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Introduction Despite its prognostic impact, nutritional status has not yet been integrated into the assessment of hepatocellular carcinoma (HCC). This study investigated the association between geriatric nutritional risk index (GNRI) and overall survival (OS) in patients with HCC using a nationwide registry. Methods Data from the Korea Central Cancer Registry between 2008 and 2019 were analyzed. We explored the integration of the GNRI with the albumin–bilirubin (ALBI) grade for prognostic stratification. Restricted cubic spline regression was used to assess the association between GNRI and survival, stratified by ALBI grade. Results Among the 16,416 treatment-naïve HCC patients, the ALBI grades were distributed as follows: grade 1, 7,409; grade 2, 7,445; and grade 3, 1,562. Patients were categorized according to Barcelona Clinic Liver Cancer (BCLC) stages: 5,132 stage 0/A, 2,608 stage B, 5,289 stage C, and 968 stage D. The median OS for all patients was 3.1 years (95% CI: 3.0–3.2) and significantly differed with the inclusion of ALBI grade and GNRI (P < 0.001). The effect of combining ALBI grade and GNRI was further evaluated for each BCLC stage. This risk stratification showed a significant correlation with OS for each BCLC stage (all P < 0.001), except for stage D (P = 0.082). Multivariate analysis revealed that a combination of favorable ALBI grade and high GNRI score was independently associated with decreased mortality risk. Conclusion The GNRI was significantly correlated with OS across ALBI grades and BCLC stages. Integrating the GNRI into the ALBI grade may enhance risk stratification for patients with HCC.

Backgrounds/Aims The treatment landscape for hepatocellular carcinoma (HCC) has significantly evolved over the past decade. We aimed to analyze trends in treatment patterns for HCC using a nationwide claims database from the Korean Health Insurance Review and Assessment Service. Methods This retrospective population-based cohort study analyzed 171,002 newly diagnosed HCC patients between 2008 and 2022. Etiologies and treatment modalities were categorized based on the ICD-10 codes and insurance data. Results The annual incidence decreased from 11,814 in 2008 to 10,443 in 2022. However, patients aged ≥70 increased noticeably, with those aged ≥80 rising from 3.8% in 2008 to 13.1% in 2022. From 2008 to 2022, the predominant cause of hepatitis B virus decreased from 68.9% to 59.7%, whereas nonalcoholic fatty liver disease increased from 8.9% to 15.8%. The initial treatment trends shifted: surgical resection and systemic therapy increased from 12.2% to 21.3% and from 0.2% to 9.6%, whereas transarterial therapy decreased from 49.9% to 36.6%. Best supportive care decreased from 31.7% to 21.3%. In the subgroup analysis, laparoscopic resection rate increased from 10.6% to 60.6% among the surgical resections. Sorafenib initially accounted for 100%, lenvatinib peaked at 36.5% in 2021, and atezolizumab-bevacizumab became the most widely used (63.1%) by 2022 among the systemic therapies. Conclusions This study demonstrates the temporal changes in the treatment patterns of Korean HCC patients. Surgical resection, particularly laparoscopic liver resection, and systemic therapy has increased significantly. These changes may have been influenced by reimbursement policies and advances in clinical research.

Background/Aims: Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients. Methods: We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted. Results: The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p

Background/Aims Four high-genetic barrier nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB), namely entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and besifovir dipivoxil maleate (BSV), have been established. The aim of this study is to investigate the efficacy of four high-genetic barrier NAs using a network meta-analysis of randomized trials and propensity score-matched cohorts. Methods Systematic search was performed using PubMed, Cochrane library, and EMBASE and included randomized controlled trials and cohort studies that used propensity score matching. Studies on treatment-naïve CHB patients treated with ETV, TDF, TAF, or BSV were included. Outcomes included alanine aminotransferase normalization and hepatitis B e antigen seroclearance at week 48 and undetectable hepatitis B virus DNA at weeks 48 and 96. Network meta-analysis was performed to synthesize the results. Results In total, 15,000 patients from 16 studies were included. In terms of 48- and 96-week virologic response (VR), TDF outperformed ETV with statistical significance (48 weeks: odds ratio [OR], 1.38; p < 0.001; 96 weeks: OR, 1.57; p = 0.004). ETV was ranked first for 48-week biochemical response (BR) and outperformed TDF (OR, 0.76; p = 0.028). In the sensitivity analyses, 48-week VR from randomized-controlled trials were compiled, and the same trend toward the superiority of TDF over ETV was found (OR, 1.51; p = 0.030). Conclusions Four high-genetic barrier NAs were compared, and TDF was more likely to achieve a VR after 48 weeks, while ETV provided a superior BR after 48 weeks.

BackgroundMetabolic dysfunction-associated steatohepatitis (MASH) is characterized by persistent inflammatory cascades, with macrophage activation playing a pivotal role. Chitinase 1 (CHIT1), produced by activated macrophages, is a key player in this cascade. In this study, we aimed to explore the role of CHIT1 in MASH with progressive liver fibrosis.MethodsFibrotic liver tissue and serum from distinct patient groups were analyzed using nCounter MAX, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. A MASH mouse model was constructed to evaluate the effectiveness of OATD-01, a chitinase inhibitor. Macrophage profiling was performed using single-nuclei RNA sequencing and flow cytometry.ResultsCHIT1 expression in fibrotic liver tissues was significantly correlated with the extent of liver fibrosis, macrophages, and inflammation. Single-nuclei RNA sequencing demonstrated a notable increase in macrophages numbers, particularly of lipid-associated macrophages, in MASH mice. Treatment with OATD-01 reduced non-alcoholic fatty liver disease activity score and Sirius red-positive area. Additionally, OATD-01-treated mice had lower CHIT1, F4/80, and α-smooth muscle actin positivity, as well as significantly lower levels of inflammatory markers, pro-fibrotic genes, and matrix remodeling-related mRNAs than vehicle-treated mice. Although the population of F4/80+CD11b+ intrahepatic mononuclear phagocytes remained unchanged, their infiltration and activation (CHIT1+MerTK+) significantly decreased in OATD-01-treated mice, compared with that observed in vehicle-treated mice.ConclusionsOur study underscores the pivotal role of CHIT1 in MASH. The observed significant improvement in inflammation and hepatic fibrosis, particularly at higher doses of the CHIT1 inhibitor, strongly suggests the potential of CHIT1 as a therapeutic target in MASH accompanied by progressive liver fibrosis.

