Machine learning-based clinical decision support system for treatment recommendation and overall survival prediction of hepatocellular carcinoma: a multi-center study.

The treatment decisions for patients with hepatocellular carcinoma are determined by a wide range of factors, and there is a significant difference between the recommendations of widely used staging systems and the actual initial treatment choices. Herein, we propose a machine learning-based clinical decision support system suitable for use in multi-center settings. We collected data from nine institutions in South Korea for training and validation datasets. The internal and external datasets included 935 and 1750 patients, respectively. We developed a model with 20 clinical variables consisting of two stages: the first stage which recommends initial treatment using an ensemble voting machine, and the second stage, which predicts post-treatment survival using a random survival forest algorithm. We derived the first and second treatment options from the results with the highest and the second-highest probabilities given by the ensemble model and predicted their post-treatment survival. When only the first treatment option was accepted, the mean accuracy of treatment recommendation in the internal and external datasets was 67.27% and 55.34%, respectively. The accuracy increased to 87.27% and 86.06%, respectively, when the second option was included as the correct answer. Harrell's C index, integrated time-dependent AUC curve, and integrated Brier score of survival prediction in the internal and external datasets were 0.8381 and 0.7767, 91.89 and 86.48, 0.12, and 0.14, respectively. The proposed system can assist physicians by providing data-driven predictions for reference from other larger institutions or other physicians within the same institution when making treatment decisions.

The Epidemiology of Hepatitis B Virus Infection in Korea: 15-Year Analysis.

BACKGROUND: The purpose of this study is to investigate the epidemiological changes in chronic hepatitis B (CHB) and assess the impact of coronavirus disease 2019 (COVID-19) over the past 15 years in a region endemic to hepatitis B virus (HBV). METHODS: National Health Insurance Service claims data of hepatitis B patients spanning from 2007 to 2021 was utilized. To compare the characteristics of the hepatitis B group, a control group adjusted for age and gender through propensity score matching analysis was established. RESULTS: The number of patients with CHB has consistently increased over the past 15 years. The average age of the CHB patient group has shown a yearly rise, while the prevalence of male dominance has gradually diminished. The proportions of hepatocellular carcinoma, liver cirrhosis, and decompensation have exhibited a declining pattern, whereas the proportion of liver transplants has continuously risen. Patients with CHB have demonstrated significantly higher medical and medication costs compared to the control group. Moreover, patients with CHB have shown a higher prevalence of comorbidities along with a significantly higher rate of concomitant medication usage. During the COVID period, the HBV group experienced a substantial decrease in the number of outpatient visits and overall medical costs compared to the control group. CONCLUSION: The epidemiology of CHB has undergone significant changes over the past 15 years, encompassing shifts in prevalence, severity, medical costs, and comorbidities. Furthermore, the impact of COVID-19 has been observed to decrease healthcare utilization among patients with CHB when compared to controls.

Proposal of a Novel Serological Algorithm Combining FIB-4 and Serum M2BPGi for Advanced Fibrosis in Nonalcoholic Fatty Liver Disease.

Background/Aims: Noninvasive methods have become increasingly critical in the diagnosis of fibrosis in chronic liver diseases. Herein, we compared the diagnostic performance of serum Mac2 binding protein glycosylation isomer (M2BPGi) and other serological panels for fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) and proposed an improved two-step diagnostic algorithm for advanced fibrosis. Methods: We enrolled 231 patients diagnosed with NAFLD who underwent a liver biopsy. We subsequently evaluated the diagnostic performance of serological panels, including serum M2BPGi, a fibrosis index based on four factors (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), and NAFLD fibrosis score (NFS), in predicting the stage of liver fibrosis. We then constructed a two-step algorithm to better differentiate advanced fibrosis. Results: The areas under the receiver operating characteristic curves of serum M2BPGi, FIB-4, APRI, and NFS for advanced fibrosis (≥F3) were 0.823, 0.858, 0.779, and 0.827, respectively. To reduce the performance of unnecessary liver biopsy, we propose a two-step algorithm using FIB-4 as an initial diagnostic tool and serum M2BPGi (≥0.6) as an additional diagnostic method for patients classified as intermediate (23%). Using the proposed algorithm, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 0.812, 0.814, 0.814, 0.600, and 0.927, respectively. Conclusions: Serum M2BPGi is a simple and effective test for advanced fibrosis in patients with NAFLD. Application of the two-step algorithm based on FIB-4 and M2BPGi proposed here can improve diagnostic performance and reduce unnecessary tests, making diagnosis easily accessible, especially in primary medical centers.

