Residual effect of reductions in red blood cell count and haematocrit and haemoglobin levels after 10-month withdrawal of pioglitazone in patients with Type 2 diabetes.

AIM: To investigate the recovery of thiazolidinedione-induced body weight gain and haematopoietic changes after stopping pioglitazone treatment in patients with Type 2 diabetes. METHODS: This retrospective cohort study included 214 patients divided into three groups according to pioglitazone treatment status. The first study arm included patients who received pioglitazone for 38 months then interrupted this for 10 months (pioglitazone-interruption group). The second arm consisted of patients who received pioglitazone throughout the 48 months (pioglitazone-continuous group); the third arm included patients who had never received pioglitazone therapy (control group). RESULTS: Red blood cell count and haematocrit and haemoglobin levels decreased significantly, while body weight increased in the two pioglitazone-treated groups as compared with the control group at 38 months. Multivariate regression analysis showed that the reductions in red blood cell count/haemoglobin levels were associated with pioglitazone use. In the pioglitazone-interruption group, no recoveries of red blood cells, or haematocrit or haemoglobin levels were observed after stopping pioglitazone for 10 months compared with the pioglitazone-continuous group, but body weight gain decreased to a level that was significantly lower than that in the pioglitazone-continuous group and did not differ significantly from the control group. CONCLUSION: In this study, we observed a reversal of body weight gain but no recoveries in red blood cells or haematocrit or haemoglobin levels after stopping pioglitazone for 10 months in patients treated with pioglitazone for 38 months. This finding should prompt a reconsideration of the sustained effect of thiazolidinediones on the haematopoietic system in patients with Type 2 diabetes.

Hepatitis C transmission from viremic donors in hematopoietic stem cell transplant.

Transmission of hepatitis C virus (HCV) to recipients of hematopoietic stem cell transplant (HSCT) occurs frequently from HCV viremic donors and causes complications. Here, we report the outcomes of 3 cases from our 265 allogeneic HSCTs, whose donors had HCV infections. Successful prevention of HCV transmission was noted in 1 recipient by pretreatment of the donor with peginterferon/ribavirin to undetectable levels of HCV viremia before stem cell harvest. This case stressed the important role of effective antiviral therapy and HCV RNA seronegativity before cell harvest for prevention of HCV transmission in HSCT.

The contributing role of real-life hand skill performance in self-care function of children with and without disabilities.

BACKGROUND: Children's hand skills when performing in real-life contexts have been commonly thought as a possible determinant of their self-care function; however, there is a paucity of research investigating this potential predictive relationship. The purpose of this study was to provide evidence regarding whether children's real-life hand skill performance is contributive to or predictive of their self-care function by considering other child and cultural factors. METHODS: A total of 139 typically developing children and 114 with disabilities, ages 2-12 years from Australia and Taiwan, participated in the study. The outcome measures used were the Assessment of Children's Hand Skills (a measure of real-life hand skill performance) and the Personal Living Skills subscale of the Vineland Adaptive Behavior Scales - Classroom Edition (a measure of self-care function). RESULTS: Hierarchical regression analysis revealed that the children's demographic variables (age, gender, disability status, handedness and cultural context) accounted for 43% of the variance of the self-care function in the combined group of children with and without disabilities. Age, presence of disability and cultural context were the statistically significant independent factors. However, after the entry of the real-life hand skill performance factor, the contributing values of age and disability status decreased and the age factor became non-significant. The hand skill performance factor was found to be the strongest, and its addition led to significant increments of 24.6% of the explained variance for children's self-care function. Similar results were also found in the regression analyses based on separate groups of typically developing children or those with disabilities. CONCLUSIONS: The findings provide evidence that children's real-life hand skill performance is a contributing factor of their self-care function. The assessment of children's hand skill performance in real-life contexts is therefore needed.

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Abnormal liver function test results are related to metabolic syndrome and BMI in Taiwanese adults without chronic hepatitis B or C.

