French National Cohort Research Articles

Profiles of learner readers and their early literacy skills and environmental predictors: a large-scale longitudinal study from preschool to grade 1

As part of the French national cohort ELFE, a two-year longitudinal study was conducted and children’s literacy skills were assessed twice (N = 2,767), namely at the end of preschool (t1) and at the end of Grade 1 (t2). At t1, letter-name knowledge (LNK), phonological skills (PhoSk) and vocabulary were assessed and at t2, phonemic segmentation, word reading, listening and reading comprehension. Latent profile analyses conducted at t2 resulted in five profiles, ranging from good readers (48.8%), to average readers above the mean (16.2%), readers with very low phonological awareness skill (8.2%), poor readers with low reading comprehension skill (19.4%), and poor readers with general difficulties (7.4%). Two early literacy skills (LNK and PhoSk) and two environmental variables (parents’ educational level and household income) constituted good predictors of membership of a profile. However, home literacy practices also predicted membership of the good reader/poor reader profiles, albeit at a lower level.

Germline JAK2 E846D Substitution as the Cause of Erythrocytosis?

The discovery in 2005 of the JAK2 V617F gain-of-function mutation in myeloproliferative neoplasms and more particularly in polycythemia vera has deeply changed the diagnostic and therapeutic approaches to polycythemia. More recently, the use of NGS in routine practice has revealed a large number of variants, although it is not always possible to classify them as pathogenic. This is notably the case for the JAK2 E846D variant for which for which questions remain unanswered. In a large French national cohort of 650 patients with well-characterized erythrocytosis, an isolated germline heterozygous JAK2 E846D substitution was observed in only two cases. For one of the patients, a family study could be performed, without segregation of the variant with the erythrocytosis phenotype. On the other hand, based on the large UK Biobank resource cohort including more than half a million UK participants, the JAK2 E846D variant was found in 760 individuals, associated with a moderate increase in hemoglobin and hematocrit values, but with no significant difference to the mean values of the rest of the studied population. Altogether, our data as well as UK Biobank cohort analyses suggest that the occurrence of an absolute polycythemia cannot be attributed to the sole demonstration of an isolated JAK2 E846D variant. However, it must be accompanied by other stimuli or favoring factors in order to generate absolute erythrocytosis.

Abstract 5224: Genome-wide interaction study of smoking and bladder cancer risk: results from the COBLAnCE cohort

Abstract Introduction: Bladder Cancer (BC) is the 6th most common cancer and the 9th leading cause of cancer death among men worldwide. Tobacco smoking is the main risk factor for BC. Accumulating evidence has found that genetic variants are also associated with the risk of BC. More insights into the biological mechanism of the disease have been gained through candidate gene-environment interaction studies, with the most known examples of the interactions between cigarette smoking and NAT2 and GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), while focusing on three important smoking behavior characteristics. Materials and Methods: The COBLAnCE cohort comprises 1,800 BC patients included within 14 centers in France between 2012 and 2018. Peripheral blood samples and complete history of tobacco smoking were collected at enrollment and genotyping was performed using the Illumina Global Screening Array with a Multi-Disease drop-in panel. After the quality control and imputation, 9,719,614 Single Nucleotide Polymorphisms (SNPs) were investigated. Genotyping data of 1,674, 1,283 and 1,342 patients were analyzed for smoking status, average tobacco consumption and age at smoking initiation, respectively. Genome-wide association study (GWAS) was conducted using logistic (for smoking status) and linear (for age at smoking initiation and average tobacco consumption, both log-transformed) regression models with each of the imputed SNPs as the independent variable adjusting for gender, age and first ten genetic principal components. Results: For smoking status, none of the SNPs reached the GWAS significant threshold of 5e-08, but results are suggesting tentative loci at 1p31.3 (rs114073636: OR [95%CI] = 0.31 [0.20-0.47], p = 8.68e-08; rs116571608: OR = 0.31 [0.20-0.47], p = 8.87e-08) and 4q22.1 (rs542541627: OR = 1.69 [1.39-2.06], p = 1.81e-07; rs1533294: OR = 1.63 [1.34-1.98], p = 1.01e-06). Analyses of age at smoking initiation revealed three significant SNPs: rs531756449, rs77186197 and rs78947799 with positive interaction associations (β (SE) = 0.3 (0.05), p = 8.26e-09; β = 0.29 (0.05), p = 3.74e-09; β = 0.31 (0.06), p = 3.97e-08, respectively). Only one SNP at 11q24.1, reached the significant threshold for the average tobacco consumption analyses: rs2714069 (β = 0.63 (0.11), p = 1.35e-08). The locus 16p13.3 seems to have protective variants for the interaction with average tobacco consumption: rs113683380 (β = -0.66 (0.12), p = 6.44e-08) and rs113590624 (β = -0.64 (0.12), p = 2.74e-07). Conclusion: Our study suggests new candidate loci interacting with smoking behavior for the risk of BC. Based on a case-only approach, our results need to be validated in a case-control or cohort study. A large-scale meta-analysis GWAS would be needed to identify SNPs with small Minor Allele Frequencies. Citation Format: Maryam Karimi, Sebastian Mendez-Pineda, Hélène Blanché, Anne Boland, Jean-François Deleuze, Xiang-Yu Meng, Karine Groussard, Thierry Lebret, Julia Bonastre, Yves Allory, François Radvanyi, Simone Benhamou, Stefan Michiels. Genome-wide interaction study of smoking and bladder cancer risk: results from the COBLAnCE cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5224.

