Search

Summary Background Patients with COVID-19 pneumonia can have increased inflammation and elevated cytokines, including interleukin (IL)-6, which might be deleterious. Thus, sarilumab, a high-affinity anti-IL-6 receptor antibody, might improve the outcome of patients with moderate-to-severe COVID-19 pneumonia. Methods We did a multicentric, open-label, Bayesian randomised, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalised with COVID-19 in six French centres, requiring at least 3L/min of oxygen but without ventilation assistance and a WHO Clinical Progression Scale [CPS] score of 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomisation list stratified on centre and with blocks randomly selected among 2 and 4, to receive usual care plus 400 mg of sarilumab intravenously on day 1 and on day 3 if clinically indicated (sarilumab group) or usual care alone (usual care group). Primary outcomes were the proportion of patients with WHO-CPS scores greater than 5 on the 10-point scale on day 4 and survival without invasive or non-invasive ventilation at day 14. This completed trial is closed to new participants and is registered with ClinicalTrials.gov , NCT04324073 . Findings 165 patients were recruited from March 27 to April 6, 2020, and 148 patients were randomised (68 patients to the sarilumab group and 80 to the usual care group) and followed up for 90 days. Median age was 61·7 years [IQR 53·0–71·1] in the sarilumab group and 62·8 years [56·0–71·7] in the usual care group. In the sarilumab group 49 (72%) of 68 were men and in the usual care group 59 (78%) of 76 were men. Four patients in the usual care group withdrew consent and were not analysed. 18 (26%) of 68 patients in the sarilumab group had a WHO-CPS score greater than 5 at day 4 versus 20 (26%) of 76 in the usual care group (median posterior absolute risk difference 0·2%; 90% credible interval [CrI] −11·7 to 12·2), with a posterior probability of absolute risk difference greater than 0 of 48·9%. At day 14, 25 (37%) patients in the sarilumab and 26 (34%) patients in the usual care group needed ventilation or died, (median posterior hazard ratio [HR] 1·10; 90% CrI 0·69–1·74) with a posterior probability HR greater than 1 of 37·4%. Serious adverse events occurred in 27 (40%) patients in the sarilumab group and 28 (37%) patients in the usual care group (p=0·73). Interpretation Sarilumab treatment did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia. Further studies are warranted to evaluate the effect of sarilumab on long-term survival. Funding Assistance publique—Hopitaux de Paris

BackgroundLung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed.MethodsAmong 1482 children (ResultsThe median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease.First-line vinblastine–corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine:n = 7; etoposide-aracytine:n = 3; targeted therapyn = 2). A total of 6 children (35%) died (repeated pneumothorax:n = 3; diffuse micronodular lung infiltration in the context of multisystem disease:n = 2; following lung transplantation:n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging.ConclusionsSevere lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplastic disease driven by activating mutations in the mitogen-activating protein kinase signalling pathway, including the BRAFV600E mutation and BRAF deletions (BRAFdel). Next-generation sequencing and whole exome sequencing (WES) are valuable and powerful approaches for BRAFdel identification, but these techniques are costly and time consuming. Pyrosequencing is an alternative method that has the potential to rapidly and reliably identify gene deletions. We developed a custom pyrosequencing assay to detect the exon-12 BRAFdel in 18 biopsies from adult patients with LCH, which were all genotyped in parallel using Sanger sequencing and WES. A BRAFdel was detected in 7/18 (39%), 6/18 (33%) and 3/18 (17%) LCH lesions using WES, pyrosequencing and Sanger, respectively, with good concordance between the WES and pyrosequencing results (Kappa-coefficient=0.88). Therefore, our pyrosequencing assay is reliable and useful for detecting BRAFdel, particularly in BRAFV600E-negative LCH lesions, for which targeted treatment is indicated.

