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ObjectivesTo evaluate the diagnostic performance of attenuation imaging (ATI) in the detection of hepatic steatosis compared with a histopathology gold standard.MethodsWe prospectively enrolled 108 consecutive patients (35 males; median age, 54.0 years) who underwent percutaneous liver biopsy for evaluation of diffuse liver disease between January 2018 and November 2018 in a tertiary academic center. Grayscale ultrasound examination with ATI was performed just before biopsy, and an attenuation coefficient (AC) was obtained from each patient. The degree of hepatic steatosis, fibrosis stage, and necroinflammatory activity were assessed on histopathologic examination. The significant factor associated with the AC was found by a linear regression analysis, and the diagnostic performance of the AC for the classification into each hepatic steatosis stage was evaluated by receiver operating characteristic (ROC) analysis.ResultsThe distribution of hepatic steatosis grade on histopathology was 53/11/22/16/6 for none/mild (< 10%)/mild (≥ 10%)/moderate/severe steatosis, respectively. The area under the ROC curve, sensitivity, specificity, and optimal cutoff AC value for detection of hepatic steatosis ranged from 0.843–0.926, 74.5–100.0%, 77.4–82.8%, and 0.635–0.745, respectively. Multivariate analysis revealed that the degree of steatosis was the only significant determinant factor for the AC.ConclusionsThe AC from ATI provided good diagnostic performance in detecting the varying degrees of hepatic steatosis. The degree of steatosis was the only significant factor affecting the AC, whereas fibrosis and inflammation were not.Key Points• Attenuation imaging (ATI) is based on two-dimensional grayscale ultrasound images that can incorporate into routine ultrasound examinations with less than 2 min of acquisition time.• ATI provided good diagnostic performance in detecting the varying degrees of hepatic steatosis with an area under the ROC curves ranging from 0.843 to 0.926, and there was no technical failure in this study indicating high applicability of this technique.• The degree of hepatic steatosis was the only significant factor affecting the result of ATI examination.

Circulating microbial dysbiosis is associated with chronic liver disease including nonalcoholic steatohepatitis and alcoholic liver disease. In this study, we evaluated whether disease-specific alterations of circulating microbiome are present in patients with cirrhosis and hepatocellular carcinoma (HCC), and their potential as diagnostic biomarkers for HCC. We performed cross-sectional metagenomic analyses of serum samples from 79 patients with HCC, 83 with cirrhosis, and 201 matching healthy controls, and validated the results in the same number of subjects. Serum bacterial DNA was analyzed using high-throughput pyrosequencing after amplification of the V3–V4 hypervariable regions of 16S rDNA. Blood microbial diversity was significantly reduced in HCC, compared with cirrhosis and control. There were significant differences in the relative abundances of several bacterial taxa that correlate with the presence of HCC, thus defining a specific blood microbiome-derived metagenomic signature of HCC. We identified 5 microbial gene markers-based model which distinguished HCC from controls with an area under the receiver-operating curve (AUC) of 0.879 and a balanced accuracy of 81.6%. In the validation, this model accurately distinguished HCC with an AUC of 0.875 and an accuracy of 79.8%. In conclusion, circulating microbiome-based signatures may be potential biomarkers for the detection HCC.

