Extrahepatic Malignancies and Antiviral Drugs for Chronic Hepatitis B: A Nationwide Cohort Study.

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<0.1, 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.

Mechanistic Evidence for Hg Removal from Wastewater by Biologically Produced Sulfur.

A significant quantity of biologically produced sulfur (BPS) is generated as a by-product of chemical and biological desulfurization processes applied to landfill gas treatment. The beneficial upcycling of BPS has seen limited use in the environmental context. The effectiveness and underlying mechanism of BPS as an adsorbent for removing Hg2+ from both solution and wastewater were elucidated based on experiments encompassing surface characterization, adsorption isotherms, kinetics, and thermodynamics. The BPS exhibited remarkable efficacy in removing Hg2+ from solution, with the Langmuir model accurately describing the adsorption process and showing a maximum adsorption capacity of 244 mg g-1. Surface analysis through X-ray photoelectron spectroscopy and scanning electron microscopy revealed that Hg2+ complexed with sulfide on BPS surfaces, forming stable HgS. The adsorbed Hg was strongly retained in BPS, with less than 0.2% of the adsorbed Hg desorbed by strong acids. Adsorption kinetics followed the double-exponential first-order model, showing an initial rapid adsorption phase wherein 75% of the initial Hg2+ was removed within 5 min, followed by a slower adsorption rate. The thermodynamic parameters suggested that adsorption of Hg2+ by BPS was a spontaneous and endothermic process. Additionally, BPS effectively removed Hg2+ from wastewater, showing preference for Hg over other co-existing metals. These findings underscore the potential of BPS as an effective adsorbent for Hg2+ removal from wastewater.

No-Touch Radiofrequency Ablation Using Twin Cooled Wet Electrodes for Recurrent Hepatocellular Carcinoma Following Locoregional Treatments.

OBJECTIVE: To evaluate the therapeutic outcomes of no-touch radiofrequency ablation (NT-RFA) using twin cooled wet (TCW) electrodes in patients experiencing recurrent hepatocellular carcinoma (HCC) after undergoing locoregional treatments. MATERIALS AND METHODS: We conducted a prospective, single-arm study of NT-RFA involving 102 patients, with a total of 112 recurrent HCCs (each ≤ 3 cm). NT-RFA with TCW electrodes was implemented under the guidance of ultrasonography (US)-MR/CT fusion imaging. If NT-RFA application proved technically challenging, conversion to conventional tumor puncture RFA was permitted. The primary metric for evaluation was the mid-term cumulative incidence of local tumor progression (LTP) observed post-RFA. Cumulative LTP rates were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard regression was used to explore factors associated with LTP. Considering conversion cases from NT-RFA to conventional RFA, intention-to-treat (ITT; including all patients) and per-protocol (PP; including patients not requiring conversion to conventional RFA alone) analyses were performed. RESULTS: Conversion from NT-RFA to conventional RFA was necessary for 24 (21.4%) out of 112 tumors. Successful treatment was noted in 111 (99.1%) out of them. No major complications were reported among the patients. According to ITT analysis, the estimated cumulative incidences of LTP were 1.9%, 6.0%, and 6.0% at 1, 2, and 3 years post-RFA, respectively. In PP analysis, the cumulative incidence of LTP was 0.0%, 1.3%, and 1.3% at 1, 2, and 3 years, respectively. The number of previous locoregional HCC treatments (adjusted hazard ratio [aHR], 1.265 per 1 treatment increase; P = 0.004), total bilirubin (aHR, 7.477 per 1 mg/dL increase; P = 0.012), and safety margin ≤ 5 mm (aHR, 9.029; P = 0.016) were independently associated with LTP in ITT analysis. CONCLUSION: NT-RFA using TCW electrodes is a safe and effective treatment for recurrent HCC, with 6.0% (ITT analysis) and 1.3% (PP analysis) cumulative incidence of LTP at 2 and 3-year follow-ups.

Gamma-glutamyl transferase and the risk of all-cause and disease-specific mortality in patients with diabetes: A nationwide cohort study.