BackgroundThe long-term outcomes of adult pulmonary Langerhans cell histiocytosis (PLCH), particularly survival, are largely unknown. Two earlier retrospective studies reported a high rate of mortality, which contrasts with our clinical experience.MethodsTo address this issue, all patients with newly diagnosed PLCH referred to the French national reference centre for histiocytoses between 2004 and 2018 were eligible for inclusion. The primary outcome was survival, which was defined as the time from inclusion to lung transplantation or death from any cause. Secondary outcomes included the cumulative incidences of chronic respiratory failure (CRF), pulmonary hypertension (PH), malignant diseases and extrapulmonary involvement in initially isolated PLCH. Survival was estimated using the Kaplan–Meier method.Results206 patients (mean age 39±13 years, 60% female, 95% current smokers) were prospectively followed for a median duration of 5.1 years (IQR 3.2–7.6 years). Of these, 12 patients (6%) died. The estimated rate of survival at 10 years was 93% (95% CI 89–97%). The cumulative incidences of CRF and/or PH were ConclusionThe long-term prognosis of PLCH is significantly more favourable than has previously been reported. Patients must be closely monitored after diagnosis to detect severe complications early.

International audience; Background: Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods: In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.Findings: Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).Interpretation: Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.Funding: The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

Background The prevalence of psychological symptoms and the co-occurrence of substance abuse disorders in adult patients with Langerhans cell histiocytosis (LCH) has not been previously explored. We aimed to use validated scales to evaluate depression and anxiety symptoms experienced by adult LCH patients. Methods In this cross-sectional study, all consecutive adult LCH patients seen at our national reference center between January 2012 and January 2013 were asked to complete the following instruments: the Hospital Anxiety and Depression scale (HADS); Barratt Impulsiveness Scale, Version 10 (BIS-10); and Cannabis Use Disorders Identification Test (CUDIT). Self-reported scores on these scales were used to determine the point prevalence of clinically significant psychological symptoms and substance use disorders in LCH patients. Patient profiles in terms of psychological features were assessed by principal component analysis including the HADS and BIS-10 instruments values, followed by hierarchical clustering. Fisher exact tests and Wilcoxon tests were used to examine the associations between disease-related parameters and high levels of anxiety and impulsivity. Results Seventy-one adult LCH patients, mainly with pulmonary LCH (PLCH), completed the evaluations. Clinically significant anxiety and depression symptoms were reported by 22 (31%) and 4 (6%) subjects, respectively. Impulsivity was detected in 14% (10/71) of the patients. Seventeen percent (12/71) of the patients used cannabis on a regular basis, with 50% of these individuals (6/12) exhibiting scores consistent with cannabis use disorder. Three derived clusters of patients were identified in the principal component analysis; these patient clusters differed in successful weaning from tobacco at the time of evaluation (p = 0.03). In univariate analyses, isolated PLCH and the use of psychotropic treatments were statistically associated with clinically significant anxiety symptoms. Conclusions High levels of anxiety and impulsivity are common in adult patients with LCH. The consequences of these symptoms for the management of LCH patients warrant further evaluation.

Introduction: The long-term outcome of adult pulmonary Langerhans cell histiocytosis (PLCH) is unclear and an association with malignancy is strongly suspected. Aims and Objectives: Our objectives were to determine the overall survival of adult PLCH patients and the incidence of chronic respiratory failure (CRF), pulmonary hypertension (PH), and malignant disorders during follow-up. Methods: All PLCH patients newly diagnosed at adulthood at the French National Reference Centre for Histiocytoses between January 2004 and April 2018 and prospectively registered were included. Results: Two hundred and six patients (39 ± 13 years, 60% females, 95% current smokers) were followed for a median time of 5.1 years; IQR 3.2; 7.6. Twelve patients died during the study. The main cause of death was malignancy (42%, mostly lung cancer). The estimated rates of survival at 5 and 10 years after PLCH diagnosis were 94% (95%CI 90; 98) and 93% (95%CI 89; 97), respectively. The 5 year cumulative incidence of CRF and PH was 6.3% (95%CI 3.4; 10.4) and 5.5% (95%CI 2.8; 9.5), respectively, with no further events after 5 years. Twenty-seven malignancies (11 lung cancer, 41%) were observed in 23 patients, before (n=11), at the time (n=6), or after PLCH diagnosis (n=10, within a median time of 4.1 years; IQR 3.1; 5.0). The incidence of lung cancer was significantly higher than that expected using age- and sex-specific rates from the French population (SIR=16.7, 95%CI 7.3; 38.1). Conclusions: Our findings provide important clues for the management of adult PLCH patients. Further studies are needed to identify risk factors for CRF and clarify the underlying mechanisms of cancer excess in PLCH.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplastic disease driven by activating mutations in the mitogen-activating protein kinase signalling pathway, including the