Whether a sustained virological response (SVR) improves long-term outcomes in chronic hepatitis C patients with earlier-stage fibrosis has not been established. We investigated the differential effect of SVR on the risk of outcomes according to hepatic fibrosis grade. Fibrosis grade was categorised using FIB-4: <1.45, low-probability of significant fibrosis; 1.45–3.25, intermediate-probability; and ≥3.25, high-probability. Primary and secondary endpoints were hepatocellular carcinoma (HCC) occurrence and death, respectively. Among 1,373 included chronic hepatitis C patients, 744 patients were treated with interferon-based or –free regimens and 622 (83.6%) achieved SVR. SVR was independently associated with lower risk of HCC ( vs . untreated: adjusted hazard ratio [aHR], 0.165; 95% confidence interval [CI], 0.077–0.350; P  < 0.001) and overall death ( vs . untreated; aHR, 0.146; 95% CI, 0.050–0.424; P  < 0.001) during the median observation of 3.5 (interquartile range, 1.9–6.6) years. The SVR group had significantly lower risk of HCC than the untreated group among patients with intermediate-probability ( n  = 492: aHR, 0.171; 95% CI, 0.051–0.578; P  = 0.004) and high-probability ( n  = 446: aHR, 0.243; 95% CI, 0.107–0.551; P  < 0.001) of significant fibrosis. HRs were maintained after balancing with inverse probability weighting. SVR was associated with reduced risk of HCC development and all-cause mortality in patients with chronic hepatitis C.

Background/Aims: The association between aspirin use and hepatocellular carcinoma (HCC) risk in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study evaluated the effect of aspirin on HCC development in MASLD patients using Korean National Health Insurance Service (NHIS) and UK Biobank (UKB) databases.Methods: A retrospective cohort analysis was conducted using the NHIS database with a 3-year landmark design. Baseline characteristics were balanced using inverse probability of treatment weighting (IPTW) and 1:3 propensity score matching (PSM). Additionally, Mendelian randomization analysis was performed in the UKB cohort using a genomic risk score (GRS) for salicylic acid, based on genetic variants related to aspirin metabolism, as a proxy for aspirin use.Results: In the NHIS cohort, 6,584,155 eligible patients were included, of whom 1,723,435 had MASLD. After PSM, aspirin use was associated with a significantly lower risk of HCC compared to no aspirin use, in both the overall population (adjusted subdistribution hazard ratio [ASHR]=0.86; 95% confidence interval [CI] 0.78–0.95; P=0.002) and MASLD group (ASHR=0.86; 95% CI 0.75–0.99; P=0.036). Similar results were reproduced in the IPTW population and several sensitivity and subgroup analyses. In the UKB cohort, individuals in the top 95% of GRS had a significantly lower risk of HCC compared to those in the bottom 5%, in both the overall population (ASHR=0.61; 95% CI 0.39–0.95; P=0.028) and MASLD group (ASHR=0.47; 95% CI 0.29–0.76; P=0.002).Conclusions: Findings from both population-based and genetic analyses suggest a possible protective association between aspirin use and HCC in patients with MASLD, which warrants further validation.

Background/Aims: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment.Methods: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders.Results: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88–1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60–0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81–0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62–0.75, P<0.01; E-value for SHR=2.30).Conclusions: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

ObjectiveThe association between baseline pretreatment serum HBV DNA levels and on-treatment hepatocellular carcinoma (HCC) risk remains controversial in patients with chronic hepatitis B (CHB). We aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in CHB patients without cirrhosis.DesignUsing a multicentre historical cohort study including 4693 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, adult CHB patients without cirrhosis who initiated antiviral treatment, HCC risk was estimated by baseline HBV viral load as a categorical variable.ResultsDuring a median of 7.6 years of antiviral treatment, 193 patients developed HCC (0.53 per 100 person- years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a non-linear, parabolic pattern. Patients with moderate baseline viral loads (5.00–7.99 log10 IU/mL) exhibited the highest HCC risk (HR, 2.60; p<0.001), followed by those with low viral loads (3.30–4.99 log10 IU/mL; HR, 1.66; p=0.11). Patients with high viral loads (≥8.00 log10 IU/mL) presented the lowest HCC risk. Particularly, patients with baseline HBV DNA levels 6.00–6.99 log10 IU/mL had the highest on-treatment HCC risk (HR, 3.36; p<0.001) compared with those with baseline HBV DNA levels≥8.00 log10 IU/mL. These findings were more prominent among HBeAg-positive patients, younger patients, or those with less advanced hepatic fibrosis.ConclusionPatients with moderate baseline viral load, particularly around 6 log10 IU/mL, demonstrated the highest on-treatment HCC risk, despite long-term antiviral treatment. Early initiation of antiviral treatment, tailored to viral load, should be considered to minimise HCC risk in adult CHB patients without cirrhosis.

