Systemic lupus erythematosus and autoimmune hepatitis overlap disease in a hospitalized systemic lupus erythematosus cohort.

Liver dysfunction in systemic lupus erythematosus (SLE) is caused by disease activity or secondary conditions like coexistent autoimmune liver diseases. In Taiwan, despite sporadically reported cases of SLE-autoimmune hepatitis (AIH) overlap disease, larger-scale monocentric investigations for such overlapping patients are not available. Retrospective analyses were performed in a hospitalized SLE cohort with 805 patients for identifying co-existent AIH from 2014 to 2023, focusing on distinct therapeutic modalities and differential diagnosis between SLE-AIH overlap and lupus hepatitis (LH). There were 5 cases (a 0.6% occurrence), all females aged 25-58 years (44 ± 13). Ages for the SLE diagnosis were 19-51 years (30 ± 13), while ages for the AIH diagnosis were 22-57 years (36 ± 14). Contradictory to interface hepatitis in SLE-AIH overlap, liver biopsy only demonstrated non-specific abnormalities in LH. Liver cirrhosis was identified in SLE-AIH overlap but not in LH. After corticosteroids/azathioprine therapy, there were normalized liver function in all LH. In 2 SLE-AIH overlap cases refractory to such therapy, one received B-cell depletion therapy (annual rituximab infusion, 375 mg/m2 weekly × 4) and another accepted living-donor liver transplantation from sibling due to advanced liver cirrhosis, leading to improved hepatic dysfunction in both.

Hepatic arterial infusion chemotherapy and immune checkpoint inhibitors, alone or in combination, in advanced hepatocellular carcinoma with macrovascular invasion: a single-centre experience in Taiwan.

Background: The presence of vascular invasion is associated with poor survival in advanced hepatocellular carcinoma (HCC). We compared the effectiveness of hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs), alone or in combination, in patients with advanced HCC. Methods: We retrospectively reviewed medical records of adult patients with unresectable HCC and macrovascular invasion (MVI) who were treated with HAIC or ICIs alone or in combination at a single centre in Taiwan. Overall tumour response, vascular thrombi response, overall survival (OS) and progression-free survival (PFS) in 130 patients were analysed. Results: The treatment group showed no significant effect on the overall tumour response [objective response rate (ORR), 22.86% for HAIC, 26.09% for ICI, 50.00% for HAIC+ICI; P=0.111], but showed a significant effect on vessel response (objective response rate of tumour thrombi (ORRT), 38.57% for HAIC, 45.65% for ICI, 78.57% for HAIC+ICI; P=0.023). Post-hoc comparisons followed by Bonferroni correction revealed that vessel ORRT was significantly different between the HAIC+ICI and HAIC groups (P=0.014). A significant effect of treatment group on portal vein tumour thrombus (PVTT) was also detected (ORRT, 40.00% for HAIC, 50.00% for ICI, 90.00% for HAIC; P=0.013), with significant difference between the HAIC+ICI and HAIC groups (P=0.005). Patients treated with HAIC, ICI, and HAIC+ICI respectively had 12-month OS rates of 44.9%, 31.4%, and 67.5% (P=0.127) and 12-month PFS rates of 21.2%, 24.6%, and 33.2% (P=0.091). In multivariate analysis of PFS, HAIC+ICI was associated with reduced risk of progression or death compared with HAIC alone (adjusted hazard ratio: 0.46; 95% confidence interval: 0.23-0.94; P=0.032). Conclusions: HAIC combined with ICIs had a superior response of PVTT compared to HAIC alone, and was associated with reduced risk of progression or death. Future studies are needed to address the survival benefit of the combination therapy in advanced HCC with MVI.

Real-World Effectiveness of Sorafenib versus Lenvatinib Combined with PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICIs) combined with multitarget tyrosine kinase inhibitors (MTKIs) exert a synergistic effect and are effective in unresectable hepatocellular carcinoma (uHCC). However, precise data regarding the real-world clinical applications of these combination therapies in uHCC are lacking. This study compared the treatment efficacy of sorafenib versus lenvatinib in combination with programmed cell death protein-1 (PD-1) inhibitors in patients with uHCC in a clinical setting. Among 208 patients with uHCC treated with PD-1 inhibitors, 88 were administered with ICIs in combination with sorafenib or lenvatinib. The treatment response and survival outcomes were evaluated. Predictors of survival were assessed by multivariate analysis. A total of 49 patients were treated with PD-1 inhibitors combined with sorafenib, and 39 patients were treated with PD-1 inhibitors combined with lenvatinib. The lenvatinib group exhibited a stronger objective response rate (ORR) (20.51% vs. 16.33%) and had a higher disease control rate (41.03% vs. 28.57%) than did the sorafenib group. The median overall survival was longer in the lenvatinib group than the sorafenib group (13.1 vs. 7.8 months; hazard ratio = 0.39, p = 0.017). The incidence of treatment-related adverse events was similar. PD-1 inhibitors combined with lenvatinib can be a feasible treatment strategy for HCC patients receiving MTKI-based combination therapy. PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Additional larger-scale and prospective studies should be conducted to verify the study results.