Langerhans cell histiocytosis (LCH) is currently considered a rare neoplastic disease with an inflammatory component, driven by genomic alterations in the mitogen-activating protein kinase (MAPK) pathway, including BRAFV600E, MAP2K1 mutations and BRAF deletions [1, 2]. Lung involvement is frequently observed in adult LCH patients, almost exclusively in young smokers of both sexes [3]. The aetiology of LCH, including pulmonary LCH (PLCH), remains unknown. A viral triggering factor of LCH has long been suspected, but the results of studies are inconclusive [4, 5]., Compared to control lung tissues from smokers, MCPyV DNA is rarely detected in PLCH lesions and is not associated with alterations of the MAPK pathway. A viral trigger in PLCH pathogenesis remains elusive. https://bit.ly/2xKmkIo

Introduction Le pronostic a long terme de l’histiocytose Langerhansienne pulmonaire (HLP) de l’adulte est mal connu. On ne dispose que de 2 etudes retrospectives anciennes qui rapportent une mortalite importante des patients ayant une HLP avec une survie mediane d’environ 13 ans, ce qui ne correspond pas a notre experience clinique. De plus, le risque de survenue d’un cancer bronchique chez ces patients necessite d’etre precise. L’objectif principal de cette etude etait de determiner la survie des patients adultes atteints d’HLP. Les objectifs secondaires etaient d’evaluer l’incidence cumulee de l’insuffisance respiratoire chronique (IRC), de l’hypertension pulmonaire (HTP), des atteintes extra-pulmonaires dans les formes initialement localisees au poumon et des cancers au cours du suivi. Methodes Tous les patients adultes atteints d’HLP nouvellement diagnostiques au Centre de reference national des histiocytoses entre janvier 2004 et avril 2018 ont ete inclus. Les donnees ont ete recueillies prospectivement dans le registre du centre. La survie et les incidences cumulees ont ete estimees avec la methode de Kaplan-Meier. Resultats Deux cent six patients (39 ± 13 ans, 60 % de femmes, 95 % de fumeurs) ont ete suivis pendant une duree mediane de 5,1 ans, IQR [3,2; 7.6]. Douze patients sont decedes au cours de l’etude. Les principales causes de deces etaient un cancer bronchique, l’IRC terminale ou une pathologie cardiaque. Les taux de survie a 5 et a 10 ans apres le diagnostic de l’HLP etaient respectivement de 94 %, IC a 95 % [90; 98] et 93 %, IC a 95 % [89; 97]. Les incidences cumulees a 5 ans de l’IRC et de l’HTP etaient respectivement de 4,5 % et 3,9 % et restaient identiques a 10 ans. Parmi les 157 patients avec une HLP initialement isolee, 7 patients ont developpe une atteinte extra-pulmonaire au cours du suivi (incidence cumulee a 5 et 10 an s de 6 %). Vingt-sept tumeurs malignes ont ete observees chez 23 (11 %) patients: avant (n = 11); au moment (n = 6); apres le diagnostic de l’HLP (n = 10, dans un delai median de 4,1 ans, IQR [3,1; 5,0]). Le risque de cancer du poumon etait significativement plus eleve que celui attendu pour la population generale francaise (ratio d’incidence standardise = 17, IC a 95 % [7,3; 38,1]). Conclusion Dans cette cohorte prospective, la survie des patients avec une HLP etait nettement meilleure que precedemment rapporte. Les resultats de cette etude permettent aussi de guider la prise en charge et le suivi evolutif de ces patients.