Plug-Assisted Retrograde Transvenous Obliteration for the Treatment of Duodenal Variceal Bleeding - A Case Report and Literature Review.

Duodenal varices are uncommon complications of portal hypertension. Although duodenal variceal bleeding is infrequent, it is a life-threatening condition with a high mortality rate. Non-surgical methods for duodenal variceal bleeding include endoscopic band ligation, endoscopic sclerotherapy, transjugular intrahepatic portosystemic shunt, and retrograde transvenous obliteration. On the other hand, an optimal treatment strategy for this rare condition has not been established. A 38-year-old male with a history of alcoholic liver cirrhosis presented with hematemesis. An emergency esophagogastroduodenoscopy (EGD) revealed large, multiple varices in the second portion of the duodenum, and plug-assisted retrograde transvenous obliteration (PARTO) was performed accordingly. Gastrointestinal bleeding was resolved after the procedure. Follow-up EGD conducted after 11 weeks revealed complete obliteration of the previously observed duodenal varices. PARTO may be considered a viable option for treating duodenal variceal bleeding.

Risk of Hepatitis C Virus Transmission through Acupuncture: A Systematic Review and Meta-Analysis.

Background/Aims: Chronic hepatitis C is a major risk factor for liver cirrhosis, hepatocellular carcinoma, and hepatic failure. Although traditional practices, including acupuncture, tend to increase the risk of HCV infection, the association remains controversial. Therefore, the current meta-analytical study was undertaken to evaluate the risks of acupuncture and hepatitis C transmission. Methods: Two researchers independently screened studies from the databases encompassing the period from inception to May 12, 2022. Baseline demographics, HCV transmission OR, and 95% CIs were extracted, pooled, and analyzed using random-effect models. Subgroup analyses utilizing study design and ethnicity were performed. Heterogeneity and publication bias were analyzed using the Higgins I2 test and funnel plots, respectively. Results: In all, 28 studies with 194,826 participants (178,583 controls [91.7%] vs. 16,243 acupuncture users [8.3%]) were included in the final analysis. The pooled analysis showed that acupuncture users had a significantly higher HCV transmission rate than controls with heterogeneity (OR, 1.84 [1.46-2.32]; p<0.001; I2 =80%). In the subgroup analysis, both cross-sectional case-control (n=14; OR, 1.96 [1.47-2.61]; p<0.001; I2 =88%) and cross-sectional studies (n=12; OR, 1.85 [1.32-2.61]; p<0.001; I2 =0%) showed significantly higher HCV infection rates in the acupuncture group than in the control group. Both Asian and non-Asian acupuncture users showed a higher HCV transmission risk than the controls (all Ps<0.001). No significant publication bias was observed. Conclusions: Our findings indicate that acupuncture increases the risk of HCV transmission. Due to HCV's contagiousness, unsafe medical and social practices (including acupuncture) should be performed with caution.

Tenofovir disoproxil fumarate versus tenofovir alafenamide on risk of osteoporotic fracture in patients with chronic hepatitis B: A nationwide claims study in South Korea.