BACKGROUND: There exists a paucity of data regarding whether gamma-glutamyl transferase is associated with disease-specific mortality in patients with type 2 diabetes mellitus. This study aimed to investigate the association of serum gamma-glutamyl transferase levels with all-cause and disease-specific mortality in patients with diabetes mellitus using a Korean nationwide health-screening database. METHODS: A total of 9 687 066 patients without viral hepatitis or liver cirrhosis who underwent health examination in 2009 were included. These patients were divided into four groups according to sex-specific quartiles of serum gamma-glutamyl transferase levels. RESULTS: During a median follow-up period of 8.1 years, 222 242 deaths were identified. The all-cause mortality rate increased as the serum gamma-glutamyl transferase levels became higher (highest quartile vs lowest quartile: hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.55-1.59; p for trend <.001). Similar trends were observed for cardiovascular disease (HR, 1.57; 95% CI, 1.53-1.62), ischemic heart disease (HR, 1.40; 95% CI, 1.33-1.48), and stroke (HR, 1.72; 95% CI, 1.60-1.85) in the highest quartile, as compared with the lowest quartile (p for trend <.001). As the gamma-glutamyl transferase quartiles became higher, mortality rates related to cancer (HR, 1.56; 95% CI, 1.52-1.60), liver disease (HR, 9.42; 95% CI, 8.81-10.07), respiratory disease (HR, 1.55; 95% CI, 1.49-1.62), and infectious disease (HR, 1.73; 95% CI, 1.59-1.87) also increased in the highest quartile, compared with the lowest quartile (p for trend <.001). CONCLUSIONS: Serum gamma-glutamyl transferase levels may be useful for the risk assessment of all-cause and disease-specific mortality among patients with type 2 diabetes mellitus.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

BACKGROUND AND AIMS: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. APPROACH AND RESULTS: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. CONCLUSIONS: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

Alginate-encapsulated biochar as an effective soil ameliorant for reducing Pb phytoavailability to lettuce (Lactuca sativa L.).

The alginate-biochar formulation for metal removal from aquatic environments has been widely tried but its use for lowering phytoavailability of metals in the soil-crop continuum is limited. Biochar has been increasingly used as a soil amendment due to its potential for soil carbon sequestration and sorption capacity. Handling of powdery biochar as a soil top-dressing material is, however, cumbersome and vulnerable to loss by water and wind. In this experiment, biochar powder, which was pyrolyzed from oak trees, was encapsulated into beads with alginate, which is a naturally occurring polysaccharide found in brown algae. Both batch and pot experiments were conducted to examine the effects of the alginate-encapsulated biochar beads (BB), as compared to its original biochar powdery form (BP), on the Pb adsorption capacity and phytoavailability of soil Pb to lettuce (Lactuca sativa L.). The BB treatment improved reactivity about six times due to a higher surface area (287 m2 g-1) and five times due to a higher cation exchange capacity (50 cmolc kg-1) as compared to the BP treatment. The maximum sorption capacity of Pb was increased to 152 from 81 mg g-1 because of surface chemosorption. Adsorption of Pb onto BB followed multiple first-order kinetics and comprised fast and slow steps. More than 60% of the Pb was adsorbed in the fast step, i.e., within 3 h. Also, the BB treatment, up to the 5% level (w/w), increased soil pH from 5.4 to 6.5 and lowered the phytoavailable fraction of Pb in soil from 5.7 to 0.3 mg kg-1. The Pb concentrations in lettuce cultivated at 5% for the BP and BB treatments were similar but 63 and 66% lower, respectively, than those of the control soil. The results showed that the encapsulation of biochar with alginate enhanced adsorption by the biochar.

High-dose proton pump inhibitor treatment is associated with a higher mortality in cirrhotic patients: A multicentre study.

