Weight Gain and Increased Body Mass Index in Patients with Hepatitis C after Eradication Using Direct-Acting Antiviral Therapy in Taiwan.

Few studies have reported weight gain in patients with hepatitis C virus (HCV) infection treated with direct-acting antiviral agents (DAAs). This retrospective cohort study identified factors associated with substantial weight gain after DAA treatment in Taiwan. This study involved patients treated using DAAs at the Chiayi and Yunlin branches of Chang Gung Memorial Hospital from 1 January 2017 to 31 October 2020. Body weight data were collected at the start of DAA therapy and 2 years after the confirmation of a sustained virologic response. We performed multiple logistic regression to evaluate the clinical and laboratory parameters associated with a large body mass index (BMI) increase (≥5%). The mean BMI was 25.56 ± 4.07 kg/m2 at baseline and 25.77 ± 4.29 kg/m2 at the endpoint (p = 0.005). A considerable reduction in fibrosis-4 (FIB-4) score was a significant predictor of a large BMI increase (OR: 1.168; 95% CI: 1.047-1.304, p = 0.006). By contrast, older age (OR: 0.979; 95% CI: 0.963-0.996, p = 0.013) and a higher baseline BMI (OR: 0.907; 95% CI: 0.863-0.954, p < 0.001) were associated with a reduced risk of a large increase in BMI at the endpoint. In summary, a larger BMI increase was closely associated with a younger age, lower baseline BMI, and higher FIB-4 score reduction. Notably, differences in DAA regimens did not affect outcomes. Future studies are needed to elucidate the long-term effects and metabolic outcomes associated with this body weight change and investigate the exact underlying mechanisms.

Factors Associated with Large Renal Function Decline in Patients with Chronic Hepatitis C Successfully Treated with Direct-Acting Antiviral Therapy.

The findings regarding changes in renal function in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs) are controversial. This study attempted to identify the factors associated with the large decline in renal function following DAA treatment. This retrospective cohort study included patients treated with DAAs at Chiayi and Yunlin Chang Gung Hospitals, Taiwan, from 1 January 2017 to 31 October 2020. Estimated glomerular filtration rate (eGFR) data were collected within 90 days prior to DAA therapy and 2 years after the confirmation of a sustained virologic response (SVR). We performed multiple logistic regression to evaluate the clinical or laboratory parameters associated with a large eGFR decline (≥10%). Among the enrolled 606 patients, the mean eGFR at the baseline and endpoint were 84.11 ± 24.38 and 78.88 ± 26.30 mL/min/1.73 m2, respectively (p < 0.001). The factors associated with a large eGFR decline 2 years after the SVR included hypertension (OR: 1.481; 95% CI: 1.010-2.173, p = 0.044) and a higher baseline eGFR (OR: 1.016; 95% CI: 1.007-1.024, p < 0.001). A higher albumin level reduced the risk of a large eGFR decline (OR: 0.546; 95% CI: 0.342-0.872, p = 0.011). In the patients with HCV treated with DAAs, a larger renal function decline was more commonly observed in those with hypertension, a lower (but within normal range) albumin level, and a higher baseline eGFR, while DAA treatment had no effect. The clinical significance of these findings has to be further defined. Although some risk factors associated with chronic kidney disease may be alleviated after DAA treatment, the regular control and follow-up of risk factors and renal function are still recommended in at-risk patients after HCV eradication.

Direct-Acting Antivirals Reduce the De Novo Development of Esophageal Varices in Patients with Hepatitis C Virus Related Liver Cirrhosis.

