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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.

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.

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.

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 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.

Oxidative stress is key in type 2 diabetes-associated nonalcoholic fatty liver disease (NAFLD). We explored whether extracellular superoxide dismutase (EC-SOD) activates adenosine monophosphate-activated protein kinase (AMPK) to enhance antioxidant synthesis and lipid metabolism in NAFLD. Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Target molecules involved in oxidative stress and lipid metabolism were investigated. hEC-SOD improved insulin resistance and systemic and hepatic oxidative stress characterized by increases in urinary 8-hydroxy-deoxyguanosine and 8-isoprostane levels in db/db mice and a decrease in DHE expression in the liver, respectively. Hepatic SOD3 expression in db/db mice was reversed by hEC-SOD, which improved hepatic steatosis, inflammation with M2 polarization, apoptosis, autophagy, fibrosis and lipid metabolism in db/db mice, as reflected by the changes in serum and hepatic markers, monocyte chemoattractant protein-1, tumor necrosis factor-α, TUNEL-positive cells, Bcl-2/BAX ratio, beclin1 and LC3-II/LC3-1. At the molecular level, hEC-SOD increased phosphorylated-AMPK related to CaMKKß, activation of peroxisome proliferative-activated receptor-gamma coactivator (PGC)-1α and dephosphorylation of forkhead box O (FoxO)1 and their subsequent downstream signaling. In HepG2Cs cells using AMPKα1 and AMPKα2 siRNA, hEC-SOD demonstrated a protective effect via the direct activation of both AMPK-PGC-1α and AMPK-FoxO1. EC-SOD might be a potential therapeutic agent for NAFLD through the activation of AMPK-PGC-1α and AMPK-FoxO1 signaling in hepatocytes, which modulates lipid metabolism, leading to anti-inflammatory, antioxidative and antiapoptotic effects and improving autophagy in the liver.

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 (

Background and purpose: Although the prevalence of nonalcoholic steatohepatitis (NASH) is rapidly increasing, effective therapy is lacking. Tenofovir alafenamide (TAF) is a widely used antiviral drug for hepatitis B. In this study, we investigated the potential pharmacological effects of TAF on NASH. Experimental approach: Two different NASH mouse models were established: 1) by subcutaneous injection of streptozotocin (0.2 mg) and feeding the mice a high-fat, high-cholesterol (HFHC) diet, and 2) feeding the mice a choline-deficient, L-amino acid-defined, high-fat (CDAHF) diet. Key results: Serum alanine aminotransferase and triglyceride levels in TAF-treated NASH mice were significantly lower than those in the mock-treated ones. The livers from the TAF-treated NASH mice showed attenuated mononuclear phagocyte (MP) infiltration compared to those from the mock-treated ones. TAF-treated NASH mice exhibited decreased liver infiltration of activated MPs (IAIE+/PD-L1+/MerTK+). In ex vivo experiments using sorted human CD14+ monocytes treated with lipopolysaccharide (LPS) and/or TAF, we confirmed the decreased level of phosphorylated AKT in TAF-treated LPS-stimulated monocytes compared to that in the mock-treated ones. Mouse liver immunoblotting showed that phosphorylation levels of AKT were significantly lower in the TAF-treated NASH group than in the mock-treated group. Conclusion and implications: TAF exerts anti-inflammatory effects in NASH livers by attenuating AKT phosphorylation in intrahepatic activated MPs. Therefore, TAF may serve as a new therapeutic option for NASH.

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 & 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: Atezolizumab+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 methods: This real-world multicenter study analysed patients with HCC who received AB (n=169) or lenvatinib (n=177). Results: First, 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. Conclusion: Our 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. [ABSTRACT FROM AUTHOR]

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.