BACKGROUND: As tenofovir disoproxil fumarate (TDF) requires long-term use, a reduction in bone density should be considered a possibility when treating patients with chronic hepatitis B (CHB) with aging and systemic diseases. Patients treated with tenofovir alafenamide (TAF) have improved bone mineral density loss compared to patients treated with TDF. Although improvements in bone density caused by TAF have been reported, studies on the actual reduction of fractures are insufficient. AIM: To evaluate the impact of TAF on the risk of osteoporotic fractures in comparison with that of TDF. METHODS: Using the national claims data of the Health Insurance Review and Assessment Service, we conducted a retrospective cohort study of 32,582 patients with CHB who had been initially treated with TDF or TAF between November 2017 and December 2020. The numbers of patients treated with TDF and TAF were 20,877 and 11,705, respectively. The annual fracture rate per 100 patients in each group was calculated, and the Cox proportional hazard ratio (HR) was analysed after applying inverse probability treatment weights (IPTW) for both groups. RESULTS: Among 32,582 patients, the average age was 47.8 ± 11.2 years, 64.5% were men, and the follow-up period was 24.4 ± 11.6 months. The incidence of osteoporotic fractures was 0.78 and 0.49 per 100 person-years in the TDF and TAF groups, respectively. After application of IPTW, the HR was 0.68 (95% confidence interval 0.55-0.85, p = 0.001). CONCLUSION: TAF-treated patients with CHB had a significantly lower risk of osteoporotic fracture than TDF-treated patients.

Inverse Propensity Score-Weighted Analysis of Entecavir and Tenofovir Disoproxil Fumarate in Patients with Chronic Hepatitis B: A Large-Scale Multicenter Study.

Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) in preventing hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients; however, it remains controversial. This study aimed to conduct comprehensive comparisons between the two antivirals. CHB patients initially treated with ETV or TDF between 2012 and 2015 at 20 referral centers in Korea were included. The primary outcome was the cumulative incidence of HCC. The secondary outcomes included death or liver transplantation, liver-related outcome, extrahepatic malignancy, development of cirrhosis, decompensation events, complete virologic response (CVR), seroconversion rate, and safety. Baseline characteristics were balanced using the inverse probability of treatment weighting (IPTW). Overall, 4210 patients were enrolled: 1019 received ETV and 3191 received TDF. During the median follow-ups of 5.6 and 5.5 years, 86 and 232 cases of HCC were confirmed in the ETV and TDF groups, respectively. There was no difference in HCC incidence between the groups both before (p = 0.36) and after IPTW was applied (p = 0.81). Although the incidence of extrahepatic malignancy was significantly higher in the ETV group than in the TDF group before weighting (p = 0.02), no difference was confirmed after IPTW (p = 0.29). The cumulative incidence rates of death or liver transplantation, liver-related outcome, new cirrhosis development, and decompensation events were also comparable in the crude population (p = 0.24-0.91) and in the IPTW-adjusted population (p = 0.39-0.80). Both groups exhibited similar rates of CVR (ETV vs. TDF: 95.1% vs. 95.8%, p = 0.38), and negative conversion of hepatitis B e antigen (41.6% vs. 37.2%, p = 0.09) or surface antigen (2.8% vs. 1.9%, p = 0.10). Compared to the ETV group, more patients in the TDF group changed initial antivirals due to side effects, including decreased kidney function (n = 17), hypophosphatemia (n = 20), and osteoporosis (n = 18). In this large-scale multicenter study, ETV and TDF demonstrated comparable effectiveness across a broad range of outcomes in patients with treatment-naïve CHB during similar follow-up periods.

Transient elastography with controlled attenuation parameter versus two-dimensional shear wave elastography with attenuation imaging for the evaluation of hepatic steatosis and fibrosis in NAFLD.