The real-world benefits of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on the de novo occurrence and progression of esophageal varices (EV) remain unclear in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). This is a retrospective cohort study evaluating all patients with Child-Pugh class A HCV-related LC during 2013 to 2020 in the Chang Gung Medical System. A total of 215 patients fit the inclusion criteria and were enrolled. Of them, 132 (61.4%) patients achieved DAA induced-SVR and 83 (38.6%) did not receive anti-viral treatment. During a median follow-up of 18.4 (interquartile range, 10.1−30.9) months, the 2-year incidence of de novo EV occurrence was 8 (7.0%) in the SVR group and 7 (12.7%) in the treatment-naïve group. Compared to the treatment-naïve group, the SVR group was associated with a significantly lower incidence of EV occurrence (adjusted hazard ratio [aHR]: 0.47, p = 0.030) and a significantly lower incidence of EV progression (aHR: 0.55, p = 0.033). The risk of EV progression was strongly correlated with the presence of baseline EV (p < 0.001). To the best of our knowledge, this is the first study to demonstrate that DAA-induced SVR is associated with decreased risk of de novo EV occurrence and progression in the real world.

Sorafenib is an antagonist of the aryl hydrocarbon receptor.

Sorafenib is an orally administered inhibitor of several tyrosine protein kinases. Treatment with sorafenib induces autophagy, which may suppress the growth of hepatocellular carcinoma (HCC) and other cancers. Aryl hydrocarbon receptor (AhR) is activated by xenbiotics and is involved in detoxification, but also plays other physiological roles. The following results were obtained. ITE and ß-NF are endogenous and synthetic AhR ligands, respectively. One µM sorafenib can strongly suppress baseline as well as 0.5 µM ITE- and 1 µM ß-NF-induced transcriptional activity of the aryl hydrocarbon response element (AHRE) in both human and mouse cells. Cytochrome p450 (CYP) 1A1 is mainly transcribed by activated AhR. Sorafenib (2-15 µM) strongly and dose-dependently suppressed baseline as well as 2 µM ITE- and 10 µM ß-NF-induced CYP1A1 mRNA and protein expression. Ligand-activated AhR translocates from the cytoplasm to the nucleus. While sorafenib was found to suppress AhR activity, the drug alone was able to induce AhR translocation into the nucleus. Sorafenib's antagonistic action on AhR was comparable to that of the known AhR antagonist CH-223191 in human liver and ovarian cell lines. In summary, we demonstrate that sorafenib is a potent AhR antagonist and likely endocrine disruptor of the AhR. Moreover, sorafenib offers potential benefit for diseases treatable through AhR suppression strategies. Further investigation is warranted into sorafenib's AhR antagonistic behavior.

Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients.

BACKGROUND: An increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined. AIM: To identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer. METHODS: Coculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival. RESULTS: RNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori). CONCLUSION: F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.

Real-world efficacy and safety of pangenotypic direct-acting antivirals against hepatitis C virus infection in Taiwan.

Clinical trials showed pangenotypic direct-acting antivirals' (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.

Sofosbuvir/velpatasvir is an effective treatment for patients with hepatitis C and advanced fibrosis or cirrhosis in a real-world setting in Taiwan.

INTRODUCTION: Real-world data regarding the impact of hepatic fibrosis on the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) treatment is limited in the Asian population. METHODS: We analyzed data for all 823 patients with hepatitis C virus treated with SOF/VEL from June 2019 to September 2020 at Chang Gung Memorial Hospital in Chiayi, Taiwan. The degree of fibrosis was determined using the fibrosis-4 (FIB-4) index, with advanced fibrosis or cirrhosis defined as a FIB-4 score of > 3.25. The primary treatment outcome was the rate of sustained virologic response 12 weeks after treatment cessation (SVR). Adverse events (AEs) were also evaluated. RESULTS: SVR rates did not significantly differ (p > 0.05) between patients with FIB-4 scores of ≤ 3.25 and those with scores of > 3.25. In the per protocol analysis, 99.2% (593/598) of the FIB-4 ≤ 3.25 group and 100% (172/172) of the FIB-4 > 3.25 group achieved SVR; in the evaluable population analysis, 93.4% (593/635) of the FIB-4 ≤ 3.25 group and 91.5% (172/188) of the FIB-4 > 3.25 group achieved SVR. Five patients with FIB-4 scores of ≤ 3.25 did not attain SVR: two relapsed and three had no response. The most common AEs were comparable (p > 0.05) for the FIB-4 ≤ 3.25 group and the FIB-4 > 3.25 group and included abdominal discomfort (4.4% vs. 5.9%), fatigue (4.1% vs. 5.9%), and skin itching (3.6% vs. 3.2%). Laboratory abnormalities were more common in the FIB-4 > 3.25 group (p < 0.001). Six patients with FIB-4 scores of > 3.25 had total bilirubin elevation > 3 × the upper normal limit (UNL). Alanine transaminase elevation > 5 × the UNL was observed in two patients with FIB-4 scores of ≤ 3.25 and one patient with a FIB-4 score of > 3.25. No AEs resulted in treatment discontinuation. CONCLUSIONS: SOF/VEL treatment is well tolerated and achieves high SVR rates for patients of Taiwanese ethnicity with HCV, regardless of cirrhosis status.

