Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours.

BACKGROUND & AIMS: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours. METHODS: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure. RESULTS: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96). CONCLUSIONS: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes. IMPACT AND IMPLICATIONS: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Liver stiffness and spleen stiffness predict distinct liver-related events after hepatitis C eradication with direct-acting antivirals.

BACKGROUND: /Purpose: This study aimed to directly compare the utility of liver stiffness (LS) and spleen stiffness (SS) at sustained virologic response (SVR) for predicting hepatocellular carcinoma (HCC) and non-HCC events in patients with chronic hepatitis C (CHC) after direct-acting antiviral therapy. METHODS: This retrospective study included 695 CHC patients who achieved SVR and underwent LS and SS measurements. LS and SS were measured using point shear wave elastography and compared head-to-head. RESULTS: During a median follow-up of 29.5 months, 49 (7.1%) patients developed liver-related events (LREs), including 28 HCC and 22 non-HCC events after SVR. Multivariable Cox regression analysis revealed that age, albumin level, and LS (≥ versus <1.46 m/s) at SVR (adjusted hazard ratio [aHR]: 5.390; 95% confidence interval [CI]: 2.349-12.364; p < 0.001), but not SS at SVR, significantly predicted the overall risk of post-SVR LREs (n = 49). Furthermore, age and LS (≥ versus <1.46 m/s) at SVR (aHR: 6.759; 95% CI: 2.317-19.723; p < 0.001), but not SS at SVR, independently predicted the risk of post-SVR incident HCC. In contrast, SS (≥ versus <2.87 m/s) at SVR (aHR: 11.212; 95% CI: 1.564-20.132; p = 0.021) and albumin level, but not LS at SVR, significantly predicted the risk of post-SVR non-HCC events. CONCLUSION: Post-SVR LS better predicts HCC risk. Post-SVR SS helps predict non-HCC risk after antiviral therapy for CHC. LS and SS at SVR provide complementary prognostic information regarding risks of HCC and non-HCC events in the post-SVR setting. Further validation is warranted in larger cohorts.

A Systemic Approach to Isolate, Retrieve, and Characterize Trophoblasts from the Maternal Circulation Using a Centrifugal Microfluidic Disc and a Multiple Single-Cell Retrieval Strategy.

Rare cells in the blood often have rich clinical significance. Although their isolation is highly desirable, this goal remains elusive due to their rarity. This paper presents a systemic approach to isolate and characterize trophoblasts from the maternal circulation. A microfluidic rare cell disc assay (RaCDA) was designed to process an extremely large volume of up to 15 mL of blood in 30 min, depleting red blood cells (RBCs) and RBC-bound white blood cells (WBC) while isolating trophoblasts in the collection chip. To minimize cell loss, on-disc labeling of cells with fluorescent immuno-staining identified the trophoblasts. Retrieval of trophoblasts utilized an optimized strategy in which multiple single cells were retrieved within the same micropipette column, with each cell encapsulated in a fluid volume (50 nL) separated by an air pocket (10 nL). Further, whole-genome amplification (WGA) amplified contents from a few retrieved cells, followed by quality control (QC) on the success of WGA via housekeeping genes. For definitive confirmation of trophoblasts, short-tandem repeat (STR) of the WGA-amplified content was compared against STR from maternal WBC and amniocytes from amniocentesis. Results showed a mean recovery rate (capture efficiency) of 91.0% for spiked cells with a WBC depletion rate of 99.91%. The retrieval efficiency of single target cells of 100% was achieved for up to four single cells retrieved per micropipette column. Comparison of STR signatures revealed that the RaCDA can retrieve trophoblasts from the maternal circulation.

Posttreatment nonalcoholic fatty liver disease fibrosis scores for predicting liver-related complications in patients with chronic hepatitis C receiving direct-acting antiviral agents.