Real-World Comparative Effectiveness of Nivolumab versus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma.

PURPOSE: Immune checkpoint inhibitors are effective therapies for advanced hepatocellular carcinoma (HCC); however, comparisons of the clinical efficacy and safety profile for these drugs are still scarce. Thus, the aims of this study were to investigate the differences in efficacy and safety between nivolumab and pembrolizumab in unresectable HCC patients in a real-world setting. PATIENTS AND METHODS: A total of 115 patients who received treatment with nivolumab (n = 73) or pembrolizumab (n = 42) in combination with or without tyrosine kinase inhibitors was enrolled. Therapeutic response, survival outcomes, and safety profiles were compared among these groups. Multivariate analysis of survival response was performed using Cox proportional hazards regression. RESULTS: Patients treated with pembrolizumab demonstrated a significantly higher objective response rate than those with nivolumab (38.1% vs. 15.1%; odds ratio 4.18, p = 0.005) regardless of the combination strategies. In addition, pembrolizumab performed a better overall survival (OS) than nivolumab, (34.9 vs. 9.5 months; hazard ratio (HR) = 0.39, p = 0.004). In subgroup analysis, pembrolizumab exhibited favorable OS than nivolumab for monotherapy (HR = 0.16, p = 0.001) or combination therapy (HR = 0.33, p = 0.006) as second-line or later-line (HR = 0.19, p = 0.001) therapy and those with (HR = 0.31, p = 0.006) or without (HR = 0.15, p = 0.004) well-compensated liver disease. The incidence of adverse events was comparable for both treatments. CONCLUSION: Both pembrolizumab and nivolumab had significant effects for HCC therapy, and pembrolizumab had a significant survival benefit as compared with nivolumab.

Clinical Implications of Serum Hepatitis B Virus Pregenomic RNA Kinetics in Chronic Hepatitis B Patients Receiving Antiviral Treatment and Those Achieving HBsAg Loss.

Serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) is correlated with covalently closed circular DNA. We aimed to investigate the utility of serum HBV pgRNA in chronic hepatitis B patients receiving nucleos(t)ide analogue treatment and those achieving HBsAg loss. One hundred and eighty-five patients were enrolled for studying long-term HBV pgRNA kinetics during treatment. Twenty patients achieving HBsAg loss after treatment were enrolled for examining HBV pgRNA kinetics around HBsAg loss. HBV pgRNA significantly decreased in the high baseline HBV pgRNA (≥6 log copies/mL) group but significantly increased in the low baseline HBV pgRNA (<4 log copies/mL) group after 3-month entecavir treatment. Among the 20 patients achieving HBsAg loss, 13 (65%) patients had serum HBV pgRNA higher than the limit of detection (LOD, 1466 copies/mL) when they achieved HBsAg loss. Finally, all 20 patients had HBV pgRNA going below the LOD within 3 years after achieving HBsAg loss. In conclusion, baseline serum HBV pgRNA alone is insufficient for predicting the trajectory of HBV pgRNA. Most patients still had HBV pgRNA higher than the LOD when they achieved HBsAg loss. Further studies on HBV pgRNA kinetics around HBsAg loss would provide an enhanced basis for further applications of HBV pgRNA.

Real-world outcome of immune checkpoint inhibitors for advanced hepatocellular carcinoma with macrovascular tumor thrombosis.