Background/Aims Pegylated interferon (PEG-IFN) treatment with a high rate of off-therapy host immune control is still an attractive treatment for chronic hepatitis B virus (HBV) infection. There remains uncertain about the prognosis of sustained responder after PEG-IFN treatment who do not need nucleos(t)ides (NAs). We investigated the long-term outcomes of PEG-IFN treatment focused on tolerant patients without NAs up to 13 years. Methods A consecutive 172 patients treated with PEG-IFN for chronic hepatitis B or compensated liver cirrhosis between 2005 and 2014 were enrolled and finally 122 patients who fully completed PEG-IFN treatment were analyzed. The definition of response for PEG-IFN treatment at 6months posttreatment were as follows: hepatitis B e antigen (HBeAg) positive patients, achieve both virologic response (VR; <2,000 IU/mL of HBV DNA) and serologic response (HBeAg loss or seroconversion); HBeAg negative patients, reach VR. During follow-up period, we analyzed the number of patients with HBsAg loss, starting NAs due to viral activation and disease progression including liver cirrhosis and hepatocellular carcinoma (HCC). Results The median follow-up period of 122 patients were 7.2 years (range, 1.1 to 13.2 years). Of 122 patients, 43 patients (35.2%) had a response at 6 months posttreatment. During follow-up, 69 patients (56.6%) started NAs and the patients who had a response for PEG-IFN significantly lower rate of starting NAs (14/43 vs 55/79, p<0.001). HBsAg loss occurred in nine patients (7.4%) and sustained responders without further NAs treatment had significantly high rate of HBsAg loss compared to the patients with starting NAs (13.2% vs 2.9%, p=0.01). Eight patients (6.6%) developed disease progression including HCC (n=3). All of them were nonsustained responders who started NAs after PEG-IFN therapy compared to sustained responders (p=0.03). Conclusions Sustained responders without further NAs treatment after PEG-IFN treatment had a favorable clinical outcome in HBsAg loss and no disease progression up to 13 years. [ABSTRACT FROM AUTHOR]

Background/Aims Transarterial radioembolization (TARE) is a form of radiation therapy performed by selective intra-arterial injection of microspheres loaded with Yttrium-90. TARE is known to be effective in the management of unresectable hepatocellular carcinoma (HCC). The aim of this study is to identify prognostic factors for overall survival (OS) and time to progression (TTP) in patients with HCC undergoing TARE. Methods This study included 73 consecutive HCC patients who underwent TARE from July 2009 to January 2018. The tumor responses to TARE were assessed according to modified Response Evaluation Criteria in Solid Tumors. Results The patients' baseline characteristics were as follows: median age was 66 years, 74% of male. The median tumor size was 9 cm and 41% of the patients had tumors larger than 10 cm. Multifocal HCCs identified in 58% and 26% of the patients showed infiltrative tumor. Sixty-three percent of the patients did not have portal vein tumor thrombus (PVTT), 10% had VP 1-2, and 27% had VP 3-4 of PVTT. Among 73 patients, five (7%) obtained complete response and 25 (34%) showed partial response at 3 months after TARE. Median OS was 27.6 months and TTP was 3.2 months. Multivariate analysis revealed that the absence of PVTT (hazard ratio [HR], 0.137; 95% confidence interval [CI], 0.057 to 0.331; p<0.001) was independent factor for OS. The absence of PVTT (HR, 0.330; 95% CI, 0.172 to 0.632; p=0.001) and tumor diameter ≤10 cm (HR, 0.287; 95% CI, 0.135 to 0.611, p=0.001) were independent prognostic factors for TTP. Conclusions TARE is an effective therapy for patients with advanced HCC. Absence of PVTT before TARE is an independent predictive factor for both OS and TTP. [ABSTRACT FROM AUTHOR]