Abstract 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.

Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

Introduction: Variability in response to atezolizumab plus bevacizumab (AB) treatment of hepatocellular carcinoma (HCC) underscores the critical need for the development of effective biomarkers. We sought to identify peripheral blood biomarkers reflecting response to AB treatment. Methods: We analyzed dynamic changes in peripheral blood mononuclear cells from a prospective, multicenter cohort of 65 patients with HCC, using flow cytometry to evaluate the T-cell population before and 3 weeks after the first AB treatment. Results: We found a unique response of the CD8+ T cells in terms of both frequency and phenotype, in contrast to CD4+ T cells and regulatory T cells. Notably, CD8+ T cells showed significant changes in expression of Ki-67 and T-cell immunoreceptors with Ig and ITIM domains (TIGIT). These distinct responses were observed particularly in the programmed cell death receptor-1 (PD-1)+ subpopulation of CD8+ T cells. Interestingly, the baseline differentiation status of PD-1+CD8+ T cells, particularly the central memory T-cell subset, correlated positively with greater proliferation (higher Ki-67 expression) of PD-1+CD8+ T cells after treatment. Moreover, effector memory cells expressing CD45RA correlated negatively with the increase in TIGIT+/PD-1+CD8+ T cells. The increase in TIGIT+/CD8+ T cells was associated with the development of immune-related adverse events, whereas increase in Ki-67+/PD-1+CD8+ T cells was associated with the better objective response rate. Importantly, dynamic shifts of Ki-67+/PD-1+CD8+ T cells and TIGIT+/CD8+ T cells significantly predicted progression-free survival and overall survival, as confirmed by multivariate analysis. Conclusion: These findings highlight the potential of dynamic changes in CD8+ T cells as an on-treatment prognostic biomarker. Our study underscores the value of peripheral blood profiling as a noninvasive and practical method for predicting the clinical outcomes of AB treatment in patients with HCC.

Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8–12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3+ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20+, CD38+, or CD68+ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.

BackgroundAtezolizumab+bevacizumab (AB) and lenvatinib have been proposed as first-line treatment options for patients with advanced hepatocellular carcinoma (HCC), but comparative efficacy and associated factors are controversial.Materials and methodsThis real-world multicenter study analysed patients with HCC who received AB (n=169) or lenvatinib (n=177).ResultsFirst, 1:1 propensity score matching (PSM) was performed, resulting in 141 patients in both the AB and lenvatinib groups. After PSM, overall survival (OS) was better in the AB group than in the lenvatinib group [hazard ratio (HR)=0.642, P=0.009], but progression-free survival (PFS) did not vary between the two groups (HR=0.817, P=0.132). Objective response rate (ORR) was also similar between AB and lenvatinib (34.8% vs. 30.8%, P=0.581). In a subgroup of patients with objective responses (OR, n=78), OS (HR=0.364, P=0.012) and PFS (HR=0.536, P=0.019) were better in the AB group (n=41) than in the lenvatinib group (n=37). Time-to-progression from time of OR was also better in the AB group (HR=0.465, P=0.012). Importantly, residual liver function was a significant factor related to OS in both treatments. Child-Pugh score following cessation of the respective treatments was better in the AB group (n=105) than in the lenvatinib group (n=126) (median 6 versus 7, P=0.008), and proportion of salvage treatment was also higher in the AB group (52.4% versus 38.9%, P=0.047). When we adjusted for residual liver function or salvage treatment, there was no difference in OS between the two treatments.ConclusionOur study suggests that residual liver function and subsequent salvage treatments are major determinants of clinical outcomes in patients treated with AB and lenvatinib; these factors should be considered in future comparative studies.

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

Background/Aims Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir for 12 weeks in HCV-infected Korean adults. Methods This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir–velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir–velpatasvir–voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment. Results Of 53 participants receiving sofosbuvir–velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir–velpatasvir–voxilaprevir achieved SVR 12. Overall, sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported. Conclusions Treatment with sofosbuvir–velpatasvir or sofosbuvir–velpatasvir–voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.

Abstract Background Many previous studies evaluated a combination of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) for treating early hepatocellular carcinoma (HCC); however, studies evaluating combination therapy for beyond-the-Milan criteria HCC are scarce. Methods A total of 120 patients with beyond-the-Milan criteria HCC who have viable tumour after first TACE will be enrolled in this multi-institutional, parallel, pragmatic, randomized controlled trial. Patients with metastasis, vascular invasion, or a sum of tumour diameter > 8 cm will be excluded. Eligible patients will be randomly assigned to combination TACE and RFA therapy or TACE monotherapy groups. Patients in the combination therapy group will receive a second TACE and subsequent RFA at the viable tumour. Patients in the TACE monotherapy group will receive only second TACE. Patients in both groups will undergo magnetic resonance imaging 4–6 weeks after second TACE. The primary endpoint is 1-month tumour response, and secondary endpoints are progression-free survival, overall response rate, number of treatments until CR, overall survival, and change in liver function. Discussion Although TACE can be used to treat intermediate-stage HCC, it is difficult to achieve CR by first TACE in most intermediate-stage patients. Recent studies show a survival advantage of combination therapy over monotherapy. However, most studies evaluating combination therapy included patients with a single tumour sized

The long-term kinetics of quantitative HBsAg levels in HBV-infected patients treated with entecavir or tenofovir, as well as the role of quantitative HBsAg in predicting functional cure (HBsAg loss) and low HBsAg levels (p < 0.05), with another stepwise decrease between year 6–7. These trends were pronounced in patients with chronic hepatitis and HBeAg-positivity compared to those with cirrhosis and HBeAg-negativity, respectively. Baseline HBsAg of ≤3 log IU/mL and the first-year HBsAg reduction were key predictors for both functional cure and low HBsAg levels (p < 0.05). In conclusion, our findings elucidate the stepwise reduction in quantitative HBsAg dynamics during high-potency NA therapy (entecavir or tenofovir) along with variations based on different conditions. We also underscore the significance of quantitative HBsAg titer in predicting functional cure and low-HBsAg levels.

