The efficacy of multi-disciplinary lifestyle modifications in Taiwanese nonalcoholic steatohepatitis patients.

Lifestyle modification is the standard of care for nonalcoholic fatty liver disease (NAFLD) patients. We aimed to investigate the efficacy of a short-term lifestyle modification program in the disease course of Taiwanese nonalcoholic steatohepatitis (NASH) patients with paired biopsies. All patients received a 6-month, strict multidisciplinary program of lifestyle modifications led by physicians, dieticians, and nursing staff. The histopathological and clinical features were assessed. The endpoints were normalization of transaminase levels, metabolic parameters, a decrease in the NAFLD activity score (NAS) ≥1, and a decrease in the fibrosis stage ≥1. We also aimed to elucidate the predictors associated with disease progression. A total of 37 patients with biopsy-proven NASH were enrolled. The normalization of transaminase levels increased from 0% to 13.5%. There were also significantly increased proportions of patients with normal total cholesterol, triglyceride, and hemoglobin A1c levels. Fifteen (40.5%) patients had an increased NAS ≥1, whereas 10 (27.0%) patients had NAS regression. Twelve (32.4%) patients had increased fibrosis ≥1 stage. Only 2 (5.4%) patients experienced fibrosis regression. A high fasting plasma glucose (FPG) level was associated with NAS progression. Older age and higher transaminase and FPG levels were factors associated with fibrosis progression. Seven (18.9%) patients achieved a body weight reduction >3%, and 4 (57.1%) of them experienced NAS regression. No significant effect of weight reduction on the progression of fibrosis was observed. The short-term lifestyle modification program significantly decreased liver enzymes and metabolic parameters in NASH patients. A more precise or intensive program may be needed for fibrosis improvement.

Dose Consideration of Lenvatinib's Anti-Cancer Effect on Hepatocellular Carcinoma and the Potential Benefit of Combined Colchicine Therapy.

PURPOSE: The dose-dependent anti-cancer effect of lenvatinib on hepatocellular carcinoma (HCC) cells and the potential benefit of combined colchicine therapy were investigated. METHODS: Four primary cultured HCC (S103, S143, S160, S176) cell lines were investigated by differential expressions of genes (11 lenvatinib target genes and NANOG) and anti-proliferative effect using clinically achievable plasma lenvatinib (250, 350 ng/mL) and colchicine (4 ng/mL) concentrations. RESULTS: Colchicine showed an anti-proliferative effect on all cell lines. Lenvatinib at 250 ng/mL inhibited proliferation in all cell lines, but 350 ng/mL inhibited only three cell lines. For lenvatinib target genes, colchicine down-regulated more genes and up-regulated less genes than lenvatinib did in three cell lines. Lenvatinib up-regulated NANOG in all cell lines. Colchicine down-regulated NANOG in three cell lines but up-regulated NANOG with less magnitude than lenvatinib did in S103. Overall, combined colchicine and 250 ng/mL lenvatinib had the best anti-cancer effects in S143, with similar effects with combined colchicine and 350 ng/mL lenvatinib in S176 but less effects than combined colchicine and 350 ng/mL lenvatinib in S103 and S160. CONCLUSIONS: Lenvatinib does not show a dose-dependent anti-cancer effect on HCC. Combined colchicine and lenvatinib can promote the total anti-cancer effects on HCC.

Unawareness of hepatitis B infection and lack of surveillance are associated with severity of hepatocellular carcinoma.

Unawareness of hepatitis B virus (HBV) infection and lack of surveillance may serve as major barriers to HBV control and contributors to severe hepatocellular carcinoma (HCC) at presentation. This study evaluated the risk of HBV unawareness and its relationship with HCC severity. This retrospective study was conducted in a tertiary hospital in Taiwan. Patients with HBV-related HCC diagnosed from 2011 to 2021 were enrolled. The demographic, clinical, and HCC characteristics were collected and compared between patients with HBV unawareness and awareness with and without surveillance. Of 501 HBV-related HCC patients enrolled, 105 (21%) patients were unaware of HBV infection at the time of HCC diagnosis. Patients with HBV unawareness were significantly younger and had poorer liver function than those with HBV awareness. Patients with HBV unawareness also had a significantly higher rate of detectable HBV DNA and an advanced stage of HCC. Ninety-one (23%) of the HBV-aware patients did not receive regular surveillance. Patients with HBV unawareness and awareness without surveillance shared similar clinical characteristics with more severe HCC status. Further regression analysis demonstrated that HBV awareness with periodic surveillance was associated with early stage HCC. Meanwhile, we observed that there was no change in the proportion of HBV awareness over the past 10 years. Patients with surveillance also had better HCC survival than patients without surveillance or unawareness. HBV unawareness and lack of regular surveillance correlated with advanced HCC at presentation. Efforts to improve HBV education, disease awareness, and HCC surveillance are needed.