PURPOSE: This study compared the controlled attenuation parameter (CAP) to attenuation imaging (ATI) in the diagnosis of steatosis and transient elastography (TE) to two-dimensional shear wave elastography (2D-SWE) for the diagnosis of fibrosis in a prospectively constructed nonalcoholic fatty liver disease (NAFLD) patient cohort. METHODS: Participants who underwent TE with CAP were included from a previously constructed NAFLD cohort with multiparametric ultrasound data. The degree of hepatic steatosis and stage of liver fibrosis were assessed. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUROC) for the grades of steatosis (S1-3) and fibrosis (F0-F4). RESULTS: There were 105 participants. The distribution of hepatic steatosis grades (S0-S3) and liver fibrosis stages (F0-F4) was as follows: S0, n=34; S1, n=41; S2, n=22; S3, n=8; F0, n=63; F1, n=25; F2, n=5; F3, n=7; and F4, n=5. No significant difference was found between CAP and ATI in detecting ≥S1 (AUROC: 0.93 vs. 0.93, P=0.956) or ≥S2 (0.94 vs. 0.94, P=0.769). However, the AUROC of ATI in detecting ≥S3 was significantly higher than that of CAP (0.94 vs. 0.87, P=0.047). Regarding the detection of liver fibrosis, no significant difference was found between TE and 2D-SWE. The AUROCs of TE and 2D-SWE were as follows: ≥F1, 0.94 vs. 0.89 (P=0.107); ≥F2, 0.89 vs. 0.90 (P=0.644); ≥F3, 0.91 vs. 0.90 (P=0.703); and ≥F4, 0.88 vs. 0.92 (P=0.209). CONCLUSION: 2D-SWE and TE showed comparable diagnostic performance in assessing liver fibrosis, and ATI provided significantly better performance in detecting ≥S3 steatosis than CAP.

Chemogenetic stimulation of the parasympathetic nervous system lowers hepatic lipid accumulation and inflammation in a nonalcoholic steatohepatitis mouse model.

AIMS: The role of the parasympathetic nervous system (PNS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) is largely unknown. In this study, the effect of PNS modulation on NASH was investigated using chemogenetics. MAIN METHODS: A streptozotocin (STZ) and high-fat diet (HFD)-induced NASH mouse model was used. To activate or inhibit the PNS, chemogenetic human M3-muscarinic receptor coupled with either Gq or Gi protein-containing viruses was injected into the dorsal motor nucleus of the vagus at week 4 and clozapine N-oxide was administered intraperitoneally for a week from week 11. Three groups (PNS-stimulation, PNS-inhibition, and control) were compared in terms of heart rate variability (HRV), histological lipid droplet area, nonalcoholic fatty liver disease activity score (NAS), the area of F4/80-positive macrophages, and biochemical responses. KEY FINDINGS: The STZ/HFD-treated mouse model showed typical histological characteristics of NASH. HRV analysis confirmed that PNS-stimulation and PNS-inhibition groups had significantly higher and lower PNS activity, respectively (both P < 0.05). The PNS-stimulation group showed a significantly smaller hepatic lipid droplet area (14.3 % vs. 20.6 %, P = 0.02) and lower NAS (5.2 vs. 6.3, P = 0.047) than the control group. The area of F4/80-positive macrophages was significantly smaller in the PNS-stimulation group than in the control group (4.1 % vs. 5.6 %, P = 0.04). The PNS-stimulation group showed a lower serum aspartate aminotransferase level than the control group (119.0 vs. 356.0 U/L, P = 0.04). SIGNIFICANCE: In STZ/HFD-treated mice, chemogenetic stimulation of the PNS significantly reduced hepatic fat accumulation and inflammation. The hepatic PNS may play a pivotal role in the pathogenesis of NASH.

Baseline and on-treatment HBcrAg levels as predictors of HBeAg seroconversion in chronic hepatitis B patients treated with antivirals.