BACKGROUND: Proton pump inhibitors (PPI) are frequently used in patients with cirrhosis. AIMS: This study aimed to determine whether PPI use is associated with the prognosis of cirrhotic patients. METHODS: We conducted a multicentre retrospective cohort study involving 1485 patients who had experienced hepatic encephalopathy (HE) from 7 referral centres in Korea. The primary outcome was overall survival and secondary outcomes included the development of cirrhotic complications, including recurrent HE, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), and gastrointestinal bleeding. Patients treated with PPI with a mean defined daily dose (mDDD) ≥0.5 (high-dose PPI group) were compared to those treated with PPI of an mDDD < 0.5 (No or low-dose PPI group) for each outcome. RESULTS: Among 1485 patients (median age, 61 years; male, 61%), 232 were assigned to the high-dose PPI group. High-dose PPI use was independently associated with a higher risk of death (adjusted HR [aHR] = 1.71, 95% confidence interval [CI] = 1.38-2.11, p < 0.001). This result was reproducible after propensity score-matching (PSM) (aHR = 1.90, 95% CI = 1.49-2.44, p < 0.001). High-dose PPI use was an independent risk factor of recurrent HE (before PSM: aHR = 2.04, 95% CI = 1.66-2.51, p < 0.001; after PSM: aHR = 2.16, 95% CI = 1.70-2.74, p < 0.001), SBP (before PSM: aHR = 1.87, 95% CI = 1.43-2.43, p < 0.001; after PSM: aHR = 1.76, 95% CI = 1.31-2.36, p = 0.002), HRS (before PSM: aHR = 1.48, 95% CI = 1.02-2.15, p = 0.04; after PSM: aHR = 1.47, 95% CI = 0.95-2.28, p = 0.09), and gastrointestinal bleeding (before PSM: aHR = 1.46, 95% CI = 1.12-1.90, p = 0.006; after PSM: aHR = 1.74, 95% CI = 1.28-2.37, p < 0.001). CONCLUSIONS: The use of high-dose PPI was independently associated with increased risks of mortality and cirrhotic complications.

Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin ß1.

BACKGROUND: Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. METHODS: We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). RESULTS: CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. CONCLUSIONS: These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.

Risk of hepatocellular carcinoma after curative treatment when switching from tenofovir disoproxil fumarate or entecavir to tenofovir alafenamide: A real-world multicenter cohort study.

AIM: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high-quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence. METHODS: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time-varying effect of NA use on HCC recurrence was analyzed using various statistical methods. RESULTS: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68-1.47; p = 1.00) by time-varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67-1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51-2.33; p = 0.82 for ETV). Kaplan-Meier analysis showed comparable HCC recurrence-free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time-varying Cox analyses in various subgroups confirmed the primary findings. CONCLUSIONS: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment.

Stakeholder analysis for effective implementation of water management system: Case of groundwater charge in South Korea.

Groundwater Charge was introduced in 2005 as one of the sustainable resource management measures in South Korea. The implementation rate, however, stagnated around 37 %, indicating that most local governments chose not to adopt this 'optional' regulation. While previous Stakeholder Analysis studies mainly blamed exclusion - or limited involvement - of stakeholders in the designing and structuring stage of policy-making process for policy failures, this study focused on the interest conflicts and dynamics hindered implementation process. This is because the issue with the subject policy, i.e., Groundwater Charge in South Korea, is low 'implementation rate' not the 'collection rate' or 'tax deficit.' If it was simply design or structural issue, the Charge should suffer from tax deficit problem due to lower tax income than operational costs. Thus, in order to investigate the reasons of low Charge adoption rate at the local government level, the Stakeholder Analysis Theory was applied to examine each stakeholder of the Charge to distinguish the interaction among supportive and opposing groups. The analysis revealed that there are only strong opponents of the policy without clearly identifiable supporters. Having agricultural & fishery industry and small independent businesses in spas, hotels, and swimming pool as strong Players, the Context setters (local governments) are not motivated to enforce Groundwater charge. Furthermore, today's social norm governed by economic efficiency is preventing the environmentalists and other Subjects to counteract Players. Under these circumstances, this study recommends the Subject to transform the Crowds (general public) into policy supporters through education. Environmental education is the only viable means to encourage necessary paradigm shift to enable effective implementation of environmental policies like Groundwater charge.

Urinary microbiome-based metagenomic signature for the noninvasive diagnosis of hepatocellular carcinoma.