Community-centered Disease Severity Assessment of Metabolic Dysfunction-associated Fatty Liver Disease.

Background and Aims: Disease severity across the different diagnostic categories of metabolic dysfunction-associated fatty liver disease (MAFLD) remains elusive. This study assessed the fibrosis stages and features of MAFLD between different items. We also aimed to investigate the associations between advanced fibrosis and risk factors. Methods: This multicenter cross-sectional study enrolled adults participating in liver disease screening in the community. Patients were stratified following MAFLD diagnostic criteria, to group A (395 patients) for type 2 diabetes, group B (1,818 patients) for body mass index (BMI)>23 kg/m2, and group C (44 patients) for BMI≤23 kg/m2 with at least two metabolic factors. Advanced fibrosis was defined as a fibrosis-4 index>2.67. Results: Between 2009 and 2020, 1,948 MAFLD patients were recruited, including 478 with concomitant liver diseases. Advanced fibrosis was observed in 125 patients. A significantly larger proportion of patients in group C (25.0%) than in group A (7.6%) and group B (5.8%) had advanced fibrosis (p<0.01). Logistic regression analysis found that hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection (odds ratio [OR]: 12.14, 95% confidence interval [CI]: 4.04-36.52; p<0.01), HCV infection (OR: 7.87, 95% CI: 4.78-12.97; p<0.01), group C (OR: 6.00, 95% CI: 2.53-14.22; p<0.01), and TC/LDL-C (OR: 1.21, 95% CI: 1.06-1.38; p<0.01) were significant predictors of advanced fibrosis. Conclusions: A higher proportion of lean MAFLD patients with metabolic abnormalities had advanced fibrosis. HCV infection was significantly associated with advanced fibrosis.

Decision tree algorithm predicts hepatocellular carcinoma among chronic hepatitis C patients following viral eradication.

Successful eradication of the hepatitis C virus (HCV) cannot eliminate the risk of hepatocellular carcinoma (HCC). Next-generation RNA sequencing provides comprehensive genomic insights into the pathogenesis of HCC. Artificial intelligence has opened a new era in precision medicine. This study integrated clinical features and genetic biomarkers to establish a machine learning-based HCC model following viral eradication. A prospective cohort of 55 HCV patients with advanced fibrosis, who achieved a sustained virologic response after antiviral therapy, was enrolled. The primary outcome was the occurrence of HCC. The genomic signatures of peripheral blood mononuclear cells (PBMC) were determined by RNA sequencing at baseline and 24 weeks after end-of-treatment. Machine learning algorithms were implemented to extract the predictors of HCC. HCC occurred in 8 of the 55 patients, with an annual incidence of 2.7%. Pretreatment PBMC DEFA1B, HBG2, ADCY4, and posttreatment TAS1R3, ABCA3, and FOSL1 genes were significantly downregulated, while the pretreatment ANGPTL6 gene was significantly upregulated in the HCC group compared to that in the non-HCC group. A gene score derived from the result of the decision tree algorithm can identify HCC with an accuracy of 95.7%. Gene score = TAS1R3 (≥0.63 FPKM, yes/no = 0/1) + FOSL1 (≥0.27 FPKM, yes/no = 0/1) + ABCA3 (≥2.40 FPKM, yes/no = 0/1). Multivariate Cox regression analysis showed that this gene score was the most important predictor of HCC (hazard ratio = 2.38, 95% confidence interval [CI] = 1.06-5.36, P = 0.036). Combining the gene score and fibrosis-4 index, a nomogram was constructed to predict the probability of HCC with an area under the receiver operating characteristic curve up to 0.950 (95% CI = 0.888-1.000, P = 7.0 × 10-5). Decision curve analysis revealed that the nomogram had a net benefit in HCC detection. The calibration curve showed that the nomogram had optimal concordance between the predicted and actual HCC probabilities. In conclusion, down-regulated posttreatment PBMC TAS1R3, ABCA3, and FOSL1 expression were significantly correlated with HCC development after HCV eradication. Decision-tree-based algorithms can refine the assessment of HCC risk for personalized HCC surveillance.