BACKGROUND: Metabolic syndrome (MS) is considered a cause of abnormal deposition of fat into hepatocytes, which might be associated with hepatic steatosis or abnormal liver function. OBJECTIVE: The aim of this study was to explore the factors associated with MS and the relationship between MS and abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels in Taiwanese subjects without chronic hepatitis B (CHB) or C (CHC). SUBJECTS: We enrolled 2539 Taiwanese adults without CHB or CHC (age range: 16-88 years old) and investigated the factors related to MS using the NCEP-ATP (National Cholesterol Education Program-Adult Treatment Panel) III criteria; body mass index (BMI) was measured using Asia-Pacific criteria. RESULTS: The prevalence rate of MS in Taiwanese adults without CHB or CHC was 16.9% using the modified ATP III criteria and 15.4% using the International Diabetes Federation criteria. Males had a significantly higher prevalence rate than females (P<0.001), and subjects with MS were significantly older and had significantly higher BMI values and AST, ALT and GGT levels (all P<0.001). In univariate analyses, the abnormality of liver function test results were related to gender, level of fasting sugar, systolic blood pressure, triglyceride, high-density lipoprotein, BMI and MS (all P<0.05). Multivariate analysis showed that the male gender, a higher BMI value and MS were related to abnormal liver function test results. The cutoff value for ALT in relation to MS is 31 IU l(-1) for male and 18 IU l(-1) for female. CONCLUSION: The prevalence of MS in Taiwanese adults without hepatitis B or C was found to be high, and MS and BMI were identified as being related to abnormal liver function test results in these adults.

Anti-viral therapy is associated with improved survival but is underutilised in patients with hepatitis B virus-related hepatocellular carcinoma: real-world east and west experience.

BACKGROUND: Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. It remains incompletely understood in the real world how anti-viral therapy affects survival after HCC diagnosis. METHODS: This was an international multicentre cohort study of 2518 HBV-related HCC cases diagnosed between 2000 and 2015. Cox proportional hazards models were utilised to estimate hazard ratios (HR) with 95% (CI) for anti-viral therapy and cirrhosis on patients' risk of death. RESULTS: Approximately, 48% of patients received anti-viral therapy at any time, but only 17% were on therapy at HCC diagnosis (38% at US centres, 11% at Asian centres). Anti-viral therapy would have been indicated for >60% of the patients not on anti-viral therapy based on American criteria. Patients with cirrhosis had lower 5-year survival (34% vs 46%; P < 0.001) while patients receiving anti-viral therapy had increased 5-year survival compared to untreated patients (42% vs 25% with cirrhosis and 58% vs 36% without cirrhosis; P < 0.001 for both). Similar findings were seen for other patient subgroups by cancer stages and cancer treatment types. Anti-viral therapy was associated with a decrease in risk of death, whether started before or after HCC diagnosis (adjusted HR 0.62 and 0.79, respectively; P < 0.001). CONCLUSIONS: Anti-viral therapy improved overall survival in patients with HBV-related HCC across cancer stages and treatment types but was underutilised at both US and Asia centres. Expanded use of anti-viral therapy in HBV-related HCC and better linkage-to-care for HBV patients are needed.

Sustained virological response to interferon reduces cirrhosis in chronic hepatitis C: a 1,386-patient study from Taiwan.

BACKGROUND: The long-term benefits of interferon-based therapy on preventing cirrhosis at non-cirrhotic stage in chronic hepatitis C patients are not fully clarified. AIM: To evaluate the effectiveness of interferon-based therapy regarding to cirrhosis prevention in non-cirrhotic chronic hepatitis C patients. METHODS: A total of 1386 biopsy-proven, non-cirrhotic chronic hepatitis C patients (892 received interferon-based therapy and 494 untreated) were enrolled. RESULTS: Fifty-six untreated and 51 treated (24 sustained virologic responders and 27 non-responders) patients developed cirrhosis during a mean follow-up period of 5.0 (1-16) and 5.1 (1-15.3) years, respectively. The annual incidences of cirrhosis in untreated and treated groups were 2.26 and 1.11% (non-responders: 1.99%, sustained responders: 0.74%), respectively. The 15-year cumulative incidence of cirrhosis was significantly lower in treated (9.9%) than untreated patients (39.8%, P = 0.0008, log-rank test). The 14.5-year cumulative incidence of cirrhosis was significantly lower in sustained responders (4.8%) compared with non-responders (21.6%, P = 0.0007) and untreated patients (36.6%, P < 0.0001). The difference was not significant between non-responders and untreated controls. Cox proportional hazards regression showed sustained virologic responders and younger age were independent negative factors for cirrhosis development. CONCLUSION: A sustained virologic response secondary to IFN-based therapy could reduce cirrhosis development in chronic hepatitis C patients.