Background: The prevalence of neuropsychiatric symptoms and substance abuse disorders, in adult patients with pulmonary Langerhans cell histiocytosis (PLCH) has not been explored. Objectives: The aim of this study was to examine the psychological healthcare burden faced by PLCH patients. Methods: All PLCH patients seen during one year completed the Hospital Anxiety and Depression scale (HAD), the Barratt Impulsiveness Scale, Version 10 (BIS-10) and the Cannabis Use Disorders Identification Test (CUDIT) questionnaires. Scores were used to determine the prevalence of psychological and substance abuse problems, and were associated with clinical assessment of the disease. The primary endpoint of the study was the proportion of patients having definite or doubtful anxious state (HAD-A scores of 11 or higher or between 8 and 10, respectively). Logistic regression models were used to quantify the strength of association of various disease-related parameters and the occurrence of anxiety, depression or impulsivity. Results: Sixty-eight patients were included. Definite anxious and depressive states were identified in 29% and 6% patients, respectively, and doubtful anxious and depressive states in 34% and 6%, respectively. Impulsive behaviour was detected in 13% of the cohort. Eleven patients (16%) consumed cannabis on a regular basis, and in 55% of them CUDIT scores suggested cannabis abuse or dependence. Increasing time from diagnosis and successful cessation of cigarette smoke exposure were associated with decreased risk of anxiety. Conclusions: Psychological abnormalities commonly co-exist in adult PLCH patients and should be considered while making their management decisions.

Background: The clinical significance of the BRAFV600E mutation in tissue lesions from patients with pulmonary Langerhans cell histiocytosis (PLCH) has not been evaluated. Objective: To search for an association between BRAFV600E mutation and PLCH presentation and outcome. Methods:BRAFV600E genotyping was performed in biopsies from 83 patients with PLCH (43 males, median age 36 years, 65 current smokers). The outcome was based on variations of lung function tests and the occurrence of a new pneumothorax during the study [1]. Cox models were used to estimate the strength of association of baseline characteristics on the hazard of PLCH progression. P-values ≤0.05 denoted statistical significance. Results: A BRAFV600E mutation was detected in 31(37%) cases. No difference was identified in PLCH presentation, including smoking status (p=0.42), pneumothorax (p=0.29), or lung function (p>0.05), according to BRAF status. Patients were followed for a median time of 5 years. Thirty-eight (46%) patients experienced lung progression. BRAF status was not associated with PLCH outcome (Figure). In multivariable analysis, airflow obstruction at diagnosis was associated with increased risk of lung progression (p=0.028). Conclusions:BRAFV600E mutation was not associated with clinical features or outcome in adult PLCH patients. Airflow obstruction at diagnosis was the main factor associated with the risk of lung progression overtime.

The mitogen-activated protein kinase (MAPK) pathway is constantly activated in Langerhans cell histiocytosis (LCH). Mutations of the downstream kinasesBRAFandMAP2K1mediate this activation in a subset of LCH lesions. In this study, we attempted to identify other mutations which may explain the MAPK activation in nonmutatedBRAFandMAP2K1LCH lesions.We analysed 26 pulmonary and 37 nonpulmonary LCH lesions for the presence ofBRAF,MAP2K1,NRASandKRASmutations. Grossly normal lung tissue from 10 smoker patients was used as control. Patient spontaneous outcomes were concurrently assessed.BRAFV600Emutations were observed in 50% and 38% of the pulmonary and nonpulmonary LCH lesions, respectively. 40% of pulmonary LCH lesions harbouredNRASQ61K/Rmutations, whereas noNRASmutations were identified in nonpulmonary LCH biopsies or in lung tissue control. In seven out of 11NRASQ61K/R-mutated pulmonary LCH lesions,BRAFV600Emutations were also present. Separately genotyping each CD1a-positive area from the same pulmonary LCH lesion demonstrated that these concurrentBRAFandNRASmutations were carried by different cell clones.NRASQ61K/Rmutations activated both the MAPK and AKT (protein kinase B) pathways. In the univariate analysis, the presence of concurrentBRAFV600EandNRASQ61K/Rmutations was significantly associated with patient outcome.These findings highlight the importance ofNRASgenotyping of pulmonary LCH lesions because the use of BRAF inhibitors in this context may lead to paradoxical disease progression. These patients might benefit from MAPK kinase inhibitor-based treatments.