Background/Aims To evaluate the efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) therapy in hepatitis C virus (HCV)-infected Korean patients in a real clinical setting. Methods A total of 273 patients who received LDV/SOF therapy between May 2016 and February 2021 were consecutively enrolled and analyzed. A per-protocol analysis was performed to evaluate the virologic response. Results Seventy-five percent were infected with genotype 1, and 25% were infected with genotype 2. A hundred eighty-one (66.3%) patients had chronic hepatitis, 74 (27.1%) had compensated cirrhosis, eight (2.9%) had decompensated cirrhosis, and 10 (3.7%) had undergone liver transplantation. Undetectable HCV RNA at week 4 was achieved in 90.2% (231/256) of patients, 99.2% (250/252) achieved the end of treatment response, and 98.1% (202/206) achieved sustained virologic response at 12 weeks post-treatment (SVR12). According to liver function, the SVR12 rates were 99.3% (135/136) in chronic hepatitis, 96.4% (53/55) in compensated cirrhosis, and 100% (6/6) in decompensated cirrhosis. The SVR12 rates according to the genotype were 98.2% (167/170) for genotype 1 and 97.2% (35/36) for genotype 2. An 8-week LDV/SOF treatment in treatment-naïve chronic hepatitis patients with HCV RNA < 6,000,000 IU/mL at baseline resulted in 100% (23/23) SVR12 rates. Overall, LDV/SOF was tolerated well, with a 0.7% (2/273) discontinuation rate due to adverse events that were unrelated to LDV/SOF. Conclusions LDV/SOF is effective and safe for treating HCV-infected Korean patients with high SVR12 rates.

Budd-Chiari syndrome (BCS) is defined by the obstruction of the hepatic venous outflow between the small hepatic veins and the junction of the inferior vena cava (IVC) with the right atrium. BCS with IVC obstruction occasionally progresses to hepatocellular carcinoma (HCC). Here, we report the case of a patient with HCC arising from a cirrhotic liver with BCS, in whom the hepatic portion of the IVC was obstructed, and who had a favorable outcome with a multidisciplinary approach and IVC balloon angioplasty.

Background/Aims To evaluate the effectiveness and safety of direct acting antivirals (DAAs) available in chronic kidney disease (CKD) patients with hepatitis C virus (HCV) infection in Korea. Methods In a retrospective, multicenter cohort study, 362 patients were enrolled from 2015 to 2019. The effectiveness and safety of DAAs including glecaprevir/pibrentasvir, sofosubvir/ribavirin, ledipasvir/sofosbuvir, and daclatasvir/asunaprevir were analyzed for patients according to CKD stage. We evaluated sustained virologic response at week 12 after treatment (SVR12) as primary endpoint. The effectiveness and safety were also evaluated according to CKD stage. Results Among 362 patients, 307 patients completed DAAs treatment and follow-up period after end of treatment. The subjects comprised 87 patients (62 with CKD stage 3 and 25 with CKD stage (4–5), of whom 22 were undergoing hemodialysis). HCV patients with CKD stage 1 and 2 (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2) showed SVR12 of 97.2% and 95.4% respectively. SVR12 of CKD stage 3 and 4–5 (eGFR < 60 mL/min/1.73 m2) patients was 91.9% and 91.6% respectively. Patients undergoing hemodialysis achieved SVR12 (90.9%). Treatment failure of DAAs in stage 1, 2, 3, and 4–5 was 2.8%, 2.7%, 1.6%, and 4%. DAAs showed good safety profile and did not affect deterioration of renal function. Conclusions DAAs shows comparable SVR12 and safety in CKD patients (stage 3, 4, and 5) with HCV compared with patients with stage 1 and 2. The effectiveness and safety of DAAs may be related to the treatment duration. Therefore, it is important to select adequate regimens of DAAs and to increase treatment adherence.

IntroductionIn this study, we examined the natural course of untreated hepatocellular carcinoma (HCC) and identified predictors of survival in an area where hepatitis B is the predominant cause of HCC.MethodsWe identified 1,045 patients with HCC who did not receive HCC treatment and were registered in the Korean Primary Liver Cancer Registry between 2008 and 2014, and were followed-up up to December 2018. Thereafter, we analyzed the clinical characteristics of patients who survived for

BackgroundIdiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI.MethodsFrom January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days.ResultsThe numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days.ConclusionsActivated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.