Clinical evaluation of the COBAS Amplicor HBV monitor test for measuring serum HBV DNA and comparison with the Quantiplex branched DNA signal amplification assay in Taiwan.

AIMS: To evaluate the performance characteristics and clinical usefulness of the COBAS Amplicor HBV monitor (COBAS-AM) test in Taiwan and to examine its correlation with the Quantiplex branched DNA signal amplification (bDNA) assay for measuring serum hepatitis B virus (HBV) DNA concentrations. METHODS: HBV DNA was measured by the COBAS-AM test in 149 sera from chronic HBV infected patients that had previously been analysed by the bDNA assay. RESULTS: The COBAS-AM test showed good reproducibility, with acceptable intra-assay and interassay coefficients of variation (1.6% and 0.9%, respectively) and good linearity (r2=0.98). The overall sensitivity of the COBAS-AM test was significantly higher than that of the bDNA assay (95.3% v 83.2%): 69.6% of samples with HBV DNA below the detection limit of the bDNA assay could be measured by the COBAS-AM test. There was a significant correlation between the results of the two assays (r=0.901; p<0.0001). On average, the results derived from the COBAS-AM test were 0.55 log lower than those of the bDNA assay. HBV DNA concentrations were significantly higher among HBV e antigen (HBeAg) positive patients than negative ones, and higher among patients with abnormal alanine aminotransferase (ALT) concentrations than those with normal ALT concentrations (p=0.0003). CONCLUSIONS: The COBAS-AM assay, more sensitive in HBeAg negative samples than the bDNA assay, can effectively measure HBV DNA concentrations in Taiwanese patients. HBV DNA values measured by the COBAS-AM test and bDNA assay correlate significantly.

Bacterial infection and neutropenia during peginterferon plus ribavirin combination therapy in patients with chronic hepatitis C with and without baseline neutropenia in clinical practice.

BACKGROUND: Peginterferon-alpha-based therapy frequently leads to neutropenia. It remains unclear whether neutropenia is associated with bacterial infection in chronic hepatitis C (CHC). AIM: To evaluate the risk of bacterial infection and neutropenia in patients with CHC treated with peginterferon-alpha/ribavirin. METHODS: In all, 207 patients with CHC with (group A, n = 30) and without (group B, n = 177) baseline neutropenia were treated with peginterferon-alpha/ribavirin. RESULTS: Group A had significantly higher rates of moderate (<750 cells/microL) and severe (<500 cells/microL) neutropenia than group B (70.0% and 26.7% vs. 20.3% and 8.5% respectively, both P < 0.0001). The sustained virological response rate was similar between patients with and without neutropenia, at baseline or during treatment. Bacterial infection occurred in 4.3% of patients. Group A and patients with lower baseline neutrophil counts had substantially higher rates of bacterial infection. Patients with cirrhosis had significantly higher rates of infection during combination therapy than those without cirrhosis (15%, 3 of 20 vs. 3.2%, 6 of 187, P = 0.045). Nadir neutrophil counts were not correlated to infection episodes. CONCLUSIONS: Bacterial infection during peginterferon-based therapy for CHC was associated with comorbidity of cirrhosis, but not with neutropenia, whether at baseline or during treatment. Neutropenic CHC patients might be treated safely with close monitoring.

Antinuclear antibody is associated with a more advanced fibrosis and lower RNA levels of hepatitis C virus in patients with chronic hepatitis C.

