324 and 236 patients, respectively. In the PP group, the organ-specific response rate of lung and lymph node (LN) metastases at both initial and best responses were higher than those of intrahepatic lesions and macrovascular tumour thrombosis. Lung and LN-specific response rates were 21.1% and 23.5%, respectively, at initial response, and 24.7% and 31.4%, respectively, at best response. Both initial pulmonary and lymphatic progressors (adjusted hazard ratios [95% confidence intervals], 6.37 [2.10-19.3], and 8.36 [2.16-32.4], respectively) were independently associated with survival regardless of intrahepatic response. CONCLUSIONS: The response of metastatic HCC to the Atezo/Bev regimen may be used to determine whether to continue treatment or switch to second-line treatment at an early phase of therapy.

Characterization of lymphocyte-rich hepatocellular carcinoma and the prognostic role of tertiary lymphoid structures.

BACKGROUND & AIMS: Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is largely unknown and a rare subtype of HCC with immune-rich stroma. Tertiary lymphoid structures (TLS), frequently observed in LR-HCC, are known to be prognostically significant in various malignancies; however, their significance in HCC remains unevaluated. METHODS: Clinicopathologic data of 191 cases of surgically resected conventional HCC (C-HCC, n = 160) and LR-HCC (n = 31) were retrieved. Immunohistochemistry, multiplex immunofluorescence staining, RNA sequencing and proteomic analysis were conducted. Differences between the subtypes were statistically evaluated. RESULTS: LR-HCC was significantly correlated to larger tumour size, higher Edmondson-Steiner grade, presence of TLS and higher CD3-, CD8- and FOXP3-positive T cell, high PD-1 and PD-L1 expression (p < .001 for all) compared to C-HCC. Patients with LR-HCC exhibited significantly better overall survival (OS) (p = .044) and recurrence-free survival (RFS) (p = .025) than C-HCC. LR-HCC demonstrated TLS signatures with significantly higher proteomic-based immune scores in 14 of 17 types of tumour-infiltrating immune cells. Furthermore, C-HCC with secondary follicles, the most mature form of TLS, exhibited significantly better OS (p = .031) and RFS (p = .033) than those without. Across the global proteome, LR-HCC was well-differentiated from C-HCC and a map of protein-protein interactions between tumour-infiltrating lymphocytes and HCC in tumour microenvironment was completed. CONCLUSION: LR-HCC is clinicopathologically and molecularly distinct and shows better prognosis compared to C-HCC. Also, the presence of secondary follicle can be an important prognostic marker for better prognosis in both LR-HCC and C-HCC.

Improving the hepatitis C virus care cascade with the in-hospital Reflex tEsting ALarm-C (REAL-C) model.

BACKGROUND: The World Health Organization (WHO) has set targets to eliminate viral hepatitis, including hepatitis C virus (HCV) infection, by 2030. We present the results of the in-hospital Reflex tEsting ALarm-C (REAL-C) model, which incorporates reflex HCV RNA testing and sending alerts to physicians. METHODS: We conducted a retrospective study analysing the data of 1730 patients who newly tested positive for anti-HCV between March 2020 and June 2023. Three distinct periods were defined: pre-REAL-C (n = 696), incomplete REAL-C (n = 515) and complete REAL-C model periods (n = 519). The primary outcome measure was the HCV RNA testing rate throughout the study period. Additionally, we assessed the referral rate to the gastroenterology department, linkage time for diagnosis and treatment and the treatment rate. RESULTS: The rate of HCV RNA testing increased significantly from 51.0% (pre-REAL-C) to 95.6% (complete REAL-C). This improvement was consistent across clinical departments, regardless of patients' comorbidities. Among patients with confirmed HCV infection, the gastroenterology referral rate increased from 57.1% to 81.1% after the REAL-C model. The treatment rate among treatment-eligible patients was 92.4% during the study period. The mean interval from anti-HCV positivity to HCV RNA testing decreased from 45.1 to 1.9 days. The mean interval from the detection of anti-HCV positivity to direct-acting antiviral treatment also decreased from 89.5 to 49.5 days with the REAL-C model. CONCLUSION: The REAL-C model, featuring reflex testing and physician alerts, effectively increased HCV RNA testing rates and streamlined care cascades. Our model facilitated progress towards achieving WHO's elimination goals for HCV infection.

Chemoembolization versus radiofrequency ablation for single small (≤ 3 cm) hepatocellular carcinoma: a propensity score matching analysis.

OBJECTIVES: To compare the efficacy of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for patients with single small (≤ 3 cm) hepatocellular carcinoma (HCC) and preserved liver function (Child-Pugh class A). MATERIALS AND METHODS: The clinical features of treatment-naïve patients who underwent TACE and RFA as first-line treatment were balanced through propensity score matching (PSM). The primary endpoint was overall survival (OS), and the secondary endpoints were local tumor recurrence (LTR) and recurrence-free survival (RFS). RESULTS: The analysis included 440 patients who received TACE, and 430 patients who received RFA. After PSM adjustment (323 pairs), the 5- and 10-year OS rates were 81% and 61%, respectively, in patients who underwent RFA, and 77% and 51%, respectively, for patients who underwent TACE (p = 0.021). Subgroup analyses showed that OS, LTR, and RFS were homogeneously better in the RFA group. CONCLUSION: RFA was associated with better survival outcomes than TACE in patients with single small HCC and preserved liver function. CLINICAL RELEVANCE STATEMENT: This large-scale comparative study provides evidence that radiofrequency ablation has a better overall survival rate than chemoembolization for small (≤ 3 cm) hepatocellular carcinomas. KEY POINTS: • The relative effectiveness of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for early HCC is unclear. • Overall survival rate was significantly higher in the RFA group. • The effects of RFA on overall survival, local tumor recurrence, and recurrence-free survival were homogeneously better in all subgroups.

Revisiting the steatosis-associated fibrosis estimator score in young Asian subjects with steatotic liver disease and consideration for population variability.

BACKGROUND AND AIM: The steatosis-associated fibrosis estimator (SAFE) score has been developed to distinguish clinically significant fibrosis in patients with steatotic liver disease (SLD). However, validation of its performance in Asian subjects is limited. This study aimed to evaluate the performance of the SAFE score in Asian subjects with biopsy-proven SLD and in different subgroups according to age, sex, and body mass index. METHODS: We retrospectively analyzed 6383 living liver donors who underwent a liver biopsy between 2005 and 2023. Of these, 1551 subjects with biopsy-proven SLD were included. The performance of the SAFE score was evaluated using areas under the curve and compared with those of the nonalcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 index (FIB-4). RESULTS: The prevalence of clinically significant fibrosis in the cohort was 2.2%. The proportion of subjects with a "low-risk" SAFE score was the highest (91.0%), followed by those with "intermediate-risk" (7.8%) and "high-risk" (1.2%) scores. The prevalence of fibrosis in subjects with low-risk, intermediate-risk, and high-risk scores was 1.6%, 6.6%, and 21.1%, respectively. The SAFE outperformed FIB-4 and NFS (area under the curve: 0.70 vs 0.64 for both NFS and FIB-4). However, it showed low diagnostic accuracy and sensitivity (27%) at the low cutoff (SAFE < 0) in subjects aged 30-39 years (fibrosis: 1.2%), despite having a high negative predictive value (0.99). CONCLUSION: While the SAFE score demonstrates superior performance compared with other noninvasive tests in Asian subjects with SLD, its performance varies across age groups. In younger subjects, particularly, its performance may be more limited.

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

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

Low Level of Hepatitis B Viremia Compared With Undetectable Viremia Increases the Risk of Hepatocellular Carcinoma in Patients With Untreated Compensated Cirrhosis.

INTRODUCTION: The initiation of antiviral treatment in patients with chronic hepatitis B with compensated cirrhosis and low-level viremia (LLV; HBV DNA 15-2,000 IU/mL) remains controversial. We sought to compare the long-term outcomes of these untreated patients according to their viremic status. METHODS: Six hundred twenty-seven untreated patients with chronic hepatitis B with compensated cirrhosis were analyzed retrospectively. The risk of hepatocellular carcinoma (HCC) and liver-related clinical events, including hepatic decompensation, were compared between patients with LLV and undetectable HBV DNA. Patients who received antiviral treatment were censored during treatment initiation. RESULTS: The mean age of the patients was 54.7 years, 64.4% of whom were male. During the study period, 59 patients developed HCC (20 and 39 in the undetectable and LLV groups, respectively) with an annual incidence of 2.44/100 person-years. Multivariable analysis revealed that the LLV group was associated with a significantly higher risk of HCC (adjusted hazard ratio: 2.36, P = 0.002) than the undetectable group. In the 204 propensity score-matched cohort, the LLV group had a 2.16-fold greater risk of HCC than the undetectable group ( P = 0.014). Liver-related clinical events occurred in 121 patients with an annual incidence of 5.25/100 person-years. Despite not reaching statistical significance, the LLV group tended to have a higher risk of liver-related events in the propensity score-matched cohort (hazard ratio: 1.14, P = 0.50). DISCUSSION: Compared with patients with undetectable HBV DNA, those with compensated cirrhosis and LLV had a significantly higher risk of HCC. Antiviral treatment should be advised for these patients.

Liver Cirrhosis Increases the Risk of Herpes Zoster: A Nationwide Population-Based Cohort Study.

INTRODUCTION: Limited data are available regarding the association between liver cirrhosis (LC) and the risk of herpes zoster (HZ). This study aimed to determine the risk of HZ in patients with LC. METHODS: HZ was defined as the presence of the International Classification of Diseases-10th revision code for HZ and concomitant prescription of antiviral medication. The incidence rates and standardized incidence ratios (SIRs) of HZ in patients with LC were analyzed using data from the Health Insurance Review and Assessment Service in Korea claims database from 2009 to 2019. RESULTS: A total of 504,986 Korean patients with LC were included. The mean age was 52.4 years, and 60.8% were men. Chronic hepatitis B was the most common cause of LC. The incidence rates for HZ and HZ-related hospitalization were 21.6 of 1,000 and 1.81 of 1,000 person-years, respectively. The SIRs for HZ and HZ-related hospitalization were 1.09 (95% confidence interval [CI]: 1.08-1.09) and 1.48 (95% CI: 1.44-1.52), respectively, which were significantly higher than those in the general population. Patients with LC aged 20-29, 30-39, and 40-49 years had SIRs for HZ of 1.41 (95% CI: 1.33-1.48), 1.16 (1.13-1.19), and 1.17 (1.13-1.19), respectively. In multivariable analysis, woman (adjusted hazard ratio [AHR]: 1.48), steroid (AHR: 1.20), immunosuppressant use (AHR: 1.26), and combined comorbidities were associated with an increased risk of HZ among patients with LC. DISCUSSION: Patients with LC, particularly those who are not currently recommended for HZ vaccination, were at an increased risk of HZ and HZ-related hospitalization compared with the general Korean population.

Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

BACKGROUND AND AIMS: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors. APPROACH AND RESULTS: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA. CONCLUSIONS: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.

Multiple arterial-phase MRI with gadoxetic acid improves diagnosis of hepatocellular carcinoma ≤3.0 cm.

BACKGROUND AND AIMS: Multiple arterial-phase magnetic resonance imaging (MA-MRI) was introduced to overcome the limitations of gadoxetic acid-enhanced MRI, but its clinical impacts on hepatocellular carcinoma (HCC) diagnosis have not been well assessed. We investigated whether MA-MRI with gadoxetic acid could improve the diagnosis of HCC ≤3.0 cm in comparison with single arterial-phase MRI (SA-MRI). METHODS: This retrospective study included 397 patients from two tertiary institutions who underwent gadoxetic acid-enhanced MRI (243 patients with 271 lesions in cohort-1 underwent SA-MRI, and 154 patients with 166 lesions in cohort-2 underwent MA-MRI). The patients had 437 hepatic lesions ≤3.0 cm with pathologic confirmation. The arterial-phase image quality and diagnostic performance of SA-MRI and MA-MRI were analysed and compared. To minimize the effects of selection bias because of potential confounding between the two groups, propensity score-matching was additionally performed. RESULTS: MA-MRI showed a significantly higher percentage of optimal arterial-phase timing (94.2% vs. 74.5%, p < .001) and lower incidence of inadequate examinations (1.3% vs. 5.8%, p = .034) than SA-MRI. MA-MRI had a significantly higher non-rim arterial-phase hyperenhancement (APHE) detection rate (94.9% vs. 85.5%, p = .005) and sensitivity for diagnosing HCC (87.4% vs. 70.0%, p < .001) than SA-MRI, but no significant difference in specificity (92.9% vs. 93.1%, p = .966). In 123 pairs of propensity score-matched patients, MA-MRI had significantly higher sensitivity (89.1% vs. 74.5%, p = .006) than SA-MRI with equal specificity (92.3% vs. 92.3%, p > .999). CONCLUSIONS: Compared with SA-MRI, MA-MRI with gadoxetic acid can detect more non-rim APHE and significantly improve sensitivity for diagnosing HCC ≤3.0 cm, without a significant decrease in specificity.

Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment.

BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. METHODS: This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. RESULTS: The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3-4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. CONCLUSIONS: In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.

Extrahepatic carcinogenicity of oral nucleos(t)ide analogues in chronic hepatitis B carriers: A 35,000-Korean outcome study.

Evidence on the carcinogenicity of oral nucleos(t)ide analogues (NAs) is inconclusive and lacks data on the effects by chemical structure of the NAs in patients with chronic hepatitis B (CHB). We aimed to provide definitive results on this issue using a large set of CHB patients and data on all major NA drugs. The study population consisted of 10,331 patients with CHB receiving primary NA treatment for more than 6 months, and 24,836 untreated controls followed for at least as long as the treated patients. Using the inverse-probability-of-treatment-weighted (IPTW) method, the cumulative incidence of extrahepatic cancers was compared in the treated and untreated patients and across the cyclopentane, L-nucleoside and acyclic phosphonate categories of NAs. Analyses of individual cancers as sub-endpoints were also performed. The cumulative incidence of overall extrahepatic malignancies did not differ between the two groups in the IPTW cohort (hazard ratio [HR] 1.002; 95% confidence interval [CI] [0.859-1.169]). Similar statistical trends were observed in analyses across the three NA chemical subsets and controls. Per-cancer analyses indicated that NA treatment was significantly associated with increased risks of colorectal/anal cancers (HRs [95% CI], 1.538 [1.175-2.013]) and lymphoma (1.784 [1.196-2.662]). Conversely, breast cancer (HRs [95% CI], 0.669 [0.462-0.967]) and prostate cancer (0.521 [0.329-0.825]) were less prevalent in the NA-treated group. In conclusion, prolonged NA treatment presents carcinogenic risks for colorectal/anal and lymphoid tissues in CHB patients, although it does not affect most extrahepatic organs. The protective effect of NAs on breast and prostate cancers should be confirmed.

Stereotactic body radiation therapy as a salvage treatment for single viable hepatocellular carcinoma at the site of incomplete transarterial chemoembolization: a retrospective analysis of 302 patients.

BACKGROUND: To evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE). METHODS: Patients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10-15 Gy per fraction were given over 3-4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03. RESULTS: A total of 302 patients were analyzed. The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6-41.7) and the median tumor size was 2.0 cm (range, 0.7-6.9). The local control (LC) and overall survival rates at 3 years were 91.2 and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9-4.7), and 39.9 and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field. CONCLUSION: SBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE.

Treatment patterns for hepatocellular carcinoma in patients with Child-Pugh class B and their impact on survival: A Korean nationwide registry study.

BACKGROUND AND AIMS: There are no established practice guidelines for treating hepatocellular carcinoma (HCC) in patients with Child-Turcotte-Pugh (CTP) class B liver function. To evaluate the impact of various initial treatment modalities on these patients, we conducted a nationwide registry study in Korea. MATERIALS AND METHODS: Treatment patterns and overall survival (OS) of patients with HCC and CTP class B according to initial treatment modalities in each Barcelona Clinic Liver Cancer (BCLC) stage were analysed using data from the Korean Primary Liver Cancer Registry between 2008 and 2016. Initial treatment modalities were categorized as standard, alternative treatment and supportive care only, referring to the 2018 BCLC guidelines, irrespective of liver function. RESULTS: Of the 2318 newly diagnosed Korean patients with HCC and CTP class B, 29.7%, 60.3% and 15.6% of patients in BCLC stages A, B and C, respectively, underwent standard treatment. Adjusted OS hazard ratios of alternative treatment referring to standard treatment were 1.55 (95% confidence interval [CI], 1.25-1.94; p < .001) in BCLC-A, 0.82 (95% CI, 0.43-1.56; p = .550) for curative alternative treatment, 1.89 (95% CI, 0.97-3.68; p = .059) for non-curative alternative treatment in BCLC-B, 0.40 (95% CI, 0.28-0.56; p < .001) for curative alternative treatment, 0.84 (95% CI, 0.69-1.02; p = .076) for non-curative alternative treatment for BCLC-C. CONCLUSION: Regardless of BCLC stages, chemoembolization was conducted the most among patients with CTP class B. Treatment in line with the BCLC treatment algorithm resulted in favourable OS outcomes, except for those with BCLC stage C, as systemic therapy showed poor OS.

Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in treatment-naïve chronic hepatitis B.

BACKGROUND AND AIMS: We used real-world data to evaluate the efficacy and safety of tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) in treatment-naïve patients with CHB. METHODS: We analysed 2747 patients with CHB under TAF (n = 502) or TDF (n = 2245) treatments. Virological responses (VR: HBV DNA <15 IU/ml), on-treatment ALT normalization, the incidence of HCC, renal function and lipid profiles were compared between these groups. Propensity score matching of 495 pairs was conducted for these comparisons. RESULTS: The mean age of the total cohort was 48.6 years and 58.2% of the subjects were male. Cirrhosis had a 33.3% prevalence in the population. VRs at 12, 24 and 36 months were achieved in 70.3%, 81.2% and 83.3% of the TAF and 67.9%, 84.3% and 86.1% in the TDF cases respectively (p > 0.05 for all). Normalized ALT, as determined by local laboratory criteria (<40 U/L), occurred in 79.7%, 90.6% and 86.2% of TAF the group and 78.2%, 85.8% and 85.7% of the TDF group at 12, 24 and 36 months respectively (p > 0.05 for all). The HCC risk did not statistically differ across the entire cohort or in the PS-matched cohort. The TAF group showed a lower median increase in serum creatinine from baseline during the early study period. Compared with the TAF, the TDF group showed significant decreases in total cholesterol, triglyceride and HDL, but not in LDL. CONCLUSIONS: Real-word data indicate that TAF has comparable efficacies to TDF in terms of VR and ALT normalization, with no higher risk of HCC.

Prognostic Molecular Indices of Resectable Hepatocellular Carcinoma: Implications of S100P for Early Recurrence.

BACKGROUND: Although hepatocellular carcinomas (HCCs) often recur in patients undergoing hepatectomy, there are no reliable biomarkers of this undesirable event. Recent RNA-based efforts have developed valuable genetic indices prognostic of cancer outcomes. We aimed to identify molecular predictors of early recurrence after resection of HCC, and reveal the genomolecular structure of the resected tumors. METHOD: Based on the transcriptomic and genomic datasets of 206 HCC samples surgically resected in the Asan Medical Center (AMC), we performed a differential gene expression analysis to identify quantitative markers associated with early recurrence and used the unsupervised clustering method to classify genomolecular subtypes. RESULTS: Differential gene expression profiling revealed that S100P was the highest-ranked overexpressed gene in HCCs that recurred within 2 years of surgery. This trend was reproduced in immunohistochemical studies of the original cohort and an independent AMC cohort. S100P expression also independently predicted HCC-specific mortality post-resection (adjusted hazard ratio 1.09, 95% confidence interval 1.01-1.19; p = 0.042). Validation in a Chinese cohort and in in vitro experiments confirmed the prognostic value of S100P in HCC. We further identified five discrete molecular subtypes of HCC; a subtype with stem cell features ('AMC-C4') was associated with the worst prognosis, both in our series and another two Asian datasets, and S100P was most strongly upregulated in that subtype. CONCLUSION: We identified a promising prognostic biomolecule, S100P, associated with early recurrence after HCC resection, and established the genomolecular architecture of tumors affecting clinical outcomes, particularly in Asian patients. These new insights into molecular mediators should contribute to effective care for affected patients.

Variceal bleeding is aggravated by portal venous invasion of hepatocellular carcinoma: a matched nested case-control study.

BACKGROUND: We hypothesized that portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) increases portal pressure and causes esophageal varices and variceal bleedings. We examined the incidence of high-risk varices and variceal bleeding and determined the indications for variceal screening and prophylaxis. METHODS: This study included 1709 asymptomatic patients without any prior history of variceal hemorrhage or endoscopic prophylaxis who underwent upper endoscopy within 30 days before or after initial anti-HCC treatment. Of these patients, 206 had PVTT, and after 1:2 individual matching, 161 of them were matched with 309 patients without PVTT. High-risk varices were defined as large/medium varices or small varices with red-color signs and variceal bleeding. Bleeding rates from the varices were compared between matched pairs. Risk factors for variceal bleeding in the entire set of patients with PVTT were also explored. RESULTS: In the matched-pair analysis, the proportion of high-risk varices at screening (23.0% vs. 13.3%; P = 0.003) and the cumulative rate of variceal bleeding (4.5% vs. 0.4% at 1 year; P = 0.009) were significantly greater in the PVTT group. Prolonged prothrombin time, lower platelet count, presence of extrahepatic metastasis, and Vp4 PVTT were independent risk factors related to high-risk varices in the total set of 206 patients with PVTT (Adjusted odds ratios [95% CIs], 1.662 [1.151-2.401]; 0.985 [0.978-0.993]; 4.240 [1.783-10.084]; and 3.345 [1.457-7.680], respectively; Ps < 0.05). During a median follow-up of 43.2 months, 10 patients with PVTT experienced variceal bleeding episodes, 9 of whom (90%) had high-risk varices. Presence of high-risk varices and sorafenib use for HCC treatment were significant predictors of variceal bleeding in the complete set of patients with PVTT (Adjusted hazard ratios [95% CIs], 26.432 [3.230-216.289]; and 5.676 [1.273-25.300], respectively; Ps < 0.05). CONCLUSIONS: PVTT in HCC appears to increase the likelihood of high-risk varices and variceal bleeding. In HCC patients with PVTT, endoscopic prevention could be considered, at least in high-risk variceal carriers taking sorafenib.