Patients with chronic hepatitis C (CHC) have a higher prevalence of hepatic steatosis and dyslipidaemia than healthy individuals. We analysed noninvasive fibrosis assessments, especially nonalcoholic fatty liver disease (NAFLD)-related noninvasive fibrosis tests, for predicting liver-related complications and hepatocellular carcinoma (HCC) occurrence in patients with CHC. This retrospective study enrolled 590 consecutive patients with CHC having a sustained virologic response (SVR) to direct-acting antiviral agent (DAA) therapy. The NAFLD fibrosis score (NFS) exhibiting the highest value of area under the receiver operating characteristic curve (AUROC) was selected for comparison with the fibrosis-4 index (FIB-4). Of the 590 patients, 188 had metabolic syndrome. A multivariate Cox regression analysis identified total bilirubin at 3 or 6 months after DAA therapy (PW12), NFS at PW12 (hazard ratio [HR]: 2.125, 95% confidence interval [CI]: 1.058-4.267, p = .034) and alpha-fetoprotein (AFP) at PW12 (HR: 1.071, 95% CI: 1.005-1.142, p = .034) as the independent predictors of liver-related complications in all patients. In patients with metabolic syndrome, NFS and AFP values at PW12 were independent predictors of liver-related complications and HCC occurrence. Time-dependent NFS AUROC values at PW12 for 1-, 2- and 3-year liver-related complications were higher than NFS values at baseline in patients with metabolic syndrome. NFS at baseline or PW12 is a more effective predictor of liver-related complications than FIB-4 values in all patients. NFS at PW12 may be a useful predictor of liver-related complications and HCC development in patients with CHC with an SVR to DAA therapy, especially in those with metabolic syndrome.

Liver and Spleen Stiffness Surveillance Through Elastography During and After Direct-Acting Antiviral Therapy in Patients With Chronic Hepatitis C.

OBJECTIVES: Direct-acting antiviral agents achieve a high cure rate, resulting in early hepatic necroinflammatory resolution and sustained fibrosis regression. This study aimed to obtain longitudinal, concurrent within-subject measurements of liver stiffness (LS) and spleen stiffness (SS) and their correlates over time. METHODS: Participants with hepatitis C (n = 592) receiving direct-acting antiviral-based therapy were monitored through point shear-wave elastography from the treatment baseline (TW0) across follow-up visits in terms of LS and SS. RESULTS: Generalized linear mixed modeling indicated that all LS values (2301 visits) were negatively correlated with the follow-up times (all P < .05) from TW0 to 24 weeks (PW24) after the end of treatment (EOT) and positively correlated with baseline LS values (P < .001). The slopes of declines (preceding minus next) differed significantly (P < .001) between TW0-TW4 (treatment week 4) (0.060 [-0.050 to 0.225] meter/second/month [m/s/mo]) and TW4-EOT (0.010 [-0.030 to 0.075] m/s/mo). All SS values (1704 visits) were negatively correlated with time only at PW24 (P < .001) and positively correlated with baseline SS values (P < .001). The slopes of the SS values differed significantly (P < .001) only between EOT-PW12 (-0.010 [-0.110 to 0.083] m/s/mo) and PW12-PW24 (0.043 [-0.063 to 0.160] m/s/mo). CONCLUSIONS: The biphasic fast-to-slow decline in LS occurred early in the on-treatment phase, which is consistent with the resolution of hepatic necroinflammation. The slow-to-fast decline in SS occurred off treatment. Future studies should investigate the association with regressions in liver fibrosis and portal hypertension.

Exosomes-Potential for Blood-Based Marker in Alzheimer's Disease.

Exosomes are believed to be secreted from multivesicular endosomes and containing proteins and nucleic acids, including mRNA and microRNAs, which have been implicated to play a role in neurodegenerative diseases. Neuron-derived exosomes at the circulation provide a unique potential as biomarkers towards assessment of Alzheimer's disease (AD), even at the pre-clinical stage. This review briefly discusses their biogenesis and transport, exosomal protein verses soluble protein, evidence for their role in AD, isolation of exosomes, and challenges and future directions to realize reliable blood-based biomarkers to meet phenomenal unmet clinical and pre-clinical need of AD.

Hepatitis C virus eradication decreases the risks of liver cirrhosis and cirrhosis-related complications (Taiwanese chronic hepatitis C cohort).