Effects of Achieving SVR on Clinical Characteristics and Surgical Outcomes in Patients Who Developed Early-Stage HCV-Related Hepatocellular Carcinoma and Received Curative Resection: Preoperative versus Postoperative SVR.

The high accessibility to healthcare and increasing awareness of hepatocellular carcinoma (HCC) surveillance after sustained virologic response (SVR) to HCV treatment allow early detection of operable HCC in Taiwan. However, the effects of achieving SVR on patient characteristics and surgical outcomes after curative resection remain elusive. We aimed to compare the clinical presentation and postoperative prognosis among patients with early-stage HCV-related HCC and different viral status. We retrospectively analyzed 208 patients with BCLC stage 0 or A-HCC, including 44 patients who remained HCV viremic, 90 patients who developed HCC after achieving SVR (post-SVR HCC), and 74 patients who subsequently achieved SVR after resection. Patients with post-SVR HCC had a lower degree of hepatitis and better liver function than those who achieved SVR or remained viremic after resection. Notably, 75.6% of patients with post-SVR HCC did not have cirrhosis. Patients with post-SVR HCC and those achieving SVR after resection exhibited comparable recurrence rates and recurrence-free survival, while patients with persistent viremia had the worst surgical outcomes. We concluded that patients with post-SVR HCC had a better liver function but similar surgical outcomes compared with patients who achieved SVR after resection. The low prevalence of cirrhosis in patients with post-SVR HCC highlights the importance of regular surveillance after SVR.

Baseline Circulating miR-125b Levels Predict a High FIB-4 Index Score in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Treatment.

The regulatory role of microRNAs (miRNAs) in HBV-associated HCC pathogenesis has been reported previously. This study aimed to investigate the association between serum miR-125b and liver fibrosis progression in chronic hepatitis B (CHB) patients after nucleos(t)ide analog (NA) treatment. Baseline serum miR-125b levels and other relevant laboratory data were measured for 124 patients who underwent 12-month NA therapy. Post-12-month NA therapy, serum miR-125, platelet, AST, and ALT levels were measured again for post-treatment FIB-4 index calculation. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for a higher post-treatment FIB-4 index. Results showed that baseline miR-125b levels were inversely correlated with the post-treatment FIB-4 index (ρ = −0.2130, p = 0.0082). In logistic regression analyses, age (OR = 1.17, p < 0.0001), baseline platelet level (OR = 0.98, p = 0.0032), and ALT level (OR = 1.00, p = 0.0241) were independent predictors of FIB-index > 2.9 post-12-month treatment. The baseline miR-125b level was not significantly associated with a higher post-treatment FIB-4 index (p = 0.8992). In 59 patients receiving entecavir (ETV) monotherapy, the alternation of serum miR-125b in 12 months and age were substantially associated with a higher post-treatment FIB-4 index (>2.9), suggesting that miR-125b is a reliable biomarker for detecting early liver fibrosis under specific anti-HBV NA treatments (e.g., ETV).

Advantage of clinical colchicine concentration to promote sorafenib or regorafenib anti-cancer effects on hepatocellular carcinoma.