Background/Aims Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis which may progress to fibrosis, cirrhosis and hepatocellular carcinoma. Micro RNAs (miRNAs) are important posttranscriptional regulators of gene expression, and the dysregulation of miRNAs is involved in various biological processes in the liver, including lipid homeostasis, inflammation, apoptosis, and cell proliferation. This study aimed at suggesting the miRNAs may be a biomarker of the fat accumulation and inflammation in NAFLD. Methods We use male mice of 6- to 8-week old had fed normal diet or 60% high fat diet for 3 months and 6 months. The accumulation of lipid in liver was examined by hematoxylin and eosin stain (H&E stain). We used human liver cell lines loaded with free fatty acids. And we performed quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting for the validation of miRNAs and lipid droplets formation markers. Results miRNAs levels were identified in NAFLD in vivo and in vitro model. In the high fat diet group, liver index and body weigh were increased. H&E stain results show that high fat diet groups had accumulated lots of fat. And in the high fat diet group, lipid droplets formation markers and inflammation markers were increased. In NAFLD in vitro model, lipid droplets formation markers and inflammation markers were increased. miRNA level of miR-26a, miR-26b, let-7f and miR-22 was increased in the NAFLD in vivo and in vitro model. But, level of miR-101 was decreased in the NAFLD in vivo ad in vitro model. Conclusions In this study we evaluated the level of miRNAs on lipid metabolism using the in vitro and in vivo NAFLD model. Our results demonstrate that miRNAs may be a biomarker in NAFLD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Oxidative stress is key in type 2 diabetes-associated nonalcoholic fatty liver disease (NAFLD). We explored whether extracellular superoxide dismutase (EC-SOD) activates adenosine monophosphate-activated protein kinase (AMPK) to enhance antioxidant synthesis and lipid metabolism in NAFLD. Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Target molecules involved in oxidative stress and lipid metabolism were investigated. hEC-SOD improved insulin resistance and systemic and hepatic oxidative stress characterized by increases in urinary 8-hydroxy-deoxyguanosine and 8-isoprostane levels in db/db mice and a decrease in DHE expression in the liver, respectively. Hepatic SOD3 expression in db/db mice was reversed by hEC-SOD, which improved hepatic steatosis, inflammation with M2 polarization, apoptosis, autophagy, fibrosis and lipid metabolism in db/db mice, as reflected by the changes in serum and hepatic markers, monocyte chemoattractant protein-1, tumor necrosis factor-α, TUNEL-positive cells, Bcl-2/BAX ratio, beclin1 and LC3-II/LC3-1. At the molecular level, hEC-SOD increased phosphorylated-AMPK related to CaMKKß, activation of peroxisome proliferative-activated receptor-gamma coactivator (PGC)-1α and dephosphorylation of forkhead box O (FoxO)1 and their subsequent downstream signaling. In HepG2Cs cells using AMPKα1 and AMPKα2 siRNA, hEC-SOD demonstrated a protective effect via the direct activation of both AMPK-PGC-1α and AMPK-FoxO1. EC-SOD might be a potential therapeutic agent for NAFLD through the activation of AMPK-PGC-1α and AMPK-FoxO1 signaling in hepatocytes, which modulates lipid metabolism, leading to anti-inflammatory, antioxidative and antiapoptotic effects and improving autophagy in the liver. [ABSTRACT FROM AUTHOR]

Simple Summary: Trans-arterial radioembolization (TARE) can effectively treat patients with locally advanced hepatocellular carcinoma (HCC). However, TARE is not widely used in clinical practice due to the lack of consensus on how to select the best candidates for this therapy. Therefore, it is crucial to find predictive biomarkers or clinical parameters that can differentiate the patients who will respond well to TARE and improve their outcomes. Low skeletal muscle mass (LSMM) is one of the factors that affects the prognosis of HCC patients and has been extensively studied in relation to different treatments. We used a semi-automated program that has been validated and proven to be reliable for assessing LSMM. In this study, we aimed to identify prognostic factors, including pre-treatment LSMM, for survival outcomes in patients with HCC undergoing TARE. Trans-arterial radioembolization (TARE) is a form of radiation therapy performed for hepatocellular carcinoma (HCC) via selective intra-arterial injection of Yttrium-90-loaded microspheres. This was a multi-center retrospective study of consecutive patients with HCC who underwent TARE between July 2009 and May 2019. Using pre-treatment computed tomography imaging, the total cross-sectional area (cm2) of the abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI) was calculated by normalizing the muscle area to patient height. In total, 347 patients (median age, 65 years; 284 male) were included in the study. A total of 108 (31.1%) patients had portal vein tumor thrombus (PVTT), and 126 (36.3%) were classified as LSMM. The median overall survival (OS) was 28.1 months (95% CI, 24.8–35.7), and median progression-free survival was 8.0 months (95% CI, 6.4–9.4). Multivariate Cox regression analysis revealed that LSMM (hazard ratio [HR], 1.36; 95% CI, 1.00–1.85, p = 0.05), PVTT (HR, 1.82; 95% CI, 1.33–2.49, p < 0.01), alpha-fetoprotein (AFP) (≥200 ng/mL) (HR 1.41; 95% CI, 1.04–1.92, p = 0.03), and albumin–bilirubin grade (2–3) (HR 1.74; 95% CI, 1.24–2.43, p < 0.01) were independently associated with poor OS. TARE provided favorable long-term outcomes for patients with advanced HCC. Pre-treatment LSMM independently associated with survival, suggesting its utility as a surrogate biomarker for identifying TARE candidates. [ABSTRACT FROM AUTHOR]