Programmed cell death protein-1 (PD-1) inhibitors have shown promising results for treating advanced hepatocellular carcinoma (HCC). However, the clinical utility of such inhibitors in HCC patients with vascular tumor thrombosis remains unclear. This study investigated PD-1 inhibitor efficacy in advanced HCC with macrovascular invasion in a clinical setting. Among the 110 patients with unresectable HCC treated with PD-1 inhibitors, 34 patients with vascular metastases in the portal vein and inferior vena cava were retrospectively compared with 34 patients without tumor thrombi. The vascular response and its effect on survival were assessed. Predictors of survival were identified using multivariate analysis. Among patients achieving objective response, those with and without thrombi exhibited similar response to immunotherapy and comparable survival. Among the 34 patients with tumor thrombi, including 13 receiving PD-1 inhibitors alone and 21 receiving it in combination with tyrosine kinase inhibitors, the median overall survival was 8.9 months (95% confidence interval 3.2-12.6). The objective response rate of vascular metastasis was 52.9%, and vascular responders had a significantly longer survival than did non-responders (11.1 vs 3.9 months). Failure to obtain a vascular response correlated significantly with increased post-treatment Child-Pugh score or class. Multivariate analysis showed that vascular response was a significant positive factor for longer overall survival. Treatment-related grade 3/4 adverse events occurred in 3 (8.8%) of the patients with tumor thrombi. Immunotherapy with PD-1 inhibitors may be a feasible treatment option for HCC with tumor thrombi owing to the high response rate of tumor thrombi and favorable survival outcomes.

Effectiveness and safety of ledipasvir/sofosbuvir for genotype 2 chronic hepatitis C infection: Real-world experience from Taiwan.

BACKGROUND/PURPOSE: Genotype 2 (GT2) hepatitis C virus infection is the second common genotype in Taiwan. Real-world experience of ledipasvir/sofosbuvir (LDV/SOF) for GT2 infection is limited. The aim of this study is to evaluate the effectiveness and safety of LDV/SOF in patients with GT2 chronic hepatitis C (CHC) infection. METHODS: CHC patients with GT2 infection receiving 12 weeks LDV/SOF from three hospitals were enrolled. HCV RNA was checked at baseline, end-of-treatment and 12 weeks after completing treatment. Demographic data, adverse events, renal function and metabolic profiles were recorded. RESULTS: Among 392 enrolled patients, 33 patients (8.4%) were cirrhotic. Sustained virological response (SVR) rate was 96.7% (379/392) by intention-to-treat analysis and 97.2% (379/390) by per-protocol analysis. The SVR rate was lower in cirrhotic patients than in non-cirrhotic patients (90.6% vs 97.8%, p = 0.053). Two cirrhotic patients who took LDV/SOF plus ribavirin both achieved SVR. Neither drug-related severe adverse events nor discontinuation due to drug-related adverse event were reported. The estimated glomerular filtration rate (eGFR) remained stable in patients with chronic kidney disease 3a/3b. CONCLUSION: Twelve weeks of LDV/SOF treatment provided an excellent and safe regimen for GT2 CHC infection, particularly in non-cirrhotic patients.

Impact of Immune Checkpoint Inhibitors with or without a Combination of Tyrosine Kinase Inhibitors on Organ-Specific Efficacy and Macrovascular Invasion in Advanced Hepatocellular Carcinoma.

INTRODUCTION: The tumor microenvironments of different organs often differ and thus may affect the immunotherapy response. OBJECTIVE: This study elucidated that the efficacy of programmed cell death protein-1 (PD-1) inhibitors varies across different metastatic sites among individuals with advanced hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed treatment outcomes in advanced HCC patients receiving PD-1 inhibitors with or without a combination of tyrosine kinase inhibitors (TKIs). Both the overall response rate (ORR) and organ-specific response rate (OSRR) were assessed using Response Evaluation Criteria in Solid Tumors 1.1 criteria. A survival analysis and its predictors were determined using a multivariate analysis. RESULTS: We analyzed 42 advanced HCC patients (median age: 58.0 years; 78.6% males). Thirty (71.4%) patients were sorafenib-experienced and 27 (64.3%) were administered a combination of TKIs. The ORR was 14.3% and the disease control rate was 33.3%. The median overall survival (OS) and progression-free survival (PFS) were 12.0 and 2.9 months, respectively. The OSRRs were 14.7, 23.8, 28.6, and 50.0% for the liver, lungs, lymph nodes, and vascular response, respectively. The multivariate analysis indicated that the vascular response was significantly associated with PFS. ECOG performance status was a significant independent predictor of OS. CONCLUSIONS: PD-1 inhibitors improved OS and PFS in advanced HCC patients. Their efficacies varied among the metastatic locations regardless of the combination of TKIs; in particular, a higher response in vascular metastases was correlated with a longer PFS. PD-1 inhibitors may deliver a synergistic benefit in patients undergoing traditional therapy and progression in other organs in vascular responders.