BACKGROUND: Gut microbial dysbiosis is implicated in chronic liver disease and hepatocellular carcinoma (HCC), but the role of microbiomes from various body sites remains unexplored. We assessed disease-specific alterations in the urinary microbiome in HCC patients, investigating their potential as diagnostic biomarkers. METHODS: We performed cross-sectional analyses of urine samples from 471 HCC patients and 397 healthy controls and validated the results in an independent cohort of 164 HCC patients and 164 healthy controls. Urinary microbiomes were analyzed by 16S rRNA gene sequencing. A microbial marker-based model distinguishing HCC from controls was built based on logistic regression, and its performance was tested. RESULTS: Microbial diversity was significantly reduced in the HCC patients compared with the controls. There were significant differences in the abundances of various bacteria correlated with HCC, thus defining a urinary microbiome-derived signature of HCC. We developed nine HCC-associated genera-based models with robust diagnostic accuracy (area under the curve [AUC], 0.89; balanced accuracy, 81.2%). In the validation, this model detected HCC with an AUC of 0.94 and an accuracy of 88.4%. CONCLUSIONS: The urinary microbiome might be a potential biomarker for the detection of HCC. Further clinical testing and validation of these results are needed in prospective studies.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND/AIM: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). METHODS: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. RESULTS: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). CONCLUSION: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Extrahepatic malignancies in metabolic dysfunction-associated fatty liver disease: A nationwide cohort study.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes. METHODS: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality. RESULTS: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001). CONCLUSION: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required.

Sorafenib for 9,923 Patients with Hepatocellular Carcinoma: An Analysis from National Health Insurance Claim Data in South Korea.

Background/Aims: Sorafenib is the standard of care in the management of advanced hepatocellular carcinoma (HCC). The purpose of this study was to investigate the characteristics, treatment patterns and outcomes of sorafenib among HCC patients in South Korea. Methods: This population-based retrospective, single-arm, observational study used the Korean National Health Insurance database to identify patients with HCC who received sorafenib between July 1, 2008, and December 31, 2014. A total of 9,923 patients were recruited in this study. Results: Among 9,923 patients, 6,669 patients (68.2%) received loco-regional therapy prior to sorafenib, and 1,565 patients (15.8%) received combination therapy with concomitant sorafenib; 2,591 patients (26.1%) received rescue therapy after sorafenib, and transarterial chemoembolization was the most common modality applied in 1,498 patients (15.1%). A total of 3,591 patients underwent rescue therapy after sorafenib, and the median overall survival was 14.5 months compared to 4.6 months in 7,332 patients who received supportive care after sorafenib. The mean duration of sorafenib administration in all patients was 105.7 days; 7,023 patients (70.8%) received an initial dose of 600 to 800 mg. The longest survival was shown in patients who received the recommended dose of 800 mg, subsequently reduced to 400 mg (15.0 months). The second longest survival was demonstrated in patients with a starting dose of 800 mg, followed by a dose reduction to 400-600 mg (9.6 months). Conclusions: Real-life data show that the efficacy of sorafenib seems similar to that observed in clinical trials, suggesting that appropriate subsequent therapy after sorafenib might prolong patient survival.

Reappraisal of Portal Vein Tumor Thrombosis as a Prognostic Factor for Patients with Hepatocellular Carcinoma.

Background/Aims: : This study aimed to assess whether hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) could have favorable prognoses with proper treatment under selective conditions. Methods: : This retrospective, single-center study involved 1,168 patients diagnosed with HCC between January 2005 and December 2006, before the introduction of sorafenib. Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox proportional hazards model was used to identify and adjust the variables associated with OS. Results: : In nodular-type HCC, the OS differed significantly according to the presence of PVTT (log-rank p<0.001), and the level of PVTT, not only its presence, was a major independent factor affecting OS. PVTT at the Vp1-3 branch was associated with significantly longer OS than was PVTT at the Vp4 level (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21). In multivariate analysis, the OS was further stratified according to the PVTT level and tumor type, representing that nodular HCC without PVTT exhibited the best OS, whereas nodular HCC with Vp4 PVTT (adjusted HR, 2.59; 95% CI, 1.57 to 4.28) showed a poor prognosis similar to that of infiltrative HCC. The PVTT level was consistently correlated with OS in patients treated with transarterial chemoembolization. Nodular HCC without PVTT showed the best prognosis, while nodular HCC with Vp1-3 PVTT also exhibited a favorable OS, although inferior to that without PVTT (adjusted HR, 1.47, 95% CI, 0.92 to 2.36). Conclusions: : Active treatment such as transarterial chemoembolization can be considered for selected PVTT cases. The level of PVTT and type of HCC were independent prognostic factors.