Simple Summary: This multicenter cohort study is the first to compare the clinical outcomes between the Atezolizumab-plus-bevacizumab (Ate/Bev) and transarterial-chemoembolization-plus-radiotherapy (TACE + RT) therapies in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) who had no metastasis. Through detailed analyses, our study revealed that the Ate/Bev treatment provided superior one-year survival compared to the TACE + RT treatment. The superior outcome of the Ate/Bev therapy was constantly observed in patients with an extensive HCC burden. Meanwhile, patients with unilobar disease demonstrated comparable outcomes between the two treatment groups. Finally, in the propensity score-matching analysis, both one-year survival and progression-free survival rates were higher in the Ate/Bev treatment group. These results suggest that Ate/Bev treatment should be considered as the primary treatment option for HCC patients with PVTT. With respect to TACE + RT, this could also be considered as an alternative treatment option alongside Ate/Bev therapy in patients with unilobar intrahepatic HCC. This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims High fructose consumption leads to increased hepatic lipogenesis resulting in hepatic steatosis and the development of nonalcoholic fatty liver disease (NALFD). Naringin, a flavanone glycoside found in citrus fruit, has been reported to have antioxidant, anti-inflammatory and hypolipidemic properties. The aim of this study was to determine the effect and underlying mechanism of naringin treatment on hepatic steatosis in fructose-fed rats. Methods Male Sprague-Dawley rats were given 10% (w/v) fructose in drinking water for 12 weeks. Naringin (100 mg/kg/day)was administered orally to rats for the last 4 weeks of fructose overload. After 12 weeks, the contents of total cholesterol (TC) and triglyceride (TG) in liver homogenates were evaluated. Hepatic steatosis was evaluated using histological staining with hematoxylin and eosin (H&E) and Oil Red O staining. Hepatic expressions of lipogenesis-related proteins were detected by Western blotting. Results Results indicated that treatment of fructose-fed rats with naringin decreased TC and TG contents in liver. Naringin treatment also reduced high fructose-induced hepatic lipid accumulation, as indicated by H&E and Oil Red O staining. In addition naringin decreased the expression of lipogenesis-related proteins, including sterol regulatory element- binding protein 1c and fatty acid synthase in liver of fructose-fed rats. Conclusions The present study suggests that naringin treatment reduces high fructose- induced hepatic steatosis in rats by suppressing hepatic lipogenesis. [ABSTRACT FROM AUTHOR]

Background/Aims We aimed to validate the updated version of Korean stroop test for MHE screening. Methods Liver cirrhosis (LC) patients without history of overt HE were recruited prospectively from 13 centers. All participants completed Korean paper-pencil test (KPPT) and the Korean stroop test. Korean stroop test consisted of two stroop-off states (color and word) and two stroop-on states (inhibition and switching). Four types of "on time+off time"s were analyzed (color-plus-inhibition, color-plus-switching, word-plus-inhibition, and word-plus-switching). MHE was diagnosed when KPPT scores ≥2. Results A total of 119 LC patients and 792 healthy controls were enrolled. The most common etiology of LC was alcohol (62.8%). Mean Model for End Stage Liver Disease (MELD) score of LC patients was 11. Prevalence of MHE was 39.5% by KPPT. Four types of "on time+off time" significantly differed among healthy controls, cirrhosis patients without MHE, and cirrhosis patients with MHE. All types of "on time+off time" showed positive correlation with PHES scores (all p<0.01). The highest area under the curve (AUC) among "on time+off time"s, was for word-plus-inhibition (AUC, 0.699; 95% confidence interval, 0.603 to 0.795; p<0.001) in discrimination of MHE. Ln prothrombin time (international normalized ratio; odds ratio [OR), 197.33; p=0.008) and word-plus-inhibition (OR, 1.012; p=0.011) were significant in multivariate analysis for MHE diagnosis. The cutoff point for the highest Youden's index value was 155 seconds for word-plus-inhibition time with 78.8% of sensitivity and 60.6% of specificity. In the subgroup of patients with MELD score less than 11, on time+off time for word-plus-inhibition was the only prognostic factor in the diagnosis of MHE (OR, 1.008; p=0.037). Conclusions The Korean Stroop Test is simple and valid for screening of MHE. [ABSTRACT FROM AUTHOR]