HBeAg seroconversion is an important treatment endpoint. We aimed to identify predictors of seroconversion using serum HBsAg and hepatitis B core-related antigen (HBcrAg) in HBeAg-positive patients treated with nucleos(t)ide analogs (NAs). Data and samples from 70 HBeAg-positive patients treated with entecavir or tenofovir between January 2007 and December 2017 were retrospectively analysed. The mean follow-up period was 11 years. The predictive power for HBeAg seroconversion of HBcrAg levels at baseline and 2 years after antiviral therapy was determined using receiver operating curve analysis. Twenty-one patients (30%) achieved HBeAg seroconversion at a mean of 28 (range, 12-84) months after antiviral treatment. The median baseline HBcrAg and HBsAg levels were 6.9(5.7-7.0) vs. 5.8(5.5-6.5) log10 U/mL (p = .006), 4.9(4.5-5.1) vs. 4.5(4.1-5.0) log10 IU/mL (p = .044) in the no seroconversion group and seroconversion group, respectively. In the multivariate analysis, the serum HBcrAg levels at baseline and 2 years after antiviral therapy were predictive factors for HBeAg seroconversion ([HR]; 0.326; [CI], 0.111-0.958; p = .042 and HR, 0.4555; CI, 0.211-0.984; p = .045). HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy had sensitivities of 53.1% and 69.8%, specificities of 95.2% and 70.6%, positive predictive values of 82.6% and 50.0%, and negative predictive values of 82.6% and 84.5%, respectively, with AUROCs of 0.712 (95%CI, 0.596-0.830) and 0.745 (95%CI, 0.599-0.891) for predicting HBeAg seroconversion. In chronic hepatitis B patients treated with NAs, HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy were useful predictive factors of HBeAg seroconversion.

Comparison of spin-echo echo-planar imaging magnetic resonance elastography with gradient-recalled echo magnetic resonance elastography and their correlation with transient elastography.

PURPOSE This study aimed to assess the agreement between liver stiffness (LS) values obtained by the gradient-recalled echo (GRE) magnetic resonance elastography (MRE) and spin-echo echo-planar imaging (SE-EPI) MRE with those of transient elastography (TE), respectively. METHODS We retrospectively included 48 participants who underwent liver MRE with both GRE and SE-EPI sequences in the same session and also TE within 1 year. We obtained LS values for MRE by drawing free-hand region of interest, and TE was performed using a FibroScan device. We assessed the relationship between the mean LS values obtained by each MRE sequence and TE using the correlation coefficients and Bland-Altman plots, respectively. We also compared LS values and technical failure rates of measured values from MRE between SE-EPI and GRE sequences using the paired t-test and McNemar's test. The MRE failure was defined as the absence of pixel value with a confidence index above 95%. RESULTS The LS values from SE-EPI and GRE sequences strongly correlated with those from TE (GRE; r = 0.73, P < .001 vs. SE-EPI; r = 0.79, P < .001). In addition, the LS values from the 2 MRE sequences showed excellent relationship (intraclass correlation coefficient, 0.94 [0.89-0.97], P < .001). The LS values from SE-EPI and GRE MRE were not significantly different (4.14 kPa vs. 3.88 kPa, P = .19). Furthermore, the technical success rate of SE-EPI MRE was superior to that of GRE (100% vs. 83.8%, P = .031). CONCLUSION The measured LS values obtained using TE correlated strongly with those obtained using GRE and SE-EPI MRE techniques, even though SE-EPI-MRE resulted a higher technical success rate than GRE-MRE. Therefore, we believe that TE, GRE, and SE-EPI MR elastography techniques may complement each other according to the appropriate individual situation.

Therapeutic mechanisms and beneficial effects of non-antidiabetic drugs in chronic liver diseases.

The global burden of chronic liver disease (CLD) is substantial. Due to the limited indication of and accessibility to antiviral therapy in viral hepatitis and lack of effective pharmacological treatment in nonalcoholic fatty liver disease, the beneficial effects of antidiabetics and non-antidiabetics in clinical practice have been continuously investigated in patients with CLD. In this narrative review, we focused on non-antidiabetic drugs, including ursodeoxycholic acid, silymarin, dimethyl4,4'-dimethoxy-5,6,5',6'-dimethylenedixoybiphenyl-2,2'-dicarboxylate, L-ornithine L-aspartate, branched chain amino acids, statin, probiotics, vitamin E, and aspirin, and summarized their beneficial effects in CLD. Based on the antioxidant, anti-inflammatory properties, and regulatory functions in glucose or lipid metabolism, several non-antidiabetic drugs have shown beneficial effects in improving liver histology, aminotransferase level, and metabolic parameters and reducing risks of hepatocellular carcinoma and mortality, without significant safety concerns, in patients with CLD. Although the effect as the centerpiece management in patients with CLD is not robust, the use of these non-antidiabetic drugs might be potentially beneficial as an adjuvant or combined treatment strategy.