Pangenotypic direct-acting antiviral agents for mixed genotype hepatitis C infection: A real-world effectiveness analysis.

BACKGROUND: Pangenotypic direct-acting antiviral agents (DAAs) glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL) are effective against all hepatitis C virus (HCV) genotype infections. However, data on pangenotypic DAA treatment for mixed genotype HCV infection are sparse. METHODS: This is a retrospective, single site cohort study analyzing all patients with mixed HCV genotype infections treated with GLE/PIB or SOF/VEL from August 2018 to August 2020 in Chiayi Chang Gung Memorial Hospital, Taiwan. The primary study endpoint was sustained virologic response (SVR) 12 weeks after treatment cessation. We also reported adverse events (AEs). RESULTS: A total of 108 patients with mixed infections of any two or three genotypes of 1a, 1b, 2, 3, and 6 received pangenotypic DAAs during the study period. A total of 67 patients received GLE/PIB and 41 received SOF/VEL. The evaluable population analysis revealed SVR rates of 94% (63/67) and 95.1% (39/41) for GLE/PIB and SOF/VEL therapy, respectively, and the per-protocol analysis revealed an SVR of 100% for both regimens. Four patients in the GLE/PIB group and two patients in the SOF/VEL were lost to follow-up. The most common AEs for GLE/PIB versus SOF/VEL therapy included pruritus (14.9% vs 2.4%), fatigue (6.0% vs 7.3%), abdominal discomfort (4.5% vs 7.3%), and acid reflux (3.0% vs 4.9%). DAA-related significant laboratory abnormalities occurred in three patients with > 1.5 × elevated bilirubin level in the GLE/PIB group. None of the above AEs resulted in DAA discontinuation. CONCLUSIONS: Pangenotypic DAAs are well tolerated by and yield high SVR rates in patients with mixed genotype HCV infection.

Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer.

PURPOSE: The purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer. METHODS: MBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19). RESULTS: As compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05). CONCLUSIONS: Constitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.

High viral load predicts virologic failure in chronic genotype 2 hepatitis C virus-infected patients receiving glecaprevir/pibrentasvir therapy.