Introduction L’histiocytose Langerhansienne pulmonaire (HLP) est caracterisee par l’infiltration et la destruction de la paroi des bronchioles distales par les lesions de la maladie. Ce tropisme bronchiolaire explique la frequence d’un trouble ventilatoire obstructif (TVO), parfois reversible dans l’HLP. L’association corticosteroides et beta-2-mimetiques de longue duree d’action (CSI/LABA) inhales est utilisee de facon empirique dans l’HLP, sans preuve de son efficacite. Le but de cette etude etait d’evaluer l’effet de l’association CSI/LABA sur le volume expire maximal en 1 seconde (VEMS) dans l’HLP. Methodes Les patients ayant recu un CSI/LABA au sein de la cohorte prospective de 206 patients atteints d’HLP du Centre National de Reference des Histiocytoses entre janvier 2004 et avril 2018 etaient eligibles. La prise d’un traitement inhale ou systemique avant ou au moment de l’introduction du CS1/LABA etait un critere d’exclusion. Du fait du biais de selection potentiel, les patients traites par CSI/LABA ont ete ensuite apparies avec les patients non traites sur un score de propension comprenant l’âge, le sexe, le statut tabagique, le VEMS et le score kystique scanographique. Le critere de jugement principal etait la variation du VEMS apres 6 mois de traitement compare a l’etat basal. Resultats Trente-cinq patients (40 ± 11 ans, 66% de femmes, 83% de fumeurs actifs) ont recu un traitement par CSI/LABA (budesonide/formoterol dans 89% des cas). Leur VEMS moyen etait de 76 ± 18% de la theorique a l’initiation du traitement. Treize patients (38,2%) avaient un TVO. Le gain median de VEMS a 8,3 ± 2,3 mois apres l’initiation du traitement etait de 170 ml, IQR [−20; 435], p = 0,006, comparativement au VEMS basal. Parmi les patients traites, seuls 18 ont pu etre apparies a un patient non traite sur leur score de propension. Le VEMS median a augmente de 225 ml, [IQR −50; 448] dans le groupe traite et de 75 ml, IQR [−32; 280] dans le groupe non traite (p = 0,90). L’augmentation mediane du VEMS a 8,3 ± 2,2 mois par rapport a la valeur basale dans les groupes traites et non traites etaient respectivement de 7,5%, IQR [−2,1; 17,2] et 2,3%, IQR [0,6; 15,4], p = 0,75. Conclusion L’association CSI/LABA a augmente de facon significative le VEMS des patients apres 6 mois de traitement. Cependant cette variation n’etait pas differente de l’evolution spontanee du VEMS dans le sous-groupe de patients HLP apparies, possiblement du fait de la petite taille de l’echantillon.