Background/Aim Hepatocellular carcinoma (HCC) is associated with poor prognosis, largely due to late detection. Highly accurate biomarkers are urgently needed to detect early-stage HCC. Our study aims to explore the diagnostic performance of serum exosomal microRNA (miR)-720 in HCC. Methods Exosomal miRNA was measured via quantitative real-time PCR. A correlation analysis of exosomal miR-720 and tumor or clinico-demographic data of patients with HCC was performed. The receiver operating characteristic (ROC) curve was used to assess the diagnostic capacity of serum exosomal miR-720 for HCC, in comparison with α-fetoprotein (AFP) and prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II). Results MiR-720 was chosen as a potential HCC marker via miR microarray based on significant differential expression between tumor and non-tumor samples. Serum exosomal miR-720 was significantly upregulated in patients with HCC (n=114) versus other liver diseases (control, n=30), with a higher area under the ROC curve (AUC, 0.931) than the other markers. Particularly, serum exosomal miR-720 showed superior performance in diagnosing small HCC (

This study aimed to document the functional microbiome affecting immune homeostasis in long-term post-liver transplantation (LT) patients. We compared the frequency of regulatory T (Treg) and T helper 17 (Th17) cells in the blood and fecal microbiome of 27 LT patients to matched healthy controls (n = 20) using flow cytometry and 16S rRNA sequencing. Among the 27 LT patients, 22 patients ingested immunosuppressants (long-term post-LT group) and five were tolerant patients. The changes in Treg and Th17 cell proportion after treatment with distinct microbiomes in the long-term post-LT group were also examined in vitro . Changes in the identified functional microbiome and Treg cells in tolerant patients were evaluated. The mean time after LT of the included patients was 13.2 y. The gut microbiome of the long-term post-LT group showed lower alpha-diversity (P

Background: Aberrant expression of c-MET is known to be associated with tumor recurrence and metastasis by promoting cell proliferation, epithelial-mesenchymal transition (EMT), and migration in hepatocellular carcinoma (HCC). Recently, miR-23b-3p has been identified as a tumor suppressor, but detailed role of miR-23b-3p in HCC is still unclear. Our study aimed to investigate how miR-23b-3p is associated with the malignant potential of HCC cells. Methods: HCC tissues and their adjacent non-tumor tissues were acquired from 30 patients with HCC. Expression of EMT- or stemness-related genes were examined in the two HCC cell lines. Migration of HCC cells was analyzed using transwell and wound healing assays. Results: c-MET was overexpressed in HCC tissues compared to the adjacent non-tumor tissues. c-MET knockdown inhibited EMT and reduced migration and invasion of HCC cells. Furthermore, c-MET was a target of miR-23b-3p, and miR-23b-3p expression was decreased in HCC tissues compared to non-tumor tissues. Treatment of miR-23b-3p inhibitor in HCC cells promoted EMT, cell migration, and invasion. In contrast, miR-23b-3p overexpression suppressed EMT, cell migration, and invasion, concomitantly reducing c-MET expression. Transfection of miR-23b-3p inhibitor with concomitant c-MET knockdown mitigated the effects of miR-23b-3p inhibitor on EMT in HCC cells. In addition, transforming growth factor beta1 (TGF-β1) stimulation after miR-23b-3p overexpression induced neither the mesenchymal phenotype nor migratory property of HCC cells. Conclusion: In this study, we confirmed that miR-23b-3p downregulation significantly increased EMT, migration, and invasion of HCC cells. In addition, c-MET was confirmed to be a target of miR-23b-3p in HCC cells and regulated the functional effects of miR-23b-3p. These results suggest that miR-23b-3p can be used as a prognostic biomarker and candidate target for HCC treatment.

A combination of atezolizumab with bevacizumab (AB) is the first regimen that has shown superiority compared to sorafenib and is now being used as the systemic treatment of choice for hepatocellular carcinoma (HCC) patients with Barcelona Liver Cancer Clinic stage C. However, a considerable number of patients do not achieve survival or significant responses, indicating the need to identify predictive biomarkers for initial and on-treatment decisions in HCC patients receiving AB. In this manuscript, we summarized the current data from both experimental and clinical studies. This review will be beneficial for both clinicians and researchers in clinical practice as well as those designing experimental, translational, or clinical studies.

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 (

Multikinase inhibitors (MKIs) such as sorafenib and lenvatinib are first-line treatments for unresectable hepatocellular carcinoma (HCC) and are known to have immunomodulatory effects. However, predictive biomarkers of MKI treatment in HCC patients need to be elucidated. In the present study, thirty consecutive HCC patients receiving lenvatinib (n = 22) and sorafenib (n = 8) who underwent core-needle biopsy before treatment were enrolled. The associations of CD3, CD68, and programmed cell death-ligand-1 (PD-L1) immunohistochemistry with patient outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), were evaluated. High and low subgroups were determined according to median CD3, CD68, and PD-L1 values. Median CD3 and CD68 counts were 51.0 and 46.0 per 20,000 µm2, respectively. The median combined positivity score (CPS) of PD-L1 was 2.0. Median OS and PFS were 17.6 and 4.4 months, respectively. ORRs of the total, lenvatinib, and sorafenib groups were 33.3% (10/30), 12.5% (1/8), and 40.9% (9/22), respectively. The high CD68+ group had significantly better PFS than the low CD68+ group. The high PD-L1 group had better PFS than the low subgroup. When we analyzed the lenvatinib subgroup, PFS was also significantly better in the high CD68+ and PD-L1 groups. These findings suggest that high numbers of PD-L1-expressing cells within tumor tissue prior to MKI treatment can serve as a biomarker to predict favorable PFS in HCC patients.

The liver is frequently exposed to potentially toxic materials, and it is the primary site of clearance of foreign agents, along with many innate and adaptive immune cells. Subsequently, drug induced liver injury (DILI), which is caused by medications, herbs, and dietary supplements, often occurs and has become an important issue in liver diseases. Reactive metabolites or drug–protein complexes induce DILI via the activation of various innate and adaptive immune cells. There has been a revolutionary development of treatment drugs for hepatocellular carcinoma (HCC) and liver transplantation (LT), including immune checkpoint inhibitors (ICIs), that show high efficacy in patients with advanced HCC. Along with the high efficacy of novel drugs, DILI has become a pivotal issue in the use of new drugs, including ICIs. This review demonstrates the immunological mechanism of DILI, including the innate and adaptive immune systems. Moreover, it aims to provide drug treatment targets, describe the mechanisms of DILI, and detail the management of DILI caused by drugs for HCC and LT.

Background/Aims The role of hepatitis B virus (HBV) integration into the host genome in hepatocarcinogenesis following hepatitis B surface antigen (HBsAg) seroclearance remains unknown. Our study aimed to investigate and characterize HBV integration events in chronic hepatitis B (CHB) patients who developed hepatocellular carcinoma (HCC) after HBsAg seroclearance. Methods Using probe-based HBV capturing followed by next-generation sequencing technology, HBV integration was examined in 10 samples (seven tumors and three non-tumor tissues) from seven chronic carriers who developed HCC after HBsAg loss. Genomic locations and patterns of HBV integration were investigated. Results HBV integration was observed in six patients (85.7%) and eight (80.0%) of 10 tested samples. HBV integration breakpoints were detected in all of the non-tumor (3/3, 100%) and five of the seven (71.4%) tumor samples, with an average number of breakpoints of 4.00 and 2.43, respectively. Despite the lower total number of tumoral integration breakpoints, HBV integration sites in the tumors were more enriched within the genic area. In contrast, non-tumor tissues more often showed intergenic integration. Regarding functions of the affected genes, tumoral genes with HBV integration were mostly associated with carcinogenesis. At enrollment, patients who did not remain under regular HCC surveillance after HBsAg seroclearance had a large HCC, while those on regular surveillance had a small HCC. Conclusions The biological functions of HBV integration are almost comparable between HBsAg-positive and HBsAg-serocleared HCCs, with continuing pro-oncogenic effects of HBV integration. Thus, ongoing HCC surveillance and clinical management should continue even after HBsAg seroclearance in patients with CHB.

Background/Aims: Multiple meta-analyses and observational studies have reported that alcohol is a risk factor for liver cancer. However, whether there is a safe level of alcohol consumption remains unclear. We performed a systematic review and meta-analysis of the correlation between low-level alcohol consumption and the risk of liver cancer. Methods: Nested case-control studies and cohort studies involving the general population published prior to July 2019 were searched. In total, 28 publications (31 cohorts) with 4,899 incident cases and 10,859 liver cancer-related deaths were included. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Compared with those with low levels of alcohol consumption, moderate and heavy drinkers (≥1 drink/day for females and ≥2 drinks/day for males) had pooled ORs of 1.418 (95% CI, 1.192 to 1.687; p

Although rejection or tolerance can occur in liver transplantation (LT) patients, there are no reliable non-invasive methods for predicting immune homeostasis. In this study, we developed a humanized mouse model to predict liver immune homeostasis in patients who underwent LT. The patient-derived avatar model was developed by injecting peripheral blood mononuclear cells from healthy controls (HCs) or LT patients with stable, rejection, or tolerance into NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice, followed by injection of human hepatic stellate cells and Carbone tetrachloride (CCl4). After 7 weeks, the patient’s T-cell engraftment and liver inflammation in the avatar model were evaluated and compared with the liver histology of LT patients. Changes in liver inflammation following treatment with tacrolimus and/or biguanide derivatives were also examined. The C-X-C Motif Chemokine Receptor 3 (CXCR3)-dependently engrafted patient T cells led to differences in liver inflammation in our model according to the status of LT patients. The livers of avatar models from rejection patients had severe inflammation with more T helper 17 cells and fewer regulatory T cells compared to those of models from tolerance and HCs showing only mild inflammation. Moreover, our model classified stable post-LT patients into severe and mild inflammation groups, which correlated well with liver immunity in these patients. Our models revealed alleviation of inflammation after combination treatment with tacrolimus and biguanide derivatives or monotherapy. Consequently, using our new patient-derived avatar model, we predicted liver immune homeostasis in patients with stable LT without biopsy. Moreover, our avatar model may be useful for preclinical analysis to evaluate treatment responses while reducing risks to patients.

Abstract Currently, a reliable serum biomarker for hepatocellular carcinoma (HCC) has not been established, particularly for early‐stage HCC (single tumor 0.8. In our validation study, serum exo‐miR‐4661‐5p could diagnose HCC in all stages (AUROC = 0.917), even in early stage (AUROC = 0.923), with a greater accuracy than other candidate serum exo‐miRs and serum AFP. The panel composed of exo‐miR‐4661‐5p and exo‐miR‐4746‐5p was identified as the most accurate biomarker for early‐stage HCC (AUROC = 0.947, 95% confidence interval = 0.889‐0.980, sensitivity = 81.8%, and specificity = 91.7%). In conclusion, exo‐miR‐4661‐5p–based serum panel is a promising diagnostic marker for early‐stage HCC.

We report a case of a patient with Dubin–Johnson syndrome confirmed by a genetic study. A 50-year-old woman who had symptoms of intermittent right upper quadrant abdominal pain was diagnosed with calculous cholecystitis at another institute and was presented to our hospital for a cholecystectomy. She had no history of liver disease, and her physical examination was normal. Abdominal computed tomography showed a gallbladder stone with chronic cholecystitis. During a laparoscopic cholecystectomy for cholecystitis, a smooth, black-colored liver was noted, and a liver biopsy was performed. The biopsy specimen showed coarse, dark brown granules in centrilobular hepatocytes via hematoxylin and eosin staining. We performed a genetic study using the blood samples of the patient. In the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) mutation study, a missense mutation in exon 18 was noted. Based on the black-colored liver without nodularity, conjugated hyperbilirubinemia, the liver biopsy results of the coarse pigment in centrilobular hepatocytes, and the ABCC2 mutation, Dubin–Johnson syndrome was diagnosed. The patient was managed with conservative care using hepatotonics. One month after follow-up, total bilirubin and direct bilirubin remained in a similar range. Another follow-up was planned a month later, and the patient maintained her use of hepatotonics.

Background and Aims This retrospective study aimed to investigate the impact of positive hepatitis B core antibody (anti-HBc) and metabolic disorders on clinical characteristics of hepatocellular carcinoma (HCC) patients in an HBV-endemic area. Methods A total of 1950 consecutive patients newly diagnosed with HCC between 2002 and 2015 were included. Patient records were reviewed. We compared non-viral and non-alcoholic HCC patients with other etiological groups for HCC. In addition, we compared HCC patients with negative hepatitis B surface antigen (HBsAg) and positive anti-HBc to those with negative HBsAg and negative anti-HBc, and to those with HBV. Results The prevalence of non-viral and non-alcoholic HCC increased from 7% in 2002–2011 to 12% in 2012–2015. The proportion of non-viral and non-alcoholic HCC gradually increased with age. Patients with non-viral and non-alcoholic HCC exhibited higher rates of metabolic disorders and preserved liver function. The rate of anti-HBc positivity was similarly high in all HCC etiological groups. The clinical features of HCC patients with negative HBsAg and positive anti-HBc were similar to those with negative HBsAg and negative anti-HBc, but significantly different from those with HBV HCC. Regarding tumor characteristics, patients in the non-viral and non-alcoholic HCC group had more advanced stages of tumors (mUICC stage III–V and BCLC stage C/D). There was no significant difference in overall survival among the patient groups. The presence of anti-HBc did not affect patient survival. Conclusion Patients with non-viral and non-alcoholic HCC had a relatively high prevalence of metabolic disorders and preserved liver function. However, they had advanced tumor stage compared to patients from other etiological groups. Anti-HBc positivity did not affect the clinical characteristics or prognosis of non-HBV HCC patients in this study.

Background: Mammalian target of rapamycin (mTOR) inhibitors, such as everolimus and sirolimus, may be efficacious in preserving renal function in liver transplantation (LT) recipients while preventing hepatocellular carcinoma (HCC) recurrence.Materials and Methods: In this study, we retrospectively evaluated the safety, efficacy, and renoprotective effects of mTOR inhibitors in LT recipients. Among the 84 patients enrolled, mTOR inhibitor was commenced during the first year after LT. Renal function was measured by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation.Results: Regarding the type of mTOR inhibitor, everolimus was used in 71 patients and sirolimus in 13 patients. Concomitant tacrolimus was used in 63 patients (75.0%). For total enrolled patients, kidney function did not significantly change during 12 months after initiation of mTOR inhibitors, although tacrolimus-withdrawn patients (n = 21) showed better kidney function compared to tacrolimus-minimized patients (n = 63) after conversion. However, a significant improvement in kidney function was observed in the eGFR

Background & AimsCancer metastasis is responsible for the majority of cancer-related deaths. Exosomal miRNAs have emerged as promising biomarkers for cancer, serving as signaling molecules that can regulate tumor growth and metastasis. This study examined circulating exosomal miRNAs that could predict hepatocellular carcinoma (HCC) metastasis.MethodsExosomal miRNA was measured by quantitative real-time PCR (qRT-PCR) in a large set of patients (n = 284). To investigate the role of exosomal miRNA in HCC, we performed a series of in vitro tests, such as exosome labeling, qRT-PCR, reverse transcription PCR, wound healing assay, transwell assay, and Western blot assay.ResultsExosomal miR-125b was drastically downregulated in HCC patients with metastasis than in those without metastasis. In vitro, we observed the uptake of miR-125b by exosome in recipient cells. Exosome-mediated miR-125b significantly inhibited migration and invasion abilities and downregulated the mRNA expressions of MMP-2, MMP-9, and MMP-14 in recipient cells via intercellular communication. Further investigation revealed that miR-125b suppressed SMAD2 protein expression in recipient cells by binding to its 3′ untranslated regions. Exosome-mediated miR-125b transfer also disrupted TGF-β1–induced epithelial–mesenchymal transition and TGF-β1/SMAD signaling pathway in recipient cells by leading to a decrease of SMAD2 protein expression. Moreover, exosomal miR-125b was downregulated after metastasis compared with that at baseline in patients with serial measurements before and after metastasis.ConclusionsThe results imply that exosome-mediated miR-125b exerts anti-metastatic properties in HCC. These findings highlight that circulating exosomal miR-125b might represent a reliable biomarker with diagnostic and therapeutic implications for extrahepatic metastasis from HCC.

Background/Aims There have been numerous efforts to reduce mother-to-child transmission (MTCT) of hepatitis B virus (HBV) with antiviral agents during pregnancy. However, there are limited data regarding the outcomes of pregnant women after delivery. This study was performed to evaluate the efficacy of antiviral agents in preventing MTCT of HBV and maternal long-term outcomes. Methods The HBV-infected pregnant women treated with antiviral agents to prevent MTCT were retrospectively reviewed. Forty-one pregnant women who received telbivudine or tenofovir during late pregnancy (28-34 week) were analyzed. Hepatitis B virus surface antibody (HBsAb) positivity was tested in 43 infants after 7 months of birth. Eleven mothers were followed >1 year after delivery. Results The mean HBV DNA titer before antiviral therapy was 8.67 (6.60–9.49) log copies/mL, and the median age at delivery was 32 years (range, 22–40). Eleven patients were treated with tenofovir and 30 with telbivudine. The median duration was 57 days (range, 23–100), and the median HBV DNA titer at birth was 5.06 log copies/mL (range, 2.06–6.50). Antiviral treatments were associated with significant HBV DNA reduction (P12 months, and an antiviral agent was administered. Conclusions Antiviral treatment during late pregnancy effectively reduced MTCT. Long-term follow-up should be required in such cases. In addition, given that maternal biochemical flare occurred in 18% of mothers, re-administration of antiviral agents might be required.

Acute-on-chronic liver failure (ACLF) occurs in the presence of a chronic liver disease or cirrhosis, and often results from exacerbation of chronic hepatitis B (CHB). The efficacy of corticosteroid treatment in ACLF patients with underlying CHB remains unclear. We report the case of a 50-year-old woman who experienced ACLF due to CHB exacerbation and was treated with a combination of corticosteroids and nucleot(s)ide analogue (NUC). The patient showed rapid decompensation due to CHB exacerbation. Three months of antiviral therapy produced no improvement in liver function. Combination therapy with corticosteroids and NUC was started, which did result in improvement of liver function. This case shows that the combined therapy of corticosteroids and NUC can be effective in treating ACLF due to CHB exacerbation.