AIMS: Positive serum antinuclear antibody (ANA) is present in a number of patients with chronic hepatitis C virus (HCV) infection. This study aimed to evaluate the prevalence of ANA in patients with chronic hepatitis C (CHC) and to elucidate its clinical implications in virological and histological characteristics of CHC infection. METHODS: A total of 614 CHC patients were enrolled in this prospective, hospital-based study. The serum levels of aspartate aminotransferase, alanine aminotransferase and ANA, and HCV genotype, HCV RNA level, and histological activity index scores for liver histopathology, were determined. RESULTS: The prevalence of positive ANA (titre >1:40) was 35.0%. Women had a significantly higher prevalence than men (41.2 vs 31.0%; p = 0.012). Patients positive for ANA were significantly older (mean (SD), 53.7 (10.5) vs 49.7 (11.3) years; p<0.001) and had higher mean (SD) alanine aminotransferase levels (186.9 (178.8) vs 155.50 (113.5) IU/l; p<0.001) and lower mean (SD) HCV RNA levels (5.2 (0.9) vs 5.4 (1.0) log IU/ml; p = 0.048) than those without ANA. Among 447 patients undergoing liver biopsy, those positive for ANA had a significantly higher mean (SD) fibrosis score (2.0 (1.3) vs 1.5 (1.1); p<0.001) and a higher frequency of F3-4 (69/187, 36.9% vs 50/260, 19.2%; p<0.001) than those negative for ANA. Multivariate logistic regression analyses showed that advanced fibrosis, lower HCV RNA levels and age were significant factors related to positive ANA. CONCLUSION: ANA is associated with a more advanced liver fibrosis and lower serum HCV RNA level in patients with CHC.

Serum adiponectin levels in cholesterol and pigment cholelithiasis.

BACKGROUND: Altered adiponectin levels are associated with metabolic abnormalities. The aim of this study was to explore the role of adiponectin in cholelithiasis. METHODS: A radioimmunoassay was used to determine serum adiponectin levels in 58 patients with cholesterol gallstones and 47 with pigment gallstones, and 101 healthy controls. The chemical composition of extracted gallstones was determined by Fourier transform infrared spectroscopy. RESULTS: The mean(s.d.) adiponectin level was decreased in patients with cholesterol gallstones (7.6(4.1) microg/ml; P < 0.001) but raised in patients with pigment gallstones (17.9(9.0) microg/ml; P < 0.001) in comparison with healthy controls (11.7(6.5) microg/ml). Decreased adiponectin levels (odds ratio (OR) 0.85 (95 per cent confidence interval (c.i.) 0.76 to 0.96); P = 0.008) and female sex (OR 6.06 (95 per cent c.i. 2.10 to 17.46); P = 0.001) were associated with cholesterol gallstone formation. Increased adiponectin levels (OR 1.11 (95 per cent c.i. 1.01 to 1.22); P = 0.025) and increased age (OR 1.06 (95 per cent c.i. 1.01 to 1.12); P = 0.029) were associated with pigment gallstone formation. Raised serum aspartate aminotransferase concentration was a risk factor for both cholesterol (OR 1.16 (95 per cent c.i. 1.03 to 1.30); P = 0.013) and pigment (OR 1.23 (95 per cent c.i. 1.10 to 1.38); P < 0.001) gallstones. CONCLUSION: Gallstone formation is associated with altered serum adiponectin levels. Serum adiponectin might serve as a novel marker for cholesterol and pigment cholelithiasis.

Viral hepatitis and proteinuria in an area endemic for hepatitis B and C infections: another chain of link?

BACKGROUND AND OBJECTIVES: Virus hepatitis may lead to nephropathy as one of its multiple extrahepatic manifestations. Proteinuria by dipstick, a simple test in practice, is a useful and cardinal sign of underlying renal abnormalities. The aim of this study was to elucidate the impact of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections on the occurrence of proteinuria amongst adults. DESIGN AND SETTING: A prospective, cross-sectional, community-based study was conducted in an HBV/HCV endemic area of southern Taiwan. Eligible subjects aged 40-65 years (n=9934) underwent testing of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV) and other related biochemical profiles. Urinalysis with repeated dipstick for proteinuria detection was performed. RESULTS: Anti-HCV-positive rate amongst proteinuria subjects was significantly higher than nonproteinuria subjects (9.6% vs. 6.2%, P<0.001). By contrast, HBsAg-positive rate did not differ between subjects with and without proteinuria (13.0% vs. 13.8%, P=0.57). Prevalence of proteinuria amongst anti-HCV-positive subjects (10.2%) was significantly higher than that in HBsAg-positive subjects (6.4%, P=0.004) and in HBsAg-negative or anti-HCV-negative subjects (7.0%, P=0.004). The difference persisted even after excluding diabetics. Multivariate logistic regression analyses showed that diabetes was the most important significant factor associated with proteinuria, followed by hypertension, anti-HCV seropositivity, body mass index, age and triglyceride levels. CONCLUSION: We demonstrated the significant association between proteinuria and HCV, but not HBV, infection in this HBV/HCV-endemic area.