Genotyping of immune-related loci associated with delayed HBeAg seroconversion in immune-active chronic hepatitis B patients.

The progression of chronic hepatitis B (CHB) is associated with single-nucleotide polymorphisms (SNPs). In this study, we demonstrated the association between immune-related SNPs and delayed spontaneous HBeAg seroconversion in immune-active CHB patients. In addition, we investigated the impact of delayed spontaneous HBeAg seroconversion-related SNPs on HBeAg seroconversion within 3 years during antiviral treatment. We enrolled 332 CHB patients and genotyped 124 SNPs associated with HBV-infected clinical outcomes, including 32 interleukin-related genes, 62 HLA genes, 9 CD marker genes, 7 NK cell receptor genes, and 14 other genes, using ABI OpenArray as a platform. Comparing the immune-active CHB patients with delayed spontaneous HBeAg seroconversion (persistent HBeAg seropositivity, older than 40 years) to those with early inefficient HBeAg seroconversion (HBeAg seroconversion with high viremia, younger than 40 years), logistic analysis revealed that rs3820998 (TANK), rs2621377 (HLA-DOB), rs3130215 (HLA-DPB2), rs2255336 (KLRK1), and rs11614913 (MIR-196A2) were significantly associated with delayed spontaneous HBeAg seroconversion. Using multivariate analysis, we determined that high serum HBV DNA levels (OR = 1.66, 95% CI = 1.33-2.08), rs3820998 (CA, OR = 3.37, 95% CI = 1.24-9.12), rs2621377 (TC, OR = 4.96, 95% CI = 1.85-13.3), rs2255336 (TT, OR = 0.09, 95% CI = 0.01-0.86), and rs11614913 (TT, OR = 2.53, 95% CI = 1.05-6.11) were five independent risk factors for delayed spontaneous HBeAg seroconversion. After patients received nucleos(t)ide analogue treatment, rs3820998 heterozygous CA variant conversely became the only independent favorable factor for treatment-induced HBeAg seroconversion within 3 years (OR = 0.21, 95% CI = 0.06-0.78). These results indicate that distinct immune-related SNPs play a vital role in regulating HBeAg status in immune-active CHB patients with or without antiviral treatment.

Insulin Resistance Associated Disorders Pivoting Long-Term Hepatitis B Surface Antigen Decline During Entecavir Therapy.

Insulin resistance associated disorders (IRAD), including prediabetes, type 2 diabetes mellitus (T2DM), and fatty liver are significant risk factors of liver-related death in chronic hepatitis B (CHB). However, their relationship remains unclear. We aimed to evaluate how IRAD influence the kinetics of serum hepatitis B surface antigen (HBsAg) in patients with CHB during long-term entecavir treatment. We enrolled 140 patients with CHB receiving at least 3 years of consecutive entecavir treatment in this retrospective study. A linear mixed effects model was adopted to examine the effects of variables and their interaction over time on the HBsAg trajectory. Furthermore, we acquired cytokine profiles and baseline fibrosis-4 index (FIB-4) scores for in-depth analysis. The median treatment time was 6.90 (4.47-9.01) years. Multivariate analysis revealed that older patients or those with prediabetes or T2DM had a significantly slower HBsAg decline over time (p = 0.0001 and p < 0.0001, respectively). Conversely, advanced fatty liver engendered a more rapid HBsAg decrease (p = 0.001). Patients with prediabetes or T2DM possessed higher IP-10 levels six years after entecavir therapy (p = 0.013). Compared to patients without prediabetes or T2DM, diabetic patients had more unfavorable features at the baseline, especially higher FIB-4 scores. Prediabetes or T2DM delays the clearance of HBsAg, but advanced hepatic fatty change counterbalances the effect. Additionally, IRAD could cause hepatic sequelae in CHB through immune-metabolic pathways.

Fully galactosyl-fucosyl-bisected IgG1 reduces anti-HBV efficacy and liver histological improvement.

N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG1 on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgG1N-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG1 on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG1 GlcNAc bisection were also addressed using mouse IgG1-producing hybridoma cells. We found that IgG1 bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG1-G2FN ≧ 1.5% was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG1-G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95% confidence interval = 0.466-0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95% confidence interval = 0.279-0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-ß1 treatment downregulated mannosyl ß-1,4-N-acetylglucosaminyltransferase 3 and ß-1,4-galactosyltransferase 1 activities and thereby IgG1-G2FN production, and this phenomenon reflected an inverse correlation between IgG1-G2FN and TGF-ß1 in sera of patients (r = -0.431, P < 0.001). In conclusion, IgG1-G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.