COVID-19 Vaccination Alters NK Cell Dynamics and Transiently Reduces HBsAg Titers Among Patients With Chronic Hepatitis B.

Coronavirus disease 2019 (COVID-19) vaccination may non-specifically alter the host immune system. This study aimed to evaluate the effect of COVID-19 vaccination on hepatitis B surface Ag (HBsAg) titer and host immunity in chronic hepatitis B (CHB) patients. Consecutive 2,797 CHB patients who had serial HBsAg measurements during antiviral treatment were included in this study. Changes in the HBsAg levels after COVID-19 vaccination were analyzed. The dynamics of NK cells following COVID-19 vaccination were also examined using serial blood samples collected prospectively from 25 healthy volunteers. Vaccinated CHB patients (n=2,329) had significantly lower HBsAg levels 1-30 days post-vaccination compared to baseline (median, -21.4 IU/ml from baseline), but the levels reverted to baseline by 91-180 days (median, -3.8 IU/ml). The velocity of the HBsAg decline was transiently accelerated within 30 days after vaccination (median velocity: -0.06, -0.39, and -0.04 log10 IU/ml/year in pre-vaccination period, days 1-30, and days 31-90, respectively). In contrast, unvaccinated patients (n=468) had no change in HBsAg levels. Flow cytometric analysis showed that the frequency of NK cells expressing NKG2A, an NK inhibitory receptor, significantly decreased within 7 days after the first dose of COVID-19 vaccine (median, -13.1% from baseline; p<0.001). The decrease in the frequency of NKG2A+ NK cells was observed in the CD56dimCD16+ NK cell population regardless of type of COVID-19 vaccine. COVID-19 vaccination leads to a rapid, transient decline in HBsAg titer and a decrease in the frequency of NKG2A+ NK cells.

A circulating cell-free DNA methylation signature for the detection of hepatocellular carcinoma.

To address the shortcomings of current hepatocellular carcinoma (HCC) surveillance tests, we set out to find HCC-specific methylation markers and develop a highly sensitive polymerase chain reaction (PCR)-based method to detect them in circulating cell-free DNA (cfDNA). The analysis of large methylome data revealed that Ring Finger Protein 135 (RNF135) and Lactate Dehydrogenase B (LDHB) are universally applicable HCC methylation markers with no discernible methylation level detected in any other tissue types. These markers were used to develop Methylation Sensitive High-Resolution Analysis (MS-HRM), and their diagnostic accuracy was tested using cfDNA from healthy, at-risk, and HCC patients. The combined MS-HRM RNF135 and LDHB analysis detected 57% of HCC, outperforming the alpha-fetoprotein (AFP) test's sensitivity of 45% at comparable specificity. Furthermore, when used with the AFP test, the methylation assay can detect 70% of HCC. Our findings suggest that the cfDNA methylation assay could be used for HCC liquid biopsy.

Tumor Endothelial Cells-Associated Integrin Alpha-6 as a Promising Biomarker for Early Detection and Prognosis of Hepatocellular Carcinoma.

HCC remains a lethal cancer type, with early detection being critical for improved patient outcomes. This study introduces a comprehensive methodological approach to identify the ITGA6 gene as a potential blood marker for early HCC (eHCC) detection. We initially analyzed the GSE114564 dataset encompassing various stages of liver disease, identifying 972 differentially expressed genes in HCC. A refined analysis yielded 59 genes specifically differentially expressed in early HCC, including ITGA6. Subsequent validation in multiple datasets confirmed the consistent upregulation of ITGA6 in HCC. In addition, when analyzing progression-free survival (PFS) within the entire patient cohort and overall survival (OS) specifically among patients classified as tumor grade G1, the group of patients characterized by high expression levels of ITGA6 displayed an elevated risk ratio in relation to prognosis. Further analyses demonstrated the predominant expression of ITGA6 in TECs and its enrichment in angiogenesis-related pathways. Additionally, positive correlations were found between ITGA6 expression and pro-tumorigenic immune cells, but not with anti-tumorigenic immune cells. Our study elucidates the potential of ITGA6 as a blood-based marker for HCC early detection and diagnosis and its complex interplay with the tumor microenvironment. Further research may lead to novel strategies for HCC management and patient care.

