Prevalence, proportions of elevated liver enzyme levels, and long-term cardiometabolic mortality of patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIM: This study estimated the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long-term impacts of MASLD on all-cause and cardiometabolic-specific mortality were evaluated. METHODS: We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self-reported medication use and clinical seromarkers. All-cause and cardiometabolic-specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020. RESULTS: The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (Pfor trend < 0.001). After follow-up, patients with MASLD had a 9%-29% higher risk of all-cause, cardiovascular-related, or diabetes-related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate-adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05-1.25) and 1.10 (1.03-1.17), respectively, and those for diabetes deaths were 1.42 (1.05-1.93) and 1.24 (0.98-1.57), respectively, compared with those in the non-MASLD group (Pfor trend < 0.001). DISCUSSION: Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all-cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

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.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

INTRODUCTION: Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). METHODS: The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. RESULTS: A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. CONCLUSION: Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Long-term Risks of Cirrhosis and Hepatocellular Carcinoma Across Steatotic Liver Disease Subtypes.

INTRODUCTION: The prospective study aimed to investigate the long-term associated risks of cirrhosis and hepatocellular carcinoma (HCC) across various subtypes of steatotic liver disease (SLD). METHODS: We enrolled 332,175 adults who participated in a health screening program between 1997 and 2013. Participants were categorized into various subtypes, including metabolic dysfunction-associated SLD (MASLD), MASLD with excessive alcohol consumption (MetALD), and alcohol-related liver disease (ALD), based on ultrasonography findings, alcohol consumption patterns, and cardiometabolic risk factors. We used computerized data linkage with nationwide registries from 1997 to 2019 to ascertain the incidence of cirrhosis and HCC. RESULTS: After a median follow-up of 16 years, 4,458 cases of cirrhosis and 1,392 cases of HCC occurred in the entire cohort, resulting in an incidence rate of 86.1 and 26.8 per 100,000 person-years, respectively. The ALD group exhibited the highest incidence rate for cirrhosis and HCC, followed by MetALD, MASLD, and non-SLD groups. The multivariate adjusted hazard ratios for HCC were 1.92 (95% confidence interval [CI] 1.51-2.44), 2.91 (95% CI 2.11-4.03), and 2.59 (95% CI 1.93-3.48) for MASLD, MetALD, and ALD, respectively, when compared with non-SLD without cardiometabolic risk factors. The pattern of the associated risk of cirrhosis was similar to that of HCC (all P value <0.001). The associated risk of cirrhosis for ALD increased to 4.74 (95% CI 4.08-5.52) when using non-SLD without cardiometabolic risk factors as a reference. DISCUSSION: This study highlights elevated risks of cirrhosis and HCC across various subtypes of SLD compared with non-SLD, emphasizing the importance of behavioral modifications for early prevention.

Clinical outcome of bevacizumab or ramucirumab combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as the first line therapy in susceptible EGFR-mutated advanced non-small-cell lung.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an anti- vascular endothelial growth factor (VEGF) agent, bevacizumab or ramucirumab, is indicated for advanced lung adenocarcinoma harboring EGFR mutation. This study aimed to show the real-world data of combination therapy and compare the effectiveness between bevacizumab and ramucirumab in combination with an EGFR-TKI. This retrospective study enrolled 47 patients diagnosed of stage IV lung adenocarcinoma with exon 19 deletion or L858R point mutation, receiving a first-line EGFR-TKI with anti-VEGF agent, including 34 (72%) and 13 (28%) patients receiving bevacizumab and ramucirumab, respectively. The response rate was similar in both groups (p = 0.38). Patients receiving bevacizumab had similar progression free survival (PFS) as those receiving ramucirumab (median PFS: 21.9 vs. 24.2 months, p = 0.4871); similar finding was noted in overall survival (OS) (median OS: 33.5 months vs. not reached, p = 0.4618). Patients receiving ramucirumab experienced a significantly high-grade hypertension compared to those receiving bevacizumab (p = 0.0351). Multivariable Cox regression analysis found independent risk factors for worse PFS included poorer ECOG performance status, multiple (≥3) metastatic sites, brain metastasis, and pleural metastasis/effusion, while the type of anti-VEGF agent was not a risk factor. Pericardial metastasis/effusion was the only one independent risk factor for worse OS. In summary, ramucirumab may have similar effectiveness as bevacizumab in combination with an EGFR-TKI as first line therapy for advanced lung adenocarcinoma harboring susceptible EGFR mutation. Further large-scale registry-based cohort studies may be needed to validate our findings.