BACKGROUND AND AIM: It is currently unknown how hepatitis C virus (HCV) eradication with pegylated interferon and ribavirin (PR) therapy affects the incidence of new-onset liver cirrhosis (LC) in patients without cirrhosis and the incidence of decompensated liver disease (DLD) or hepatocellular carcinoma (HCC) in patients with cirrhosis. METHODS: Taiwanese chronic hepatitis C cohort (T-COACH) is a nationwide HCV registry cohort from 23 hospitals in Taiwan recruited between 2003 and 2015. This study enrolled 10 693 patients with chronic hepatitis C (CHC), linked to the Taiwan National Health Insurance Research Database, receiving PR therapy for at least 4 weeks for new-onset LC and liver-related complications (DLD or HCC). RESULTS: Of the 10 693 patients, 1372 (12.8%) patients had LC, and the mean age was 54.0 ± 11.4 years. The mean follow-up duration was 4.38 ± 2.79 years, with overall 46 798 person-years. The 10-year cumulative incidence rates of new-onset LC were 5.0% (95% confidence interval [CI]: 3.2-7.7) in patients without cirrhosis with a sustained virologic response (SVR) and 21.9% (95% CI: 13.4-32.4) in those without SVR (hazard ratio [HR]: 0.22, P < 0.001). The 10-year cumulative incidence rates of liver-related complications were 21.4% (95% CI: 11.1-37.2) in patients with cirrhosis with SVR and 47.0% (95% CI: 11.1-86.0) in those without SVR after adjustment for age, sex, and competing mortality (HR: 0.52, P < 0.001). CONCLUSIONS: Hepatitis C virus eradication with PR therapy decreased the incidence of new-onset LC in noncirrhotic patients and the incidence of liver-related complications in cirrhotic patients with CHC.

Performance of Acoustic Radiation Force Impulse Elastography for Staging Liver Fibrosis in Patients With Chronic Hepatitis C After Viral Eradication.

BACKGROUND: Data on noninvasive liver fibrosis staging after viral eradication are unclear. This histology-based study validated the performance of liver stiffness (LS) measurements after viral eradication. METHODS: Consecutive participants with chronic hepatitis C (CHC) who received concomitant LS measurements through acoustic radiation force impulse (ARFI) elastography and percutaneous liver biopsy were prospectively screened and analyzed. RESULTS: Of the 644 patients, 521 (80.9%) underwent a biopsy at treatment baseline, and the remaining 123 (19.1%) underwent a biopsy at 3 years (median; interquartile range, 0.1) after the sustained virological response (SVR) to pegylated interferon-based and direct-acting antiviral treatments. The proportions of histological fibrosis stages did not differ significantly between the pretreatment and post-SVR groups (P = .0615). However, the LS values differed significantly (P < .0001). The median LS values (presented as shear wave velocities in meters per second) were 1.51 (0.92) for the pretreatment group and 1.22 (0.77) for the post-SVR group. The cutoffs (areas under the receiver operating characteristic curve, obtained using the bootstrap method) to dichotomize between METAVIR fibrosis stage F1 versus stages F2-F4, F1-F2 versus F3-F4, and F1-F3 versus F4 were 1.47 (0.8333, 95% confidence interval [CI] 0.7981-0.8663), 1.81 (0.8763, 95% CI 0.8376-0.9107), and 1.86 (0.8811, 95% CI 0.8378-0.9179) in the pretreatment group, respectively, and 1.22 (0.7872, 95% CI 0.7001-0.8624), 1.59 (0.8808, 95% CI 0.8034-0.9422), and 1.75 (0.9018, 95% CI 0.8201-0.9644) in the post-SVR group, respectively. CONCLUSIONS: The performance of LS measurements through ARFI elastography is promising to determine the liver fibrosis stage on necroinflammation-resolved histology in CHC after viral eradication.

Rapid decline of noninvasive fibrosis index values in patients with hepatitis C receiving treatment with direct-acting antiviral agents.

BACKGROUND: Studies on temporal changes in noninvasive fibrosis indices and liver stiffness measurement (LSM) in patients with chronic hepatitis C (CHC) treated with direct-acting antiviral agents (DAAs) are limited. METHODS: We retrospectively enrolled consecutive patients with CHC who had received DAAs. RESULTS: In total, we recruited 395 consecutive patients, of which 388 (98.2%) achieved a sustained virologic response (SVR) at 12 weeks after therapy. In patients who received DAA therapy and achieved SVR 12 weeks after therapy (n = 388), the median aspartate aminotransferase/platelet ratio index (APRI) value decreased from 1.19 (0.62-2.44) at baseline to 0.50 (0.32-0.95), 0.51 (0.31-0.92), 0.48 (0.31-0.88), and 0.52 (0.33-0.92) at week 2, week 4, end of therapy, and PW12, respectively (all P < 0.001). The median FIB-4 value decreased from 2.88 (1.56-5.60) at baseline to 2.10 (1.30-3.65), 2.15 (1.30-3.65), 2.11 (1.37-3.76), and 2.22 (1.45-3.82) at week 2, week 4, end of therapy, and PW12, respectively (all P < 0.001). The median alanine aminotransferase level significantly decreased from week 2 until PW12 (all P < 0.001). The platelet count significantly increased from 2 weeks after DAA therapy initiation until PW12 (all P < 0.001); however, the magnitude of changes in the platelet count was low. In patients with paired LSMs obtained using acoustic radiation force impulse elastography at baseline and PW12 (n = 199), the median LSM decreased from 1.78 (1.25-2.30) m/s at baseline to 1.38 (1.14-1.88) m/s at PW12 (P < 0.001). CONCLUSIONS: Noninvasive fibrosis indices, namely APRI and FIB-4, exhibited a rapid and sustained decline from week 2 until PW12 in patients with CHC who achieved SVR to DAA therapy. The rapid decline in APRI and FIB-4 values might mainly result from improvement in necroinflammation.

Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats.

BACKGROUND: Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS: In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS: By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

Improved Survival in Hepatocellular Carcinoma Patients with Cardiac Arrhythmia by Amiodarone Treatment through Autophagy.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. In basic studies, the regulation of autophagy has offered promising results for HCC treatment. This study aimed to address the question of whether amiodarone can improve survival rates in HCC patients associated with autophagy. Using datasets from the National Health Insurance Research Database, we enrolled patients over 18 years of age that had been diagnosed with HCC between January 1997 and December 2010. Amiodarone and non-amiodarone users were matched at a 1:1 frequency, according to all variables. Additionally, HepG2 cells treated with amiodarone were evaluated by cell viability and autophagic change. Autophagic signaling was examined by immunoblotting and tissue array immunohistochemistry. Of the 10,946 patients diagnosed with HCC, each cohort included 221 patients after 1:1 propensity score matching. The median survival was 36.70 months for the amiodarone users, and 24.48 months for the non-amiodarone users. After adjusting for age, gender, comorbidities and treatment, amiodarone users had a significantly lower risk of mortality. Amiodarone users also demonstrated an improved 3-year survival rate. Furthermore, amiodarone treatment-induced autophagy in HepG2 cells was demonstrated by autophagosome formation associated with increasing LC3B-II, P62, and Beclin-1 expression. Autophagic flux also increased following amiodarone treatment with bafilomycin A1. SiRNA of LC3B knocked down endogenous LC3B formation and restored HepG2 cell viability. This study provides epidemiologic evidence that amiodarone via autophagic degradation machinery may offer survival benefits for HCC patients with a history of arrhythmia. Further randomized, blinded, and placebo-controlled trials are warranted for patients with HCC.

Trajectories of serum hepatitis B surface antigen kinetics in patients with chronic hepatitis B receiving long-term nucleos(t)ide analogue therapy.