Two-dimensional Shear-Wave Elastography and US Attenuation Imaging for Nonalcoholic Steatohepatitis Diagnosis: A Cross-sectional, Multicenter Study.

Background Multiparametric US examination may have potential in the comprehensive evaluation of nonalcoholic fatty liver disease (NAFLD), but multicenter studies are lacking. Purpose To evaluate the diagnostic performance of multiparametric US with the attenuation coefficient (AC) from attenuation imaging (ATI) and liver stiffness (LS) and dispersion slope (DS) from two-dimensional (2D) shear-wave elastography (SWE) in a multicenter study of patients with NAFLD. Materials and Methods This prospective study enrolled consecutive participants between December 2019 and June 2021 with suspected nonalcoholic steatohepatitis (NASH) who were scheduled to undergo liver biopsy in five tertiary hospitals. Before the procedure, all participants underwent US with ATI and 2D SWE according to the study protocol. Multivariable linear regression analyses were performed to determine the significant determinant factors for AC, LS, and DS. Diagnostic performance was decided based on the areas under the receiver operating characteristic curve (AUCs). Results A total of 132 participants (median age, 38 years; IQR, 27-54 years; 69 women) were evaluated. Among the participant characteristics, including pathologic findings, demographic characteristics, body mass index, and serum markers, hepatic steatosis for AC (P < .001), lobular inflammatory activity for DS (P = .007), and both fibrosis (P = .01) and lobular inflammatory activity (P = .04) for LS were significant determinant factors. At histopathologic examination, 53 of the 132 participants (40.2%) had NASH. The risk score system obtained using unweighted sum of scores from AC and DS showed the best diagnostic performance in the detection of NASH (AUC = 0.94; 95% CI: 0.89, 0.98; P < .05 for all), as compared with serum markers or other US parameters alone (AUC ≤ 0.88). Conclusion US attenuation imaging and two-dimensional shear-wave elastography were useful for assessing hepatic steatosis, lobular inflammation, and fibrosis. The risk score system obtained using the attenuation coefficient and dispersion slope showed the best diagnostic performance fo r nonalcoholic steatohepatitis. cris.nih.go.kr no. KCT0004326 © RSNA, 2022 Online supplemental material is available for this article.

Low Incidence of Hepatocellular Carcinoma after Antiviral Therapy in Patients with Chronic Hepatitis C and Hemophilia.

Background: Hepatocellular carcinoma (HCC) rarely develops in patients with chronic hepatitis C (CHC) who achieve sustained virological response (SVR). We assessed the incidence of HCC in CHC patients with hemophilia after treatment with pegylated interferon plus ribavirin (PegIFN/RBV) and direct-acting antivirals (DAAs). Methods: Patients (n = 202) were enrolled between March 2007 and July 2019. A total of 139 patients were treated with PegIFN/RBV (genotype 1, n = 98; genotype 2, n = 41). Sixty-three patients were treated with DAAs (genotype 1, n = 44; genotype 2, n = 19). The cumulative incidence rates of HCC were estimated using the Kaplan−Meier method and compared using the log-rank test. Results: For genotype 1, SVR was achieved in 78.6% (77/98) and 90.9% (40/44) of patients in the PegIFN/RBV and DAAs groups, respectively. For genotype 2, SVR was achieved in 95.1% (39/41) and 94.7% (18/19) of patients in the PegIFN/RBV and DAAs groups, respectively. Six HCC cases were identified. The cumulative incidence of HCC was 4.1% at 14 years in PegIFN/RBV and 1.7% at 5 years in DAAs. The 14-year cumulative incidence of HCC was 1.9% in the SVR group and 21.7% in the no-SVR group in the PegIFN/RBV group (p < 0.001). Conclusions: Treatment with PegIFN/RBV led to stable SVR and a low incidence of HCC. Although the follow-up period was short, DAAs led to more stable SVR than PegIFN/RBV and a low incidence of HCC in CHC patients with hemophilia.