Anatomical ablation for small hepatocellular carcinomas using multiple applicators: a preliminary study.

BACKGROUND: Anatomical ablation, defined as thermal ablation of tumor-bearing small portal territories, may provide excellent local tumor control in peripherally-located small hepatocellular carcinomas (HCC), which has been a major concern with percutaneous ablation alone. PURPOSE: To evaluate the technical feasibility and therapeutic outcomes of anatomical ablation using multiple radiofrequency (RF) applicators for the ablation of tumor-bearing small portal territories of peripherally-located small (≤ 4 cm) HCCs. MATERIALS AND METHODS: Patients with peripherally-located single HCCs (≤ 4 cm) to be treated with anatomical ablation using multiple RF applicators between January 2020 and March 2022 were enrolled in this prospective study. Anatomical ablation was performed for the index tumor under real-time US-CT/MR fusion imaging guidance, with one or two clustered electrode needles placed across the tumor-bearing portal vein branches. Technical success and complications of anatomical ablations were assessed. Cumulative incidence of local tumor progression (LTP) and recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Fifty-five HCCs (mean size, 1.77 ± 0.59 cm) in 55 participants (mean age, 66.4 ± 7.7 years; 39 men, 16 women) were treated with anatomical ablation; 98.2% (54/55) technical success was achieved. No major complications were noted. Among the 55 participants, LTP occurred in only one patient who had experienced technical failure of anatomical ablation. Estimated 1- and 2-year cumulative incidences of LTP were 0% and 3.7%, respectively. Five patients developed intrahepatic remote recurrence during the median follow-up period of 19.2 months (range, 3.7-28.8 months); therefore, estimated 1- and 2-year recurrence-free survival was 91.7% and 85.0%, respectively. CONCLUSION: Anatomical ablation using multiple RF applicators provided the excellent results of local tumor control in patients with peripherally-located small (≤ 4 cm) HCCs. TRIAL REGISTRATION: clinicaltrial.gov identifier: NCT05397860.

Association between daily aspirin therapy and risk of hepatocellular carcinoma according to metabolic risk factor burden in non-cirrhotic patients with chronic hepatitis B.

BACKGROUND: Several studies have demonstrated chemopreventive effects of aspirin against hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). AIMS: To investigate the associations of aspirin use with risks of HCC, liver-related mortality, and major bleeding according to metabolic risk factor burden among non-cirrhotic patients with CHB METHODS: Using the Korean National Health Insurance Service database, we identified 282,611 non-cirrhotic adults with CHB. Data on obesity, diabetes, high blood pressure, and hypercholesterolemia were collected. Subjects were stratified into lower and higher metabolic risk groups (≤2 and ≥3 risk factors, respectively). Propensity score-matched cohorts of aspirin users and non-users were generated. Risks of HCC, liver-related death and major bleeding were analyzed. RESULTS: During the median follow-up of 7.4 years, positive associations between metabolic risk factor burden and outcomes were verified (all ptrend < 0.001). In the lower metabolic risk group (13,104 pairs), the association between aspirin use and HCC risk was not significant after multivariable adjustment (adjusted subdistribution hazard ratio [aSHR]: 0.93; 95% CI: 0.84-1.03); however, aspirin use was associated with elevated major bleeding risk (aSHR: 1.22; 95% CI: 1.08-1.39). In the higher metabolic risk group (2984 pairs), aspirin use was associated with reduced risks of HCC (aSHR: 0.72; 95% CI: 0.57-0.91) and liver-related mortality (aSHR: 0.69; 95% CI: 0.50-0.96) without an increase in risk of major bleeding (aSHR: 1.02; 95% CI: 0.79-1.32). CONCLUSIONS: Aspirin therapy was associated with reduced risks of HCC and liver-related death without excess risk of major bleeding, in non-cirrhotic patients with CHB who had a higher metabolic risk factor burden.