The advantage of colchicine to promote sorafenib or regorafenib anti-cancer effects on hepatocellular carcinoma (HCC) was investigated. Four primary cultured HCC cell lines (S103, S143, S160, S176) were studied by clinically achievable plasma sorafenib (5, 10 µg/mL), regorafenib (2, 4 µg/mL) and colchicine (4 ng/mL) concentrations. Sorafenib and regorafenib target genes and cancer stem cell markers (NANOG, POU5F1) were selected for experiments. Colchicine inhibited proliferation in all cell lines. Sorafenib inhibited proliferation only in S143 (5 µg/mL). Combined colchicine with sorafenib reversed the sorafenib effect on cellular proliferation from promotive to inhibitory in S103, and demonstrated anti-proliferative effects on other cell lines. Regorafenib inhibited proliferation in S103 (2 µg/mL), S176 (2 µg/mL) and S160 (4 µg/mL). Combined colchicine with regorafenib demonstrated equal or stronger anti-proliferative effects than regorafenib alone in all cell lines except S160. Combined colchicine obliterated or reduced the number of up-regulated target genes induced by sorafenib, and demonstrated equal or increased number of down-regulated target genes as compared with regorafenib alone. However, combined colchicine with regorafenib increased one up-regulated target gene in three cell lines. Colchicine obliterated or decreased the magnitude of up-regulated NANOG induced by sorafenib (S103, S143, S176) or regorafenib (S143), and combined with regorafenib could down-regulate NANOG (S160, S176). Adding colchicine to sorafenib or regorafenib showed inconsistent influence on POU5F1 expression as compared with sorafenib or regorafenib alone. The above results suggest that the anti-cancer effects of combined sorafenib with colchicine may be better than sorafenib alone. Colchicine may be added to regorafenib non-responders.

Amelioration of glucose intolerance through directly acting antiviral agents in chronic hepatitis C cirrhotic patients without overt diabetes.

Hepatitis C virus (HCV) eradication through antivirals ameliorates metabolic profiles. The changes in 2-h plasma glucose (2HPG) levels by oral glucose tolerance test (OGTT), in chronic hepatitis C (CHC) patients who receive directly acting antivirals (DAAs) was elusive. Five hundred and thirty-three CHC patients who achieved sustained virological response (SVR, undetectable HCV RNA throughout 3 months after the end-of-treatment) by DAAs were consecutively enrolled. Pre- and posttreatment 2HPG levels and glucose status were compared. The proportion of patients with improved, worsened, and stable 2HPG was 14.4% (n = 77), 18.6% (n = 99), and 67.0% (n = 357), respectively. Compared with patients with worsening 2HPG, those with improved 2HPG had a higher proportion of cirrhosis (45.5% vs. 24.2%, p = 0.004) and higher pretreatment 2HPG levels (175.3 vs. 129.5 mg/dl, p < 0.001). High baseline 2HPG was independently associated with improved 2HPG in multivariate analysis (odds ratio [OR]/CI: 1.05/1.03-1.06, p < 0.001). When baseline 2HPG was not taken into account, cirrhosis was the only factor independently associated with improved 2HPG status (OR/CI: 2.58/1.29-5.15, p = 0.007). Linear regression analysis revealed that factors independently correlated to changes in 2HPG levels were female sex (ß: 8.78; 95% CI:2.34, 15.22; p = 0.01), diabetes (ß: -27.72; 95% CI: -50.16, -5.28; p = 0.02), liver cirrhosis (ß: -8.91; 95% CI: -16.75, -2.20; p = 0.01), and genotype 1 of HCV (ß: -0.12; 95% CI: -15.19, -2.43; p = 0.01). 2HPG improved after HCV eradication by DAAs, particularly in cirrhotic patients.

Different profiles of neurocognitive impairment in patients with hepatitis B and C virus infections.

The direct impact of chronic hepatitis B and hepatitis C on neurocognition remains elusive due to the frequent comorbidities, and the domains of the neurocognitive functions affected have rarely been investigated comprehensively. We cross-sectionally assessed the neurocognitive functions of the individuals with chronic hepatitis B, chronic hepatitis C, treated chronic hepatitis C with a sustained virologic response, and their healthy control counterparts. Laboratory examinations were used to investigate the impact of inflammation on neurocognition, exclude the medical conditions that could interfere with neurocognition assessment, and assess liver function and fibrotic severity of the liver of the participants. This study found the detrimental impact of chronic hepatitis B on language and executive functions. In contrast, individuals with chronic hepatitis C showed deficits in executive functions, psychomotor speed, memory, and attention. Successful elimination of hepatitis C resulted in improved liver function, but not neuropsychological test performance. Moreover, erythrocyte sedimentation rate level was found to mediate the deficits in the attention of individuals with chronic hepatitis C. These results demonstrate the neurocognitive deficits and the difference in the profiles of neurocognitive deficits in individuals with chronic hepatitis B and chronic hepatitis C. Our study also provided results suggesting the mediation by systemic inflammation on the attention deficit in individuals with chronic hepatitis C.