Effect of tenofovir alafenamide vs. tenofovir disoproxil fumarate on hepatocellular carcinoma risk in chronic hepatitis B.

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.

Impact of tenofovir alafenamide vs. entecavir on hepatocellular carcinoma risk in patients with chronic hepatitis B.

BACKGROUND AND AIMS: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC. METHODS: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method. RESULTS: In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743). CONCLUSIONS: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.

Effectiveness of Transarterial Chemoembolization-First Treatment for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients. PATIENT AND METHODS: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response. RESULTS: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P<0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort. CONCLUSION: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.

Clinical Characteristics of Long-Term Survivors After Sorafenib Treatment for Unresectable Hepatocellular Carcinoma: A Korean National Multicenter Retrospective Cohort Study.

BACKGROUND/AIM: Sorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment. METHODS: This multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles. RESULTS: The patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (>1,000 ng/mL; HR = 0.361; P < 0.001). CONCLUSION: This large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.

Independent Risk Factors for Hepatocellular Carcinoma Recurrence after Direct-Acting Antiviral Therapy in Patients with Chronic Hepatitis C.

Background/Aims: This study was performed to evaluate the efficacy of direct-acting antivirals (DAAs) in Korean patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and to investigate the risk factors associated with HCC recurrence. Methods: A total of 100 patients with HCV-related HCC, who were treated with DAAs between May 2015 and December 2016, were recruited from seven university hospitals in Korea. Claim data of 526 patients with HCC obtained from the Health Insurance Review and Assessment Service in South Korea were used for external validation of the results. Results: Among the 100 patients, 88% achieved a sustained virological response (SVR) 12 weeks after the end of DAA therapy (SVR12), and 37% experienced HCC recurrence after DAA therapy. Short last HCC treatment durability (<12 months) before DAA commencement was independently associated with HCC recurrence (hazard ratio [HR], 2.89; p=0.011). In the nationwide validation cohort, 20.3% of the patients experienced HCC recurrence. The last HCC treatment with a noncurative method, a short last HCC treatment durability (<12 months), and a longer total duration of HCC treatment (≥18 months) were independently related with HCC recurrence (HR 3.73, p<0.001; HR 3.34, p<0.001; and HR 1.74, p=0.006; respectively). Conclusions: DAA therapy showed an acceptable SVR12 rate in patients with HCV-related HCC. Short last HCC treatment durability (<12 months) was associated with HCC recurrence after DAA therapy. This finding suggests that the last HCC treatment durability is an important predictor of HCC recurrence after DAA therapy.

Changes in serum fibronectin levels predict tumor recurrence in patients with early hepatocellular carcinoma after curative treatment.

Fibronectin, a matrix glycoprotein aberrantly expressed in various tumor cells, is a known candidate biomarker for the early diagnosis of hepatocellular carcinoma (HCC). In this study, we investigated whether serum fibronectin levels could predict tumor recurrence in patients with early-stage HCC after curative treatment. A total of 83 patients who showed complete response after initial curative treatment were included. The levels of serum fibronectin at baseline and 4-6 weeks after initial treatment were analyzed with regard to their associations with recurrence. Multivariate logistic regression analyses were performed to construct a prognostic nomogram. Baseline fibronectin levels were not significantly correlated with tumor size, number, stage, and serum α-fetoprotein levels. However, decrease in serum fibronectin levels after treatment was significantly associated with reduced HCC recurrence in multivariate logistic regression (odds ratio, 0.009; p < 0.001). Furthermore, a nomogram consisting of gender and changes in serum fibronectin showed a good discriminatory capability for the prediction of HCC recurrence with an area under the receiver-operating curve of 0.87. In conclusion, changes in serum fibronectin levels may be a surrogate indicator for assessment of treatment response in patients with early HCC after curative treatment.