84 results on '"Rondeau, V."'
Search Results
2. 695P Effectiveness and quality-of-life (QoL) data from real-world study (ProNiHN) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) treated with nivolumab (nivo) in France
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Le Tourneau, C., primary, Salas, S., additional, Pointreau, Y., additional, Ceruse, P., additional, Babin, E., additional, Rondeau, V., additional, Guigay, J., additional, Rotarski, M., additional, Chehimi, M., additional, Toullec, C., additional, Marie, G., additional, Sire, C., additional, Darut Jouve, A., additional, Theron, A., additional, Calderon, B., additional, Houessinon, A., additional, Cotté, F-E., additional, Lavignon, M., additional, Even, C., additional, and Fayette, J., additional
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- 2022
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3. Time to next treatment or death as a candidate surrogate endpoint for overall survival in advanced melanoma patients treated with immune checkpoint inhibitors: an insight from the phase III CheckMate 067 trial
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Branchoux, S., Sofeu, C.L., Gaudin, A.-F., Kurt, M., Moshyk, A., Italiano, A., Bellera, C., Rondeau, V., Admin, Oskar, Bristol-Myers Squibb [Rueil-Malmaison], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Bristol-Myers Squibb [Princeton], Institut Bergonié [Bordeaux], UNICANCER, and Bristol-Myers Squibb
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Cancer Research ,Time to next treatment ,Advanced melanoma ,Ipilimumab ,Immune checkpoint inhibitors ,Nivolumab ,Clinical Trials, Phase III as Topic ,Oncology ,Surrogate endpoint ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Overall survival ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Melanoma ,Biomarkers ,Original Research - Abstract
Background Time to next treatment or death (TNT-D) may be a patient-relevant endpoint in patients treated with immune checkpoint inhibitors. This study investigated TNT-D as a surrogate endpoint (SE) for overall survival (OS) in previously untreated advanced melanoma patients. Methods Patient-level data from the 60-month results of the CheckMate 067 randomised, controlled trial were used. Analyses were carried out for nivolumab monotherapy or nivolumab with ipilimumab versus ipilimumab monotherapy. The SE 1-step validation method based on a joint frailty-copula model was used where the country of enrolment was applied to define clusters. Kendall’s τ and the coefficient of determination (R2trial) were estimated for respective measurements of association at the individual and cluster levels. The surrogate threshold effect, the maximum threshold hazard ratio for TNT-D that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was carried out to evaluate model robustness. Results Fifteen clusters of data were generated from 945 patients. For both nivolumab-containing arms, the association between TNT-D and OS was deemed acceptable at the individual level (Kendall’s τ > 0.60) and strong at the cluster level, with R2trial fairly close to 1, with narrow confidence intervals. The estimated surrogate threshold effects were 0.61 for nivolumab versus ipilimumab and 0.49 for nivolimub + ipilimumab versus ipilimumab. Cross-validation results showed minimum variation of the correlation measures and satisfactory predictive accuracy for the model. Conclusion Results suggest that TNT-D may be a valuable SE in previously untreated advanced melanoma patients treated with immune checkpoint inhibitors. Surrogacy analyses considering multiple randomised controlled trials are warranted for confirming these findings., Highlights • This is the first study to assess the surrogacy properties of TNT-D for OS in immune checkpoint inhibitor-treated patients. • TNT-D is a clinically relevant, pragmatic and often measurable endpoint that reflects the result of a therapeutic decision. • TNT-D appears to be a promising SE for OS in advanced melanoma patients treated with immune checkpoint inhibitors.
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- 2021
4. Twenty Five Year Mortality and Air Pollution: Results from the French PAARC Survey
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Filleul, L., Rondeau, V., Vandentorren, S., Moual, N. Le., Cantagrel, A., Annesi-Maesano, I., Charpin, D., Declercq, C., Neukirch, F., Paris, C., Vervloet, D., Brochard, P., Tessier, J-F., Kauffmann, F., and Baldi, I.
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- 2005
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5. Real life practice of gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC) depending on epidermal growth factor receptor (EGFR) mutation status: Results from the prospective EPIDAURE study: 168P
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Cadranel, J., Brambilla, E., Morere, J. F., Rondeau, V., Fabre, E., Lemaire, B., Monnet, I., Licour, M., and Perol, M.
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- 2016
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6. Statistical models for recurrent events and death: Application to cancer events
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Rondeau, V.
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- 2010
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7. 923P Nivolumab in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) progressing on/or after a platinum-based therapy: Interim analysis of a prospective French real-world study (ProNiHN)
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Le Tourneau, C., primary, Salas, S., additional, Pointreau, Y., additional, Ceruse, P., additional, Babin, E., additional, Chehimi, M., additional, Rotarski, M., additional, Toullec, C., additional, Darut Jouve, A., additional, Najem, A., additional, Combe, P., additional, Burlacu, D., additional, Bourahla, I., additional, Boin, A., additional, Rondeau, V., additional, Even, C., additional, and Fayette, J., additional
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- 2021
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8. 938P Nivolumab (nivo) in recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN): real-world effectiveness, quality of life (QoL) of patients and their caregivers in France (ProNiHN study)
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Le Tourneau, C., Even, C., Salas, S., Pointreau, Y., Ceruse, P., Babin, E., Fayette, J., Rondeau, V., Grumberg, V., Cotté, F-E., Govart, A., Baumstarck, K., and Guigay, J.
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- 2023
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9. Levels and determinants of pesticide exposure in re-entry workers in vineyards: Results of the PESTEXPO study☆
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Baldi, Isabelle, Lebailly, P., Bouvier, G., Rondeau, V., Kientz-Bouchart, V., Canal-Raffin, M., and Garrigou, A.
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- 2014
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10. PCN29 Time to Next Treatment As a Candidate Surrogate Endpoint for Overall Survival in Previously Untreated Advanced Melanoma Patients Treated with Immune-Checkpoint Inhibitors
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Branchoux, S., primary, Sofeu, C.L., additional, Gaudin, A.F., additional, Kurt, M., additional, Moshyk, A., additional, Italiano, A., additional, Bellera, C., additional, and Rondeau, V., additional
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- 2020
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11. EX3 Investigating Time to Next Treatment As a Surrogate Endpoint for Overall Survival in Previously Untreated Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma Patients: An Insight from the Phase III CheckMate-214
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Branchoux, S., primary, Sofeu, C.L., additional, Kurt, M., additional, Gaudin, A.F., additional, Italiano, A., additional, Rondeau, V., additional, and Bellera, C., additional
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- 2020
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12. Agricultural exposures to carbamate herbicides and fungicides and central nervous system tumour incidence in the cohort AGRICAN
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Piel, C., POUCHIEU, C., Carles, C., BEZIAT, B., Boulanger, M., Bureau, M., Busson, A., Gruber, A., Lecluse, Y., Migault, L., RENIER, M., Rondeau, V., SCHWALL, X., Tual, S., Lebailly, Pierre, Baldi, Isabelle, Admin, Oskar, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER
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[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,Herbicides ,Dithiocarbamates ,CNS tumors ,Occupational exposure ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,Risk factors ,Thiocarbamates ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Cohort studies ,[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Carbamates ,Fungicides - Abstract
International audience; BACKGROUND: Pesticides exposures could be implicated in the excess of Central Nervous System (CNS) tumors observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate derivative pesticides, including herbicides and fungicides (i.e. (thio/dithio)-carbamates), have shown evidence of carcinogenicity in experimental studies in animals. In the French AGRICAN cohort, we assessed the associations between potential exposures to carbamate herbicides and fungicides and the incidence of CNS tumors, overall and by histological subtype.METHODS: AGRICAN enrolled 181,842 participants involved in agriculture. Incident CNS tumors were identified by linkage with cancer registries from enrollment (2005-2007) until 2013. Individual exposures were assessed by combining information on lifetime periods of pesticide use on crops and the French crop-exposure matrix PESTIMAT, for each of the 14 carbamate and thiocarbamate herbicides and the 16 carbamate and dithiocarbamate fungicides registered in France since 1950. Associations were estimated using proportional hazard models with age as the underlying timescale, adjusting for gender, educational level and smoking. RESULTS: During an average follow-up of 6.9years, 381 incident cases of CNS tumors occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumors with overall exposure to carbamate fungicides (Hazard Ratio, HR=1.88; 95% CI: 1.27-2.79) and, to a lesser extent, to carbamate herbicides (HR=1.44; 95% CI: 0.94-2.22). Positive associations were observed with specific carbamates, including some fungicides (mancozeb, maneb, metiram) and herbicides (chlorpropham, propham, diallate) already suspected of being carcinogens in humans.CONCLUSIONS: Although some associations need to be corroborate in further studies and should be interpreted cautiously, these findings provide additional carcinogenicity evidence for several carbamate fungicides and herbicides.