BACKGROUND & AIMS: The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients remains unclear. We investigated the patterns of serum HBsAg kinetics and their association with therapeutic outcomes in genotype B- or C-infected CHB patients receiving long-term NA therapy. METHODS: We enrolled 329 treatment-naive CHB patients receiving NA therapy for >5 years to analyse the kinetic patterns by using group-based trajectory models (GBTMs). RESULTS: Most patients (82.4%) received entecavir therapy. The median treatment duration was 83.6 (68.5-89.7) months. The GBTMs revealed three groups for both the hepatitis B e antigen (HBeAg)-positive and -negative patients. The median annual decline in serum HBsAg levels during the first 5 years was significantly higher in Group 1 than in Groups 2 and 3 in HBeAg-positive (0.78 vs 0.10 vs 0.10 log10 IU/mL) and HBeAg-negative (0.71 vs 0.08 vs 0.09 log10 IU/mL) patients. HBsAg levels at the baseline and 12 months combined with an HBsAg decline from the baseline to 12 months of treatment predicted trajectory pattern 1 in HBeAg-positive (sensitivity, 77.8%; specificity, 99.1%; positive predictive value [PPV], 87.5%; and negative predictive value [NPV], 98.2%) and HBeAg-negative (sensitivity, 100%; specificity, 99.5%; PPV, 88.9%; and NPV, 100%) patients. The trajectory patterns were significantly associated with HBeAg loss in the HBeAg-positive patients and the achievement of HBsAg <100 IU/mL or HBsAg loss in HBeAg-positive and HBeAg-negative patients. CONCLUSIONS: The trajectory of serum HBsAg levels predicts HBsAg loss in CHB patients receiving long-term NA therapy.

Identification of risk factors for neoplastic colonic polyps in young adults with bloody stool in comparison with those without symptom.

BACKGROUND AND AIMS: The incidence and disease burden of colorectal cancer (CRC) in young adults were increasing. However, there was a dearth of advice on how to identify young population at risk for neoplastic colonic polyps (NCPs) and CRC. We aimed to identify risk factors for NCPs and CRC in young adults presenting with bloody stool. METHODS: A total of 1496 subjects younger than 40 years old who underwent colonoscopy due to bloody stool from 2005 to 2014 were enrolled in this retrospective study as the study group, and 1481 age-matched and gender-matched asymptomatic subjects who underwent colonoscopy for health checkup from 2011 to 2016 were enrolled as the control group at a tertiary center hospital. RESULTS: Multivariate analysis results showed that increasing age (odds ratio [OR] = 1.11, 95% confidence interval [CI]: 1.07-1.15, P < 0.001), higher body mass index (BMI) (OR = 1.07, 95%CI: 1.03-1.12, P = 0.001), diabetes mellitus (OR = 2.80, 95%CI: 1.06-7.42, P = 0.038), and positive family history of CRC (OR = 13.28, 95%CI: 5.70-30.97, P < 0.001) were identified as independent risk factors for NCPs in study group. The best cut-off values by receiver operating characteristic curve for age and BMI were 32 years old and 24.8 kg/m2 , respectively. More risk factors were associated with the higher risk for NCPs (OR = 2.17 every increasing one risk factor, P < 0.001). In the control group, no independent risk factors were identified. CONCLUSIONS: Adults aged ≤ 40 years with bloody stool who had increasing age (> 32 years old), higher BMI (> 24.8 kg/m2 ), diabetes mellitus, and positive family history of CRC had a higher detection rate of NCPs and CRC.

Significant association of elevated serum galectin-9 levels with the development of non-alcoholic fatty liver disease in patients with rheumatoid arthritis.

Background: Non-alcoholic fatty liver disease (NAFLD) is prevalent among rheumatoid arthritis (RA) patients, but its pathogenesis has rarely been explored. Galectin-9 (Gal-9) interacts with T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3) expressed on hepatocytes and thus regulates T cell proliferation in a murine model of NAFLD. We aimed to examine the pathogenic role of the Gal-9/TIM-3 pathway in RA-NAFLD. Methods: Serum levels of Gal-9, soluble TIM-3 (sTIM-3), fatty acid-binding proteins (FABP)1, and FABP4 were determined by ELISA in forty-five RA patients and eleven healthy participants. Using Oil-red O staining and immunoblotting, we examined the effects of Gal-9 and free fatty acid (FFA) on lipid accumulation in human hepatocytes and FABP1 expression. Results: Serum Gal-9, sTIM-3 and FABP1 level were significantly higher in RA patients (median 5.02 ng/mL, 3.42 ng/mL, and 5.76 ng/mL, respectively) than in healthy participants (1.86 ng/mL, 0.99 ng/mL, and 0.129 ng/mL, all p < 0.001). They were also significantly higher in patients with moderate-to-severe NAFLD compared with none-to-mild NAFLD (p < 0.01; p < 0.05; and p < 0.01, respectively). Serum Gal-9 levels were positively correlated with sTIM-3, FABP1, FABP4 levels, and ultrasound-fatty liver score, respectively, in RA patients. Multivariate regression analysis revealed that Gal-9 (cut-off>3.30) was a significant predictor of NAFLD development, and Gal-9 and sTIM-3 were predictors of NAFLD severity (both p < 0.05). The cell-based assay showed that Gal-9 and FFA could upregulate FABP1 expression and enhance lipid droplet accumulation in hepatocytes. Conclusion: Elevated levels of Gal-9 and sTIM3 in RA patients with NAFLD and their positive correlation with NAFLD severity suggest the pathogenic role of Gal-9 signaling in RA-related NAFLD.