Galectin-1 orchestrates an inflammatory tumor-stroma crosstalk in hepatoma by enhancing TNFR1 protein stability and signaling in carcinoma-associated fibroblasts.

Most cases of hepatocellular carcinoma (HCC) arise with the fibrotic microenvironment where hepatic stellate cells (HSCs) and carcinoma-associated fibroblasts (CAFs) are critical components in HCC progression. Therefore, CAF normalization could be a feasible therapy for HCC. Galectin-1 (Gal-1), a ß-galactoside-binding lectin, is critical for HSC activation and liver fibrosis. However, few studies has evaluated the pathological role of Gal-1 in HCC stroma and its role in hepatic CAF is unclear. Here we showed that Gal-1 mainly expressed in HCC stroma, but not cancer cells. High expression of Gal-1 is correlated with CAF markers and poor prognoses of HCC patients. In co-culture systems, targeting Gal-1 in CAFs or HSCs, using small hairpin (sh)RNAs or an therapeutic inhibitor (LLS30), downregulated plasminogen activator inhibitor-2 (PAI-2) production which suppressed cancer stem-like cell properties and invasion ability of HCC in a paracrine manner. The Gal-1-targeting effect was mediated by increased a disintegrin and metalloprotease 17 (ADAM17)-dependent TNF-receptor 1 (TNFR1) shedding/cleavage which inhibited the TNF-α → JNK → c-Jun/ATF2 signaling axis of pro-inflammatory gene transcription. Silencing Gal-1 in CAFs inhibited CAF-augmented HCC progression and reprogrammed the CAF-mediated inflammatory responses in a co-injection xenograft model. Taken together, the findings uncover a crucial role of Gal-1 in CAFs that orchestrates an inflammatory CSC niche supporting HCC progression and demonstrate that targeting Gal-1 could be a potential therapy for fibrosis-related HCC.

Low disease awareness as a contributing factor to the high prevalence of hepatitis C infection in Tzukuan, a hyperendemic area of southern Taiwan.

Understanding the barriers and tackling the hurdles of hepatitis C virus (HCV) care cascades is key to HCV elimination. The current study aimed to investigate the rates of disease awareness, link-to-care, and treatment uptake of HCV in a hyperendemic area in Taiwan. Tzukuan residents from 2000 to 2018 were invited to participate in the questionnaire-based interviews for HCV. The rates of disease awareness, accessibility, and anti-HCV therapy were evaluated in anti-HCV-seropositive participants. Among 10,348 residents, 1789 (17.3%) were anti-HCV seropositive. Of these 1789 anti-HCV-seropositive participants, data of 594 participants from questionnaire-based interviews in 2005-2018 were analyzed for HCV care cascades. Overall, 24.9% of anti-HCV-seropositive HCV participants had disease awareness, 53.9% of aware participants had accessibility, and 79.8% of assessed participants had received HCV treatment, with a community effectiveness of 10.7%. HCV prevalence decreased over time, from 21.2% in the early cohort to 9.3% in the recent cohort. Disease awareness increased over time, from 15.6% to 41.7%, with the community effectiveness increasing from 1.3% to 28.8%. Lower education levels and normal liver biochemistry were associated with a lower rate of disease awareness. Notably, 68% of participants with abnormal liver biochemistry and 69% of those with advanced fibrosis (FIB-4 > 3.25) were unaware of their HCV disease. We demonstrated huge gaps in disease awareness, link-to-care, and treatment uptake in the HCV care cascade in an HCV-hyperendemic area, even in the initial era of direct-acting antiviral agents. There is an urgent need to overcome these hurdles to achieve HCV elimination.