Intraventricular Hemorrhage in Very Preterm Children: Mortality and Neurodevelopment at Age 5.

The objectives were to describe mortality and causes of death in children with intraventricular hemorrhage (IVH) and to study neurodevelopmental outcomes. The study was a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. Children were recruited in 2011. A standardized assessment was conducted at age 5. Children born before 32 weeks' gestation and admitted to a NICU were eligible. Exposure was IVH defined by the Papile classification. Main outcomes were mortality, causes of death, and neurodevelopmental outcomes at age 5. Among the 3468 children included, 578 (16.7%) had grade 1 IVH, 424 (12.2%) grade 2 IVH, and 114 (3.3%) grade 3 IVH; 144 (4.1%) had intraparenchymal hemorrhage (IPH). Mortality was 29.7% (36 of 114) for children with grade 3 IVH and 74.4% (109 of 144) for those with IPH; 67.6% (21 of 31) and 88.7% (86 of 97) of deaths, respectively, were because of withholding and withdrawing of life-sustaining treatment. As compared with no IVH, low-grade IVH was not associated with measured neurodevelopmental disabilities at age 5. High-grade IVH was associated with moderate and severe neurodevelopmental disabilities, reduced full-scale IQ, and cerebral palsy. Rates of neurodevelopmental disabilities at age 5 did not differ between children without IVH and those with low-grade IVH. For high-grade IVH, mortality rate was high, mostly because of withholding and withdrawal of life-sustaining treatment, and we found a strong association with overall neurodevelopmental disabilities in survivors.

Tracking clusters of patients over time enables extracting information from medico-administrative databases

Context:Identifying clusters (i.e., subgroups) of patients from the analysis of medico-administrative databases is particularly important to better understand disease heterogeneity. However, these databases contain different types of longitudinal variables which are measured over different follow-up periods, generating truncated data. It is therefore fundamental to develop clustering approaches that can handle this type of data. Objective:We propose here cluster-tracking approaches to identify clusters of patients from truncated longitudinal data contained in medico-administrative databases. Material and Methods:We first cluster patients at each age. We then track the identified clusters over ages to construct cluster-trajectories. We compared our novel approaches with three classical longitudinal clustering approaches by calculating the silhouette score. As a use-case, we analyzed antithrombotic drugs used from 2008 to 2018 contained in the Échantillon Généraliste des Bénéficiaires (EGB), a French national cohort. Results:Our cluster-tracking approaches allow us to identify several cluster-trajectories with clinical significance without any imputation of data. The comparison of the silhouette scores obtained with the different approaches highlights the better performances of the cluster-tracking approaches. Conclusion:The cluster-tracking approaches are a novel and efficient alternative to identify patient clusters from medico-administrative databases by taking into account their specificities.

P404 Persistence of subcutaneous infliximab after switching from intravenous in a French national cohort of IBD patients in remission

Abstract Background Subcutaneous infliximab (IFX-SC) was launched in France for the treatment of patients with inflammatory bowel disease (IBD) in 2021. Real-life and pharmacokinetic (PK) data after switching from intravenous infliximab (IFX-IV) to IFX-SC are needed. The PEREM study is a French multicenter prospective cohort aiming to describe the persistence of IFX-SC after switch from IFX-IV. Methods IBD patients in steroid-free clinical remission [Harvey Bradshaw Index (HBI) ≤ 4 for Crohn’s disease (CD) and partial Mayo score (PMS) ≤ 2 with each subscore ≤ 1 for UC] for at least 6 months on IFX-IV therapy were proposed to switch to IFX-SC as part of routine care. Patients were included in 40 centers between Oct 2021 and May 2022. Clinical scores (HBI, PMS), biological samples (CRP and fecal calprotectin - FC), PK and anti IFX antibodies (ATI) were evaluated 3, 6, 12 and 24 months after switch. In case of IFX-SC discontinuation, time and reason for withdrawal were documented. Safety and adverse events of interest were recorded. The primary endpoint was IFX-SC persistence at 12 months. As not all patients met this primary endpoint at the time of writing this abstract, we present here the results at 6 months (M6). Results Among the 444 patients included [44% female, median age: 37 years (Min, Max: 18-88), 72% Crohn’s], 71% were receiving IFX-IV at a dose of 5 mg/kg every 8 weeks and 84% were treated on monotherapy. Among the 417 patients analyzed, five withdrew their consent before the M6 visit and 324 were assessed at M6; 25/324 (7.7%) discontinued IFX-SC before M6 (seven for relapse, twelve for intolerance, two for pregnancy, four for unknown reasons) including one (0.3%) switch back to IFX-IV. Rate of survival without IFX-SC discontinuation at M6 was 92.6% (95% CI 89.3-95.1). Among the patients evaluated at M6, median clinical scores did not vary between inclusion and M6: HBI from 0 (IQR: 0-1) to 0 (IQR: 0-1), PMS from 0 (IQR: 0-0) to 0 (IQR: 0-0), respectively. The median CF and CRP levels were respectively 52 μg/g (IQR: 19-142) at inclusion and 37 μg/g (IQR: 14-129) at M6, and 1 mg/L (IQR: 1-4) at inclusion and 1 mg/L (IQR 0-4) at 6 months. At baseline, median infliximab levels were 6.6 μg/mL (min, max: 0-29) and 20 μg/mL (min, max: 0.3- 79.2) at M6. No major safety signals were recorded. Conclusion In a national real-life multicenter cohort, rate of persistence of IFX-SC after 6 months was 92.6% in IBD patients switched in remission, without significant clinical or biological changes. Treatment switch was associated with an increase in IFX levels. These data are confirming the good efficacy and safety of IFX-SC after switch.

Impact of Early Hemoglobin Levels on Neurodevelopment Outcomes of Two-Year-Olds in Very Preterm Children

To evaluate, in very preterm infants, the hemoglobin (Hb) levels during the first 24 h and the neurodevelopment outcomes at 24 months of corrected age. We conducted a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. The eligible study participants were live-born singletons who were born before 32 weeks of gestational age, with early Hb levels who were admitted to the neonatal intensive care unit. The early Hb levels for an outcome survival at 24 months of corrected age without neurodevelopmental impairment were measured. The secondary outcomes were survival at discharge and without severe neonatal morbidity. Of the 2158 singletons of <32 weeks with mean early Hb levels of 15.4 (±2.4) g/dL, 1490 of the infants (69%) had a follow-up at two years of age. An early Hb of 15.2 g/dL is the minimum receiving operating characteristic curve at the 24 months risk-free level, but the area under the curve at 0.54 (close to 50%) indicates that this rate was not informative. In logistic regression, no association was found between early Hb levels and outcomes at two years of age (aOR 0.966; 95% CI [0.775-1.204]; p = 0.758) but rather there was a correlation found with severe morbidity (aOR 1.322; 95% CI [1.003-1.743]; p = 0.048). A risk stratification tree showed that male newborns of >26 weeks with Hb of <15.5 g/dL (n = 703) were associated with a poor outcome at 24 months (OR 1.9; CI: [1.5-2.4] p < 0.01). Early low Hb levels are associated with major neonatal morbidities in VP singletons, but not with neurodevelopment outcomes at two years of age, except in male infants of >26 Weeks GA.

