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International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)

Introduction. Chronic rhinitis is defined as nasal inflammation with the presence of minimum two symptoms such as nasal obstruction, rhinorrhea, sneezing and/or itching one hour daily for a minimum of 12 weeks/year. According their etiology, four groups of rhinitis are described: allergic, infectious, non-allergic non-infectious and mixed.Chronic rhinitis is frequently associated with asthma, shares similar mechanisms of the pathogenesis and has a negative impact of its outcomes sustaining the concept of unified airways disease.Areas covered. The present review summarizes the complex relationship between chronic rhinitis and asthma on the basis of recent epidemiological data, clinical characteristics, diagnosis and therapeutic management. All four groups are discussed with the impact of their specific treatment on asthma outcomes. Some medications are common for chronic rhinitis and asthma while others are more specific but able to treat the associated comorbidity.Expert opinion. The systematic assessment of chronic rhinitis in patients with asthma and its specific treatment improves both disease outcomes. Conversely, several therapies of asthma demonstrated beneficial effects on chronic rhinitis. Treating both diseases at the same time by only one medication is an interesting option to explore in the future in order to limit drugs administration, related costs and side effects.

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.

The large amount of evidence and the renewed interest in upper and lower airways involvement in infectious and inflammatory diseases has led Interasma (Global Asthma Association) to take a position on United Airways Diseases (UAD).Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto developed by Interasma scientific network (INES) members.The manifesto describes the evidence gathered to date and defines, states, advocates, and proposes issues on UAD (rhinitis, rhinosinusitis and nasal polyposis), and concomitant/comorbid lower airways disorders (asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, obstructive sleep apnoea) with the aim of challenging assumptions, fostering commitment, and bringing about change. UAD refers to clinical pictures characterized by the coexistence of upper and lower airways involvement, driven by a common pathophysiological mechanism, leading to a greater burden on patient's health status and requiring an integrated diagnostic and therapeutic plan. The high prevalence of UAD must be taken into account. Upper and lower airways diseases influence disease control and patient's quality of life.Patients with UAD need to have a timely and adequate diagnosis, treatment, and, when recommended, referral for management in a specialized center. Diagnostic testing including skin prick or serum specific IgE, lung function, fractional exhaled nitric oxide (FeNO), polysomnography, allergen-specific immunotherapies, biological therapies and home based continuous positive airway pressure (CPAP) whenever these are recommended, should be part of the management plan for UAD. Education of medical students, physicians, health professionals, patients and caregivers on the UAD is needed.

Several studies have shown that lung cancer screening, using annual low-dose computed tomography (CT) scan in a targeted population of smokers and ex-smokers reduces overall and lung cancer specific mortality rates. This form of screening strategy is not currently established for use in France by the French High Authority for Health. Quitting smoking is the most important measure in reducing mortality from lung cancer. The maximum benefit in reducing mortality from lung cancer should be seen through an effective combination of smoking cessation intervention and chest CT screening to identify early, curable disease. However, current data to guide clinicians in the choice of smoking cessation interventions in this specific context are limited due to the small number of randomized studies that have been carried out. The optimal approach to smoking cessation during lung cancer screening needs to be clarified by new studies comparing different motivation strategies, establishing the ideal moment to propose stopping smoking and the most effective therapies to use.

BACKGROUND: Macrophages control innate and acquired immunity but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort. METHODS: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically- and alternatively-activated macrophages: M1 and M2 respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs). RESULTS: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all p

Background: Although antibody deficiency (AD) is a well-known cause of recurrent respiratory infections, there are few data on its impact in adults with asthma. The objective of the present study was to assess outcomes in adults with severe asthma and AD after treatment with either azithromycin or subcutaneous immunoglobulins (SCIg). Methods: We performed a 5-year, prospective, observational, two-centre study of adults with severe asthma and AD in France. Bronchiectasis was ruled out by high-resolution computed tomography. Patients were treated for one year with either azithromycin (250 mg every other day) or SCIg (0.4–0.6 g/kg/months, weekly). All patients were evaluated for exacerbations, asthma control and lung function at baseline and then one year after treatment initiation. Results: Thirty-nine patients with severe asthma were included in the study: 14 had been treated with azithromycin and 25 had been treated with SCIg. Before the initiation of treatment for AD, all patients had an Asthma Control Questionnaire (ACQ-7) score > 1.5 (mean ± SD: 2.71 ± 0.53) despite treatment at GINA step 4 or 5, and had a high exacerbation rate requiring oral corticosteroids and/or rescue antibiotics (∼7.2 ± 2.1/patient/year). One year after treatment initiation, we observed a significantly higher FEV1 (mean: 0.18 ± 0.22 L) and ACQ-7 score (1.26 ± 0.68), and a significantly lower exacerbation rate (1.63 ± 1.24/patient/year). Conclusions: Treatment of AD dramatically improved asthma outcomes - suggesting that adults with severe asthma and recurrent respiratory infections should be screened and (if appropriate) treated for AD. Keywords: Antibody deficiency, Asthma, Azithromycin, Immunoglobulin replacement, Respiratory infections

IntroductionAsthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsA total of 90 metabolites were identified, with 40 significantly altered (p−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

Anaplastic lymphoma kinase (ALK) rearrangement is a therapeutically targetable oncogenic driver found in 5% of patients with non-small-cell lung cancer (NSCLC). The objective of this paper is to synthesise current knowledge on ALK rearrangement and its impact on the management of advanced NSCLC. Several inhibitors of the tyrosine kinase of ALK (crizotinib, ceritinib, alectinib) have been approved as first line therapies in patients with advanced ALK positive NSCLC, which are associated with a better median progression-free survival than conventional chemotherapy. Unfortunately, the emergence of drug resistance leads to tumor progression. In patients with oligoprogressive disease if local ablative therapy can be effected, continuing with the same ALK tyrosine kinase inhibitor is one option. In patients with progression, clinicians may consider switching to another therapy. Rebiopsy of the tumor or liquid biopsy could be attempted to identify the mechanisms of resistance and to customize ALK-target therapy. The emergence of crizotinib drug resistance has prompted the development of next generation drugs including ceritinb, alectinib, brigatinib and lorlatinib. The ability to quickly develop targeted therapies against specific oncogenic drivers will require close co-operation between pathologists, pulmonologists and oncologists in the future to keep pace with drug discoveries and to define optimal therapeutic strategies.

INTRODUCTION: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. METHODS: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). RESULTS: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. CONCLUSIONS: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:16 issue:9 pages:1547-1558 ispartof: location:United States status: published

Background: Severe asthma is a serious condition with a significant burden on patients' morbidity, mortality, and quality of life. Some biological therapies targeting the IgE and interleukin-5 (IL5) mediated pathways are now available. Due to the lack of direct comparison studies, the choice of which medication to use varies. We aimed to explore the beliefs and practices in the use of biological therapies in severe asthma, hypothesizing that differences will occur depending on the prescribers’ specialty and experience. Methods: We conducted an online survey composed of 35 questions in English. The survey was circulated via the INterasma Scientific Network (INESNET) platform as well as through social media. Responses from allergists and pulmonologists, both those with experience of prescribing omalizumab with (OMA/IL5) and without (OMA) experience with anti-IL5 drugs, were compared. Results: Two hundred eighty-five (285) valid questionnaires from 37 countries were analyzed. Seventy-on percent (71%) of respondents prescribed biologics instead of oral glucocorticoids and believed that their side effects are inferior to those of Prednisone 5 mg daily. Agreement with ATS/ERS guidelines for identifying severe asthma patients was less than 50%. Specifically, significant differences were found comparing responses between allergists and pulmonologists (Chi-square test, p < 0.05) and between OMA/IL5 and OMA groups (p < 0.05). Conclusions: Uncertainties and inconsistencies regarding the use of biological medications have been shown. The accuracy of prescribers to correctly identify asthma severity, according to guidelines criteria, is quite poor. Although a substantial majority of prescribers believe that biological drugs are safer than low dose long-term treatment with oral steroids, and that they must be used instead of oral steroids, every effort should be made to further increase awareness. Efficacy as disease modifiers, biomarkers for selecting responsive patients, timing for outcomes evaluation, and checks need to be addressed by further research. Practices and beliefs regarding the use of asthma biologics differ between the prescriber's specialty and experience; however, the latter seems more significant in determining beliefs and behavior. Tailored educational measures are needed to ensure research results are better integrated in daily practice.

Introduction: Patients with asthma often have important co-morbidities which reduce the likelihood of gaining optimal asthma control. Beta2-blockers are commonly prescribed for the treatment of different clinical indications, including coronary artery disease, cardiac arrhythmia, arterial hypertension, heart failure and glaucoma. Areas covered: The aim of this reviw is to summarize current evidence on the effect of systemic and local β-blockers on asthma outcomes based on their pharmacologic properties,and to help clinicians when prescribing for patients with asthma and co-morbidities. Current data suggest that risk of asthma worsening from systemic and local use of non-selective β-blockers outweighs any potential benefits for their clinical indications. Recent studies confirm that topical and systemic prescription of cardio-selective β-blockers is not associated with a significant increased risk of moderate or severe asthma exacerbations. Expert opinion: Non-selective β-blockers should not be prescribed for the management of comorbidities in patients with asthma while cardio-selective β-blockers, preferably in low doses, may be used when strongly indicated and other therapeutic options are not available. More prospective real-life studies are needed to evaluate the risk of long-term use of β-blockers in patients with asthma.