Both trans-arterial radioembolization (TARE) and conventional trans-arterial chemoembolization (TACE) can effectively control hepatocellular carcinoma (HCC) in patients who are not suitable for curative resection. This study compared the effectiveness of TARE and conventional TACE as the initial trans-arterial treatment for hepatocellular carcinoma (HCC) assessed by tumor response and clinical outcomes. Data were retrospectively analyzed the propensity score-matched cohort for overall survival (OS), progression-free survival (PFS), and intrahepatic PFS in patients who have received TARE or TACE as the first HCC treatment from March 2012 to December 2017. A total of 138 patients initially treated with TARE (n = 54) or TACE (n = 84) was included in this study. Of 138 patients, median age was 59 years and the mean follow-up period was 27.6 months. TARE showed better OS (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.31-0.92, log-rank = 0.02), better PFS (HR = 0.51, 95% CI = 0.36-0.97, log-rank = 0.04), and better intrahepatic PFS (HR = 0.51, 95% CI = 0.30-0.88, log-rank = 0.01) compared with TACE. TARE was an independent prognostic factor for OS (adjusted HR [aHR] = 0.52, 95% CI = 0.30-0.90, = 0.02), PFS (aHR = 0.57, 95% CI = 0.35-0.94, = 0.03), and intrahepatic PFS (aHR = 0.49, 95% CI = 0.28-0.84, = 0.01). TARE as initial trans-arterial treatment is associated with better clinical outcomes such as longer OS compared with TACE in patients with HCC.

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. 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. 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, =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, =0.02) and multivariable analyses (adjusted HR=0.58, =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, =0.048; HR=0.52, =0.003) or infiltrative HCC (HR=0.42, <0.001; HR=0.30, =0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, =0.03) within the PS-matched cohort. 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.

Background Most adjuvant therapies for hepatocellular carcinoma (HCC) have failed except for autologous cytokine-induced killer (CIK) therapy, which prolonged recurrence-free survival (RFS) in a previously reported randomized controlled trial (RCT) and real-world data (RWD). Methods This study aimed to assess the long-term outcomes of adjuvant CIK therapy using both an extended follow-up of the original RCT and a retrospective cohort study. An extended follow-up analysis of the RCT included 226 patients (114 in the CIK group and 112 in the control group). The follow-up duration was extended from 2 to 9 years after the enrollment of the last patient. In parallel, a retrospective RWD study was performed involving 577 patients from two tertiary centers in Korea, including 251 who received adjuvant CIK therapy and 326 controls. Propensity score matching (PSM) was applied to adjust for baseline imbalances. The primary endpoint was RFS in both studies. Results In the RWD study (median follow-up = 57.2 months), the CIK group demonstrated significantly prolonged RFS than controls both before PSM (median = 101.2 versus 64.7 months; HR = 0.69, 95% CI 0.53–0.90, P  = 0.006) and after PSM (median = 101.2 vs. 65.7 months; HR = 0.64, 95% CI 0.45–0.91, P  = 0.01). In the extended follow-up of the RCT (median follow-up = 116.1 months), the CIK group exhibited significantly prolonged RFS (median = 44.0 vs. 30.0 months; hazard ratio [HR] = 0.72, 95% confidence interval [CI] 0.54–0.97, P  = 0.033) compared to the control group. Conclusions Adjuvant CIK cell therapy significantly improved RFS in both a RWD study and a 9-year extended RCT follow-up, supporting its reproducible benefit in reducing recurrence after curative treatment of HCC. These consistent findings provide strong evidence for the clinical utility of CIK therapy as a durable adjuvant immunotherapeutic strategy for HCC.