Fetal growth disorders following medically assisted reproduction: due to maternal context or techniques? A national French cohort study

Research questionWhat part do maternal context and medically assisted reproduction (MAR) techniques play in the risk of fetal growth disorders? DesignThis retrospective nationwide cohort study uses data available in the French National Health System database and focuses on the period from 2013 to 2017. Fetal growth disorders were divided into four groups according to the origin of pregnancy: fresh embryo transfer (n = 45,201), frozen embryo transfer (FET, n = 18,845), intrauterine insemination (IUI, n = 20,179) and natural conceptions (n = 3,412,868). Fetal growth disorders were defined from the percentiles of the weight distribution according to gestational age and sex: small and large for gestational age (SGA and LGA) if <10th and >90th percentiles, respectively. Analyses were performed using univariate and multivariate logistic models. ResultsCompared with births following natural conception, multivariate analysis showed that the risk of SGA was higher for births following fresh embryo transfer and IUI (adjusted odds ratio [aOR] 1.26 [1.22–1.29] and 1.08 [1.03–1.12], respectively) and significantly lower following FET (aOR 0.79 [0.75–0.83]). The risk of LGA was higher for births following FET (aOR 1.32 [1.27–1.38]), especially in artificial cycles when compared with ovulatory cycles (aOR 1.25 [1.15–1.36]). In the subgroup of births without any obstetrical or neonatal morbidity, the same increased risk of SGA and LGA were observed following fresh embryo transfer or IUI and FET (aOR 1.23 [1.19–1.27] or 1.06 [1.01–1.11] and aOR 1.36 [1.30–1.43], respectively). ConclusionsAn effect of MAR techniques on the risks for SGA and LGA is suggested independently from maternal context and obstetrical or neonatal morbidities. Pathophysiological mechanisms remain poorly understood and should be further evaluated, as well as the influence of embryonic stage and freezing techniques.

Characteristics and survival of patients with advanced heart failure treated with left ventricular assist device (LVAD) as an effective bridge to heart transplantation vs. destination therapy through a French national retrospective cohort

Characteristics and survival of patients with advanced heart failure treated with left ventricular assist device (LVAD) as an effective bridge to heart transplantation vs. destination therapy through a French national retrospective cohort

84. One-month Humoral Response Following Two Doses of Covid-19 Vaccines in Specific populations – ANRS0001S COV POPART Cohort Study

Abstract Background We evaluated the immune response to COVID-19 vaccines in several specific populations at high risk of severe COVID-19. Methods Participants from the French national multi-center prospective cohort study ANRS0001S COV-POPART were included (11 specific subpopulations: and 2 control groups (18–64 years and over 65 years)). In this preliminary analysis patients and controls who had received at least two vaccine doses have been included. Percentages (95% confidence intervals (CI)) of participants with anti-Spike SARS-CoV-2 IgG antibodies (ELISA) and specific neutralizing antibodies (in vitro neutralization assay) were evaluated at one month after the second dose of COVID-19 vaccine. Results 3703 were included: 2650 participants from specific subpopulations (171 solid cancers, 160 SOT, 100 HCT, 91 chronic renal failures, 141 systemic autoimmune diseases, 157 autoimmune inflammatory rheumatic diseases, 361 multiple sclerosis (MS) or neuromyelitis optica spectrum disorders, 61 hypogammaglobulinemia, 401 diabetic, 739 obeses non-diabetic and 476 HIV) and 1053 controls (893: 18–64 years and 160 over 65 years). Median age was 51.7 years [InterQuartile range: 40.8 – 60.9] and 50.7% were male. Most of the participants received BNT162b2 vaccine (86.4%). In the control group, 100% (95%CI: 99.6;100.0) of those aged 18–64 and 99.4% (96.6; 100.0) of those over 65 years developed anti-Spike IgG antibodies. PLWHIV, cancer and diabetic patients had high rate of responders after two doses with 98.3% (97.2;99.1), 93.0% (88.1;96.3) and 92.0% (88.9;94.5), respectively. The lowest percentage of responders was found in patients with SOT (13.8% (8.8;20.1), HSCT (34.0% (24.8;44.2) and hypogammaglobulinemia (52.5% 39.3;65.4). In both control groups, the frequency of neutralizing antibodies was similar to the anti-Spike IgG antibody response. In the immunodeficient populations, neutralizing antibodies responders tended to be less frequent than anti-Spike antibodies responders. Similar trends than for IgG antibody were identified (Figure 1). Anti-Spike and Neutralizing antibody (Ab) responses (95% CI) one month after the second dose of COVID-19 vaccine in specific and control populations. Conclusion Lower COVID-19 vaccine humoral response was observed in specific populations than in controls, especially in patients with hypogammaglobulinemia, HSCT and SOT. Disclosures Paul LOUBET, MD, PhD, pfizer: Board Member Odile Launay, MD, PhD, AstraZeneca: Financial|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Johnson &amp; Johnson: Advisor/Consultant|Johnson &amp; Johnson: Grant/Research Support|MD: Advisor/Consultant|Moderna: Advisor/Consultant|MSD: Data safety monitoring board|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support|Sanofi Pasteur: Data safety monitoring board.

