Saccharomyces cerevisiae I-3856 in irritable bowel syndrome with predominant constipation.

BACKGROUND: Probiotics are a promising solution for managing irritable bowel syndrome (IBS). Saccharomyces cerevisiae (S. cerevisiae) I-3856 has already demonstrated beneficial effects in IBS subjects, particularly in IBS with predominant constipation (IBS-C). AIM: To confirm the efficacy of S. cerevisiae I-3856 in the management of gastrointestinal symptoms in IBS-C. METHODS: A randomized, double-blind, placebo-controlled clinical study was performed in a total of 456 subjects. After a run-in period, subjects were randomly assigned to the group receiving S. cerevisiae I-3856 (8 × 109 CFU daily) or the placebo for 8 wk, and they performed daily self-evaluations of gastrointestinal symptoms. The primary objective was to assess the effect of the probiotic on abdominal pain. The secondary objectives were the evaluation of other gastrointestinal symptoms, bowel movement frequency and consistency, and quality of life (QOL). RESULTS: A significantly higher proportion of abdominal pain responders was reported in the Probiotic group (45.1% vs 33.9%, P = 0.017). A nonsignificant difference in the area under the curve for abdominal pain over the second month of supplementation was observed in subjects receiving probiotic vs placebo [P = 0.073, 95%CI: -0.59 (-1.23; 0.05)]. No statistically significant differences were reported in the evolution of bowel movement frequency and stool consistency between the groups. After 8 wk of supplementation, the overall QOL score was significantly higher in the Probiotic group than in the Placebo group [P = 0.047, 95%CI: 3.86 (0.52; 7.20)]. Furthermore, exploratory analyses showed statistically significant and clinically relevant improvements in QOL scores in abdominal pain responders vs nonresponders. CONCLUSION: The results of this clinical study confirmed the abdominal pain alleviation properties of S. cerevisiae I-3856 in IBS-C. Abdominal pain relief was associated with improved QOL. ClinicalTrials.gov identifier: NCT03150212.

Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer.

PURPOSE: MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy. We investigated the predictive role of this biomarker in the FIRE-3 study population, including its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy. EXPERIMENTAL DESIGN: MiR-31-3p expression was measured in primary tumors obtained from 340 patients with RAS WT mCRC enrolled in the FIRE-3 Trial. This included 164 patients randomized to receive FOLFIRI plus cetuximab (FOLFIRI+Cetux) and 176 to FOLFIRI plus bevacizumab (FOLFIRI+Beva). Patients were divided into subgroups defined by low or high miR-31-3p expression using a prespecified cut-off and by treatment arm. Analyses were performed to assess treatment efficacy by subgroup. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and Cox regression models. Investigator-assessed objective response (iOR), early tumor shrinkage at 6 weeks (ETS), and centrally reviewed objective response (cOR) were analyzed using logistic regression models. The predictive value of miR-31-3p expression level was assessed through a treatment interaction test using multivariate models adjusted for potential confounding factors. RESULTS: Low miR-31-3p expressers benefited from cetuximab compared with bevacizumab for PFS [HR, 0.74; 95% confidence interval (CI), 0.55-1.00; P = 0.05], OS (HR, 0.61; 95% CI, 0.41-0.88; P < 0.01), iOR (OR, 4.0; 95% CI, 1.9-8.2; P < 0.01), ETS (OR, 4.0; 95% CI, 2.1-7.7; P < 0.01 and cOR (OR, 4.9; 95% CI, 2.3-10.5; P < 0.01) in multivariate analyses. There was no difference in outcomes for high expressers between treatment arms. MiR-31-3p expression level was predictive of treatment effect for PFS (P = 0.03), OS (P = 0.05), iOR (P = 0.02), ETS (P = 0.04), and cOR (P < 0.01). CONCLUSIONS: MiR-31-3p expression level was validated as a predictive biomarker of cetuximab therapy efficacy for patients with RAS WT mCRC.

Association between miR-31-3p expression and cetuximab efficacy in patients with KRAS wild-type metastatic colorectal cancer: a post-hoc analysis of the New EPOC trial.

BACKGROUND: High miR-31-3p expression is associated with inferior outcomes in KRAS wild-type (WT) advanced colorectal cancer patients treated with anti-EGFR therapy. This study evaluated miR-31-3p expression in patients with operable colorectal liver metastases (LM) enrolled in the New EPOC study. METHODS: MiR-31-3p expression was measured in primary tumors (PT) from 149 KRAS WT patients including 71 receiving chemotherapy alone (CT) and 78 receiving chemotherapy plus cetuximab (CTX). Each treatment arm was split into tertiles based on miR-31-3p expression levels. MiR-31-3p expression was also measured in LM from 94 patients with tumor tissue available. RESULTS: The median progression-free survival for the combined populations with mid or high miR-31-3p expression was shorter in the CTX versus the CT arm (26.7 months versus 12.3 months, HR=2.28 95%CI 1.27; 4.09 p=0.006). Low miR-31-3p expressers had similar outcomes irrespective of treatment (HR=1.06 95%CI 0.43; 2.61 p=0.9). MiR-31-3p expression was correlated between paired PT and LM samples in the CT group but not in the CTX group. CONCLUSIONS: Patients with low miR-31-3p expression in the New EPOC study were not harmed by the addition of cetuximab. This supports miR-31-3p as a promising predictive biomarker for anti-EGFR therapy in KRAS WT advanced colorectal cancer.

Field seasonal influenza vaccine effectiveness: evaluation of the screening method using different sources of data during the 2010/2011 French influenza season.

Thanks to the screening method, we estimated among target groups the 2010/2011 field vaccine effectiveness (FVE) against laboratory confirmed influenza cases seen in general practice. We also compared the values of FVE estimations obtained by using three sources of the population vaccination coverage (VC) based on three different methodologies: (1) administrative data from the main social security scheme (Caisse Nationale d'Assurance Maladie des Travailleurs Salariés--CNAMTS) covering about 85% of the French population, (2) a cross-sectional national telephone survey in the general population, and (3) a declarative survey in the population seen in a one-day general practitioner (GP) consultations. The FVE estimates among target groups were stratified by age (< 65 y old with reported chronic illness; ≥65 y old and overall). Using the VC of the CNAMTS, the FVE of the 2010/2011 seasonal trivalent vaccine against laboratory confirmed infection with any influenza virus was 59% (95% Confidence Interval, 17 to 81). It was 85% (17 to 99) and 50% (-16 to 80) for A(H1N1)pdm09 and B influenza infections, respectively. The values of FVE using the influenza VC obtained in a sample of the general population and of the population of GPs' patients were 73% (45 to 87) and 82% (63 to 92), respectively. We estimated a moderate influenza FVE in preventing confirmed influenza viruses in target groups by using the VC of the CNAMTS. We also observed that the screening method generates FVE values dependent on the choice of the source of VC and thus should be used cautiously.

Rates of immunization against pandemic and seasonal influenza in persons at high risk of severe influenza illness: a cross-sectional study among patients of the French Sentinelles general practitioners.

BACKGROUND: Three main categories of persons are targeted by the French influenza vaccination strategy: all persons aged 65 years or over, those aged less than 65 years with certain underlying medical conditions and health care workers. The main objective of this study was to estimate rates of influenza immunization in these target groups attending a medical consultation for two consecutive influenza seasons: 2009-2010 (seasonal and pandemic vaccines) and 2010-2011 (seasonal vaccine). METHODS: A standardized questionnaire was mailed to 1323 general practitioners (GPs) of the Sentinelles Network, collecting data on all patients seen on a randomly assigned day. For every patient, following information was collected: age, gender, BMI, presence of any medical condition that increases risk of severe influenza illness, and vaccination status for the three vaccines mentioned. RESULTS: Two hundred and three GPs agreed to participate and included 4248 patients. Overall, in persons with high risk of severe influenza, the estimated vaccine coverages (VC) were 60%, (95% CI = 57%; 62%) for the seasonal vaccine in 2010-2011, 61% (59%; 63%) for the seasonal vaccine in 2009-2010 and 23% (21%; 25%), for the pandemic vaccine in 2009-2010. Among people aged 65 years and over (N=1259, 30%) VC was estimated for seasonal vaccines at 72% (70%; 75%) in 2010-2011 and 73% (71%; 76%) in 2009-2010, and 24% (22%; 26%) for the pandemic vaccine. The lowest seasonal VC were observed in younger persons (<65 years) with underlying medical conditions, in particular pregnant women (<10%) and overweight persons (<30%). CONCLUSIONS: Our study shows that influenza vaccination coverage among patients of the French Sentinelles general practitioners remains largely below the target of 75% defined by the 2004 French Public Health Law, and underscores the need for the implementation of public health interventions likely to increase vaccination uptake.

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project.

BACKGROUND: Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the IL18 gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, IL18R1 and IL18RAP, with the risk of developing CVD. METHODS: Eleven tagging SNPs, 5 in IL18R1 and 6 in IL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD. RESULTS: We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 IL18 SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful. CONCLUSION: Our analysis suggests that the variability of IL18R1 and IL18RAP genes are unlikely to contribute to modulate the risk of CVD.

Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: the MORGAM Project.

Interleukin-18 (IL-18) is a key inflammatory molecule suspected of being involved in the etiology of cardiovascular diseases (CVD). Five single nucleotide polymorphisms (SNPs) capturing the common genetic variation of the IL-18 gene (tag SNPs) were genotyped in five European prospective CVD cohorts including 1933 cases and 1938 non-cases as part of the MORGAM Project. Not a single SNP was found associated with CVD. However, a significant (P=0.002) gene-smoking interaction was observed. In smokers, the -105T allele was more frequent in cases than in non-cases (0.29 vs 0.25) and associated with an increased risk of disease (odds ratio (OR)=1.25 (1.07-1.45), P=0.005), whereas the inverse relationship tended to be observed in non-smokers (OR=0.90 (0.78-1.02), P=0.131). The gene-smoking interaction was broadly homogenous across the cohorts and was also observed through haplotype analyses. In conclusion, using the concerted effort of several European prospective CVD cohorts, we are able to show that one IL-18 tag SNP interacts with smoking to modulate the risk of developing CVD.