Applications of next-generation sequencing analysis for the detection of hepatocellular carcinoma-associated hepatitis B virus mutations.

BACKGROUND: Next-generation sequencing (NGS) is a powerful and high-throughput method for the detection of viral mutations. This article provides a brief overview about optimization of NGS analysis for hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) mutations, and hepatocarcinogenesis of relevant mutations. MAIN BODY: For the application of NGS analysis in the genome of HBV, four noteworthy steps were discovered in testing. First, a sample-specific reference sequence was the most effective mapping reference for NGS. Second, elongating the end of reference sequence improved mapping performance at the end of the genome. Third, resetting the origin of mapping reference sequence could probed deletion mutations and variants at a certain location with common mutations. Fourth, using a platform-specific cut-off value to distinguish authentic minority variants from technical artifacts was found to be highly effective. One hundred and sixty-seven HBV single nucleotide variants (SNVs) were found to be studied previously through a systematic literature review, and 12 SNVs were determined to be associated with HCC by meta-analysis. From comprehensive research using a HBV genome-wide NGS analysis, 60 NGS-defined HCC-associated SNVs with their pathogenic frequencies were identified, with 19 reported previously. All the 12 HCC-associated SNVs proved by meta-analysis were confirmed by NGS analysis, except for C1766T and T1768A which were mainly expressed in genotypes A and D, but including the subgroup analysis of A1762T. In the 41 novel NGS-defined HCC-associated SNVs, 31.7% (13/41) had cut-off values of SNV frequency lower than 20%. This showed that NGS could be used to detect HCC-associated SNVs with low SNV frequency. Most SNV II (the minor strains in the majority of non-HCC patients) had either low (< 20%) or high (> 80%) SNV frequencies in HCC patients, a characteristic U-shaped distribution pattern. The cut-off values of SNV frequency for HCC-associated SNVs represent their pathogenic frequencies. The pathogenic frequencies of HCC-associated SNV II also showed a U-shaped distribution. Hepatocarcinogenesis induced by HBV mutated proteins through cellular pathways was reviewed. CONCLUSION: NGS analysis is useful to discover novel HCC-associated HBV SNVs, especially those with low SNV frequency. The hepatocarcinogenetic mechanisms of novel HCC-associated HBV SNVs defined by NGS analysis deserve further investigation.

Clinical utility of hepatitis B surface antigen kinetics in treatment-naïve chronic hepatitis B patients during long-term entecavir therapy.

AIM: To investigate the utility of hepatitis B surface antigen (HBsAg) kinetics in chronic hepatitis B patients during long-term entecavir treatment. METHODS: This retrospective study included treatment-naïve chronic hepatitis B patients who received at least 2 years of consecutive entecavir treatment. Patients were followed up at three to six month intervals with liver biochemistry, hepatitis B virus DNA, and abdominal sonography. In hepatitis B e antigen (HBeAg)-positive patients, HBeAg levels were assessed every three to six month until results became negative. Serum HBsAg levels were determined at the baseline, one-year and five-year time points. Liver cirrhosis was diagnosed through liver biopsy, imaging examinations, or clinical findings of portal hypertension. Hepatocellular carcinoma was diagnosed by histological examination or dynamic image studies. RESULTS: A total of 211 patients were enrolled. The median treatment time was 5.24 (2.00-9.62) years. Multivariate analysis showed that lower baseline HBsAg levels were associated with an earlier virological response, earlier hepatitis B e antigen (HBeAg) seroconversion, and earlier biochemical response in HBeAg-positive patients (cut-off value: 4 log IU/mL) and an earlier virological response in HBeAg-negative non-cirrhotic patients (cut-off value: 2.4 log IU/mL). Although HBsAg levels decreased slowly during long-term entecavir treatment, higher HBsAg decrease rates were found in the first year for HBeAg-positive non-cirrhotic patients, and patients with higher baseline HBsAg levels. More favorable clinical outcomes were not observed by a rapid HBsAg decline per se, but depended on lower baseline HBsAg levels. CONCLUSION: Baseline HBsAg can be used to predict treatment responses. HBsAg levels and decrease rates should be considered together according to disease status while interpreting HBsAg changes.

Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus.

This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Favorable Response to Long-term Nucleos(t)ide Analogue Therapy in HBeAg-positive Patients with High Serum Fucosyl-Agalactosyl IgG.