Survival and neurodevelopmental impairment of outborn preterm infants at 5.5 years of age: an EPIPAGE-2 prospective, matched study using multiple imputation

ObjectiveTo determine whether birth outside a level-3 centre (outborn) is associated with a difference in the combined outcome of mortality or moderate-to-severe neurological impairment at 5.5 years of age compared...

Prevalence and risk factors associated with prediabetes and undiagnosed diabetes in France: The national CONSTANCES cohort

AimsTo assess the prevalence of prediabetes and diabetes in France between 2013 and 2014 using data from the CONSTANCES cohort, and to identify factors associated with prediabetes and undiagnosed diabetes. MethodsThe study population comprised participants recruited in 2013–2014 in CONSTANCES, an ongoing French national prospective cohort following participants aged 18–69 years who are covered by France's general health insurance scheme. Participants completed a questionnaire at baseline and underwent a medical examination which included providing blood samples. Undiagnosed diabetes was defined as a fasting plasma glucose (FPG) ≥ 7 mmol/l and diagnosed diabetes as self-report or identification of reimbursements for anti-diabetics. Prediabetes was defined as a FPG ≥ 6 mmol/l but < 7 mmol/l. Results25,137 participants were included in the analyses. The overall prevalence of prediabetes was 7.2% [95% confidence interval: 6.7–7.7], 1.6% [1.4–1.9] for undiagnosed diabetes, and 4.0% [3.6–4.4] for diagnosed diabetes. These rates were significantly higher in men, in older persons, in persons with obesity, and in those with lower education levels. In multivariate regression models, excessive corpulence was the variable most strongly associated with undiagnosed diabetes (adjusted Odds Ratio=9.31) and prediabetes (aOR=3.85). Additionally, male sex, older age, family history of diabetes, at-risk alcohol use, and lower education level were all positively associated with undiagnosed diabetes and prediabetes. ConclusionDiabetes and prediabetes prevention together with screening for undiagnosed diabetes must be strengthened for persons with low socioeconomic status and for those with obesity or overweight.

Toxic Occupational Exposures and Membranous Nephropathy.