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- 2019
13. Surrogate endpoints in advanced sarcoma trials: a meta-analysis
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Savina, M., Litiere, S., Italiano, A., Burzykowski, T., Bonnetain, F., Gourgou, S., Rondeau, V., Blay, J.Y., Cousin, S., Duffaud, F., Gelderblom, H., Gronchi, A., Judson, I., Cesne, A. Le, Lorigan, P., Maurel, J., Graaf, W.T.A. van der, Verweij, J., Mathoulin-Pelissier, S., Bellera, C., Savina, M., Litiere, S., Italiano, A., Burzykowski, T., Bonnetain, F., Gourgou, S., Rondeau, V., Blay, J.Y., Cousin, S., Duffaud, F., Gelderblom, H., Gronchi, A., Judson, I., Cesne, A. Le, Lorigan, P., Maurel, J., Graaf, W.T.A. van der, Verweij, J., Mathoulin-Pelissier, S., and Bellera, C.
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Contains fulltext : 200421.pdf (publisher's version ) (Open Access), Background: Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS). Results: A total of 21 trials originally met the selection criteria and 14 RCTs (N = 2846) were included in the analysis. Individual-level associations were moderate (highest for 12-month PFS: Spearman's rho = 0.66; 95% CI [0.63; 0.68]). Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion. Materials and Methods: We performed a meta-analysis using individual-patient data (IPD). Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual- and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines. Conclusions: Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS.
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- 2018
14. Surrogate endpoints in advanced sarcoma trials: A meta-analysis
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Savina, M. (Marion), Litière, S. (Saskia), Italiano, A., Burzykowski, T. (Tomasz), Bonnetain, F., Gourgou, S. (Sophie), Rondeau, V. (Virginie), Blay, J.Y. (Jean Yves), Cousin, S. (S.), Duffaud, F. (Florence), Gelderblom, H. (Hans), Gronchi, A. (Alessandro), Judson, I.R. (Ian), Cesne, A. (Axel) le, Lorigan, P.C. (P.), Maurel, J. (Joan), Graaf, W.T.A. (Winette) van der, Verweij, J. (Jaap), Mathoulin-Pélissier, S., Bellera, C.A. (Carine A.), Savina, M. (Marion), Litière, S. (Saskia), Italiano, A., Burzykowski, T. (Tomasz), Bonnetain, F., Gourgou, S. (Sophie), Rondeau, V. (Virginie), Blay, J.Y. (Jean Yves), Cousin, S. (S.), Duffaud, F. (Florence), Gelderblom, H. (Hans), Gronchi, A. (Alessandro), Judson, I.R. (Ian), Cesne, A. (Axel) le, Lorigan, P.C. (P.), Maurel, J. (Joan), Graaf, W.T.A. (Winette) van der, Verweij, J. (Jaap), Mathoulin-Pélissier, S., and Bellera, C.A. (Carine A.)
- Abstract
Background: Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS). Results: A total of 21 trials originally met the selection criteria and 14 RCTs (N = 2846) were included in the analysis. Individual-level associations were moderate (highest for 12-month PFS: Spearman's rho = 0.66; 95% CI [0.63; 0.68]). Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion. Materials and Methods: We performed a meta-analysis using individual-patient data (IPD). Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual-and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines. Conclusions: Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS.
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- 2018
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15. Factors associated with breast cancer recurrences or mortality and dynamic prediction of death using history of cancer recurrences: the French E3N cohort.
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Lafourcade, A, His, M, Baglietto, L, Boutron-Ruault, M-C, Dossus, L, Rondeau, V, Lafourcade, A, His, M, Baglietto, L, Boutron-Ruault, M-C, Dossus, L, and Rondeau, V
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BACKGROUND: In addition to tumor characteristics and lifestyle factors, cancer relapses are often related to the risk of death but have not been jointly studied. We investigate the prognostic factors of recurrent events and death after a diagnosis of breast cancer and predict individual deaths including a history of recurrences. METHODS: The E3N (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l'Education Nationale) study is a prospective cohort study that was initiated in 1990 to investigate factors associated with the most common types of cancer. Overall survival and three types of recurrent events were considered: locoregional recurrence, metastasis, and second primary breast cancer. Recurrent events and death were analyzed using a joint frailty model. RESULTS: The analysis included 4926 women from the E3N cohort diagnosed with a first primary invasive breast cancer between June 1990 and June 2008; during the follow-up, 1334 cases had a recurrence (median time of follow-up is 7.2 years) and 469 women died. Cases with high grade, large tumor size, axillary nodal involvement, and negative estrogen and progesterone receptors had a higher risk of recurrence or death. Furthermore, smoking increased the risk of relapse. For cases with a medium risk profile in terms of tumor characteristics and lifestyle factors, the probability of dying between 5 and 10 years after diagnosis was 6, 20 and 36% for 0, 1 or 2 recurrences within the first 5 years after diagnosis, respectively. CONCLUSIONS: Our study showed the importance of considering baseline lifestyle characteristics and history of relapses to dynamically predict the risk of death in breast cancer cases. Medical experience coupled with an estimate of a patient's survival probability that considers all available information for this patient would enable physicians to make better informed decisions regarding their actions and thus improve clinical output.
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- 2018
16. Surrogate endpoints in advanced sarcoma trials: a meta-analysis
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Savina, M, Litiere, S, Italiano, A, Burzykowski, T, Bonnetain, F, Gourgou, S, Rondeau, V, Blay, J-Y, Cousin, S, Duffaud, F, Gelderblom, H, Gronchi, A, Judson, I, le Cesne, A, Lorigan, P, Maurel, J, de Graaf, W, Verweij, Jaap, Mathoulin-Pelissier, S, Bellera, C, Savina, M, Litiere, S, Italiano, A, Burzykowski, T, Bonnetain, F, Gourgou, S, Rondeau, V, Blay, J-Y, Cousin, S, Duffaud, F, Gelderblom, H, Gronchi, A, Judson, I, le Cesne, A, Lorigan, P, Maurel, J, de Graaf, W, Verweij, Jaap, Mathoulin-Pelissier, S, and Bellera, C
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- 2018
17. Morbidity and healthcare resource utilisation in HIV-infected children following antiretroviral therapy (ART) initiation in Côte d’Ivoire, 2004–2009
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Desmonde, S., Essanin, J.B, Aka, E.A, Messou, E., Amorissani-Folquet, M., Rondeau, V., Ciaranello, A., and Leroy, V.