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.

Chronic Viral Hepatitis B and C Outweigh MASLD in the Associated Risk of Cirrhosis and HCC.

BACKGROUND & AIMS: The impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the development of cirrhosis and hepatocellular carcinoma (HCC) by chronic hepatitis B (CHB) or C infection and antiviral treatment statuses is not well-known. METHODS: A total of 336,866 adults aged ≥30 years were prospectively enrolled in a health screening program between 1997-2013. MASLD was identified by abdominal ultrasonography and cardiometabolic profiles. Data linkage was performed using 3 nationwide databases-National Health Insurance, Cancer Registry, and Death Certification System-to obtain information on antiviral treatment, vital status, and newly diagnosed cirrhosis and HCC. Follow-up was conducted until December 31, 2019. RESULTS: In the total population, 122,669 (36.4%) had MASLD. Over a mean follow-up of 15 years, 5562 new cases of cirrhosis and 2273 new cases of HCC were diagnosed. Although MASLD significantly increased the cumulative risks of cirrhosis or HCC (P < .0001), the associated risk was more pronounced when comparing CHB or C infection with the presence of MASLD. Stratifying the participants based on their MASLD and CHB or C statuses, hazard ratios (HRadj) with 95% confidence intervals for HCC were 8.81 (7.83-9.92) for non-steatotic liver disease (SLD) with CHB or C, 1.52 (1.32-1.74) for MASLD without CHB or C, and 8.86 (7.76-10.12) for MASLD with CHB or C, compared with non-SLD without CHB or C (all P < .0001). Among CHB or C patients who received antivirals during follow-up, MASLD was associated with increased risks of cirrhosis and HCC, with HRadj of 1.23 (1.01-1.49) and 1.32 (1.05-1.65), respectively. CONCLUSIONS: These findings underscore the need to prioritize treatment of chronic viral hepatitis before addressing MASLD.

Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients.

BACKGROUND: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.

Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations.

The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.

Clinical and Genotypic Insights Into Higher Prevalence of Palbociclib Associated Neutropenia in Asian Patients.

BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.

A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

Genetic Susceptibility of HLA Alleles to Non-Steroidal Anti-Inflammatory Drug Hypersensitivity in the Taiwanese Population.

BACKGROUND: Human leukocyte antigen (HLA) genes are important in many immune processes and contribute to many adverse drug reactions. Whether genetic variations in the HLA region are associated with non-steroid anti-inflammatory drug (NSAID) hypersensitivity remains uncertain. Therefore, the aim of our study was to identify HLA genetic variations in patients with NSAID hypersensitivity in the Taiwanese population. METHODS: This hospital-based, retrospective case-control study enrolled 37,156 participants with NSAID exposure from the Taiwan Precision Medicine Initiative (TPMI), who were all genotyped and imputed to fine map HLA typing. Our study assigned 1217 cases to the NSAID allergy group and 12,170 controls to a matched group. Logistic regression analyses were utilized to explore associations between HLA alleles and NSAID hypersensitivity. RESULTS: Overall, 13,387 patients were genotyped for eight major HLA alleles. Allele frequencies were different between the two groups. In the NSAID allergy group, the genotype frequencies of HLA-A*02:01, HLA-A*34:01, and HLA-DQA1*06:01 were found to be markedly elevated compared to the control group, a significance that persisted even after applying the Bonferroni correction. Furthermore, the risk of NSAID allergy demonstrated a significant association with HLA-A*02:01 (OR = 1.29, p < 0.001) and HLA-A*34:01 (OR = 9.90, p = 0.001), in comparison to their respective counterparts. Notably, the genotype frequency of HLA-B*46:01 exhibited a significant increase in the severe allergy group when compared with the mild allergy group. CONCLUSIONS: We identified HLA genotypes linked to the onset and severity of NSAID hypersensitivity. Our findings establish a basis for precision prescription in future clinical applications.

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.

Risk of Hepatocellular Carcinoma After Spontaneous Clearance of Hepatitis C Virus and in Noncirrhosis Chronic Hepatitis C Patients With Sustained Virological Response: A Systematic Review.

In a hepatitis C virus (HCV)-controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan, and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible.

IFNL4 Genotype Frequencies in Asian Populations Support Shorter Duration Therapy with Sofosbuvir-Based Hepatitis C Virus Regimens to Increase the Number Cured.