Membranous nephropathy is a rare autoimmune kidney disease whose increasing prevalence in industrialized countries pleads for the involvement of an environmental factor in the development of the disease. In addition, the predominance of men in membranous nephropathy, classically attributed to biologic or genetic differences between men and women, could also be due to different occupational exposures. To support this hypothesis, we sought to describe the toxic occupational exposures of patients with membranous nephropathy. In this observational epidemiologic study, we compared the occupations and toxic occupational exposures of 100 patients with membranous nephropathy with those of the general population, consisting of two cohorts of 26,734,000 and 26,500 French workers. We then compared the characteristics of patients exposed to an occupational toxic substance with those of unexposed patients. Patients with membranous nephropathy worked more frequently in the construction sector than the general population (33% versus 7%, P<0.001). This difference remained significant by age and sex. They were also more frequently exposed to toxic substances, such as asbestos (16% versus 5%, P<0.001), lead (9% versus 1%, P<0.001), or organic solvents (37% versus 15%, P<0.001), than the general population. The predominance of men in the subgroup of patients occupationally exposed to toxic substances was not observed in unexposed individuals (organic solvents: 80% men versus 41%, P<0.001; asbestos: 90% men versus 55%, P=0.004). In addition, patients with phospholipase A2 receptor 1 (PLA2R1) epitope spreading were more frequently exposed to asbestos and organic solvents than patients without epitope spreading (32% versus 7%, P=0.02 and 74% versus 43%, P=0.02, respectively), with a dose-dependent effect. Patients with membranous nephropathy were more frequently exposed to certain occupational toxic substances, such as asbestos and organic solvents, than the general population. This occupational exposure was more frequent in men and in patients with PLA2R1 epitope spreading. Immunopathological Analysis in a French National Cohort of Membranous Nephropathy (IHMN), NCT04326218. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_10_25_CJN02930322.mp3.

Early childcare type and child development at age 3.5 years, data from the French ELFE cohort

Abstract Background Early childcare has been linked to child development in some countries. The aim of this study is to evaluate the impact of early childcare in the French context, where children can attend different types of childcare facilities prior to age 3 when they enter kindergarten, and development at age 3.5 years. Methods 10,683 children from the ELFE French national birth cohort were classified into 4 groups depending on their main type of childcare between birth and age three: childminder (n = 5,014), centre-based childcare (n = 2,583), informal childcare (n = 777) and parents only (n = 2,465). Children's development was measured with the short form of the Child Development Inventory (CDI) via parents-reports at age 3.5 years. The CDI score was transformed into a Development Quotient (DQ) taking into account the child's age, and global developmental delay was defined as DQ &amp;lt; 90. Missing data was imputed by Fully Conditional Multiple Imputation with 10 imputations. Multinomial analyses were carried out adjusted by Inverse Probability Weighting based on Propensity Scores calculated using main selection and confounding variables. Results Compared to children who were cared for by parents only, children who were cared for by a childminder or in a centre-based childcare had a higher DQ (103.0 and 104.8 respectively) as well as a lower likelihood of global developmental delay (propensity-score weighted OR = 0.84, [95% CI 0.70-1.01] and propensity-score weighted OR = 0.54, [95% CI 0.44-0.66]) respectively. Conclusions In the French context, early centre-based childcare attendance is significantly associated with a lower risk of global child delay. Policies should make centre-based childcare more accessible to a broader number of children. Key messages • Early childcare type is linked to child development in France. • Children in centre-based childhood had a lower likelihood of developmental delay compared to those looked after by parents only.

Validation of a data collection set for the psychiatric, addiction, sleep and chronobiological assessments of patients with depression: A Delphi study for the SoPsy-depression French national cohort

ObjectivesDespite international efforts to identify biomarkers of depression, none has been transferred to clinical practice, neither for diagnosis, evolution, nor therapeutic response. This led us to build a French national cohort (through the clinical and research network named SoPsy within the French biological psychiatry society (AFPBN) and sleep society (SFRMS)), to better identify markers of sleep and biological rhythms and validate more homogeneous subgroups of patients, but also to specify the manifestations and pathogeneses of depressive disorders. Before inclusions, we sought to provide a predefined, standardized, and robust set of data to be collected in all centers. MethodsA Delphi process was performed to achieve consensus through the independent rating of invited experts, the SoPsy-depression co-investigators (n=34). The initial set open for vote included 94 questionnaires targeting adult and child psychiatry, sleep and addiction. ResultsTwo questionnaire rounds were completed with 94% participation in the first round and 100% participation in the second round. The results of the Delphi survey incorporated the consensus opinion of the 32 members who completed both rounds. Nineteen of the 94 questionnaires achieved consensus at the first round and seventy of 75 at the second round. The five remaining questionnaires were submitted to three experts involved in the steering committee during a dedicated meeting. At the end, 24 questionnaires were retained in the mandatory and 26 in the optional questionnaire set. ConclusionsA validated data collection set of questionnaires is now available to assess psychiatry, addiction, sleep and chronobiology dimensions of depressive disorders.

365P Prognostic value of Lynch syndrome, BRAFV600E and RAS mutation status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of the national Dutch and French cohorts

Current knowledge on biomarkers (BRAFV600E/RAS mutations) is mainly based on metastatic colorectal cancer (mCRC) patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same implications in deficient mismatch repair (dMMR) mCRC patients. Our aim is to provide insight on the value of Lynch syndrome, BRAFV600E and RAS mutation status and treatment regimens on survival in dMMR mCRC patients treated outside clinical trials. This observational cohort study combined the national Dutch cohort, including almost all Dutch centers (2014-2019), and national French cohort, including 18 French centers (2007-2017). Clinical, molecular and survival data were collected in mCRC patients with dMMR tumors receiving chemotherapy ± targeted therapy. Multivariable Cox proportional hazard regression was used to analyze the prognostic value of BRAFV600E and RAS mutation status and Lynch syndrome on progression-free survival (PFS) and overall survival (OS). Inverse probability weighing was used to analyze impact of treatment regimens on survival. In our large real-world evidence cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line systemic therapy. Mean age of first-line treated patients was 61.9 years and 40% had a proven/suspected Lynch syndrome. Most tumors were right-sided (74%) with synchronous metastases (62%). BRAFV600E and RAS mutations were observed in 42% and 33%, respectively. Median PFS and OS were 6.0 months and 19.3 months from start of first-line therapy. Multivariable regression analysis showed known clinical and pathological characteristics as predictors for OS and PFS, but not Lynch syndrome, mutation of BRAFV600E or RAS. In addition, there were no survival differences according to type of chemo- and targeted therapy used. BRAFV600E and RAS mutation status are not associated with poor prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Our findings may aid in estimating prognosis and clinical decision-making in dMMR mCRC treated with chemotherapy and targeted therapy.

995P Effectiveness of combination of osimertinib with another targeted therapy in advanced EGFR mutated non-small cell lung cancer harbouring other oncogenic drivers: The real-world COMPOSIT study

Identification of resistance mechanisms is crucial to guide therapeutic approaches in patients receiving osimertinib (O). The COMPOSIT study is a French national cohort reporting the effectiveness and tolerance of O in combination with another targeted therapy (TT) in patients with advanced EGFR mutated NSCLC harboring other oncogenic drivers. Patients (pts) treated with O between 01.01.2017 and 30.04.2021 who received a combination of O with another TT were included. Clinical pathological and molecular data were retrospectively collected. The primary endpoint was real-world progression free survival (rwPFS). 55 pts were included from 14 centers. Median age was 59 years (range 29-83); 56.3% were women, 60% never smokers and DelEx19 of EGFR was observed in 69% of cases. Combination therapy was administered to 23 pts who received O as 1st line (41.8%) and to 32 pts in whom O was administrated after receiving chemotherapy and/or 1st or 2nd generation EGFR TT (58.2%). MET pathway was the most targeted mechanism by combination therapies (66.1%). Real world PFS data was available for 54 combinations. Median follow-up was 16.7 months (95% CI; 13.3-19.1). The median rwPFS was 4.1 months (95% CI; 3.2-5.5). Overall response rate (ORR) was 49.0% (95% CI; 35.3-62.7%). The median overall survival (OS) was 11.9 months (95% CI; 8.6-19.6). In MET pathway alterations, rwPFS was 5.3 months (95 CI; 3.9-6.7), ORR 59.4% (95% CI; 42.4-76.4) and OS 14.8 months (95% CI; 7.4-33.2). Adverse events (AE) of grade >2 were reported in 13 patients (23.6%), mainly not related to O (93%). The frequency of drug interruption due to AE was 12.7%.Table: 995PCombination therapies with osimertinib (O) evaluated in COMPOSIT StudyPatients (n=55)Alteration targetedO + Targeted therapy36MET amplificationO + crizotinib (n=19) O + capmatinib (n=7) O + savolitinib (n=4) O + tepotinib (n=5) O + crizotinib then O + capmatinib (n=1)5BRAF fusionO + trametinib5BRAF V600EO + trametinib (n=1) O + dabrafenib (n=2) O + dabrafenib Trametinib (n=2)2EGFR C797S + T790MO + brigatinib1EGFR C797S + T790M cisO + gefitinib1EGFR L861Q + G724S + T790MO + afatinib2RET rearrangementO + praseltinib1ALK rearrangementO + crizotinib1FGFR1 amplificationO + erdafitinib1HER2 amplificationO + trastuzumab Open table in a new tab To our knowledge, this is the largest real-world study of combination therapies in patients with advanced EGFR-mutated NSCLC harboring other oncogenic drivers. Combination approaches with O are already used to overcome resistance by clinicians.

Association between kidney retransplantation and survival according to age in the French national cohort of dialysis patients

The mean age of patients returning to dialysis after a first kidney transplantation (KT) has increased in the past decades. We aimed to assess the association between second KT (2KT) and survival according to age at the time of return to dialysis. Data of 5334 patients registered in the French Renal Epidemiology and Information Network (REIN) (mean age 56.6 ± 13.6 years) who returned to dialysis after a first KT were collected. The association of 2KT with death was assessed using a propensity score‐based analysis taking into account baseline and follow‐up variables. In relisted patients (3272 patients, 61.3%), retransplantation was associated with better overall survival in comparison with patients who remained in dialysis (adjusted HR 0.75 [0.63–0.89], p = .0009). The survival advantage conferred by retransplantation gradually declined with increasing age (adjusted HR 0.41 [0.24–0.70] in patients <50, HR 0.94 (0.69–1.27) in patients aged 70 or older, p for interaction 0.034 for age considered as a continuous variable). 2KT is associated with better survival as opposed to remaining on dialysis after a first kidney graft failure. Nevertheless, this survival benefit is age dependent and diminishes with increasing age. The risk/benefit ratio should be comprehensively assessed in the oldest patients when relisting is considered.

In-hospital Outcomes and Early Hemodynamic Management According to Echocardiography Use in Hypotensive Preterm Infants: A National Propensity-Matched Cohort Study.

BackgroundHypotension is a common condition during the first postnatal days of very preterm infants and has been associated with an increased risk of adverse outcomes but its management remains controversial. There is a consensus to promote the use of neonatologist-performed echocardiography (NPE) in hypotensive very preterm infants, although no clinical trial ever assessed this practice.MethodsWe conducted a retrospective analysis of prospectively collected data from the French national EPIPAGE-2 cohort to evaluate the association of NPE with survival, severe morbidity, and therapeutic management in very preterm infants with early hypotension. Reasons for administering antihypotensive treatments were also analyzed. We included infants born before 30 weeks of gestation with hypotension within 72 h of birth. Infants managed with (NPE group) or without (no-NPE group) NPE use were compared after matching on gestational age and a propensity score, reflecting each patient's probability of having an NPE based on his/her baseline covariates. This matching procedure intended to control for the indication bias of NPE.ResultsAmong 966 eligible infants, 809 were included (NPE group, n = 320; no-NPE group, n = 489), and 229 from each group could be matched. The NPE group did not differ significantly from the no-NPE group for survival (OR 1.01, 95% CI 0.64 to 1.60; p = 0.95) or survival without severe morbidity at discharge (OR 0.92, 95% CI 0.63 to 1.34; p = 0.66), but received more antihypotensive treatments [144/229 (62.9%) vs. 99/229 (43.0%), p < 0.001]. Isolated hypotension was the main reason for treatment in both groups. Among treated infants, volume expansion was administered at equal rates to the NPE and no-NPE groups [118/144 (82.1%) vs. 79/99 (80.1%), p = 0.67], but the NPE group received inotropic drugs more often [77/144 (53.7%) vs. 37/99 (37.8%), p = 0.023].ConclusionNPE use in hypotensive preterm infants was not associated with in-hospital outcomes and had little influence on the nature of and reasons for antihypotensive treatments. These results suggest the need to optimize NPE use.

Quality of life of children with capillary malformations of the lower limbs: Evolution and associated factors. Data from the French national paediatric cohort, CONAPE

Quality of life of children with capillary malformations of the lower limbs: Evolution and associated factors. Data from the French national paediatric cohort, CONAPE