Effect of metabolic dysfunction on the risk of liver-related events in patients cured of hepatitis C virus.

The impact of metabolic dysfunction or metabolic dysfunction-associated fatty liver disease (MAFLD) on liver-related events (LREs) in patients with chronic hepatitis C (CHC) who had achieved a sustained virologic response (SVR) to direct-acting antiviral agents (DAAs) is unknown. A total of 924 patients with cured CHC and documented body mass index (BMI) were included in the analysis, and the data period was from September 2012 to April 2022. Hepatic steatosis was identified either through ultrasonography or blood biomarkers. Metabolic dysfunction was defined as the presence of overweight or obesity (BMI ≥ 23 kg/m2), type 2 diabetes mellitus (DM), and metabolic dysregulation. Patients may have more than one metabolic dysfunction. Variables at 12 or 24 weeks after DAA therapy (PW12) were used to identify predictors of LREs. The median age of the 924 patients was 58 (49-65) years. Of the participants, 418 (45.2%) were male. The median BMI was 24.01 (21.78-26.73) kg/m2, and 174 (18.8%) patients had DM. A multivariable Cox regression analysis revealed that age, male, albumin, total bilirubin, alpha-fetoprotein (AFP), metabolic dysfunction (hazard ratio: 1.709, 95% confidence interval: 1.128-2.591, P = .011), and FIB-4 > 3.25 were independent predictors of LREs. Type 2 DM and metabolic dysregulation exhibited a larger time-dependent area under the receiver operating characteristic curve for LREs than did overweight or obesity. Moreover, metabolic dysfunction was identified to be an independent predictor of hepatocellular carcinoma. Metabolic dysfunction increased the risk of LREs and HCC in patients with CHC who had achieved an SVR to DAA therapy.

Confinement-Induced Isosymmetric Metal-Insulator Transition in Ultrathin Epitaxial V2O3 Films.

Dimensional confinement has shown to be an effective strategy to tune competing degrees of freedom in complex oxides. Here, we achieved atomic layered growth of trigonal vanadium sesquioxide (V2O3) by means of oxygen-assisted molecular beam epitaxy. This led to a series of high-quality epitaxial ultrathin V2O3 films down to unit cell thickness, enabling the study of the intrinsic electron correlations upon confinement. By electrical and optical measurements, we demonstrate a dimensional confinement-induced metal-insulator transition in these ultrathin films. We shed light on the Mott-Hubbard nature of this transition, revealing a vanishing quasiparticle weight as demonstrated by photoemission spectroscopy. Furthermore, we prove that dimensional confinement acts as an effective out-of-plane stress. This highlights the structural component of correlated oxides in a confined architecture, while opening an avenue to control both in-plane and out-of-plane lattice components by epitaxial strain and confinement, respectively.

Risk factors for second primary neoplasia of esophagus in newly diagnosed head and neck cancer patients: a case-control study.