BACKGROUND: The real-world data of glecaprevir/pibrentasvir (GLE/PIB) therapy for patients with chronic hepatitis C virus (HCV) genotype 2 infection remained limited. We aimed to evaluate the possible predictors of virological failure and side effects of GLE/PIB therapy for chronic genotype 2 HCV-infected patients in a real-world setting. METHODS: A total of 326 compensated HCV genotype 2 patients treated with GLE/PIB 12 weeks for cirrhotic patients (n = 56) and 8 weeks for non-cirrhotic patients (n = 270) were enrolled. RESULTS: The sustained virological response 12 weeks off therapy (SVR12) was 98.1%, 100%, and 97.7% in overall, GLE/PIB 12-week, and 8-week group, respectively. There were 6 (1.8%) patients with early withdrawal, and 14.1% patients had pruritus, the major adverse effect. In multivariate analyses, end-stage renal disease (odds ratio (OR) = 4.056, 95% confidence interval (CI) = 1.477-11.14, p = 0.007) and hypertension (OR = 2.325, 95% CI = 1.171-4.616, p = 0.016) were two significant factors associated with pruritus. There were 6 patients with virologic failure. In patients receiving 8-week GLE/PIB therapy, the SVR12 rate was significant lower in high baseline viral load (≥107 IU/ml) group compared to low viral load group (90.6% v.s 98.7%, p = 0.025). Multivariate analyses showed that HCV RNA≥107 IU/ml was one of the independent factors (OR = 0.134, 95% CI = 0.024-0.748; p = 0.022) associated with SVR12. CONCLUSION: GIE/PIB is an effective, tolerable and safe agent to treat genotype 2 HCV infected patients. However, high viral load (≥107 IU/ml) may predict virologic failure in non-cirrhotic patients receiving 8 weeks GIE/PIB treatment. This result should be further validated in a large cohort in the future.

2,4-Diamino-Quinazoline, a Wnt Signaling Inhibitor, Suppresses Gastric Cancer Progression and Metastasis.

Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/ß-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor- node-metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/ß-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.

Real-world effectiveness of glecaprevir/pibrentasvir and ledipasvir/sofosbuvir for mixed genotype hepatitis C infection: A multicenter pooled analysis in Taiwan.

Data on direct-acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real-world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty-four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per-protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE-related treatment discontinuation presented with liver decompensation after 4-week GLE/PIB therapy. DAA-related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.

Clinical utility of hepatitis C virus core antigen assay in the monitoring of direct-acting antivirals for chronic hepatitis C.

BACKGROUND: Hepatitis C virus core antigen (HCV Ag) assay has been proposed as a more economical alternative to HCV RNA detection. This study aimed to investigate the clinical utility of HCV Ag assay in the monitoring of direct-acting antivirals (DAAs) for chronic hepatitis C patients. METHODS: We analyzed serum samples from 110 patients treated with paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin. The levels for both HCV Ag and HCV RNA assessed by COBAS TaqMan HCV (CTM) Test or Abbott RealTime HCV (ART) assay were evaluated at baseline, week 2, 4, and 12 during treatment and 12 weeks after completion. RESULTS: Baseline HCV Ag levels showed good correlations with HCV viral load (r = 0.879; p<0.001); whereas the correlation was slightly stronger with CTM test than with ART assay (p = 0.074). The concordance of HCV Ag and HCV RNA undetectability was significantly better in CTM test than in ART assay at week 2 (p = 0.003) and week 4 (p = 0.003). A sustained viral response 12 weeks off therapy (SVR12) was achieved in 108 patients (98%); the HCV Ag assay identified 99% of these patients. Both undetectability of serum HCV Ag and HCV RNA had high positive predictive value at week 2 (98% vs. 100%) and at week 4 (97% vs. 99%) in predicting SVR12. CONCLUSIONS: HCV Ag assay may be a feasible alternative to HCV RNA for the determination of SVR12 in patients treated with DAAs.

Incidence, risk factors and impact on virological response of anemia in chronic genotype 2 hepatitis C receiving sofosbuvir plus ribavirin.