Circulating Let-7 Family Members as Non-Invasive Biomarkers for Predicting Hepatocellular Carcinoma Risk after Antiviral Treatment among Chronic Hepatitis C Patients.

HCC, a leading cause of cancer-related mortality, is diagnosed at advanced stages. Although antiviral therapy has reduced the risk of HCC among chronic hepatitis C (CHC) patients, the risk of HCC remains, thus, highlighting the unmet need for continuous surveillance. Therefore, stable and cost-effective biomarkers, such as circulating microRNAs, must be identified. We aimed to clarify whether serum levels of the Let-7 family can predict HCC risk in patients with CHC using univariate and multivariate Cox's proportional hazards model. We analyzed the sera of 54 patients with CHC who developed HCC after antiviral therapy and compared the data with those of 173 patients without HCC development. The Let-7 family (except for let-7c) exhibited significant negative correlations with the fibrosis score (r = −0.2736 to −0.34, p = 0.0002 to <0.0001). After Cox's regression model was used to adjust for age, sex, HCV genotype, and FIB-4 ≥ 3.25, patients with CHC with let-7i median ≥ −1.696 (adjusted hazard ratio [aHR] = 0.31, 95% CI: 0.08−0.94, p = 0.0372) in the sustained virologic response (SVR) groups and ≥−1.696 (aHR = 0.09, 95% CI: 0.08−0.94, p = 0.0022) in the non-SVR group were less likely to develop HCC. Thus, circulating let-7i can be used for early CHC surveillance in patients with HCC risk after antiviral treatment.

Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication.

BACKGROUND: Chronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development. AIM: To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy. METHODS: One hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment. RESULTS: HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively. CONCLUSION: Downregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.

Limited sorafenib anticancer effects on primary cultured hepatocellular carcinoma cells with high NANOG expression.

Cancer stem cell is considered as an important cause to exacerbate the prognosis. NANOG and POU5F1 are markers for cancer stem cells. The associations between NANOG and POU5F1 expressions with the sorafenib anticancer effects in primary cultured hepatocellular carcinoma (HCC) cells were investigated. Eight primary cultured HCC parent cell lines and 13 subgroups established by flow cytometric sorting using NANOG and POU5F1 as targets were investigated with clinically achievable sorafenib plasma concentrations (5 and 10 µg/mL). Sorafenib showed obvious downregulation of RAF/MEK/ERK signaling pathways and dose-dependent anti-proliferative effects only on s003 parent cell line, which showed the lowest expression of NANOG among all tested cell lines except one downregulated NANOG with upregulated POU5F1 s020 subgroup. Sorafenib also inhibited proliferation in this s020 subgroup but promoted proliferation in its parent cell line. For the only one downregulated NANOG alone s015 subgroup, sorafenib which had no influence on its parent cell line inhibited proliferation in this subgroup. Only the above three cell lines could demonstrate sorafenib antiproliferative effects. On the contrary, sorafenib promoted proliferation in three (s003, s015, s071) out of four upregulated NANOG alone subgroups. On the other hand, Sorafenib showed diverse influence on proliferation among four upregulated POU5F1 alone subgroups. In conclusion, NANOG rather than POU5F1 expression is a critical marker for the anticancer effects of sorafenib on HCC. The sorafenib anticancer effects on HCC cells with high NANOG expression were limited. Sorafenib should be combined with other drug able to target cancer cells with high NANOG expression.

Itemization difference of patient-reported outcome in patients with chronic liver disease.

BACKGROUND AND AIMS: The itemization difference of patient-reported outcome (PRO) in hepatitis patients with different etiologies remains elusive in Asia. We aimed to assess the characteristics and the difference of health-related quality of life (HRQoL) in chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) patients. METHODS: We conducted the study in an outpatient setting. The 36-Item Short Form Health Survey (SF-36) was completed by the patients upon the initial diagnosis and recruitment for a long-term follow-up purpose. The PRO results were also assessed by disease severity. RESULTS: There were 244 patients (198 males) of CHB, 54 patients (29 males) of CHC, and 129 patients (85 males) of NAFLD, respectively. CHC patient had the mean score of 67.1 ± 23.3 in physical component summary (PCS) of the SF-36 health survey, which was significantly lower than CHB patients (76.4 ± 19.5), and NAFLD patients (77.5 ± 13.7), respectively (p = 0.001). The significantly lower performance of PCS in CHC patients was mainly attributed to the lower performance in physical functioning and bodily pain components. Higher fibrosis 4 index scores were significantly associated with lower PCS scores in all patient groups. There was no significant difference of mean mental component summary (MCS) between groups. However, NAFLD patients had significantly lower mental health scores than other groups (p = 0.02). CONCLUSIONS: The significant difference of HRQoL exists in hepatitis patients with different etiologies. Disease severity leads to a lower PCS performance.