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Male ,Adolescent ,Infant ,HIV Infections ,Article ,Cote d'Ivoire ,Anti-Retroviral Agents ,Antiretroviral Therapy, Highly Active ,Child, Preschool ,Humans ,Female ,Health Facilities ,Child ,Retrospective Studies - Abstract
We describe severe morbidity and health care resource utilization (HCRU) among HIV-infected children on antiretroviral therapy (ART) in Abidjan, Côte d'Ivoire.All HIV-infected children enrolled in an HIV-care program (2004-2009) were eligible for ART initiation until database closeout, death, ART interruption, or loss to follow-up. We calculated incidence rates (IRs) of density per 100 child-years (CYs) for severe morbidity, HCRU (outpatient care and inpatient care), and associated factors using frailty models with a Weibull distribution.Of 332 children with a median age of 5.7 years and median follow-up of 2.5 years, 65.4% were severely immunodeficient by World Health Organization (WHO) criteria, and all received cotrimoxazole prophylaxis. We recorded 464 clinical events in 228 children; the overall IR was 57.6/100 CYs [95% confidence interval (CI): 52.1 to 62.5]. Severe morbidity was more frequent in children on protease inhibitor (PI)-based ART compared to those on other regimens [adjusted hazards ratio (aHR): 1.83; 95% CI: 1.35 to 2.47] and to those moderately/severely immunodeficient compared to those not (aHR: 1.57; 95% CI: 1.13 to 2.18 and aHR: 2.53; 95% CI: 1.81 to 3.55, respectively). Of the 464 events, 371 (80%) led to outpatient care (IR: 45.6/100 CYs) and 164 (35%) to inpatient care (IR: 20.2/100 CYs). In adjusted analyses, outpatient care was significantly less frequent in children older than 10 years compared with children younger than 2 years (aHR: 0.49; 95% CI: 0.31 to 0.78) and in those living furthest from clinics compared with those living closest (aHR: 0.65; 95% CI: 0.47 to 0.90). Both inpatient and outpatient HCRU were negatively associated with cotrimoxazole prophylaxis.Despite ART, HIV-infected children still require substantial utilization of health care services.
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- 2014
18. French real-life efficacy of 1st line gefitinib in EGFR mutation-positive NSCLC in the prospective EPIDAURE study: Results by EGFR exon 19 Del and L858R mutation subtypes
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Perol, M., primary, Morère, J.-F., additional, Fabre, E., additional, Lemaire, B., additional, Monnet, I., additional, Brambilla, E., additional, Rondeau, V., additional, Licour, M., additional, and Cadranel, J., additional
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- 2016
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19. 168P: Real life practice of gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC) depending on epidermal growth factor receptor (EGFR) mutation status: Results from the prospective EPIDAURE study
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Cadranel, J., primary, Brambilla, E., additional, Morere, J.F., additional, Rondeau, V., additional, Fabre, E., additional, Lemaire, B., additional, Monnet, I., additional, Licour, M., additional, and Perol, M., additional
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- 2016
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20. A standardised approach towards PROving the efficacy of foods and Food Constituents for Health CLAIMs (PROCLAIM: providing guidance
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Gallagher, A.M., Meijer, G.W., Richardson, D.P., Rondeau, V., Skarp, M., Stasse-Wolthuis, M., Tweedie, G.C., Witkamp, R.F., Gallagher, A.M., Meijer, G.W., Richardson, D.P., Rondeau, V., Skarp, M., Stasse-Wolthuis, M., Tweedie, G.C., and Witkamp, R.F.
- Abstract
Diet is well known to have beneficial health properties that extend beyond traditionally accepted nutritional effects. The approach involved in elucidating these beneficial physiological effects is becoming more important, as reflected by increasing research being undertaken. With growing consumer awareness of foods and food constituents and their relationship to health, the key questions for regulators, scientists and the food industry continue to relate to: (1) how consumers could be protected and have confidence that the health claims on foods are well supported by the evidence; (2) how research on physiological effects of food (constituents) and their health benefits could be stimulated and supported; (3) how research findings could be used in the development of innovative new food products. The objectives of this paper are to provide a set of recommendations on the substantiation of health claims for foods, to develop further guidance on the choice of validated markers (or marker patterns) and what effects are considered to be beneficial to the health of the general public (or specific target groups). Finally, the case for developing a standardised approach for assessing the totality of the available scientific data and weighing the evidence is proposed
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- 2011
21. 1244P - French real-life efficacy of 1st line gefitinib in EGFR mutation-positive NSCLC in the prospective EPIDAURE study: Results by EGFR exon 19 Del and L858R mutation subtypes
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Perol, M., Morère, J.-F., Fabre, E., Lemaire, B., Monnet, I., Brambilla, E., Rondeau, V., Licour, M., and Cadranel, J.
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- 2016
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22. Neurobehavioral effects of long-term exposure to pesticides: results from the 4-year follow-up of the PHYTONER Study
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Baldi, I., primary, Gruber, A., additional, Rondeau, V., additional, Lebailly, P., additional, Brochard, P., additional, and Fabrigoule, C., additional
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- 2010
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23. Aluminum and Silica in Drinking Water and the Risk of Alzheimer's Disease or Cognitive Decline: Findings From 15-Year Follow-up of the PAQUID Cohort
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Rondeau, V., primary, Jacqmin-Gadda, H., additional, Commenges, D., additional, Helmer, C., additional, and Dartigues, J.-F., additional
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- 2008
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24. Joint frailty models for recurring events and death using maximum penalized likelihood estimation: application on cancer events
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Rondeau, V., primary, Mathoulin-Pelissier, S., additional, Jacqmin-Gadda, H., additional, Brouste, V., additional, and Soubeyran, P., additional
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- 2006
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25. RE: ALUMINUM IN DRINKING WATER AND COGNITIVE DECLINE IN ELDERLY SUBJECTS: THE PAQUID COHORT
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Rondeau, V., primary
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- 2001
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26. Aluminum and silica in drinking water and the risk of Alzheimer's disease or cognitive decline: findings from 15-year follow-up of the PAQUID cohort.
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Rondeau V, Jacqmin-Gadda H, Commenges D, Helmer C, and Dartigues JF
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The authors examined associations between exposure to aluminum or silica from drinking water and risk of cognitive decline, dementia, and Alzheimer's disease among elderly subjects followed for 15 years (1988-2003). They actively searched for incident cases of dementia among persons aged 65 years or over living in 91 civil drinking-water areas in southern France. Two measures of exposure to aluminum were assessed: geographic exposure and individual exposure, taking into account daily consumption of tap water and bottled water. A total of 1,925 subjects who were free of dementia at baseline and had reliable water assessment data were analyzed. Using random-effects models, the authors found that cognitive decline with time was greater in subjects with a higher daily intake of aluminum from drinking water (>or=0.1 mg/day, P=0.005) or higher geographic exposure to aluminum. Using a Cox model, a high daily intake of aluminum was significantly associated with increased risk of dementia. Conversely, an increase of 10 mg/day in silica intake was associated with a reduced risk of dementia (adjusted relative risk =0.89, P=0.036). However, geographic exposure to aluminum or silica from tap water was not associated with dementia. High consumption of aluminum from drinking water may be a risk factor for Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2009
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27. Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism.
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Lee SCS, Pyo AHA, Mohammadi H, Zhang J, Dvorkin-Gheva A, Malbeteau L, Chung S, Khan S, Ciudad MT, Rondeau V, Cairns RA, Kislinger T, McGaha TL, Wouters BG, Reisz JA, Culp-Hill R, D'Alessandro A, Jones CL, and Koritzinsky M
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- Animals, Humans, Mice, Cell Line, Tumor, Neoplasms metabolism, Neoplasms pathology, Neoplasms genetics, Polyamines metabolism, Dioxygenases metabolism, Mice, Knockout, Reactive Oxygen Species metabolism, Proline Oxidase metabolism, Proline Oxidase genetics, Cysteamine metabolism, Cell Proliferation, Proline metabolism, Mitochondria metabolism, Oxidation-Reduction, Homeostasis
- Abstract
2-Aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that sulfinylates cysteamine and amino-terminal cysteines in polypeptides. The pathophysiological roles of ADO remain largely unknown. Here, we demonstrate that ADO expression represents a vulnerability in cancer cells, as ADO depletion led to loss of proliferative capacity and survival in cancer cells and reduced xenograft growth. In contrast, generation of the ADO knockout mouse revealed high tolerance for ADO depletion in adult tissues. To understand the mechanism underlying ADO's essentiality in cancer cells, we characterized the cell proteome and metabolome following depletion of ADO. This revealed that ADO depletion leads to toxic levels of polyamines which can be driven by ADO's substrate cysteamine. Polyamine accumulation in turn stimulated expression of proline dehydrogenase (PRODH) which resulted in mitochondrial hyperactivity and ROS production, culminating in cell toxicity. This work identifies ADO as a unique vulnerability in cancer cells, due to its essential role in maintenance of redox homeostasis through restraining polyamine levels and proline catabolism.