BACKGROUND/PURPOSE: The major dose-limiting toxicity of ribavirin is hemolytic anemia. We investigated the incidence, risk factors and impact on virological response of anemia in chronic hepatitis C genotype 2 patients receiving sofosbuvir plus ribavirin therapy. METHODS: This was a retrospective real-world analysis of a single center including 293 chronic hepatitis C genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks. Severe anemia was defined as hemoglobin concentration <10 g/dl. RESULTS: Treatment was completed in 285 (97%) of patients, of whom one withdrew due to severe anemia. Ribavirin dose reduction was required in 88 (30%) of patients. After excluding those with baseline hemoglobin <10 g/dl, 79 (29%) patients had developed severe anemia during therapy. Stepwise logistic regression analysis identified that chronic kidney disease (odds ratio [OR] = 3.970, p < 0.001), baseline hemoglobin level (OR = 0.475, p < 0.001) and baseline platelet count (OR = 0.992, p = 0.022) were independent factors. The sustained viral response 12 weeks off therapy (SVR12) rate was 93.9% in the per-protocol population. Multivariate analyses showed that history of hepatocellular carcinoma significantly reduced the efficacy of sofosbuvir plus ribavirin therapy (OR = 0.172, p = 0.001). Severe anemia, dose reduction or average dose (mg/kg/day) of ribavirin was not associated with SVR12. CONCLUSION: Severe anemia was not uncommon during sofosbuvir plus ribavirin therapy for chronic hepatitis C genotype 2 patients. Careful monitoring of anemia is necessary in patients with chronic kidney disease and low baseline hemoglobin level and platelet count.

Aminotransferase Ratio Is a Useful Index for Hepatosteatosis in Children and Adolescents: A Cross-Sectional Observational Study.

Nonalcoholic fatty liver disease (NAFLD) and childhood obesity are emerging global health issues. The aim of this study was to identify a simple predictor of NAFLD in children and adolescents. This community-based study was conducted from December 2012 to September 2013 in Taiwan and included 1,222 children between 10 and 19 years of age. After excluding alcohol consumption and hepatic-related lesions, NAFLD was diagnosed according to sonographic criteria. Potential confounding factors (including age, gender, and anthropometric and laboratory data) were tested by logistic regression analysis. The cutoff value was determined using receiver operating characteristic (ROC) curve analysis. In addition to older age, heavier weight, and wider waist, subjects with NAFLD had significantly higher blood pressure, lipid disturbances, and alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratios. The correlation between NAFLD and ALT/AST ratio remained significant even after adjusting for confounders (adjusted odds ratio [OR], 2.19; 95% confidence interval [CI], 1.24-3.87; p = .007). The risk score of having a fatty liver, based on ALT/AST ratio, was greater than 0.981 according to ROC curve analysis (sensitivity, 60.5%; specificity, 80.3%; area under the curve, 0.756; CI, 0.71-0.80; p < .001). Therefore, ALT/AST ratio may represent a powerful index of hepatosteatosis in children and adolescents.

Methylomics analysis identifies a putative STAT3 target, SPG20, as a noninvasive epigenetic biomarker for early detection of gastric cancer.

Gastric cancer is a leading cause of cancer worldwide. Our previous studies showed that aberrant activation of JAK/STAT3 signaling confer epigenetically silences STAT3 target genes in gastric cancer. To further investigate the clinical significance of this phenomenon, we performed Illumina 850K methylation microarray analysis in AGS gastric cancer cells, and cells depleted of STAT3. Integrative computational analysis identified SPG20 as a putative STAT3 epigenetic target, showing promoter hypomethylation in STAT3-depleted AGS cells. Bisulphite pyrosequencing and qRT-PCR confirmed that SPG20 is epigenetically silenced by promoter hypermethylation in a panel of gastric cancer cell lines including AGS cells, but not in immortalized gastric epithelial GES cells. Expression of SPG20 could be restored by the treatment with a DNMT inhibitor, further suggesting that SPG20 is epigenetically silenced by promoter methylation. Clinically, a progressive increase in SPG20 methylation was observed in tissues samples from gastritis (n = 34), to intestinal metaplasia (IM, n = 33), to gastric cancer (n = 53). Importantly, SPG20 methylation could be detected in cell-free DNA isolated from serum samples of gastritis, IM and gastric cancer patients, having a progressive similar to tissues. Taken together, SPG20, a potential STAT3 target, is frequently methylated in gastric cancer, representing a novel noninvasive biomarker for early detection of this deadly disease.

Prevalence and predictive value of high-positive rheumatoid factor and anti-citrullinated protein antibody levels in nonarthritic patients with chronic hepatitis C infection.