Associations of tumour necrosis factor alpha promoter polymorphisms at position -308 and -238 with clinical characteristics of chronic hepatitis C.

The aim of this study was to investigate the association between G vs A transitions in the promoter region of the tumour necrosis factor (TNF) alpha at positions -308 (TNF308.2) and -238 (TNF238.2) and clinical features of chronic hepatitis C (CHC). These two promoter TNF-alpha variants were determined in 250 biopsy-proven CHC patients by polymerase chain reaction amplification, followed by the Restriction Fragment Length Polymorphism (RFLP) method. The distribution of -308 and -238 TNF-alpha promoter genotypes were TNF308.1/TNF308.1: 187 (74.8%), TNF308.1/TNF308.2: 57 (22.8%) and TNF308.2/TNF308.2: 6 (2.4%), respectively, and TNF238.1/TNF238.1: 247 (98.8%) and TNF238.1/TNF238.2: 3 (1.2%). The frequencies of the TNF308.2 and TNF238.2 promoter alleles were 13.8% and 0.6%. Increased TNF308.2 allele copy numbers were significantly associated with increased frequency of lower pretreatment hepatitis C virus (HCV) RNA levels (<800 000 IU/mL; P = 0.031) and severe fibrosis stage (F3-F4; P = 0.006) and higher mean fibrosis score (P = 0.007). The higher cytokine production (with one or two TNF308.2 alleles) was correlated significantly with lower pretreatment HCV RNA levels with a lower mean HCV RNA level (P = 0.024) and increased frequency of lower pretreatment HCV RNA levels (<800 000 IU/mL; P = 0.017). Stepwise logistic regression showed that higher fibrosis score and low HCV RNA levels were independently related to the TNF308.2 allele [odds ratio (95% CI): 1.385 (1.127-1.702) and 0.698 (0.488-0.990)]. We conclude that inheritance of the TNF-alpha promoter genotype at the position -308 appears to be associated with variability in severity of fibrosis and viral load in chronic HCV infection.

The role of thyroid autoantibodies in the development of thyroid dysfunction in Taiwanese chronic hepatitis C patients with interferon-alpha and ribavirin combination therapy.

To investigate the role of thyroid autoantibodies in the development of thyroid dysfunction among chronic hepatitis C (CHC) patients receiving interferon-alpha (IFN-alpha) plus ribavirin (RBV) combination therapy, 95 Taiwanese naïve patients with baseline euthyroidism were enrolled. They were treated with IFN-alpha2b, 6 million units thrice weekly, plus RBV 1,000-1,200 mg daily for 24 weeks. Thyroid function, anti-thyroglobulin and antiperoxidase autoantibodies were tested at enrollment (M0), at the end-of-treatment (M6) and 6 months after end-of-treatment (M12). The percentages of thyroid autoantibodies were 8.4%, 11.6% and 9.5%, at M0, M6 and M12 respectively. Fourteen (14.7%) patients developed thyroid dysfunction at M6 or M12. Thyroid dysfunction occurred during treatment in five (62.5%) of the eight patients with baseline thyroid autoantibodies, which was significantly higher than nine (10.3%) of 87 patients without baseline thyroid autoantibodies (P = 0.0001). Among 14 patients who developed thyroid dysfunction, four (80.0%) of five patients with baseline thyroid autoantibodies recovered at M12, in contrast to two (25%) of eight without baseline thyroid autoantibodies recovered at M12 (P < 0.05). In conclusion, thyroid autoantibodies, either occurred before or during IFN-alpha plus RBV combination therapy, carry a high prediction of subsequent thyroid dysfunction. There also exists difference in the clinical manifestations of thyroid dysfunction in CHC patients treated with combination therapy.