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- 2024
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28. Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid β-oxidation and inducing lipotoxicity.
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O'Brien C, Ling T, Berman JM, Culp-Hill R, Reisz JA, Rondeau V, Jahangiri S, St-Germain J, Macwan V, Astori A, Zeng A, Hong JY, Li M, Yang M, Jana S, Gamboni F, Tsao E, Liu W, Dick JE, Lin H, Melnick A, Tikhonova A, Arruda A, Minden MD, Raught B, D'Alessandro A, and Jones CL
- Subjects
- Humans, Proteomics, Neoplastic Stem Cells metabolism, Lipid Metabolism, Homeostasis, Fatty Acids metabolism, Fatty Acids pharmacology, Fatty Acids therapeutic use, Cholesterol, Sirtuin 3 genetics, Sirtuin 3 metabolism, Sirtuin 3 pharmacology, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism
- Abstract
Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease-initiating leukemia stem cells (LSC). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSC. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSC. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSC but is not essential for normal human hematopoietic stem and progenitor cell function. In order to elucidate the molecular mechanisms by which SIRT3 is essential in LSC we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support OXPHOS and ATP production in human LSC. Further, we discovered two approaches to further sensitize LSC to SIRT3 inhibition. First, we found that LSC tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSC to YC8-02 and potentiates LSC death. Second, SIRT3 inhibition sensitizes LSC to the BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.
- Published
- 2023
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29. WHIM Syndrome-linked CXCR4 mutations drive osteoporosis.
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Anginot A, Nguyen J, Abou Nader Z, Rondeau V, Bonaud A, Kalogeraki M, Boutin A, Lemos JP, Bisio V, Koenen J, Hanna Doumit Sakr L, Picart A, Coudert A, Provot S, Dulphy N, Aurrand-Lions M, Mancini SJC, Lazennec G, McDermott DH, Guidez F, Blin-Wakkach C, Murphy PM, Cohen-Solal M, Espéli M, Rouleau M, and Balabanian K
- Subjects
- Animals, Mice, Mutation, Osteogenesis genetics, Humans, Immunologic Deficiency Syndromes genetics, Osteoporosis genetics, Primary Immunodeficiency Diseases genetics, Receptors, CXCR4 genetics, Receptors, CXCR4 metabolism
- Abstract
WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers. Mechanistically, impaired CXCR4 desensitization disrupts cell cycle progression and osteogenic commitment of skeletal stromal/stem cells, while increasing their pro-osteoclastogenic capacities. Impaired osteogenic differentiation is evidenced in primary bone marrow stromal cells from WHIM patients. In mice, chronic treatment with the CXCR4 antagonist AMD3100 normalizes in vitro osteogenic fate of mutant skeletal stromal/stem cells and reverses in vivo the loss of skeletal cells, demonstrating that proper CXCR4 desensitization is required for the osteogenic specification of skeletal stromal/stem cells. Our study provides mechanistic insights into how CXCR4 signaling regulates the osteogenic fate of skeletal cells and the balance between bone formation and resorption., (© 2023. The Author(s).)
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- 2023
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30. On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models.
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Savel H, Barbier S, Proust-Lima C, Rondeau V, Thiébaut R, Meyer-Losic F, and Richert L
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- Humans, Animals, Mice, Heterografts, Computer Simulation, Disease Models, Animal, Models, Statistical, Neoplasms drug therapy
- Abstract
In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models. Mixed and joint models were compared in a real MCT ( N = 225 mice) to estimate the effect of a chemotherapy and a simulation study. Mixed models assume that death is predictable by observed tumor volumes (data missing at random, MAR) while the joint models assume that death depends on nonobserved tumor volumes (data missing not at random, MNAR). In the real dataset, of 103 deaths, 97 mice were sacrificed when reaching a predetermined tumor size (MAR data). Joint and mixed model estimates of tumor growth slopes differed significantly [0.24 (0.13;0.36)log(mm
3 )/week for mixed model vs. -0.02 [-0.16;0.11] for joint model]. By disrupting the MAR process of mice deaths (inducing MNAR process), the estimate of the joint model was 0.24 [0.04;0.45], close to mixed model estimation for the original dataset. The simulation results confirmed the bias in the slope estimate from the joint model. Using a MCT example, we show that joint model can provide biased estimates under MAR mechanisms of dropout. We thus recommend to carefully choose the statistical model according to nature of mice deaths., Significance: This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models., Competing Interests: H. Savel reports other from Ipsen during the conduct of the study; other from Ipsen outside the submitted work. F. Meyer-Losic reports other from Ipsen during the conduct of the study. L. Richert reports grants from Ipsen during the conduct of the study. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)- Published
- 2023
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31. Effects of air pollution on clinical pregnancy rates after in vitro fertilisation (IVF): a retrospective cohort study.
- Author
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Tartaglia M, Chansel-Debordeaux L, Rondeau V, Hulin A, Levy A, Jimenez C, Bourquin P, Delva F, and Papaxanthos-Roche A
- Subjects
- Female, Pregnancy, Humans, Pregnancy Rate, Retrospective Studies, Reproductive Techniques, Assisted, Particulate Matter adverse effects, Fertilization in Vitro, Air Pollution adverse effects
- Abstract
Objective: To evaluate the effect of air pollution, from oocyte retrieval to embryo transfer, on the results of in vitro fertilisation (IVF) in terms of clinical pregnancy rates, at two fertility centres, from 2013 to 2019., Design: Exploratory retrospective cohort study., Setting: This retrospective cohort study was performed in the Reproductive Biology Department of Bordeaux University Hospital localised in Bordeaux, France and the Jean Villar Fertility Center localised in Bruges, France., Participants: This study included 10 763 IVF attempts occurring between January 2013 and December 2019, 2194 of which resulted in a clinical pregnancy., Primary and Secondary Outcome Measures: The outcome of the IVF attempt was recorded as the presence or absence of a clinical pregnancy; exposure to air pollution was assessed by calculating the cumulative exposure of suspended particulate matter, fine particulate matter, black carbon, nitrogen dioxide and ozone (O
3) , over the period from oocyte retrieval to embryo transfer, together with secondary exposure due to the presence of the biomass boiler room, which was installed in 2016, close to the Bordeaux University Hospital laboratory. The association between air pollution and IVF outcome was evaluated by a random-effects logistic regression analysis., Results: We found negative associations between cumulative O3 exposure and clinical pregnancy rate (OR=0.92, 95% CI = (0.86 to 0.98)), and between biomass boiler room exposure and clinical pregnancy rate (OR=0.75, 95% CI = (0.61 to 0.91)), after adjustment for potential confounders., Conclusion: Air pollution could have a negative effect on assisted reproductive technology results and therefore precautions should be taken to minimise the impact of outdoor air on embryo culture., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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32. Two-part joint model for a longitudinal semicontinuous marker and a terminal event with application to metastatic colorectal cancer data.
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Rustand D, Briollais L, Tournigand C, and Rondeau V
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- Biomarkers, Computer Simulation, Humans, Longitudinal Studies, Colorectal Neoplasms drug therapy, Models, Statistical
- Abstract
Joint models for a longitudinal biomarker and a terminal event have gained interests for evaluating cancer clinical trials because the tumor evolution reflects directly the state of the disease. A biomarker characterizing the tumor size evolution over time can be highly informative for assessing treatment options and could be taken into account in addition to the survival time. The biomarker often has a semicontinuous distribution, i.e., it is zero inflated and right skewed. An appropriate model is needed for the longitudinal biomarker as well as an association structure with the survival outcome. In this article, we propose a joint model for a longitudinal semicontinuous biomarker and a survival time. The semicontinuous nature of the longitudinal biomarker is specified by a two-part model, which splits its distribution into a binary outcome (first part) represented by the positive versus zero values and a continuous outcome (second part) with the positive values only. Survival times are modeled with a proportional hazards model for which we propose three association structures with the biomarker. Our simulation studies show some bias can arise in the parameter estimates when the semicontinuous nature of the biomarker is ignored, assuming the true model is a two-part model. An application to advanced metastatic colorectal cancer data from the GERCOR study is performed where our two-part model is compared to one-part joint models. Our results show that treatment arm B (FOLFOX6/FOLFIRI) is associated to higher SLD values over time and its positive association with the terminal event leads to an increased risk of death compared to treatment arm A (FOLFIRI/FOLFOX6)., (© The Author 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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33. Fine-tuning of MEK signaling is pivotal for limiting B and T cell activation.
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Houde N, Beuret L, Bonaud A, Fortier-Beaulieu SP, Truchon-Landry K, Aoidi R, Pic É, Alouche N, Rondeau V, Schlecht-Louf G, Balabanian K, Espéli M, and Charron J
- Subjects
- Alleles, Animals, B-Lymphocytes metabolism, Female, Humans, Lymphocyte Activation genetics, MAP Kinase Kinase 1 physiology, MAP Kinase Kinase 2 genetics, MAP Kinase Kinase 2 physiology, MAP Kinase Signaling System genetics, MAP Kinase Signaling System physiology, Male, Mice, Mice, 129 Strain, Mitogen-Activated Protein Kinase 1 metabolism, Phosphorylation, Signal Transduction physiology, T-Lymphocytes metabolism, Lymphocyte Activation physiology, MAP Kinase Kinase 1 metabolism, MAP Kinase Kinase 2 metabolism
- Abstract
MEK1 and MEK2, the only known activators of ERK, are attractive therapeutic candidates for both cancer and autoimmune diseases. However, how MEK signaling finely regulates immune cell activation is only partially understood. To address this question, we specifically delete Mek1 in hematopoietic cells in the Mek2 null background. Characterization of an allelic series of Mek mutants reveals the presence of distinct degrees of spontaneous B cell activation, which are inversely proportional to the levels of MEK proteins and ERK activation. While Mek1 and Mek2 null mutants have a normal lifespan, 1Mek1 and 1Mek2 mutants retaining only one functional Mek1 or Mek2 allele in hematopoietic cell lineages die from glomerulonephritis and lymphoproliferative disorders, respectively. This establishes that the fine-tuning of the ERK/MAPK pathway is critical to regulate B and T cell activation and function and that each MEK isoform plays distinct roles during lymphocyte activation and disease development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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34. Mek1 and Mek2 Functional Redundancy in Erythropoiesis.
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Beuret L, Fortier-Beaulieu SP, Rondeau V, Roy S, Houde N, Balabanian K, Espéli M, and Charron J
- Abstract
Several studies have established the crucial role of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway in hematopoietic cell proliferation and differentiation. MEK1 and MEK2 phosphorylate and activate ERK1 and ERK2. However, whether MEK1 and MEK2 differentially regulate these processes is unknown. To define the function of Mek genes in the activation of the ERK pathway during hematopoiesis, we generated a mutant mouse line carrying a hematopoietic-specific deletion of the Mek1 gene function in a Mek2 null background. Inactivation of both Mek1 and Mek2 genes resulted in death shortly after birth with a severe anemia revealing the essential role of the ERK pathway in erythropoiesis. Mek1 and Mek2 functional ablation also affected lymphopoiesis and myelopoiesis. In contrast, mice that retained one functional Mek1 (1 Mek1 ) or Mek2 (1 Mek2 ) allele in hematopoietic cells were viable and fertile. 1 Mek1 and 1 Mek2 mutants showed mild signs of anemia and splenomegaly, but the half-life of their red blood cells and the response to erythropoietic stress were not altered, suggesting a certain level of Mek redundancy for sustaining functional erythropoiesis. However, subtle differences in multipotent progenitor distribution in the bone marrow were observed in 1 Mek1 mice, suggesting that the two Mek genes might differentially regulate early hematopoiesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Beuret, Fortier-Beaulieu, Rondeau, Roy, Houde, Balabanian, Espéli and Charron.)
- Published
- 2021
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35. Hematologic disorder-associated Cxcr4 gain-of-function mutation leads to uncontrolled extrafollicular immune response.
- Author
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Alouche N, Bonaud A, Rondeau V, Hussein-Agha R, Nguyen J, Bisio V, Khamyath M, Crickx E, Setterblad N, Dulphy N, Mahevas M, McDermott DH, Murphy PM, Balabanian K, and Espéli M
- Subjects
- Animals, Hematologic Diseases genetics, Humans, Mice, Mice, Transgenic, Receptors, CXCR4 genetics, Signal Transduction genetics, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases immunology, Gain of Function Mutation, Hematologic Diseases immunology, Plasma Cells immunology, Receptors, CXCR4 immunology, Signal Transduction immunology
- Abstract
The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies during infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling caused by defective receptor desensitization leads to exacerbated extrafollicular B-cell response. Using a mouse model bearing a gain-of-function mutation of Cxcr4 described in 2 human hematologic disorders, warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and Waldenström macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mechanistic target of rapamycin signaling, cycled more, and differentiated more potently into plasma cells than wild-type B cells after Toll-like receptor (TLR) stimulation. Moreover, Cxcr4 gain of function promoted enhanced homing and persistence of immature plasma cells in the bone marrow, a phenomenon recapitulated in WHIM syndrome patient samples. This translated in increased and more sustained production of antibodies after T-independent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response.
- Published
- 2021
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36. Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: a post-hoc analysis of randomized clinical trials.
- Author
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Król A, Palmér R, Rondeau V, Rennard S, Eriksson UG, and Jauhiainen A
- Subjects
- Clinical Trials, Phase III as Topic standards, Clinical Trials, Phase IV as Topic standards, Databases, Factual statistics & numerical data, Frailty diagnosis, Frailty drug therapy, Frailty epidemiology, Humans, Multicenter Studies as Topic standards, Phosphodiesterase 4 Inhibitors administration & dosage, Pulmonary Disease, Chronic Obstructive diagnosis, Risk Factors, Time Factors, Disease Progression, Pulmonary Disease, Chronic Obstructive drug therapy, Pulmonary Disease, Chronic Obstructive epidemiology, Randomized Controlled Trials as Topic standards, Withholding Treatment trends
- Abstract
Background: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned., Methods: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data., Results: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms., Conclusions: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.
- Published
- 2020
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37. How to use frailtypack for validating failure-time surrogate endpoints using individual patient data from meta-analyses of randomized controlled trials.
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Sofeu CL and Rondeau V
- Subjects
- Healthcare Failure Mode and Effect Analysis, Humans, Research Design, Biomarkers analysis, Clinical Trials, Phase III as Topic standards, Endpoint Determination statistics & numerical data, Randomized Controlled Trials as Topic standards
- Abstract
Background and Objective: The use of valid surrogate endpoints can accelerate the development of phase III trials. Numerous validation methods have been proposed with the most popular used in a context of meta-analyses, based on a two-step analysis strategy. For two failure time endpoints, two association measures are usually considered, Kendall's τ at individual level and adjusted R2 ([Formula: see text]) at trial level. However, [Formula: see text] is not always available mainly due to model estimation constraints. More recently, we proposed a one-step validation method based on a joint frailty model, with the aim of reducing estimation issues and estimation bias on the surrogacy evaluation criteria. The model was quite robust with satisfactory results obtained in simulation studies. This study seeks to popularize this new surrogate endpoints validation approach by making the method available in a user-friendly R package., Methods: We provide numerous tools in the frailtypack R package, including more flexible functions, for the validation of candidate surrogate endpoints using data from multiple randomized clinical trials., Results: We implemented the surrogate threshold effect which is used in combination with [Formula: see text] to make decisions concerning the validity of the surrogate endpoints. It is also possible thanks to frailtypack to predict the treatment effect on the true endpoint in a new trial using the treatment effect observed on the surrogate endpoint. The leave-one-out cross-validation is available for assessing the accuracy of the prediction using the joint surrogate model. Other tools include data generation, simulation study and graphic representations. We illustrate the use of the new functions with both real data and simulated data., Conclusion: This article proposes new attractive and well developed tools for validating failure time surrogate endpoints., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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38. Agricultural exposures to carbamate herbicides and fungicides and central nervous system tumour incidence in the cohort AGRICAN.
- Author
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Piel C, Pouchieu C, Carles C, Béziat B, Boulanger M, Bureau M, Busson A, Grüber A, Lecluse Y, Migault L, Renier M, Rondeau V, Schwall X, Tual S, Pierre L, and Baldi I
- Subjects
- Adult, Aged, Agriculture, Animals, Cohort Studies, Crops, Agricultural, Environmental Monitoring, Female, France epidemiology, Humans, Incidence, Male, Middle Aged, Carbamates analysis, Carcinogens analysis, Central Nervous System Neoplasms epidemiology, Fungicides, Industrial analysis, Glioma epidemiology, Herbicides analysis, Meningioma epidemiology, Occupational Exposure analysis
- Abstract
Background: Pesticides exposures could be implicated in the excess of Central Nervous System (CNS) tumors observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate derivative pesticides, including herbicides and fungicides (i.e. (thio/dithio)-carbamates), have shown evidence of carcinogenicity in experimental studies in animals. In the French AGRICAN cohort, we assessed the associations between potential exposures to carbamate herbicides and fungicides and the incidence of CNS tumors, overall and by histological subtype., Methods: AGRICAN enrolled 181,842 participants involved in agriculture. Incident CNS tumors were identified by linkage with cancer registries from enrollment (2005-2007) until 2013. Individual exposures were assessed by combining information on lifetime periods of pesticide use on crops and the French crop-exposure matrix PESTIMAT, for each of the 14 carbamate and thiocarbamate herbicides and the 16 carbamate and dithiocarbamate fungicides registered in France since 1950. Associations were estimated using proportional hazard models with age as the underlying timescale, adjusting for gender, educational level and smoking., Results: During an average follow-up of 6.9 years, 381 incident cases of CNS tumors occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumors with overall exposure to carbamate fungicides (Hazard Ratio, HR = 1.88; 95% CI: 1.27-2.79) and, to a lesser extent, to carbamate herbicides (HR = 1.44; 95% CI: 0.94-2.22). Positive associations were observed with specific carbamates, including some fungicides (mancozeb, maneb, metiram) and herbicides (chlorpropham, propham, diallate) already suspected of being carcinogens in humans., Conclusions: Although some associations need to be corroborate in further studies and should be interpreted cautiously, these findings provide additional carcinogenicity evidence for several carbamate fungicides and herbicides., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
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39. Immune-checkpoint inhibitors and candidate surrogate endpoints for overall survival across tumour types: A systematic literature review.
- Author
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Branchoux S, Bellera C, Italiano A, Rustand D, Gaudin AF, and Rondeau V
- Subjects
- Antineoplastic Agents, Immunological administration & dosage, B7-H1 Antigen antagonists & inhibitors, B7-H1 Antigen immunology, CTLA-4 Antigen antagonists & inhibitors, CTLA-4 Antigen immunology, Disease-Free Survival, Humans, Neoplasms immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Randomized Controlled Trials as Topic, Biomarkers, Neoplasms drug therapy, Neoplasms mortality
- Abstract
Background: Surrogate endpoints (SEs) for overall survival (OS) are specific to therapeutic class. The objective of this review was to document all alternative endpoints studied for their association with OS in Immune-Checkpoint Inhibitors (ICI)-treated patients., Methods: We searched PubMed and Embase for publications reporting the association between a clinical endpoint and OS in ICI-treated populations from 01/01/2003 to 03/31/2018., Results: Out of 6,335 references identified, 24 were selected. Only 3 studies assessed surrogacy at both the patient and trial levels. The main traditional alternative endpoints included progression-free survival (N = 10) and objective response rate (N = 8). New alternative endpoints, such as durable response rate (N = 1) and intermediate response endpoint (N = 1) statistically better correlate with OS in the cancer types analysed., Conclusion: Based on the published evidence, there is insufficient data to support validated SE for OS. Adequate surrogacy assessment of promising composite endpoints which consider a duration component is encouraged., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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40. Increased risk of central nervous system tumours with carbamate insecticide use in the prospective cohort AGRICAN.
- Author
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Piel C, Pouchieu C, Migault L, Béziat B, Boulanger M, Bureau M, Carles C, Grüber A, Lecluse Y, Rondeau V, Schwall X, Tual S, Lebailly P, and Baldi I
- Subjects
- Adult, Aged, Agricultural Workers' Diseases chemically induced, Agricultural Workers' Diseases pathology, Agriculture, Central Nervous System Neoplasms chemically induced, Central Nervous System Neoplasms pathology, Farmers, Female, France epidemiology, Humans, Male, Middle Aged, Occupational Exposure adverse effects, Proportional Hazards Models, Prospective Studies, Agricultural Workers' Diseases epidemiology, Central Nervous System Neoplasms epidemiology, Pesticides toxicity
- Abstract
Background: Pesticide exposures are suspected to be implicated in the excess of central nervous system (CNS) tumours observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate insecticides, used on a wide range of crops, have shown evidence of carcinogenicity in some experimental studies. In the cohort AGRICAN (AGRIculture & CANcer), we assessed the associations between potential exposures to carbamate insecticides and the incidence of CNS tumours, overall and by histological subtype., Methods: AGRICAN enrolled 181 842 participants involved in agriculture. Incident CNS tumours were identified by linkage with cancer registries from enrolment (2005-07) until 2013. Carbamate exposure was assessed by combining information on lifetime periods of pesticide use on crop or livestock and the French crop-exposure matrix PESTIMAT, individually for each of the 19 carbamate insecticides registered in France since 1950. Associations were estimated using proportional hazards models with age as the underlying time scale, adjusting for gender, educational level and smoking., Results: During a 6.9-year average follow-up, 381 incident cases of CNS tumours occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumours with overall exposure to carbamate insecticides and linear trends with duration of use of each carbamate. Considering tumour subtypes, hazard ratios for gliomas ranged from 1.18 for thiofanox to 4.60 for formetanate, and for meningiomas from 1.51 for carbaryl to 3.67 for thiofanox., Conclusions: Findings reinforce carcinogenicity evidence for already suspected active ingredients and draw attention to additional active ingredients, notably used on fruit trees, vineyards, potatoes and beets., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)
- Published
- 2019
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41. Surrogate endpoints in advanced sarcoma trials: a meta-analysis.
- Author
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Savina M, Litière S, Italiano A, Burzykowski T, Bonnetain F, Gourgou S, Rondeau V, Blay JY, Cousin S, Duffaud F, Gelderblom H, Gronchi A, Judson I, Le Cesne A, Lorigan P, Maurel J, van der Graaf W, Verweij J, Mathoulin-Pélissier S, and Bellera C
- Abstract
Background: Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS)., Results: A total of 21 trials originally met the selection criteria and 14 RCTs ( N = 2846) were included in the analysis. Individual-level associations were moderate (highest for 12-month PFS: Spearman's rho = 0.66; 95% CI [0.63; 0.68]). Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion., Materials and Methods: We performed a meta-analysis using individual-patient data (IPD). Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual- and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines., Conclusions: Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.
- Published
- 2018
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42. Cardiac Rhythm Disturbances in Hemodialysis Patients: Early Detection Using an Implantable Loop Recorder and Correlation With Biological and Dialysis Parameters.
- Author
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Sacher F, Jesel L, Borni-Duval C, De Precigout V, Lavainne F, Bourdenx JP, Haddj-Elmrabet A, Seigneuric B, Keller A, Ott J, Savel H, Delmas Y, Bazin-Kara D, Klotz N, Ploux S, Buffler S, Ritter P, Rondeau V, Bordachar P, Martin C, Deplagne A, Reuter S, Haissaguerre M, Gourraud JB, Vigneau C, Mabo P, Maury P, Hannedouche T, Benard A, and Combe C
- Subjects
- Aged, Electrodes, Implanted, Female, Humans, Male, Middle Aged, Prospective Studies, Arrhythmias, Cardiac diagnosis, Death, Sudden, Cardiac prevention & control, Electrocardiography, Ambulatory instrumentation, Renal Dialysis adverse effects
- Abstract
Objectives: The aim of this study was to identify using implantable loop recorder (ILR) monitoring the mechanisms leading to sudden death (SD) in patients undergoing hemodialysis (HD)., Background: SD accounts for 11% to 25% of death in HD patients., Methods: Continuous rhythm monitoring was performed using the remote monitoring capability of the ILR device in patients undergoing HD at 8 centers. Clinical, biological, and technical HD parameters were recorded and analyzed., Results: Seventy-one patients (mean age 65 ± 9 years, 73% men) were included. Left ventricular ejection fraction was <50% in 16%. Twelve patients (17%) had histories of atrial fibrillation or flutter at inclusion. During a mean follow-up period of 21.3 ± 6.9 months, 16 patients died (14% patient-years), 7 (44%) of cardiovascular causes. Four SDs occurred, with progressive bradycardia followed by asystole. The incidence of patients presenting with significant conduction disorder and with ventricular arrhythmia was 14% and 9% patient-years, respectively. In multivariate survival frailty analyses, a higher risk for conduction disorder was associated with plasma potassium >5.0 mmol/l, bicarbonate <22 mmol/l, hemoglobin >11.5 g/dl, pre-HD systolic blood pressure >140 mm Hg, the longer interdialytic period, history of coronary artery disease, previous other arrhythmias, and diabetes mellitus. A higher risk for ventricular arrhythmia was associated with potassium <4.0 mmol/l, no antiarrhythmic drugs, and previous other arrhythmias. With ILR monitoring, de novo atrial fibrillation or flutter was diagnosed in 14 patients (20%)., Conclusions: ILR may be considered in HD patients prone to significant conduction disorders, ventricular arrhythmia, or atrial fibrillation or flutter to allow early identification and initiation of adequate treatment. Therapeutic strategies reducing serum potassium variability could decrease the rate of SD in these patients. (Implantable Loop Recorder in Hemodialysis Patients [RYTHMODIAL]; NCT01252823)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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43. Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review.
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Savina M, Gourgou S, Italiano A, Dinart D, Rondeau V, Penel N, Mathoulin-Pelissier S, and Bellera C
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- Disease-Free Survival, Humans, Neoplasms pathology, Neoplasms therapy, Prognosis, Survival Analysis, Treatment Outcome, Biomarkers analysis, Neoplasms diagnosis, Neoplasms mortality, Randomized Controlled Trials as Topic statistics & numerical data
- Abstract
Background: In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA)., Materials and Methods: We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema., Results: Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer., Conclusion(s): The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2018
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44. Factors associated with breast cancer recurrences or mortality and dynamic prediction of death using history of cancer recurrences: the French E3N cohort.
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Lafourcade A, His M, Baglietto L, Boutron-Ruault MC, Dossus L, and Rondeau V
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- Adult, Aged, Cohort Studies, Female, France epidemiology, Humans, Life Style, Middle Aged, Prognosis, Risk Factors, Breast Neoplasms mortality, Breast Neoplasms pathology, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology
- Abstract
Background: In addition to tumor characteristics and lifestyle factors, cancer relapses are often related to the risk of death but have not been jointly studied. We investigate the prognostic factors of recurrent events and death after a diagnosis of breast cancer and predict individual deaths including a history of recurrences., Methods: The E3N (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l'Education Nationale) study is a prospective cohort study that was initiated in 1990 to investigate factors associated with the most common types of cancer. Overall survival and three types of recurrent events were considered: locoregional recurrence, metastasis, and second primary breast cancer. Recurrent events and death were analyzed using a joint frailty model., Results: The analysis included 4926 women from the E3N cohort diagnosed with a first primary invasive breast cancer between June 1990 and June 2008; during the follow-up, 1334 cases had a recurrence (median time of follow-up is 7.2 years) and 469 women died. Cases with high grade, large tumor size, axillary nodal involvement, and negative estrogen and progesterone receptors had a higher risk of recurrence or death. Furthermore, smoking increased the risk of relapse. For cases with a medium risk profile in terms of tumor characteristics and lifestyle factors, the probability of dying between 5 and 10 years after diagnosis was 6, 20 and 36% for 0, 1 or 2 recurrences within the first 5 years after diagnosis, respectively., Conclusions: Our study showed the importance of considering baseline lifestyle characteristics and history of relapses to dynamically predict the risk of death in breast cancer cases. Medical experience coupled with an estimate of a patient's survival probability that considers all available information for this patient would enable physicians to make better informed decisions regarding their actions and thus improve clinical output.
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- 2018
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45. Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization.
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Freitas C, Wittner M, Nguyen J, Rondeau V, Biajoux V, Aknin ML, Gaudin F, Beaussant-Cohen S, Bertrand Y, Bellanné-Chantelot C, Donadieu J, Bachelerie F, Espéli M, Dalloul A, Louache F, and Balabanian K
- Subjects
- Adult, Animals, Bone Marrow Cells metabolism, Bone Marrow Transplantation methods, Cell Survival genetics, Child, Flow Cytometry, Gene Expression, Humans, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes metabolism, Lymphocyte Count, Mice, Transgenic, Mutation, Primary Immunodeficiency Diseases, Receptors, CXCR4 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Spleen cytology, Spleen metabolism, Warts genetics, Warts metabolism, Cell Differentiation genetics, Hematopoietic Stem Cells metabolism, Lymphocytes metabolism, Receptors, CXCR4 genetics
- Abstract
The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients., (© 2017 Freitas et al.)
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- 2017
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46. Identification of different malaria patterns due to Plasmodium falciparum and Plasmodium vivax in Ethiopian children: a prospective cohort study.
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Seyoum D, Kifle YG, Rondeau V, Yewhalaw D, Duchateau L, Rosas-Aguirre A, and Speybroeck N
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- Child, Child, Preschool, Cohort Studies, Ethiopia epidemiology, Female, Humans, Incidence, Infant, Infant, Newborn, Longitudinal Studies, Malaria, Falciparum parasitology, Malaria, Vivax parasitology, Male, Models, Theoretical, Prospective Studies, Risk Factors, Malaria, Falciparum epidemiology, Malaria, Vivax epidemiology, Plasmodium falciparum physiology, Plasmodium vivax physiology
- Abstract
Background: The identification of epidemiological pattern of infection with Plasmodium falciparum and Plasmodium vivax in malaria-endemic area, where multiple episodes are common, is important for intervention programmes., Methods: A longitudinal cohort study based on weekly house-to-house visits was conducted between July 2008 and June 2010 in 2040 children less than 10 years of age, living nearby the Gilgel-Gibe hydroelectric power dam reservoir in order to determine factors associated with increased P. vivax and P. falciparum incidence. Two types of multivariate frailty models were applied (using time-to-first malaria episode data and time-to-recurrent malaria episode data), allowing the estimation of adjusted hazard ratios (AHR) of potential risk factors (gender, age, proximity to the dam reservoir, and season) for species-specific malaria incidence., Results: Of 2040 children in 96 weeks of follow up, 864 children experienced at least one malaria episode: 685 due to P. falciparum in 548 children, and 385 due to P. vivax in 316 children. Plasmodium vivax and P. falciparum malaria incidence rates were 8.2 (95 % CI: 7.3-9.1) and 14.6 (95 % CI: 13.4-15.6) per 1000 children per month, respectively. According to the time-to-recurrent event models, children aged ≥7 years had a lower risk of presenting P. vivax episodes (AHR = 0.6; 95 % CI: 0.4-0.9), but a higher risk of P. falciparum episodes, when compared with children under ≤3 years (AHR = 1.2; 95 % CI: 1.1-1.6). In addition, P. vivax (AHR = 2.7; 95 % CI: 2.2-3.5) and P. falciparum (AHR = 16.9; 95 % CI: 14.3-20.2) episodes were respectively 2.7 and 16.9 times more frequent in the dry season than in the long rainy season., Conclusions: The analysis of all malaria episodes (first and recurrent episodes) in the malaria cohort suggests different species-specific patterns of malaria disease in children, with mild seasonality in the incidence of P. vivax episodes mostly observed in younger age groups, and with marked seasonality in the incidence of P. falciparum episodes mainly seen in older children.
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- 2016
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47. Validation of death prediction after breast cancer relapses using joint models.
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Mauguen A, Rachet B, Mathoulin-Pélissier S, Lawrence GM, Siesling S, MacGrogan G, Laurent A, and Rondeau V
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- Adult, Breast Neoplasms mortality, Female, Humans, Middle Aged, Models, Theoretical, Prognosis, Proportional Hazards Models, Reproducibility of Results, Risk Factors, Survival Analysis, Survival Rate, Breast Neoplasms pathology, Neoplasm Recurrence, Local, Risk Assessment methods, Risk Assessment statistics & numerical data
- Abstract
Background: Cancer relapses may be useful to predict the risk of death. To take into account relapse information, the Landmark approach is popular. As an alternative, we propose the joint frailty model for a recurrent event and a terminal event to derive dynamic predictions of the risk of death., Methods: The proposed prediction settings can account for relapse history or not. In this work, predictions developed on a French hospital series of patients with breast cancer are externally validated on UK and Netherlands registry data. The performances in terms of prediction error and calibration are compared to those from a Landmark Cox model., Results: The error of prediction was reduced when relapse information was taken into account. The prediction was well-calibrated, although it was developed and validated on very different populations. Joint modelling and Landmark approaches had similar performances., Conclusions: When predicting the risk of death, accounting for relapses led to better prediction performance. Joint modelling appeared to be suitable for such prediction. Performance was similar to the landmark Cox model, while directly quantifying the correlation between relapses and death.
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- 2015
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48. Impact of close-proximity air pollution on lung function in schoolchildren in the French West Indies.
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Amadeo B, Robert C, Rondeau V, Mounouchy MA, Cordeau L, Birembaux X, Citadelle E, Gotin J, Gouranton M, Marcin G, Laurac D, and Raherison C
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- Adolescent, Child, Cross-Sectional Studies, Female, Guadeloupe epidemiology, Humans, Male, Prevalence, Respiratory Function Tests statistics & numerical data, Time Factors, Air Pollutants adverse effects, Air Pollution adverse effects, Asthma epidemiology, Lung physiopathology
- Abstract
Background: High levels of asthma prevalence and severity of respiratory symptoms have been found in the Caribbean but little is known about the impact of air pollution in these regions. This study aimed to describe air pollution and measure the associations with child lung function in Guadeloupe (French West Indies)., Methods: Data from 30 randomly chosen elementary schools (8-13 years old) were obtained using a standardized protocol adapted from the ISAAC2 study. We considered two health outcomes: peak expiratory flow (PEF) before running and the variation in peak expiratory flow (ΔPEF) after running. The associations between pollutants and outcomes were investigated using several air pollution exposure models: i) medium-term exposure to close-proximity pollution both indoor and outdoor for ozone (O₃) and nitrogen dioxide (NO₂) and ii) short- and medium-term exposure to background pollution for O₃, NO₂, sulphur dioxide (SO₂) and small particulate matter (PM10)., Results: Of 1,463 children, 277 (16%) were found to have asthma. A 1-μg/m3 increase in medium-term exposure to outdoor close-proximity pollution by O₃ was associated with a PEF decrease (β = -0.32; 95% CI: -0.61;-0.03). No association was found with NO₂ regarding close-proximity pollution. The association between medium-term exposure to background pollution and PEF decrease was stronger in asthmatic children than in non-asthmatic children for O₃. No reduction in PEF or ΔPEF was shown with NO₂, SO₂ and PM₁₀ pollutants but a significant association was found between PM₁₀ and PEF increase., Conclusions: Our results suggest that O₃ could have an acute effect on child lung function in the Caribbean even at a low concentration (below the WHO guidelines). Further research in the Caribbean is needed to confirm these findings.
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- 2015
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49. Morbidity and health care resource utilization in HIV-infected children after antiretroviral therapy initiation in Côte d'Ivoire, 2004-2009.
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Desmonde S, Essanin JB, Aka AE, Messou E, Amorissani-Folquet M, Rondeau V, Ciaranello A, and Leroy V
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- Adolescent, Child, Child, Preschool, Cote d'Ivoire, Female, Humans, Infant, Male, Retrospective Studies, Anti-Retroviral Agents therapeutic use, Antiretroviral Therapy, Highly Active, HIV Infections drug therapy, Health Facilities statistics & numerical data
- Abstract
Background: We describe severe morbidity and health care resource utilization (HCRU) among HIV-infected children on antiretroviral therapy (ART) in Abidjan, Côte d'Ivoire., Methods: All HIV-infected children enrolled in an HIV-care program (2004-2009) were eligible for ART initiation until database closeout, death, ART interruption, or loss to follow-up. We calculated incidence rates (IRs) of density per 100 child-years (CYs) for severe morbidity, HCRU (outpatient care and inpatient care), and associated factors using frailty models with a Weibull distribution., Results: Of 332 children with a median age of 5.7 years and median follow-up of 2.5 years, 65.4% were severely immunodeficient by World Health Organization (WHO) criteria, and all received cotrimoxazole prophylaxis. We recorded 464 clinical events in 228 children; the overall IR was 57.6/100 CYs [95% confidence interval (CI): 52.1 to 62.5]. Severe morbidity was more frequent in children on protease inhibitor (PI)-based ART compared to those on other regimens [adjusted hazards ratio (aHR): 1.83; 95% CI: 1.35 to 2.47] and to those moderately/severely immunodeficient compared to those not (aHR: 1.57; 95% CI: 1.13 to 2.18 and aHR: 2.53; 95% CI: 1.81 to 3.55, respectively). Of the 464 events, 371 (80%) led to outpatient care (IR: 45.6/100 CYs) and 164 (35%) to inpatient care (IR: 20.2/100 CYs). In adjusted analyses, outpatient care was significantly less frequent in children older than 10 years compared with children younger than 2 years (aHR: 0.49; 95% CI: 0.31 to 0.78) and in those living furthest from clinics compared with those living closest (aHR: 0.65; 95% CI: 0.47 to 0.90). Both inpatient and outpatient HCRU were negatively associated with cotrimoxazole prophylaxis., Conclusions: Despite ART, HIV-infected children still require substantial utilization of health care services.
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- 2014
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50. Levels and determinants of pesticide exposure in operators involved in treatment of vineyards: results of the PESTEXPO Study.
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Baldi I, Lebailly P, Rondeau V, Bouchart V, Blanc-Lapierre A, Bouvier G, Canal-Raffin M, and Garrigou A
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- France, Humans, Occupational Exposure, Pesticides toxicity, Wine
- Abstract
Exposure assessment is a critical point for epidemiological studies on pesticide health effects. PESTEXPO study provides data on levels of exposure and their determinants in real conditions of pesticide use. We described levels of exposure in vineyards during treatment tasks (mixing, spraying and cleaning) and we analysed their determinants. Sixty-seven operators using dithiocarbamates or folpet were observed. Detailed information on the tasks (general conditions, operator, farm and equipment characteristics) were collected and dermal contamination was measured, using patches placed onto the skin on eleven body parts, and washing the hands at the end of each phase. The spraying phase represented roughly half of the contamination, whereas mixing and equipment cleaning accounted for 30% and 20% of the contamination, respectively. The main determinants of exposure were the number of phases, the characteristics of the equipment, the educational level of the operator and his status (farm -worker or -owner) and the general characteristics of the vines. Algorithms were built to estimate daily external contamination, according to these characteristics during mixing, spraying or equipment cleaning. With additional information of frequency and duration of use, they will enable to develop exposure indices usable in epidemiological studies on farmers' health.
- Published
- 2012
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