AIM: In order to increase diagnostic sensitivity for early disease in rheumatoid arthritis (RA), new classification criteria were approved in 2010 by the American College of Rheumatology and the European League Against Rheumatism. One of the criteria, a high-positive rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) level, was given a high score of 3. However, the increased prevalence of RF in patients with chronic hepatitis C virus (HCV) infection markedly diminishes the diagnostic specificity of serum RF for RA in these patients. There are no published data on the prevalence and predictive value of high-positive RF and ACPA; thus, we investigated high-positive RF and ACPA levels in nonarthritic patients with chronic HCV infection. METHOD: Anti-citrullinated protein antibody and total RF were determined in serum from nonarthritic patients with chronic HCV infection (all had HCV RNA viremia). RESULT: In 271 HCV-infected patients, positive RF, positive ACPA, high-positive RF, and high-positive ACPA were detectable in 47.2%, 1.1%, 8.9% and 1.1%, respectively. In these patients, fatty liver was an independent factor for high-positive RF. CONCLUSION: In contrast to RF, ACPA is not increased in HCV infection. High-positive RF is not unusually present in nonarthritic patients with chronic HCV infection. ACPA may have improved value for the diagnosis of RA in this patient population. In patients with HCV infection, fatty liver may be a risk factor for high-positive RF.

Antiviral therapy reduces risk of haemorrhagic stroke in patients with HCV infection: a nationwide cohort study.

BACKGROUND: The tendency for haemorrhagic stroke in patients with chronic HCV infection has emerged recently but the finding may be confounded by comorbidities. Proving the causality between HCV infection and haemorrhagic stroke is mandatory. Our study was designed to investigate the incidence of intracranial haemorrhage in HCV-infected patients with and without treatment. METHODS: In the 11-year and population-based retrospective study, we acquired data from the Taiwan National Health Insurance Research Database. The patients with major comorbidities were excluded and 97,198 HCV-infected patients were included for analysis. Treated and untreated cohorts were matched with propensity score to make the confounding factors in two groups comparable. Cox proportional hazard regression analysis was performed to evaluate the hazard ratio of haemorrhagic stroke in the cohorts. We applied survival analysis to compare the cumulative incidence of outcome events between the two cohorts. RESULTS: After matching, the incidence density (ID) of haemorrhagic stroke in the untreated cohort is significantly higher than in the treated cohort (ID: 1.0 versus 0.6 events per 1,000 person-years; P=0.0014). The adjusted hazard ratio (aHR) of haemorrhagic stroke is significantly reduced in the treated group (P<0.05). Cumulative incidence of haemorrhagic stroke is significantly lower in the treated group than in the untreated group (P=0.013). CONCLUSIONS: The study demonstrates that antiviral therapy significantly reduces the events of intracranial haemorrhage in HCV-infected patients and consolidates the novel concept that chronic HCV infection is a risk factor for haemorrhagic stroke.

Inhibition of CCAR1, a Coactivator of ß-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells.

The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/ß-catenin signaling, and which plays an important role in transcriptional regulation by ß-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target.

Endoscopic treatment of Bouverets syndrome in an extremely elderly patient with Holmium: YAG laser.

Bouveret's syndrome is a rare presentation of duodenal obstruction or gastric outlet obstruction caused by a large gallstone migrating through a cholecystoduodenal or choledochoduodenal fistula. Most patients are elderly and often have underlying comorbidities, complicating surgery. Endoscopic therapy should be used as first-line treatment for these patients who are not good surgical candidates. We report a case of a 98-year-old Chinese female who presented with vomiting for three days. Esophagogastroduodenoscopy and computed tomography confirmed the diagnosis of Bouveret's syndrome. The patient successfully underwent endoscopic lithotripsy with the Holmium: Yttrium- Aluminum-Garnet (Ho: YAG) laser. Ho: YAG laser lithotripsy has been used to treat Bouveret's syndrome in four case reports. It can be recommended in patients with Bouveret's syndrome who are poor candidates for surgery. SIMILAR CASES PUBLISHED: 4.