Globally, ∼56.8 million people are chronically infected with hepatitis C virus (HCV), with about half residing in Asia. The cost and efficiency of delivering regimens based on direct-acting antiviral agents for HCV are important considerations in implementing these curative treatments. For sofosbuvir-based regimens, most patients are treated for 12 weeks; however, treatment for 8 weeks has been shown to cure HCV infection in 95% of patients without cirrhosis. Furthermore, virological failure after 8-week treatment occurs in only 1%-2% of individuals without cirrhosis, who have a favorable IFNL4 genotype, which is present in >50% of South Asians and >80% of East Asians. We propose that sofosbuvir-based treatment for 8 weeks, or perhaps shorter, would yield high response rate regimens in Asian countries and markedly increase the number of patients who could be cured for a given cost of the medication. We propose that a noninferiority trial in an East Asian population be conducted to test this hypothesis.

Association of periodontal disease with migraine: A large-scale community-based cross-sectional study.

BACKGROUND: Periodontal disease may drive a systemic inflammatory response that triggers migraine; however, the association between periodontal disease and migraine has rarely been investigated in a community-based setting. METHODS: This cross-sectional study included 66,109 participants aged 30 to 70 years from Taiwan Biobank (TWB). A structured questionnaire was administered to participants, who were also subjected to whole-genome single nucleotide polymorphism genotyping using the customized Axiom-TWB array. To identify subjects with periodontal disease and migraine, the computerized linkage of data obtained from TWB and the National Health Insurance Research Database was performed. Participants were evaluated for their genetic predisposition to migraine using a polygenic risk score. We examined and estimated the magnitude of associations between periodontal disease and migraine. RESULTS: In this study, 4618 (4618/66,109; 7%) participants with migraine and 61,491 (61,491/66,109; 83%) participants without migraine were included. Participants with migraine exhibited a higher prevalence of periodontal disease than participants without migraine (4324/4618; 94% vs. 56,036/61,491; 91%). A significant positive association was observed between periodontal disease and migraine, with an adjusted odds ratio (ORadj ) of 1.40 (95% confidence interval [CI] = 1.24-1.59; p < 0.001). The association remained consistent even after excluding participants with other comorbidities (ORadj  = 1.34; 95% CI = 1.16-1.55; p < 0.001). Moreover, the positive association between periodontal disease and migraine remained significant across the subgroups of age, sex, other comorbidities, and classified polygenic risk scores of migraine, with the ORadj ranging from 1.26 to 1.78. CONCLUSIONS: A significant positive association was observed between periodontal disease and migraine. Future studies need to explore the biological mechanisms of how periodontal disease might affect migraine.

Local Consolidative Therapy May Have Prominent Clinical Efficacy in Patients with EGFR-Mutant Advanced Lung Adenocarcinoma Treated with First-Line Afatinib.

Afatinib is an irreversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), which is utilized for the treatment of patients with advanced lung cancer that harbors EGFR mutations. No studies have evaluated the clinical efficacy of LCT in patients treated with first-line afatinib. In this study, we retrospectively enrolled patients with advanced lung adenocarcinomas harboring susceptible EGFR mutations who were diagnosed and treated with first-line afatinib in three hospitals. A total of 254 patients were enrolled, including 30 (12%) patients who received LCT (15 patients received definitive radiotherapy for the primary lung mass and 15 patients received curative surgery). Patients who received LCT had a significantly longer PFS than those who did not (median PFS: 32.8 vs. 14.5 months, p = 0.0008). Patients who received LCT had significantly longer OS than those who did not (median OS: 67.1 vs. 34.5 months, p = 0.0011). Multivariable analysis showed LCT was an independent prognostic factor for improved PFS (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 0.44 [0.26-0.73], p = 0.0016) and OS (aHR [95% CI]: 0.26 [0.12-0.54], p = 0.0004). The analyses using propensity score-weighting showed consistent results. We conclude that LCT may improve clinical outcomes, in terms of PFS and OS, in patients with advanced EGFR-mutant lung adenocarcinomas who are treated with first-line afatinib.

Biomarkers of gut barrier dysfunction and risk of hepatocellular carcinoma in the REVEAL-HBV and REVEAL-HCV cohort studies.

Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut-derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-HBV and REVEAL-HCV cohorts from Taiwan. REVEAL-HBV included 185 cases and 161 matched controls, and REVEAL-HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS-binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable-adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV-related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06-2.93; OR for LBP = 1.93, 95% CI: 1.10-3.38). None of the other markers were associated with an increased risk of HBV-related or HCV-related HCC. Results were similar when cases diagnosed in the first 5 years of follow-up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology.