Université Victor Segalen Bordeaux 2
  • Bordeaux, Aquitaine, France
Recent publications
Introduction: Because patients and patient organizations want to strengthen their role in the care pathway and drug evaluation and in order to improve pharmacovigilance activities, European competent authorities implemented regulations to allow direct reporting of adverse drug reactions related to medicinal products by patients in 2012. Objectives: Describe and study determinants and evolution of patient reporting activity in France to assess patient involvement in pharmacovigilance. Method: Using the French national pharmacovigilance database, univariate and multivariate analyses were performed to compare characteristics of patients and healthcare professionals (HCP) adverse drug reaction (ADR) report from 2011 to 2020. Then, we analyzed ADR report activities from patients according to regional demographics and economics characteristics. Results: We observed a significant and higher increase in ADR report over time from patient (r=0.89, p<0.001) compared to HCP reporting (r=0.27, p=0.002). Patient ADR report activities compared to HCP concerned more women (80% vs 55%, p<0.001), younger age classes (p<0.001) or reporting through web portal (83% vs 17%, p<0.001) and less serious events (26% vs 63%, p<0.001). In the principal component analysis, regional patient reporting activity was mainly related to socio-professional categories, age classes and densities of hospital beds and physicians. Conclusion: Our results confirm an increasing involvement of patients in ADR report activities. The determinants of patient reporting activities are not only related to drug and medical factors but also to social factors. Digital tools may also play a role in health democracy in pharmacovigilance.
Background In Benin, access to water, sanitation and hygiene (WASH) remains an issue. This study aims to provide an overview of household access to basic WASH services based on nationally representative data. Method Secondary analyses were run using the ‘HOUSEHOLD’ dataset of the fifth Demographic and Health Survey 2017–2018. The dependent variables were household access to individual and combined basic WASH services. The characteristics of the household head and those related to the composition, wealth and environment of the household were independent variables. After a descriptive analysis of all study variables, multivariate logistic regression was performed to identify predictors of outcome variables. Results The study included 14,156 households. Of these, 63.98% (95% CI = 61.63–66.26), 13.28% (95% CI = 12.10–14.57) and 10.11% (95% CI = 9.19–11.11) had access to individual basic water, sanitation and hygiene facilities, respectively. Also, 3% (95% CI = 2.53–3.56) of households had access to combined basic WASH services. Overall, the richest households and few, and those headed by people aged 30 and over, female and with higher levels of education, were the most likely to have access to individual and combined basic WASH services. In addition, disparities based on the department of residence were observed. Conclusion The authors suggest a multifactorial approach that addresses the identified determinants.
Importance: Ablation of persistent atrial fibrillation (AF) remains a challenge. Left atrial fibrosis plays an important role in the pathophysiology of AF and has been associated with poor procedural outcomes. Objective: To investigate the efficacy and adverse events of targeting atrial fibrosis detected on magnetic resonance imaging (MRI) in reducing atrial arrhythmia recurrence in persistent AF. Design, setting, and participants: The Efficacy of Delayed Enhancement-MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation of Atrial Fibrillation trial was an investigator-initiated, multicenter, randomized clinical trial involving 44 academic and nonacademic centers in 10 countries. A total of 843 patients with symptomatic or asymptomatic persistent AF and undergoing AF ablation were enrolled from July 2016 to January 2020, with follow-up through February 19, 2021. Interventions: Patients with persistent AF were randomly assigned to pulmonary vein isolation (PVI) plus MRI-guided atrial fibrosis ablation (421 patients) or PVI alone (422 patients). Delayed-enhancement MRI was performed in both groups before the ablation procedure to assess baseline atrial fibrosis and at 3 months postablation to assess for ablation scar. Main outcomes and measures: The primary end point was time to first atrial arrhythmia recurrence after a 90-day blanking period postablation. The primary safety composite outcome was defined by the occurrence of 1 or more of the following events within 30 days postablation: stroke, PV stenosis, bleeding, heart failure, or death. Results: Among 843 patients who were randomized (mean age 62.7 years; 178 [21.1%] women), 815 (96.9%) completed the 90-day blanking period and contributed to the efficacy analyses. There was no significant difference in atrial arrhythmia recurrence between groups (fibrosis-guided ablation plus PVI patients, 175 [43.0%] vs PVI-only patients, 188 [46.1%]; hazard ratio [HR], 0.95 [95% CI, 0.77-1.17]; P = .63). Patients in the fibrosis-guided ablation plus PVI group experienced a higher rate of safety outcomes (9 [2.2%] vs 0 in PVI group; P = .001). Six patients (1.5%) in the fibrosis-guided ablation plus PVI group had an ischemic stroke compared with none in PVI-only group. Two deaths occurred in the fibrosis-guided ablation plus PVI group, and the first one was possibly related to the procedure. Conclusions and relevance: Among patients with persistent AF, MRI-guided fibrosis ablation plus PVI, compared with PVI catheter ablation only, resulted in no significant difference in atrial arrhythmia recurrence. Findings do not support the use of MRI-guided fibrosis ablation for the treatment of persistent AF. Trial registration: ClinicalTrials.gov Identifier: NCT02529319.
Background and Aims The liver cancer risk test (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein A1, haptoglobin), hepatocellular carcinoma (HCC) risk factors (gender, age, gamma glutamyl transpeptidase), a marker of fibrosis (alpha2-macroglobulin), and alpha-fetoprotein, a specific marker of HCC. The aim was to externally validate LCR1-LCR2 in hepatitis B. Methods Preincluded patients were from the Hepather cohort, a multicenter, multiethnic prospective study in 6071 patients. The coprimary study outcome was the negative predictive value of LCR1-LCR2 at 5 years for the occurrence of HCC and survival without HCC according to the predetermined LCR1-LCR2 cutoffs, adjusted for risk covariables and for chronic hepatitis B treatment and quantified using time-dependent Cox proportional hazards models. A post hoc analysis compared the number of patients needed to screen one cancer by LCR1-LCR2 and PAGE-B. Results A total of 3520 patients, 191 (5.4%) with cirrhosis, with at least 1 year of follow-up were included. A total of 76 HCCs occurred over a median (interquartile range) of 6.0 years (4.8–7.3) of follow-up. Among the 3367 patients with low-risk LCR1-LCR2, the 5-year negative predictive value was 99.3% (95% confidence interval = 99.0–99.6), with a significant Cox hazard ratio (6.4, 3.1–13.0; P < .001) obtained after adjustment for exposure to antivirals, age, gender, geographical origin, HBe-Ag status, alcohol consumption, and type-2 diabetes. LCR1-LCR2 outperformed PAGE-B for number of patients needed to screen mean (95% CI), 8.5 (3.2–8.1) vs 26.3 (17.5–38.5; P < .0001), respectively. Conclusion The performance of LCR1-LCR2 to identify patients with chronic hepatitis B at very low risk of HCC at 5 years was externally validated. ClinicalTrials.gov: NCT01953458.
In the present paper we investigate the qualitative behaviour of a fractional SEIR model with general incidence rate function and time delay where the fractional derivative is defined in the Caputo sense. The basic reproduction number $\mathcal{R}_{0}$ is derived using the method of next generation matrix and we give a complete study of local stability of both free and endemic equilibrium. Using Liapunov method we prove the global stability of free and endemic equilibrium under some hypotheses on the parameters of the system. Finally to illustrate our results, we use the model to predict the first peak of the COVID-19 epidemic in Algeria.
BACKGROUND AND AIMS Elevated serum urea levels are common in moderate-to-advanced CKD. Several studies have shown that urea is a direct and indirect uremic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before kidney replacement therapy (KRT) in patients with CKD. METHOD CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 < 10.5, T2:10.5–15.1 and T3 ≥ 15.1 mmol/L). Cause-specific Cox proportional hazard models were used to estimate hazard ratios (HRs) for the first atheromatous or nonatheromatous cardiovascular (CV) events and all-cause mortality before KRT. The models were adjusted for baseline comorbidities, laboratory data, and medications. Cardiovascular events of the first 3 years of follow-up in the CKD-REIN study were assessed carefully according to the Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Each death before KRT occurring during the 5-year follow-up period was used in the all-cause mortality model. RESULTS Of the 2507 included patients {median [first quartile–third quartile (Q1–Q3)] age: 69 (61–77); mean (standard deviation) eGFR 33.5(11.6) mL/min/1.73 m²}, 54% had a history of cardiovascular disease. Over a median follow-up of 3.0 years [Q1–Q3, 2.2–3.1], 451 experienced their first atheromatous or nonatheromatous cardiovascular event (fatal or nonfatal), leading to an incidence rate (IR) [95% confidence interval (95% CI)] of 7.1 (6.4–7.7)/100 person-years (PYs) (Fig. 1). Over a median follow-up period of 4.8 (3.3–5.1) years, 407 patients died before KRT, leading to an IR of 4.0 (3.6–4.3)/100 PYs. After multiple adjustments for cardiovascular risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and nonatheromatous cardiovascular events than patients in T1 [HR (95% CI), 2.08 (1.50–2.88), Fig. 1]. A nonsignificant trend towards a higher risk was also noted for patients in T2 [1.28 (0.96–1.71)]. The adjusted HRs for death before KRT were 1.30 (0.96–1.75] and 1.73 (1.22–2.45) for patients in T2 and those in T3, respectively. CONCLUSION Beyond CV risk factors including eGFR, this hypothesis-generating study suggests that serum urea level is a predictor of cardiovascular outcomes in patients with moderate to advanced CKD. Further research is needed to confirm current findings and explore mechanisms.
Background & Aims Prediction of hepatocellular carcinoma (HCC) occurrence in patients with chronic hepatitis C (HCV) who achieved a sustained virological response (SVR) after direct acting antivirals (DAAs) remains challenging. Methods Among HCC-free HCV patients with advanced fibrosis enrolled in the ANRS CO22 HEPATHER cohort who achieved SVR 12 weeks after treatment with DAAs, HCC predictive models were developed using Cox multivariable regression. The derived score was externally validated in a large Egyptian cohort. Our main outcome was the HCC-free survival. Results During follow-up (median 3.05 years), 153 out of 3531 patients developed a HCC. Main variables associated with HCC occurrence were: male gender, HCV genotype 3, esophageal varices, albumin < 40 g/L, total bilirubin >11 µmol/L and hypercholesterolemia before DAA initiation, together with age > 58 years, FIB-4 index ≥3.25 evaluated at SVR. A score was established allowing the stratification of patients by high (score ≥ 12/22), intermediate (7 ≤ score <12) and low risk of HCC (score < 7/22) with 3-yrs HCC incidence of 18.96%, 5.50% and 1.65%, respectively. The integrated time‐dependent area under the ROC curve (i-AUC) was 0.76 in our patients and 0.61 in the validation cohort. Conclusion The externally validated HEPATHER HCC score has good short-term predictive performance in HCV- patients who achieved SVR12 after DAAs allowing to identify high-risk patients in whom HCC screening may be cost-effective and low-risk patients in whom HCC screening may be superfluous in the first 3 years after SVR.
Background and AimsLittle is known about the effects of probiotics on inflammation in the context of chronic kidney disease (CKD). We investigated the association between probiotic intake and inflammation in patients with moderate-to-advanced CKD.Methods We performed a cross-sectional study of 888 patients with stage 3–5 CKD and data on serum C-reactive protein (CRP) levels and a concomitant food frequency questionnaire. We estimated the odds ratios (ORs) [95% confidence interval (CI)] for various CRP thresholds (>3, >4, >5, >6, and >7 mg/L) associated with three intake categories (no yoghurt, ordinary yoghurt, and probiotics from yoghurts or dietary supplements) and two frequency categories (daily or less than daily).ResultsThe 888 study participants (median age: 70; men: 65%) had a median estimated glomerular filtration rate of 28.6 mL/min/1.73 m2 and a median [interquartile range] CRP level of 3.0 [1.6, 7.0] mg/L. Fifty-seven percent consumed ordinary yoghurt and 30% consumed probiotic yoghurt. The median intake frequency for yoghurt and probiotics was 7 per week. Relative to participants not consuming yoghurt, the ORs [95% CI] for CRP > 6 or >7 mg/L were significantly lower for participants consuming ordinary yoghurt (0.58 [0.37, 0.93] and 0.57 [0.35, 0.91], respectively) and for participants consuming probiotics (0.54 [0.33, 0.9] and 0.48 [0.28, 0.81], respectively), independently of age, sex, body mass index, CKD stage, cardiovascular disease, and fibre, protein and total energy intakes. The ORs were not significantly lower for CRP thresholds >3, >4, and >5 mg/L and were not significantly greater in daily consumers than in occasional consumers.Conclusion We observed independent associations between the consumption of yoghurt or probiotics and lower levels of inflammation in patients with CKD. There was no evidence of a dose-effect relationship.Clinical Trial Registration[https://www.clinicaltrials.gov/ct2/show/NCT03381950], identifier [NCT03381950].
A computer-aided diagnosis system is one of the crucial decision support tools under the medical imaging scope. It has recently emerged as a powerful way to diagnose Alzheimer’s Disease (AD) from structural magnetic resonance imaging scans. However, due to the deficit of recognition memory in the Mild Cognitive Impairment (MCI) stage, semantic feature ambiguity, and high inter-class visual similarities problems, computer-aided diagnosis of AD remains challenging. To bridge these gaps, this paper proposed a hippocampus analysis method based on a novel 3D convolutional neural network fusion strategy, called Bidirectional Gated 3D Multi-scale Feature Fusion (BG-3DM2F). The suggested BG-3DM2F framework consists of two modules: 3D Multi-Scale Chained Network (3DMS-ChaineNet) and Bidirectional Gated Recurrent Fusion Unit (Bi-GRFU). The 3DMS-ChaineNet architecture is introduced to design the subtle features and capture the variations in hippocampal atrophy, while the Bi-GRFU scheme is investigated to store 3DMS-ChaineNet levels in the forward and backward fashion and retain them in the decision-making process. For validation, our solution is completely evaluated on the public Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Practically, we conducted empirical evaluations to verify the effect of BG-3DM2F components. In comparison with the current state-of-the-art methods, the experiments show that our proposed approach provides efficient results, achieving the accuracies of 98.12%, 95.26%, and 96.97% for binary classification of Normal Control (NC) versus AD, AD versus MCI, and NC versus MCI, respectively. Therefore, we can conclude that our proposed BG-3DM2F system has the potential to dramatically improve the conventional classification methods for assisting clinical decision-making.
Introduction et but de l’étude L’effet de la consommation de probiotique sur l’inflammation dans la maladie rénale chronique (MRC) est mal connu. L’objectif était d’étudier l’association entre la consommation de probiotique et l’inflammation chez des patients avec une MRC modérée ou avancée. Matériel et méthodes Cette étude transversale est basée sur 888 patients stade 3–5 de la cohorte prospective nationale CKD-REIN. La consommation de yaourts et probiotiques a été évaluée par un questionnaire de fréquence alimentaire. Les odds-ratios d’inflammation associés à la consommation de yaourts considérée en 3 catégories (pas de yaourts, yaourts ordinaires, probiotiques : yaourts ou compléments alimentaires) ont été estimés pour différents seuils de CRP (> 3, 4, 5, 6 ou 7 mg/L) par régression logistique. L’association avec la fréquence de consommation (régulier : 1 fois par jour ou occasionnel) a aussi été évaluée. Résultats et analyse statistique Les patients (âge médian 70 ans, DFGe médian 28,6 mL/min/1,73 m²) avaient une CRP médiane de 3,0 [1,6, 7,0] mg/L. 57 % consommaient des yaourts ordinaires et 30 % des probiotiques avec une médiane de 7 par semaine. Comparés aux non-consommateurs, les patients consommant des yaourts ordinaires avaient des ORs (95 %IC) pour une CRP > 6 ou > 7 mg/L significativement plus bas, respectivement, 0,58 [0,37 ; 0,93] et 0,57 [0,35 ; 0,91], ainsi que ceux consommant des probiotiques, 0,54 [0,33 ; 0,9] et 0,48 [0,28 ; 0,81], indépendamment de l’âge, de l’IMC, du stade de la MRC, des antécédents cardiovasculaires, ainsi que des apports en fibres, en protéines et en énergie totale. Ces ORs n’étaient pas significativement plus faibles pour des seuils de CRP < 6, ni pour une fréquence de consommation occasionnelle plutôt que régulière. Conclusion Notre étude montre une association indépendante entre la consommation de probiotiques et de yaourts ordinaires avec la réduction de l’inflammation chez les patients avec une MRC, qui ne semble pas être dose dépendante.
Background: In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods: We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results: 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7-51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24-0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08-0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15-0.54, p < 0.0001), liver-related mortality (HR 0.40, 95% CI 0.17-0.96, p = 0.04), non-liver-related mortality (HR 0.17, 95% CI 0.06-0.49, p = 0.001), liver transplantation (HR 0.17, 95% CI 0.05-0.54, p = 0.003), and hepatocellular carcinoma (HR 0.52, 95% CI 0.29-0.93, p = 0.03). Conclusion: Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. Trial registration: ClinicalTrials.gov registry number: NCT01953458.
This study compared the effects of varying aerobic training programs on pulmonary diffusing capacity (TLCO), pulmonary diffusing capacity for nitric oxide (TLNO), lung capillary blood volume (Vc) and alveolar–capillary membrane diffusing capacity (DM) of gases at rest and just after maximal exercise in young athletes. Sixteen healthy young runners (16–18 years) were randomly assigned to an intense endurance training program (IET, n = 8) or to a moderate endurance training program (MET, n = 8). The training volume was similar in IET and MET but with different work intensities, and each lasted for 8 weeks. Participants performed a maximal graded cycle bicycle ergometer test to measure maximal oxygen consumption (VO2max) and maximal aerobic power (MAP) before and after the training programs. Moreover, TLCO, TLNO and Vc were measured during a single breath maneuver. After eight weeks of training, all pulmonary parameters with the exception of alveolar volume (VA) and inspiratory volume (VI) (0.104 < p < 0889; 0.001 < ES < 0.091), measured at rest and at the end of maximal exercise, showed significant group × time interactions (p < 0.05, 0.2 < ES < 4.0). Post hoc analyses revealed significant pre-to-post decreases for maximal heart rates (p < 0.0001, ES = 3.1) and improvements for VO2max (p = 0.006, ES = 2.22) in the IET group. Moreover, post hoc analyses revealed significant pre-to-post improvements in the IET for DM, TLNO, TLCO and Vc (0.001 < p < 0.0022; 2.68 < ES < 6.45). In addition, there were increases in Vc at rest, VO2max, TLNO and DM in the IET but not in the MET participants after eight weeks of training with varying exercise intensities. Our findings suggest that the intensity of training may represent the most important factor in increasing pulmonary vascular function in young athletes.
Background: The role of maintenance lenalidomide in myeloma, following autologous stem cell transplantation (ASCT) or not, is well established. However, 29% of patients discontinue the treatment with a median duration of less than 2 years with an increased rate of secondary primary malignancies (SPM). Pomalidomide could provide alternative maintenance therapy. Methods: This was a single arm phase II study of pomalidomide/dex (PD) maintenance therapy for MM patients (pts) in first relapse after treatment in the IFM 2009 trial. At first relapse, 100 pts received pomalidomide/cyclophosphamide/dex (PCD) for 4 cycles, after which half underwent ASCT (if no first line transplant) followed by 2 cycles of PCD consolidation (Arm A), or 5 cycles of PCD (if previously transplanted) (Arm B). All pts then received maintenance therapy consisting of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dex 20 mg once a week until progression (Blood 2018). The primary objective was to establish the safety and efficacy of PD as maintenance therapy. Results: A total of 75 pts were enrolled in the maintenance phase from January 2015 to November 2017 (Table 1) and the database was locked on 07/07/2021. The median age was 60 (range 39-70); 67% (50/75) were male. 53 pts had ISS stage I, 10 stage II and 3 stage III disease (9 missing). Infectious prophylaxis was antiviral in 94%, sulfamethoxazole/trimethoprim in 76%, penicillin in 69% and fluoroquinolone in 38%. A granulocyte colony stimulating factor was administered in 15 (20%) pts and immunoglobulins in 13 (17%). One quarter had thromboprophylaxis. The median follow-up was 73 months (95% CI: 68-75). Among the 75 pts, 63 (84%) left the study, 34 (54%) due to progressive disease, 19 (30%) due to AE/SAE, 7 (11%) on investigator (PI) discretion and 3 (5%) after consent withdrawal. 12 (16%) remained on therapy in July 2021.The median duration of maintenance was 23.7 months (IQR: 14.5-44). Pts received a median of 26 cycles (range 1-80) and 17 (23%) had 50 or more cycles. The reasons for pomalidomide discontinuation were progression or death in 54%, AE/SAE in 30%, PI decisions in 11% and patient decisions in 5%. 56 (75%) pts required a reduction in the dose of pomalidomide due to AE/SAE in 50%, omission in 19%, resumption of treatment in 11%, PI decisions in 16% and patient decisions in 2.7%. The reasons for dex discontinuation were progression or death in 30%, AE/SAE in 43%, PI decisions in 22% and patient decisions in 3%. 57 (76%) pts required a reduction in the dose of dex due to AE/SAE in 54%, omission in 3.4%, resumption of treatment in 0.3%, PI decisions in 38.7% and patient decisions in 3.1%. 31 SAE were reported in 22 pts: 13 (42%) infections, 5 tumors, 1 case of thrombosis, 1 diabetic ketoacidosis and 12 others. Grade 3/4 hematologic AE included neutropenia (51%), lymphopenia (35%), anemia and thrombocytopenia (0%). G3/4 drug-related non-hematologic AE (>5%) comprised 13% infections (5% pneumonia). G1/2 AE included 69% infections (49% bronchitis), 49.3% gastrointestinal disorders (20% diarrhea, 20% constipation), 48% fatigue, 31% skin disorders, 25% muscle spasms, 24% insomnia and 14.7% eye disorders (6.7% cataracts, 4% dry eyes). Concerning peripheral neuropathy, one patient had G3/4 and 45% G1/2. Eight pts developed SPM: 4 basocellular carcinoma, 1 epidermoid carcinoma, 1 melanoma, 1 colon carcinoma and 1 non small cell bronchial carcinoma. We observed an improvement in the response from the initiation of treatment: PR: 32.4 to 17.4%, VGPR: 56.8 to 49.3%, CR: 9.5 to 28%, sCR: 0 to 5.3% (at initiation to best response, respectively). A total of 33.4% of pts improved their response. The median PFS was 33.2 months (95% CI: 25.6-53.3). 41 pts died and the median OS was not reached (95% CI: 70.7-NR). All deaths were related to myeloma progression except 2 due to pulmonary infection, 1 lung carcinoma and 1 colorectal cancer. Conclusions: In the first relapse PCD trial, 75% initiated maintenance therapy. Long term administration of pomalidomide/dexamethasone as maintenance therapy is feasible. Thirty percent stopped pomalidomide because of SAE/AE, mostly related to hematologic AE, but this could be managed with dose reductions. There was generally G1/2 neuropathy, rare SPM and no other unexpected toxicity. One third of the pts improved their depth of response. The combination is safe, feasible and well tolerated and experience to date supports its further exploration with monoclonal antibodies. Figure 1 Figure 1. Disclosures Garderet: Amgen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Roussel: Amgen: Consultancy; BMS: Honoraria; GSK: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Leleu: Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Karlin: Takeda: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Abbvie: Honoraria; oncopeptide: Honoraria; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Celgene-BMS: Honoraria, Other: member of advisory board. Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Macro: abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; takeda: Honoraria; janssen: Honoraria. Jourdan: Novartis: Consultancy; Abbvie: Consultancy; bms/celgene: Consultancy. Jaccard: Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Mohty: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. OffLabel Disclosure pomalidomide as maintenance treatment
Background: The clinical course of immune thrombocytopenia (ITP) can be categorized into three phases: newly diagnosed (<3 months post-diagnosis), persistent (≥3-≤12 months) or chronic (>12 months). Having previously been restricted to use in patients with chronic ITP, romiplostim (a thrombopoietin receptor agonist) was recently approved in the USA and Europe for use across all phases of ITP in adult patients refractory to 1st line treatments. Its efficacy and safety in adult patients with ITP diagnosed for ≤6 months have been reported in a Phase 2 study (Newland, BJH 2016); however, its effect in patients with newly diagnosed ITP is not well characterized. Here we report post hoc analyses from the same Phase 2 romiplostim study stratified by duration of ITP diagnosis (<3 months and ≥3-≤12 months). Methods: Adult patients with primary ITP diagnosed within 6 months prior to study entry and an insufficient response to first-line therapies (corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin or vinca alkaloids) were enrolled in a Phase 2, interventional, single-arm study (NCT01143038). Patients had to have a single platelet count ≤30 × 10 9/L at any time during the 4-week screening period. Splenectomized patients, those who received rituximab, and those who had previously received romiplostim or other platelet-producing agents were excluded. Patients were to receive 12 months of romiplostim therapy at a starting dose of 1 µg/kg, with dose adjusted to target platelet counts ≥50-<200 ×10 9/L. Concomitant and rescue treatments were permitted to maintain platelet count. Following the 12-month treatment period, romiplostim dose was tapered for patients maintaining platelet count ≥50 × 10 9/L. Tapering could also begin earlier during the 12-month treatment period according to platelet counts and dose adjustment rules. Efficacy outcomes included the duration (expressed as a percentage of months) with platelet response (defined as median platelet count ≥50 × 10 9/L during a month without rescue medication use in the previous 8 weeks) during the 12-month treatment period; treatment-free remission (TFR; weekly platelet count ≥50 × 10 9/L for 24 consecutive weeks with no ITP treatments); time to platelet response; durable platelet response (platelet response for ≥6 of the last 8 weeks of treatment during the first 24 weeks); and sustained platelet response (platelet response for 9 weeks in any 12-week period). Safety was assessed throughout the study. Post hoc analyses were performed by subgroups of ITP duration (newly diagnosed ITP: <3 months; persistent ITP ≥3-≤12 months). Results: Of 75 patients enrolled, 45 had newly diagnosed ITP, 30 had persistent ITP. Baseline demographic are shown in the Table. Mean (standard deviation; SD) duration of platelet response was 80.1% (35.4) of months for patients with newly diagnosed ITP and 80.9% (29.9) for patients with persistent ITP (Table). Median (range) weeks to first platelet response was 2.1 (0-11) in the newly diagnosed group and 2.1 (1-25) in the persistent ITP group. In the newly diagnosed ITP group 21 (46.7%) and 31 (68.9%) patients had durable and sustained platelet response, respectively; in the persistent ITP group, 16 (53.3%) and 24 (80.0%) patients had durable and sustained platelet response, respectively. TFR was achieved by 17 (37.8%) newly diagnosed patients and 7 (23.3%) persistent ITP patients. Median (range) weeks to TFR was 21 (6-57) in the newly diagnosed group and 43 (9-53) in the persistent ITP group. The safety profile of romiplostim was broadly similar across the two groups. Conclusion: In this Phase 2 study of patients with primary ITP and disease duration of ≤6 months, romiplostim demonstrated efficacy irrespective of whether patients had newly diagnosed (<3 months duration) or persistent (≥3-≤12 months) disease. Efficacy outcomes were generally similar in both groups of patients, with rapid time to platelet response (~2 weeks) observed and around half of patients achieving a durable platelet response. Respective TFR rates were 37.8% and 23.3% in patients with newly diagnosed and persistent ITP. Safety was consistent across groups and no new safety signals were observed. This subgroup analysis was consistent with the previously reported overall findings of the study and supports the use of romiplostim for adult patients with primary ITP, including those with newly diagnosed and persistent disease. Figure 1 Figure 1. Disclosures Newland: GSK: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; BMS: Research Funding; Argenx: Consultancy, Speakers Bureau; Angle: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; UCB Biosciences: Consultancy; Roche: Speakers Bureau; Octapharma: Research Funding. Viallard: LFB: Consultancy; Grifols: Consultancy; Novartis: Consultancy; Amgen: Consultancy. López Fernández: Amgen: Honoraria. Eisen: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Hippenmeyer: Amgen: Current Employment, Current equity holder in publicly-traded company. Godeau: Novartis: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Grifols: Consultancy.
Background Photodynamic therapy (PDT) using daylight as the photoactivating light source (DL-PDT) is an effective treatment for actinic keratosis (AK). Among the artificial daylight sources, the Dermaris (Surgiris, Croix, France) is specially designed for SDL-PDT (simulated daylight PDT) of AK. To perform the PDT session, a long duration (2.5 hours) and low-intensity light exposure (2.9 mw/cm²) is used. This long duration is considered as a major limitation by both the patient and the dermatologist. Objectives The paper aims to report the clinical outcomes of SDL-PDT using the Dermaris in patients treated for AK lesions of the scalp at our medical dermatology center using only one hour low-intensity light exposure. Methods Thirty patients (19 males, 11 females), mean age: 72.8 ± 9.3, with phototype 1 (11 patients), with phototype 2(17 patients) and phototype 3 (2 patients), with grade I–II AK of the scalp were treated with a drug-light interval (DLI) of 10 minutes and a light exposure of 1 hours. The cure rate of AK lesions at six months after the treatment was determined. Erythema, crusts, discomfort and during or/and post the treatment were also evaluated. Results In total, 293 AK were treated. Six months following treatment, the cure rate of patients was 93%. Pain score reported after the first PDT session was from 0 to 1 on a visual analogue scale (VAS) ranging from 0 to 10 . Erythema was observed in 28 patients and lasted 3 days, crusts were seen in 19 patients. Discomfort was as mild or less in more than 97% of patients. Conclusions the shortening of the exposure time to one hour does not modify the efficacy of the SDL-PDT using the Dermaris. This observation is in agreement with recent published data demonstrating that that PDT can be performed successfully with half the illumination time used in daylight PDT today. Besides, this clinical study confirmed that SDL-PDT is an effective and nearly painless treatment with minimal side effects for patients with AK lesions of the scalp.
Contexte La transfusion de concentrés plaquettaires (CP) peut entraîner la survenue de réactions post-transfusionnelles encore appelées effets indésirables receveurs (EIR). Nous nous sommes intéressés aux protéines des surnageants de mélanges de CP (MCP) associés à des EIR. Méthodes Une analyse protéomique de MCP en condition EIR versus contrôles a été réalisée via le logiciel Proteome Discoverer 2.4. Les outils STRING db, KEGG pathway et IPA® ont été utilisés pour déterminer l’enrichissement des voies de signalisations. Cette analyse s’est portée sur deux études. La première à partir de MCP versus contrôles stockés pendant deux jours, la deuxième à partir de MCP versus contrôles stockés pendant quatre jours. Résultats Dans la première étude, 170 protéines ont été retrouvées différentiellement exprimées (DE), parmi lesquelles 78 protéines liées au cytosquelette. La grande majorité des protéines DE étaient sous-exprimées en condition EIR. La voie de signalisation la plus fortement impactée était celle de la régulation du remodelage du cytosquelette d’actine. Dans la seconde étude, seulement 47 protéines ont été observées comme DE, parmi lesquelles 16 protéines étaient associées au cytosquelette. Dans cette seconde étude, l’enrichissement lié au cytosquelette a aussi été mis en évidence, en particulier la voie du remodelage des jonctions d’adhérences épithéliales. Trois protéines communes à ces deux études et liées au cytosquelette se sont avérées dysrégulées en condition EIR : RAB8, ACTR3, YWHAH. Conclusion Cette étude a permis de mettre en évidence un remodelage du cytosquelette plaquettaire lors de l’apparition d’un EIR, ainsi qu’une possible activation de l’apoptose (Figure 1, Figure 2, Figure 3).
Des effets indésirables receveurs (EIR) peuvent apparaître après transfusion de mélanges de concentrés plaquettaires (MCP). L’apparition d’un EIR pourrait-elle être associée à la dégradation des plaquettes durant leur stockage ? Pour ceci, nous avons analysé le protéome du culot (C) et du surnageant (S) de MCP stockés pendant 2 jours (j2) et pendant 4 jours (j4) respectivement, transfusés et associés à un EIR. Nous avons comparé 2 S/C de MCP j2 et 2 S/C de MCP j4. L’analyse protéomique (label free LC-MS/MS) a été réalisée via le logiciel Proteome Discoverer 2.4. Les outils STRING db, KEGG pathway et IPA® ont été utilisés pour déterminer l’enrichissement des voies de signalisation. Des protéines d’intérêt identifiées ont été recherchées par Western Blot. À j2, 423 protéines différentiellement exprimées (DE) ont été identifiées dans C et 94 dans S. À j4, 129 protéines DE ont été identifiées dans C et 43 dans S. Des protéines anti-apoptotiques (ENO1 et ILK), ont été retrouvées dans S, sous-exprimées à j2 et sur-exprimées à j4. ILK est aussi liée à l’organisation des jonctions cellulaires et au cytosquelette d’actine. Par ailleurs, SRC qui a été retrouvée sous-exprimée dans S à j2, est impliquée dans l’organisation des jonctions cellulaires, mais aussi dans l’activité mitochondriale et l’apoptose. DYNC1/2, liée au cytosquelette, était sur-exprimée dans C à j4. La différence du nombre de protéines DE entre j2 et j4 pourrait s’expliquer par leur dégradation progressive, ce qui pourrait aussi impacter l’intégrité des plaquettes et la qualité des CP. De plus, les protéines anti-apoptotiques sur-exprimées dans S à j4 évoque une libération après apoptose des plaquettes.
Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox (https://CRAN.R-project.org/package=joint.Cox). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm (p-value<0.001), whereas disease-free survival remains a valid surrogate at individual level for overall survival in these trials.
Glomus tumor are rare mesenchymal neoplasm, belonging to the pericytic (perivascular) tumor family, witch recent molecular characterization has allowed highlight recurrent molecular abnormalities. In fact, glomus tumor involves frequent MIR143-NOTCH gene fusion whereas others pericytic tumor (myopericytoma and myofibroma) involve mutations of PDGFRB gene. Glomus tumor are usually developed in superficial localization. However visceral locations have been described. Cardiac location is exceptional with only one case reported in literature. Here, we report the case of cardiac glomus tumor (glomangiomyoma) developed in the left ventricle in a 34 year-old patient, diagnosed after chest pain. The length of tumor was 4cm in greatest dimension. Histologically, the tumor concerned both round glomus cells and smooth muscle cells with prominent branching thin-walled vessels. By immunohistochemistry, these two contingents exhibited diffuse expression of smooth muscle actin and heterogeneous expression of H-caldesmone whereas cytokeratins, melanocytic markers and chomogranine were negative. Next Generation molecular analysis using RNA sequencing highlighted the characteristic MIR143-NOTCH gene fusion witch supports the diagnosis of glomus tumor. In this observation, we recall histological and immunohistochemistry features of glomus tumor and we make a synthesis concerning the molecular data recently described in sporadic glomus tumor.
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1,106 members
Stéphanie Marchand
  • Institut des Sciences de la Vigne et du Vin (ISVV)
Hélène Jacqmin-Gadda
  • Unité Epidémiologie et Biostatistique
Françoise Dellu Hagedorn
  • Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (INCIA)
Francis Belloc
  • Unité Biothérapies des maladies génétiques et du cancer
Delphine Blandine Maurel
  • Unité Bioingénierie tissulaire
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