Outreach onsite treatment with a simplified pangenotypic direct-acting anti-viral regimen for hepatitis C virus micro-elimination in a prison.

BACKGROUND: Prisoners are at risk of hepatitis C virus (HCV) infection, especially among the people who inject drugs (PWID). We implemented an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic direct-acting antivirals (DAA) regimen, 12 wk of sofosbuvir/velpatasvir, in a PWID-dominant prison in Taiwan. AIM: To implement an outreach strategy in combination with universal mass screening and immediate onsite treatment with a simplified pan-genotypic DAA regimen in a PWID-dominant prison in Taiwan. METHODS: HCV-viremic patients were recruited for onsite treatment program for HCV micro-elimination with a pangenotypic DAA regimen, 12 wk of sofosbuvir/ velpatasvir, from two cohorts in Penghu Prison, either identified by mass screen or in outpatient clinics, in September 2019. Another group of HCV-viremic patients identified sporadically in outpatient clinics before mass screening were enrolled as a control group. The primary endpoint was sustained virological response (SVR12, defined as undetectable HCV ribonucleic acid (RNA) 12 wk after end-of-treatment). RESULTS: A total of 212 HCV-viremic subjects were recruited for HCV micro-elimination campaign; 91 patients treated with sofosbuvir/Ledipasvir or glecaprevir/ pibrentasvir before mass screening were enrolled as a control. The HCV micro-elimination group had significantly lower proportion of diabetes, hypertension, hyperlipidemia, advanced fibrosis and chronic kidney diseases, but higher levels of HCV RNA. The SVR12 rate was comparable between the HCV micro-elimination and control groups, 95.8% (203/212) vs 94.5% (86/91), respectively, in intent-to-treat analysis, and 100% (203/203) vs 98.9% (86/87), respectively, in per-protocol analysis. There was no virological failure, treatment discontinuation, and serious adverse event among sofosbuvir/velpatasvir-treated patients in the HCV micro-elimination group. CONCLUSION: Outreach mass screening followed by immediate onsite treatment with a simplified pangenotypic DAA regimen, sofosbuvir/velpatasvir, provides successful strategies toward HCV micro-elimination among prisoners.

Towards a safe hospital: hepatitis C in-hospital micro-elimination program (HCV-HELP study).

BACKGROUND AND AIMS: Scarce data are available on in-hospital hepatitis C virus (HCV) micro-elimination strategies. This pilot study was prospectively conducted to assess the outcomes of HCV in-hospital micro-elimination program (HCV-HELP) in a single center in Taiwan. METHODS: The study included the HCV reflex test for plans A (hospital personnel), B (outpatient surveillance), C (a call-back system for anti-HCV+ patients), and D (surveillance of cancer patients prior to chemotherapy). The primary outcome measurement was that > 80% of eligible patients were enrolled in linkage-to-treat; the secondary outcome measurement was the surveillance efficacy. RESULTS: We recruited 930, 6072, 2376 and 233 participants into plans A, B, C, and D, respectively, from Oct 2020 to May 2021. The anti-HCV-seropositivity prevalences were 0.22% for plan A, 4.3% for B, and 3.9% for D. Two staff members were identified as HCV-viremic in plan A; these staff members successfully achieved a sustained virological response (SVR). We identified 39, 95 and 2 HCV-viremic patients in plans B, C, and D, respectively. Of these 138 HCV-viremic patients, 135 (97.8%) received direct-acting antiviral therapy, and 134 achieved SVR. Two 4-month phases were stratified to compare efficacies in the liver clinic. In the late phase, the adjusted number of HCV-viremic patients was 4.36/10,000 outpatient visits (90/200,689), which was 3.18-fold higher than that of the early phase (1.37/10,000 outpatient visits [30/212,658], odds ratio 3.18; 95% confidence interval 2.10-4.81, p < 0.0001). CONCLUSION: HCV micro-elimination is achievable at the hospital level as per the structured HCV-HELP study.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein expression predicts disease severity in nonalcoholic steatohepatitis patients.