BACKGROUND: The prevalence of esophageal neoplasia in head and neck (H&N) cancer patients is not low; however, routine esophageal surveillance is not included in staging of newly-diagnosed H&N cancers. We aimed to investigate the risk factors for synchronous esophageal neoplasia and the impact of endoscopy on management of H&N cancer patients. METHODS: A total of 129 newly diagnosed H&N cancer patients who underwent endoscopy with white-light imaging, narrow-band imaging (NBI) with magnifying endoscopy (ME), and chromoendoscopy with 1.5% Lugol's solution, before definite treatment were enrolled prospectively. RESULTS: 60 esophageal lesions were biopsied from 53 (41.1%) patients, including 11 low-grade, 14 high-grade intraepithelial neoplasia and 12 invasive carcinoma in 30 (23.3%) patients. Alcohol consumption [odds ratio (OR) 5.90, 95% confidence interval (CI) 1.23-26.44], advanced stage (stage III and IV) of index H&N cancers (OR 2.98, 95% CI 1.11-7.99), and lower body mass index (BMI) (every 1-kg/m2 increment with OR 0.87, 95% CI 0.76-0.99) were independent risk factors for synchronous esophageal neoplasia. NBI with ME was the ideal screening tool (sensitivity, specificity, and accuracy of 97.3%, 94.1%, and 96.3%, respectively, for detection of dysplastic and cancerous esophageal lesions). The treatment strategy was modified after endoscopy in 20 (15.5%) patients. The number needed to screen was 6.45 (95% CI 4.60-10.90). CONCLUSIONS: NBI-ME surveillance of esophagus should be done in newly-diagnosed H&N cancer patients, especially those with alcohol drinking, lower BMI, and advanced stage of primary tumor.

Characterization of markers, functional properties, and microbiome composition in human gut-derived bacterial extracellular vesicles.

Past studies have confirmed the etiologies of bacterial extracellular vesicles (BEVs) in various diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). This study aimed to investigate the characteristics of stool-derived bacterial extracellular vesicles (stBEVs) and discuss their association with stool bacteria. First, three culture models - gram-positive (G+)BcBEVs (from B.coagulans), gram-negative (G-)EcBEVs (from E.coli), and eukaryotic cell-derived EVs (EEV, from Colo205 cell line) - were used to benchmark various fractions of stEVs separated from optimized density gradient approach (DG). As such, WB, TEM, NTA, and functional assays, were utilized to analyze properties and distribution of EVs in cultured and stool samples. Stool samples from healthy individuals were interrogated using the approaches developed. Results demonstrated successful separation of most stBEVs (within DG fractions 8&9) from stEEVs (within DG fractions 5&6). Data also suggest the presence of stBEV DNA within vesicles after extraction of BEV DNA and DNase treatment. Metagenomic analysis from full-length (FL) region sequencing results confirmed significant differences between stool bacteria and stBEVs. Significantly, F8&9 and the pooled sample (F5-F9) exhibited a similar microbial composition, indicating that F8&9 were enriched in most stBEV species, primarily dominated by Firmicutes (89.6%). However, F5&6 and F7 still held low-density BEVs with a significantly higher proportion of Proteobacteria (20.5% and 40.7%, respectively) and Bacteroidetes (24% and 13.7%, respectively), considerably exceeding the proportions in stool and F8&9. Importantly, among five healthy individuals, significant variations were observed in the gut microbiota composition of their respective stBEVs, indicating the potential of stBEVs as a target for personalized medicine and research.

Adjuvant Sorafenib for Postoperative Patients with Hepatocellular Carcinoma and Macrovascular Invasion.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. Some patients with HCC are diagnosed with macrovascular invasion (MVI), which is associated with a poorer prognosis. In Taiwan, sorafenib is the first-line therapy for patients with advanced HCC. However, the efficacy of adjuvant sorafenib therapy remains unclear for the subset of patients with HCC and MVI who are eligible for surgery. Therefore, we investigated the potential benefit of adjuvant sorafenib therapy for patients with HCC and MVI after surgery. Our study showed that the lack of improved PFS or OS of adjuvant sorafenib challenged the therapeutic benefit of postoperative sorafenib. Alcohol consumption and an α-fetoprotein level of ≥400 ng/mL were independent predictors of overall survival (OS); however, adjuvant sorafenib therapy was not a predictor of progression-free survival (PFS) or OS. In conclusion, our study indicated that adjuvant sorafenib therapy did not provide PFS or OS benefits in patients with HCC and MVI.