Background/Aims In Mongolia, 95% of the patients with liver cancer have chronic viral hepatitis and its 53% of patients infected with hepatitis B, 38.9% infected with hepatitis C and 5.6% infected with hepatitis B, C viruses. This survey was conducted among a population of the Dornod province with an aim to evaluate knowledge of population on hepatitis B, C virus infections and to define their attitudes, behaviors and practices. Our aim to assess the knowledge, attitude and behaviors of the population of Dornod province on hepatitis B virus (HBV), hepatitis C virus (HCV) infections. Methods The survey recruited 600 people, which are randomly selected from 50,864 populations of the Dornod province, aged 15 to 64 years. The survey was carried out by analytical descriptive study design. Results In total 600 people were randomly selected for the survey in order to evaluate knowledge, attitude and behaviors of the population of Dornod province on HBV, HCV infections. In the total participants aged 15 to 64 years, 49.7% (298) were male and 50.3% (302) were women. Most of the participants (77.2%) have "meanly level" of knowledge and only 1.8% of the participants evaluated as they have "good" knowledge on HBV, HCV infections. We conclude that study population have relatively positive attitudes towards the HBV, HCV infections, such as 76.39% of the population worry on HBV, HCV infections and 92.1% of them prefer diagnostic tests for HBV, HCV and 27.8% of them involved for voluntary vaccinations and 55.0% of them examined for diagnostic tests. Young people are more likely to share of a razor blade or nail clipper with another people and damaging of skin by tattoo or piercing. Conclusions Knowledge level of the population of Dornod province on HBV, HCV infections is "average." There was only 1.8% of the population has good knowledge among the population of Dornod province. [ABSTRACT FROM AUTHOR]

Background/Aims There are many attempts to predict portal pressure and esophageal varices by noninvasive method. The spleen stiffness (SS) and liver stiffness are expected to be useful in noninvasive diagnosis. We evaluate the performance of SS measured by two-dimensional shear wave elastography (2D-SWE) for predicting portal hypertension and esophageal varices. Methods From January 2017 to August 2019, 130 patients who measured SS and hepatic venous wedge pressure (HVPG) and esophagogastroduodenoscopy simultaneously were enrolled. Thirty-four patients who showed invalid measurement (n=31) and combined hematologic malignancy (n=3) and concurrent hepatocellular carcinoma (n=2) were excluded. SS was measured by three examiner using 2D-SWE (LOGIQ E9, GE healthcare) from three tertiary medical center. Results Ninety-four patients were eligible for analysis. Most common etiology was alcoholic hepatitis (n=63, 67.0%) and followed by chronic hepatitis B (n=17, 18.1%). Patients were consisted of Child-Pugh class A (n=33), B (n=46), C (n=15). The mean value of HVPG was 14.6±5.1 mmHg and 83.0% and 58.5% of patients has esophageal varices and high-risk varices. The HVPG and SS did not showed significant correlation (r=0.197, p=0.057). The presence of varices appeared significant positive correlation with SS (r=0.212, p=0.043). High-risk varices showed stronger correlation with SS (r=0.324, p=0.002). The area under receiver operating characteristics showed 0.698 (confidence interval, 0.592 to 0.804; p=0.001) Conclusions Whether SS is associated with HVPG is unclear, SS could be useful for evaluating high-risk varices. Further studies are needed to clarify the clinical implication. [ABSTRACT FROM AUTHOR]

Background/Aims Chronic hepatitis B (CHB) infection burden in Taiwan is high. Treatments goals are to suppress viral replication and achieve early normalization of alanine aminotransferase levels to decrease the liver damage risk and liver-related complications (i.e., hepatocellular carcinoma [HCC]). Notably, certain CHB treatments and increasing CHB patients' age can increase risk of bone and renal adverse events. In this study, we simulated 10-year liver and safety outcomes for 100,000 non-cirrhotic Taiwanese CHB patients comparing tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) and entecavir (ETV) treatments. Methods A health outcomes model was developed using an individual patient simulation framework tracking treatment impact on liver complications, chronic kidney disease and major osteoporotic facture. The model assumed 90% of all patients were treatment- experienced, of which 10% had lamivudine experience. Patient demographics and other inputs were drawn from published randomized controlled trials, peer-reviewed Taiwanese literature, and Taiwanese hepatologists. The treatments considered were TAF, TDF and ETV. Patients received treatment in accordance with the latest Taiwanese National Health plan reimbursement criteria. Results Over a 10-year horizon, TAF-treated patients had fewer hepatic (i.e., compensated cirrhosis-CC, decompensated cirrhosis-DCC, and HCC) events as compared to TDF and ETV (Table 1). In addition, TAF-treated patients had lower or similar rates of bone- and renal-related safety events as compared to TDF and ETV (Table 1). Conclusions Utilizing clinical data from various first-line NA treatments, this model projects TAF-treated patients to have better liver outcomes and lower adverse events rates over a 10-year time horizon compared to TDF and ETV, driven by its improved efficacy and safety profile. As Taiwanese CHB patients are aging with increasing comorbidities, careful selection of treatment is warranted. Notably, a limitation of this analysis is that CC and HCC event risks are based on untreated population data given limited treated patient data to date. [ABSTRACT FROM AUTHOR]