We examined the effect of combination therapy with metformin and tacrolimus on immune parameters including T regulatory (Treg) and type 17 helper T (Th17) cells in vitro and in vivo in mice and in liver transplantation (LT) patients. T cell proliferation and subtypes after in vitro T cell activation or allogeneic stimulation were evaluated. RNA sequencing and microarray analysis were used to evaluate differences in gene expression. Metformin and tacrolimus were administered to mice with graft-versus-host disease (GVHD) and the effects in vivo were assessed. Five LT patients were treated with metformin and the changes in Treg and Th17 cells examined. Combination therapy decreased Type 1 helper T (Th1) and Th17 cells present after in vitro T cell activation, whereas genes associated with Treg were overexpressed. During in vitro allogeneic stimulation, combination therapy increased Treg cells and decreased T cell proliferation and pro-inflammatory markers. In mice with GVHD, combination treatment decreased the clinical and pathological severity of GVHD. In LT patients, addition of metformin increased the peripheral percentage of CD4+Treg and CD8+Treg cells and decreased CD4+Th17. Our study suggests that the addition of metformin to tacrolimus may improve immunological balance by increasing Treg cells and decreasing Th17 cells.

Background Antifibrotic agent for the treatment of liver fibrosis has not been developed so far. Long term treatment of chronic hepatitis B patients with antiviral drugs tenofovir disoproxil fumarate (TDF) and entecavir (ETV) results in the regression of liver fibrosis, but the underlying mechanism has not been clarified. Therefore, we aimed to investigate the direct impact of TDF and ETV on liver fibrosis. Methods Activated hepatic stellate cell (HSC) cell lines were used to evaluate the effects of TDF and ETV. After treatment with each antiviral agent, cell viability, morphology, apoptotic features, autophagy and antifibrosis signalling pathways were examined. Then, collagen deposition, fibrosis markers and activated HSCs were measured in liver tissues of the liver fibrosis model mice. Results After TDF treatment, the viabilities of LX2 and HSC-T6 cells were decreased, and the cells exhibited apoptotic features, but ETV did not induce these effects. Cleavage of PARP and Caspase-3 and the inhibition of the antiapoptotic gene Bcl-xl indicated activated HSC apoptosis following TDF treatment. TDF simultaneously increased autophagy, which also regulated apoptosis through crosstalk. TDF inactivated the PI3K/Akt/mTOR signalling pathway, which was associated with the activation of both apoptosis and autophagy. In the liver fibrosis mouse model, the fibrotic area and activated HSC markers were decreased by TDF but not ETV treatment. Additionally, apoptotic cells were concentrated in the periportal fibrotic area after TDF treatment, which indicated the specific antifibrotic effect of TDF. Conclusions TDF directly ameliorates liver fibrosis by downregulating the PI3K/Akt/mTOR signalling pathway, which results in the apoptosis of activated HSCs. The antifibrotic effects of TDF indicate that it may be a therapeutic agent for the treatment of liver fibrosis.

Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.

This study aimed to identify the utility of diffusion-weighted magnetic resonance (MR) imaging with an apparent diffusion coefficient (ADC) map as a predictor of the response of hepatocellular carcinoma (HCC) to cisplatin-based hepatic arterial infusion chemotherapy (HAIC). We retrospectively evaluated 113 consecutive patients with Barcelona Clinical Liver Cancer (BCLC) stage B or C HCC, who underwent gadoxetic acid-enhanced and diffusion-weighted MR imaging. The appropriate cutoff for the pretreatment tumor-to-liver ADC ratio was determined to be 0.741. Of the 113 patients, 50 (44%) presented with a pretreatment tumor-to-liver ADC ratio < 0.741 (low group). Evaluation of the treatment response after 2-3 cycles of HAIC in these 50 patients revealed that 21 patients (42%) experienced an objective response to HAIC. On the other hand, only 11 of the 63 patients (17%) with a pretreatment tumor-to-liver ADC ratio ≥ 0.741 (high group) showed an objective response. Thus, the objective response rate was significantly higher in the low group than in the high group (P = 0.006). Multivariate logistic regression analysis using parameters including perfusion alteration, percentage of non-enhancing portions, and pretreatment tumor-to-liver ADC ratio revealed that a pretreatment tumor-to-liver ADC ratio < 0.741 (odds ratio 3.217; P = 0.014) was the sole predictor of an objective response to HAIC. Overall survival rates were significantly higher in patients with objective responses to HAIC than in those without objective responses (P = 0.001 by log-rank test). In conclusion, patients with BCLC stage C or C HCC with a pretreatment tumor-to-liver ADC ratio < 0.741 showed a favorable intrahepatic response to cisplatin-based HAIC. Therefore, diffusion-weighted MR imaging can play a critical role as a predictor of response to cisplatin-based HAIC in unresectable HCC.