Introduction Plusieurs groupes, dont le notre, ont identifie la mutation BRAF V600E, activatrice de la voie des mitogen activated protein kinases (MAPK), dans les lesions d’histiocytose Langerhansienne pulmonaire (HLP), mais sa signification clinique n’a pas ete etudiee. Afin d’evaluer son impact clinique dans l’HLP de l’adulte, nous avons genotype un nombre important de lesions provenant des patients suivis au centre de reference des histiocytoses et recherche une association entre la presence de la mutation BRAF V600E et leurs caracteristiques au diagnostic et au cours du suivi. Methodes La recherche de la mutation BRAF V600E a ete realisee par des techniques de biologie moleculaire dans 83 biopsies provenant de patients adultes atteints d’HLP (43 hommes, âge median 36 ans, 65 fumeurs et 16 ex-fumeurs, atteinte pulmonaire isolee n = 51). Les caracteristiques des patients ont ete extraites de la base de donnees prospective du registre des histiocytoses. Au cours du suivi, l’aggravation de l’atteinte pulmonaire etait definie par l’alteration de la fonction respiratoire et/ou la survenue d’un pneumothorax [1] . La probabilite d’aggravation au cours du suivi a ete estimee par la methode de Kaplan–Meier. Des modeles de Cox ont ete utilises pour tester l’association entre les caracteristiques des patients au diagnostic et le risque de progression ulterieure de l’atteinte pulmonaire. Resultats Une mutation BRAF V600E a ete detectee dans 31 (37 %) lesions. Il n’y avait pas de difference dans la presentation initiale de l’HLP selon le statut BRAF, en particulier pour le tabagisme (p = 0,42), la survenue d’un pneumothorax (p = 0,29), ou la fonction respiratoire (p > 0,05 pour tous les parametres fonctionnels). Les patients ont ete suivis pendant une duree mediane de 5 ans. Trente-huit (46 %) patients ont presente une progression de leur atteinte pulmonaire. L’incidence cumulee d’aggravation de l’HLP au cours de l’evolution etait similaire que les lesions soient mutees BRAF V600E ou non (p = 0,99) ( Fig. 1 ). Dans cette serie de patients, la presence d’un trouble ventilatoire obstructif au diagnostic etait associee a un risque accru de progression de l’atteinte pulmonaire, y compris en analyse multivariee (p = 0,025). Conclusion Dans cette cohorte importante de patients adultes ayant une HLP, la mutation BRAF V600E n’etait pas associee a une presentation particuliere de la maladie et ne modifiait pas le risque de progression de l’atteinte pulmonaire au cours de l’evolution.

Background: Pneumothorax (PNO) is a salient complication of PLCH, which management is not standardized. The factors associated with PNO recurrence are poorly understood. Objectives: To determine PNO outcome after thoracic surgery and search for factors associated with the risk of recurrence. Methods: All PLCH patients ≥18 years with ≥1PNO between 11/2003 and 12/2015 of the database of the National Registry for histiocytoses and followed ≥6 months were retrospectively studied. Kaplan Meier method and univariate Cox models were used for statistical analyses. Results: Among the 43 patients included (39 smokers), 53% presented at least 1 PNO recurrence during a 49 months median time (53 additional episodes, 75% ipsilateral, all within 2 years). Thoracic surgery did not modify the risk of PNO recurrence, as compared to conservative treatment (p=0.96). However, the rate of recurrences was lower after thoracotomy (TCT), as compared to video-assisted thoracoscopy (VATS) (p=0.03). In the univariate analyses, lung function air trapping at diagnosis was associated with increased hazard of PNO recurrence (p=0.03). Patients whose LCH lesion harboured the BRAFV600E mutation had a lower rate of ipsilateral recurrences (p=0.019). When incorporating all ipsilateral recurrences, VATS was associated with increased hazard of subsequent recurrence (p=0.05). Conclusions: Surgery did not decrease the risk of PNO recurrence in PLCH. Thus, no particular treatment can be recommended for the first PNO in PLCH patients. In case of recurrence, TCT which appears more effective than VATS to prevent subsequent recurrence, should be privileged. The reduced risk of PNO recurrence associated with the presence of BRAFV600E mutation needs to be confirmed.