The role of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) in the prediction of disease severity in nonalcoholic fatty liver disease (NAFLD) remains elusive. This study evaluated the performance of WFA+ -M2BP in predicting fibrosis in patients with NAFLD. A total of 80 patients with biopsy-proven nonalcoholic steatohepatitis (NASH) were enrolled. Serum WFA+ -M2BP levels were measured using standard methods. The fibrosis-4 (FIB-4) index was also measured. The mean values of WFA+ -M2BP were 1.0, 1.0, 0.8, and 2.2 in Metavir fibrosis stage F0, F1, F2, and F3-4, respectively (linear trend p = 0.005). The optimal cut-off value of WFA+ -M2BP in predicting advanced fibrosis (F3-4) was 1.37 cut-off index (COI), yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy of 75.0, 79.4, 39.1, 94.7, and 78.7%, respectively (p < 0.001). Combining WFA+ -M2BP with FIB-4 significantly increased the diagnostic performance for advanced fibrosis, yielding specificity, PPV, and accuracy of 100, 100, and 93%, respectively. The significant factors predicting advanced liver fibrosis in the multivariate regression analysis were WFA+ -M2BP ≥ 1.37 COI (OR/confidence interval [CI]: 9.49/1.63-55.21, p = 0.01) and FIB-4 ≥ 2.80 (OR/CI: 38.18/4.89-297.93, p = 0.001). Monitoring WFA+ -M2BP is suitable for noninvasive assessment of liver fibrosis in NASH patients, particularly in combination with FIB-4.

Regorafenib for Taiwanese patients with unresectable hepatocellular carcinoma after sorafenib failure: Impact of alpha-fetoprotein levels.

BACKGROUND AND AIMS: Regorafenib has demonstrated its survival benefit for unresectable hepatocellular carcinoma (uHCC) patients in a phase III clinical trial. We aimed to assess the efficacy and tolerability of regorafenib and the predictors of treatment outcomes in Taiwanese patients. METHODS: We analyzed the survival, best overall response, predictors of treatment outcomes, and safety for uHCC patients who had tumor progression on sorafenib therapy and received regorafenib as salvage therapy between March 2018 and November 2020. RESULTS: Eighty-six patients with uHCC were enrolled (median age, 66.5 years; 76.7% male). The median regorafenib treatment duration was 4.0 months (95% confidence interval [CI], 3.6-4.6). The most frequently reported adverse events were hand-foot skin reaction (44.2%), diarrhea (36.0%), and fatigue (29.1%). No unpredictable toxicity was observed during treatment. The median overall survival (OS) with regorafenib was 12.4 months (95% CI, 7.8-17.0) and the median progression-free survival (PFS) was 4.2 months (95% CI, 3.7-4.7). Of 82 patients with regorafenib responses assessable, 4 patients (4.9%) achieved a partial response, and 33 (40.2%) had stable disease, leading to a disease control rate (DCR) of 45.1% (n = 37). Patients possessing baseline AFP < 400 ng/ml exhibited a markedly longer median OS, median PFS, and higher DCR compared with their counterparts (15.7 vs. 8.1 months, 4.6 vs. 3.7 months, 60.9% vs. 27.5%, respectively). Despite possessing high baseline AFP levels, patients with early AFP response (>10% reduction at 4 weeks or >20% reduction at 8 weeks after regorafenib administration) exhibited comparable treatment outcomes to those with baseline AFP < 400 ng/ml. CONCLUSIONS: The results of this real-world study verified the tolerability and efficacy of regorafenib treatment for uHCC patients who failed prior sorafenib therapy, especially for those with lower baseline AFP levels or with early AFP response.