Real-world results of nivolumab monotherapy against HCC are lacking in the hepatitis B virus (HBV)-endemic, Asia-Pacific regions. Moreover, heterogeneous responses to immune checkpoint inhibitors have rarely been described in advanced HCC. The aim of this study is to evaluate the efficacy and safety of nivolumab monotherapy in a real-world setting in 33 Korean patients with unresectable HCC. In our cohort, twenty-nine patients (88%) showed HBsAg positivity. At the time of nivolumab initiation, 4 among 33 patients (12%) were classified as Barcelona Clinic Liver Cancer (BCLC)-B stage and 29 (88%) as BCLC-C stage, respectively. Prior sorafenib treatment was given to 31 (94%) patients, and 13 (39%) received prior regorafenib treatment. For the liver reserve, patients were classified as Child–Pugh class A (79%) and B (21%), respectively. Grade 3 toxicities occurred in one patient, who developed pneumonitis after 5 cycles of nivolumab treatment. Best overall responses were complete response in 2 patients out of the 33 enrolled patients (6%), partial response in 4 patients (12%) and stable disease in 4 patients (12%). With 29 patients having images for the response evaluation, the objective response rate was 21.4%. The median overall survival (OS) of the cohort was 26.4 weeks (range 2.3–175.1). Achieving objective responses, pre-treatment small tumors (maximal diameter

Transarterial chemoembolization using doxorubicin (TACE-DOX) is an effective therapy for advanced hepatocellular carcinoma (HCC). However, there are limited options for patients with TACE refractoriness. We compared the effectiveness between sorafenib and transarterial chemolipiodolization using epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil (5-FU; TACL-ECF) in patients with previous TACE-DOX refractoriness. We retrospectively analyzed 742 consecutively enrolled cohort patients who received TACE-DOX as the first-line therapy for HCC. Among the 94 patients who failed with TACE-DOX, 49 patients were treated with TACL-ECF and 45 patients were treated with sorafenib as a rescue therapy. The TACL-ECF regimen comprised transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-FU. Of the 94 patients, 22 and 72 patients were in Barcelona Clinic Liver Cancer stages B and C, respectively; 66% patients were classified as having Child-Pugh class A (CPC A). Overall survival (OS) after rescue therapy did not differ between the sorafenib and TACL-ECF groups (4.1 months vs 6.4 months, P = .355). Progression-free survival (PFS) did not differ between the sorafenib and TACL-ECF groups (2.8 months vs 3.5 months, P = .629). Adverse events of CTC grade 3/4 occurred more frequently in the sorafenib group than in the TACL-ECF group ( P = .024). The present study showed that the OS and PFS did not differ between patients given rescue TACL-ECF therapy and those given sorafenib therapy. The TACL-ECF treatment was better tolerated than sorafenib. The TACL-ECF might be considered as an alternative therapy for the patients with TACE-DOX refractoriness, especially CPC B and sorafenib-intolerant patients.

[This corrects the article DOI: 10.1371/journal.pone.0224318.].

Background/Aims Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy. Methods A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-β and its downstream interferon-stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs. Results The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-β. After DAA treatment, a significant decrease in the expression levels of IFN-β, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-β and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation. Conclusions Pretreatment activation of IFN-β response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA-induced alleviation of extrahepatic manifestation of chronic HCV infection.

Background/AimsAccording to the results of several studies, the outcome of hepatitis C virus (HCV) reactivation is not as severe as the outcome of hepatitis B virus reactivation. The aim of this study was to evaluate the effect of pharmacological immunosuppression on HCV reactivation.Methods : The medical records of patients who underwent systemic chemotherapy, corticosteroid therapy, or other immunosuppressive therapies between January 2008 and March 2015 were reviewed. Subsequently, 202 patients who were seropositive for the anti-HCV antibody were enrolled. Exclusion criteria were: unavailability of data on HCV RNA levels, a history of treatment for chronic hepatitis C, and the presence of liver diseases other than a chronic HCV infection.Results : Among the 120 patients enrolled in this study, hepatitis was present in 46 patients (38%). None of the patients were diagnosed with severe hepatitis. Enhanced replication of HCV was noted in nine (27%) of the 33 patients who had data available on both basal and follow-up HCV RNA loads. Reappearance of the HCV RNA from an undetectable state did not occur after treatment. The cumulative rate of enhanced HCV replication was 23% at 1 year and 30% at 2 years.Conclusion : sAlthough enhanced HCV replication is relatively common in HCV-infected patients treated with chemotherapy or immunosuppressive therapy, it does not lead to serious sequelae.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70–80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.

Background/Aims Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Methods A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS. Results The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively (P=0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014) and Child-Pugh class B (HR=1.856, P=0.008). Conclusions MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

Background/Aims Hepatic damage during transarterial chemoembolization (TACE) is a critical complication in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Apart from its role in preventing HBV reactivation, there is some evidence for the benefits of preemptive antiviral therapy in TACE. This study evaluated the effect of preemptive antiviral therapy on acute hepatic deterioration following TACE. Methods This retrospective observational study included a prospectively collected cohort of 108 patients with HBV-related HCC who underwent TACE between January 2007 and January 2013. Acute hepatic deterioration following TACE was evaluated. Treatment-related hepatic decompensation was defined as newly developed encephalopathy, ascites, variceal bleeding, elevation of the bilirubin level, prolongation of prothrombin time, or elevation of the Child-Pugh score by ≥2 within 2 weeks following TACE. Univariate and multivariate analyses were conducted to identify factors influencing treatment-related decompensation. Preemptive antiviral therapy involves directing prophylaxis only toward high-risk chronic hepatitis B patients in an attempt to prevent the progression of liver disease. We regarded at least 6 months as a significant duration of preemptive antiviral treatment before diagnosis of HCC. Results Of the 108 patients, 30 (27.8%) patients received preemptive antiviral therapy. Treatment-related decompensation was observed in 25 (23.1%) patients during the follow-up period. Treatment-related decompensation following TACE was observed more frequently in the nonpreemptive group than in the preemptive group (29.5% vs. 6.7%, P=0.008). In the multivariate analysis, higher serum total bilirubin (Hazard ratio [HR] =3.425, P=0.013), hypoalbuminemia (HR=3.990, P=0.015), and absence of antiviral therapy (HR=7.597, P=0.006) were significantly associated with treatment-related hepatic decompensation. Conclusions Our findings suggest that preemptive antiviral therapy significantly reduces the risk of acute hepatic deterioration. Preventing hepatic deterioration during TACE by applying such a preemptive approach may facilitate the continuation of anticancer therapy and thus improve long-term outcomes.