Background Vinblastine is the standard treatment for children with Langerhans cell histiocytosis (LCH). Whether this treatment could be extended to adults with LCH is questionable. This retrospective multicenter study included 35 adult patients (median age 33 years; 23 men; 80% with multisystem LCH) who were treated with vinblastine + steroids as a first-line chemotherapy and followed for a median time of 83 months. The objectives were to determine the overall response rate (based on the Histiocyte Society criteria), disease reactivation rate, toxicity, permanent consequences, and survival rate corresponding to this treatment. The lung involvement outcome was based on serial lung function tests. The distribution of right-censored end points was estimated by the Kaplan-Meier method. Univariate Cox model with time-fixed and time-varying covariates was used for the predictive analysis of reactivation in the responders. Univariate analyses of risk factors for neurotoxicity were based on nonparametric Wilcoxon rank sum tests and exact Fisher tests. Results The median duration of the first course of vinblastine was 7.6 months, with a median cumulative dose of 160 mg [IQR 120–212]. Seventy percent of the patients were responders at the end of this treatment. Subsequently, LCH reactivation occurred with a 5-year cumulative incidence of 40%. During the study, 27 reactivations were observed in 17 patients, and half of these episodes were retreated with vinblastine. At the end of the last vinblastine treatment, 70% of the patients were responders. None of the patients with impaired lung function improved. No grade 3–4 peripheral neuropathy was observed. At the final vinblastine treatment, permanent LCH consequences, primarily pituitary stalk involvement, were present in 15 (43%) patients, and all were present at the time of vinblastine initiation. The 10-year survival rate was 86.2% (95CI, 71.8–100%), and the 2 patients who died from LCH had risk organ localizations. Conclusions Vinblastine is an effective and well-tolerated first-line treatment for adult LCH except in patients with lung involvement and impaired lung function. However, a significant portion of patients experienced LCH reactivation during long-term follow up. As in childhood LCH, the presence of risk organ involvement has a negative impact on patient prognosis.

The clinical significance of the BRAFV600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAFV600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAFV600E mutation: 36%, BRAFN486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRASQ61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAFV600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAFV600E status did not influence the risk of LCH progression over time.Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAFV600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.

International audience; Background - An important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated. Methods - In this prospective, multicentre study, 54 consecutive patients with newly diagnosed clinically isolated PLCH were systematically evaluated at inclusion by bone imaging and blood laboratory testing to search for subclinical extrapulmonary LCH involvement. The patients were followed over a 2-year period. At each visit, they were asked about the presence of extrapulmonary manifestations of LCH. Results - In the absence of bone symptoms, the skeletal X-ray survey results were normal for all but two patients who had a localised bone lesion consistent with possible LCH involvement, that remained unchanged over 2 years of follow-up. Whole-body bone scintigraphy did not add information to the plain radiography findings for the detection of asymptomatic bone involvement in isolated PLCH. Conversely, it showed nonspecific focal bone uptake in 18% of the patients, mainly corresponding to post-traumatic or degenerative abnormalities unrelated to LCH. Mild leucocytosis due to neutrophilia was observed in 22% of the patients and was not related to their smoking habits. Three patients had mild isolated lymphocytosis without haematological disease, whereas two patients had mild lymphopaenia. A mild inflammatory biological syndrome was observed in a minority of patients without infection or constitutional symptoms and was not associated with progressive disease. A substantial proportion (24.5%) of the patients had abnormal biological liver test results, including elevated liver enzymes and/or cholestasis, which were not linked to LCH involvement in this cohort. Conclusions - Obtaining a thorough history and performing comprehensive physical examination are essential for staging patients diagnosed with PLCH. In the absence of symptoms or signs suggestive of extrapulmonary LCH involvement, the systematic performing of recommended bone imaging does not appear informative. Although the observed blood laboratory abnormalities were not specifically related to LCH, performing these tests in the diagnostic workup for PLCH is useful because some of these alterations may impact patient management. Trial registration - ClinicalTrials.gov: No. NCT01225601; URL: www.clinicaltrials.gov.