Aberrant IgG glycosylation is a feature of hepatitis B virus (HBV) infection but its effect on a long-term efficacy of antiviral therapy has never been addressed. After a screening of 1,085 patients, 132 eligible HBV e antigen (HBeAg)-positive and 101 HBeAg-negative patients with anti-HBV nucleos(t)ide analogue monotherapy were enrolled with on-treatment follow-ups for at least one year. IgG1 N-glycome was profiled using mass spectrometry and evaluated for its relevance in treatment responses. The results indicated that a high level of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) at baseline was associated with the severity of liver inflammation and damage but advanced treatment responses, including HBV DNA loss, HBeAg seroconversion, a reduced drug resistance rate, and a liver histological improvement at year 1, thereby improving the long-term treatment efficacy and the probability of treatment discontinuation in HBeAg-positive patients. Stepwise Cox regression analyses revealed that baseline IgG1-G0F >30% was an independent factor that links to virological response (HR 3.071, 95% CI 1.835-5.141, P < 0.001) or HBeAg seroconversion (HR 2.034, 95% CI 1.011-4.093, P = 0.046). Furthermore, a high IgG1-G0F level at the treatment endpoint was associated with an off-treatment sustained virological response. In conclusion, IgG1-G0F favors the medication outcome for HBeAg-positive chronic hepatitis B.

Stochastic resource allocation in emergency departments with a multi-objective simulation optimization algorithm.

The number of emergency cases or emergency room visits rapidly increases annually, thus leading to an imbalance in supply and demand and to the long-term overcrowding of hospital emergency departments (EDs). However, current solutions to increase medical resources and improve the handling of patient needs are either impractical or infeasible in the Taiwanese environment. Therefore, EDs must optimize resource allocation given limited medical resources to minimize the average length of stay of patients and medical resource waste costs. This study constructs a multi-objective mathematical model for medical resource allocation in EDs in accordance with emergency flow or procedure. The proposed mathematical model is complex and difficult to solve because its performance value is stochastic; furthermore, the model considers both objectives simultaneously. Thus, this study develops a multi-objective simulation optimization algorithm by integrating a non-dominated sorting genetic algorithm II (NSGA II) with multi-objective computing budget allocation (MOCBA) to address the challenges of multi-objective medical resource allocation. NSGA II is used to investigate plausible solutions for medical resource allocation, and MOCBA identifies effective sets of feasible Pareto (non-dominated) medical resource allocation solutions in addition to effectively allocating simulation or computation budgets. The discrete event simulation model of ED flow is inspired by a Taiwan hospital case and is constructed to estimate the expected performance values of each medical allocation solution as obtained through NSGA II. Finally, computational experiments are performed to verify the effectiveness and performance of the integrated NSGA II and MOCBA method, as well as to derive non-dominated medical resource allocation solutions from the algorithms.

Lipoprotein lipase liberates free fatty acids to inhibit HCV infection and prevent hepatic lipid accumulation.

Lipoprotein lipase (LPL) has been identified as an anti-hepatitis C virus (HCV) host factor, but the cellular mechanism remains elusive. Here, we investigated the cellular mechanism of LPL involving in anti-HCV. The functional activation of peroxisome proliferator-activated receptor (PPAR) α signal by LPL transducing into hepatocytes was investigated in HCV-infected cells, primary human hepatocytes, and in HCV-core transgenic mice. The result showed that the levels of transcriptional transactivity and nuclear translocation of PPARα in Huh7 cells and primary human hepatocytes were elevated by physiologically ranged LPL treatment of either very-low density lipoprotein or HCV particles. The LPL-induced hepatic PPARα activation was weakened by blocking the LPL enzymatic activity, and by preventing the cellular uptake of free unsaturated fatty acids with either albumin chelator or silencing of CD36 translocase. The knockdowns of PPARα and CD36 reversed the LPL-mediated suppression of HCV infection. Furthermore, treatment with LPL, like the direct activation of PPARα, not only reduced the levels of apolipoproteins B, E, and J, which are involved in assembly and release of HCV virions, but also alleviated hepatic lipid accumulation induced by core protein. HCV-core transgenic mice exhibited more hepatic miR-27b, which negatively regulates PPARα expression, than did the wild-type controls. The induction of LPL activity by fasting in the core transgenic mice activated PPARα downstream target genes that are involved in fatty acid ß-oxidation. Taken together, our study reveals dual beneficial outcomes of LPL in anti-HCV and anti-steatosis and shed light on the control of chronic hepatitis C in relation to LPL modulators.