Introduction Le pneumothorax complique l’HLP de l’adulte dans 15 a 20 % des cas. Les recidives sont frequentes et sa prise en charge n’est pas standardisee. Notre objectif principal etait d’evaluer le risque de recidive homolaterale associe aux differents traitements du pneumothorax au cours de l’HLP. Methodes Il s’agit d’une etude retrospective, monocentrique, a partir de la base de donnees du centre national de reference. Les patients d’âge ≥ 18 ans avec une HLP compliquee de pneumothorax, vus entre11/2003 et 12/2015, et suivis pendant au moins 6 mois etaient eligibles. Le critere de jugement principal etait le delai avant la rechute homolaterale, considerant l’hemithorax atteint au cours de chaque episode par rapport au(x) precedent(s). La distribution du delai de rechute a ete estimee par la methode de Kaplan–Meier. Resultats Quarante-trois patients (âge median 26,5 ans, 26 hommes, 39 fumeurs) ont presente 96 pneumothorax (11 bilateraux) impliquant 107 hemithorax pendant leur suivi dans l’etude (mediane 49 mois). Le 1e episode a ete traite en 1ere intention par drainage dans 30 cas. Une chirurgie thoracique a ete realisee d’emblee ou secondairement chez 50 % des patients pour obtenir un accolement pleural. Cinquante-trois pour cent des patients ont presente une rechute apres le pneumothorax initial, apres un delai median de 1,9 mois [IQR 0,3–4,6]. Le nombre median d’episodes de pneumothorax etait de 2 par patient [IQR 1–3]. Les rechutes sont survenues dans les 2 ans apres le 1e episode chez 42 patients. Durant la duree de l’etude, 44 recidives homolaterales ont ete observees. La 1re rechute homolaterale est survenue apres drainage avec un delai median de 2,1 mois [IQR 1–3,5] et apres chirurgie thoracique avec un delai median de 0,8 mois [IQR 0,4–4,6]. La chirurgie thoracique ne modifiait pas le risque de survenue de la 1re rechute homolaterale (p = 0,96). Cependant, le taux de recidives apres chirurgie etait plus faible apres thoracotomie (TCT) qu’apres video-thoracoscopie (TCS), (p = 0,03). Nous n’avons pas identifie de facteur predictif de recidive au moment du 1e pneumothorax. Conclusion Au cours de l’HLP de l’adulte, les recidives de pneumothorax sont frequentes et surviennent de facon rapprochee dans le temps. La chirurgie thoracique est souvent necessaire des le premier episode pour obtenir un accolement pleural, mais ne modifie pas le risque de survenue de la 1re recidive homolaterale. Cependant, la TCT semble plus efficace que la TCS pour la prevention des rechutes de pneumothorax.

A resin-bound furan has been efficiently synthesized from Merrifield resin. This new polymer reacts with an acetylenic dienophile to afford a thermally stable Diels–Alder adduct. Transformation of the adduct by Michael reaction with thiophenol has allowed an easy retro Diels–Alder reaction. This ‘safety-catch’ procedure leads to the formation of a chemically and stereochemically pure alkene and to the regeneration of the polymer-bound furan.

37-3 FIELD Section Title:Plastics Manufacture and Processing UMR 7610, Chimie des Polymeres, UPMC Univ Paris 06, Paris, Fr. FIELD URL: written in English; We report the straightforward photo-polymn. of polyacrylate films contg. bis-urea based self-assembled nanotubes. The obtained materials are characterized by gas adsorption measurements, 129Xe NMR spectroscopy and WAXS. The presence of the bis-ureas is shown by butane adsorption (at 273 K and ambient pressure) to be responsible for the formation of a significant microporosity. This porosity is however not detected by the classical argon adsorption procedure (at 77 K and low pressure). This effect is attributed to the contraction of the material at low temp. and pressure, and may be of general concern for other org. porous materials. One of the potential advantages of the present materials is that the porosity results from the self-assembled nanotubes and should therefore be independent of the matrix mech. properties. It should in particular be possible to adjust the flexibility of the matrix by changing the monomer compn. [on SciFinder(R)]

International audience; Low molar mass organogelators (LMOG) can turn liquids into thermoreversible gels, because they self-assemble into a fibrous network. In contrast, using the same kind of low molar mass additives to harden materials, which are already solid-like on their own, has been hardly exploited. We show here that simple dicarboxylic acids are very efficient low molar mass organogelators (LMOG) for bitumen. Indeed, they increase the range of temperatures where the bitumen is a solid. Moreover, the hardness and elastic modulus of bitumen at room temperature are also improved. This concept of improving the mechanical properties of a solid with a LMOG can probably be applied to other materials. 2