Resume Introduction L’asthme professionnel associe les caracteristiques habituelles de la maladie asthmatique et la sensibilisation a un agent present dans le milieu professionnel, responsable de cette symptomatologie. Si la prise en charge de comorbidites dans l’asthme severe est rentree dans la pratique habituelle, peu de donnees existent concernant leur lien avec l’asthme professionnel. Observations Nous presentons le cas d’un patient non-fumeur de 49 ans, diagnostique d’un asthme professionnel aux isocyanates, avec des criteres de severite, qui malgre l’eviction de l’exposition professionnelle et un traitement medical maximal, restait non controle. Apres plusieurs changements therapeutiques sans effet sur le controle de l’asthme et le nombre d’exacerbations, la recherche de comorbidites a permis d’abord la mise en evidence d’un reflux gastro-œsophagien, puis d’un syndrome d’apnees-hypopnees obstructives du sommeil. La prise en charge de ces comorbidites a permis une amelioration du controle de l’asthme et du nombre d’exacerbations, conduisant a une diminution de la pression therapeutique et la reprise d’une activite apres reclassement professionnel. Conclusions Comme dans tous les cas d’asthme severe, la recherche de comorbidites doit etre entreprise en cas d’asthme professionnel non controle malgre l’arret de l’exposition professionnelle et un traitement medical optimal. Leur prise en charge permettra un meilleur controle de la maladie asthmatique.

Resume Introduction Les donnees de la litterature concernant l’influence de l’âge sur le delai de prise en charge du cancer bronchique font l’objet de controverses et les etudes se revelent tres heterogenes en absence d’une definition consensuelle. L’objectif principal de la presente etude est de determiner la relation entre l’âge des patients et le delai de prise en charge du cancer bronchique au CHRU de Nancy. Methodes Une etude retrospective monocentrique a ete realisee sur les patients ayant recu un premier traitement specifique pour un cancer bronchique entre le 1er novembre 2014 et 31 octobre 2015. Le delai de prise en charge etait defini par l’intervalle de temps compris entre la premiere imagerie anormale et le premier traitement realise (chirurgie, chimiotherapie, radiotherapie, therapie ciblee). Les patients etaient repartis en trois groupes : groupe 1 (âge ≤ 60 ans), groupe 2 (âge entre 60 et 70 ans) et groupe 3 (âge > 70 ans). Resultats Au total, 246 patients etaient inclus avec une moyenne d’âge de 65 ± 10 ans. Le delai moyen de prise en charge du cancer bronchique est de 97 ± 41 jours. Le delai moyen de prise en charge des patients âges de > 70 ans est statistiquement plus long que celui des patients âges de ≤ 60 ans (116 ± 98 jours vs 76 ± 65 jours, p = 0,04) du fait, notamment, d’un allongement du delai de prise en charge chirurgicale (129 ± 75 jours vs 88 ± 54 jours, p = 0,03). Conclusion Le delai de prise en charge, plus long pour les patients âges de > 70 ans que pour les autres groupes, est notamment le reflet d’une attente prolongee pour realiser le bilan preoperatoire avant une prise en charge chirurgicale. Des efforts sont necessaires pour optimiser notre parcours de soins et raccourcir ce delai.

Asthma is a heterogenous disease characterized by multiple phenotypes driven by different mechanisms. The implementation of precision medicine in the management of asthma requires the identification of phenotype-specific markers measurable in biological fluids. To become useful, these biomarkers need to be quantifiable by reliable systems, reproducible in the clinical setting, easy to obtain and cost-effective. Using biomarkers to predict asthma outcomes and therapeutic response to targeted therapies has a great clinical significance, particularly in severe asthma. In the last years, significant research has been realized in the identification of valid biomarkers for asthma. This review focuses on the existent and emerging biomarkers with clinical higher applicability in the management of asthma.

Biogenesis of eukaryotic box C/D small nucleolar ribonucleoproteins initiates co-transcriptionally and requires the action of the assembly machinery including the Hsp90/R2TP complex, the Rsa1p:Hit1p heterodimer and the Bcd1 protein. We present genetic interactions between the Rsa1p-encoding gene and genes involved in chromatin organization including RTT106 that codes for the H3-H4 histone chaperone Rtt106p controlling H3K56ac deposition. We show that Bcd1p binds Rtt106p and controls its transcription-dependent recruitment by reducing its association with RNA polymerase II, modulating H3K56ac levels at gene body. We reveal the 3D structures of the free and Rtt106p-bound forms of Bcd1p using nuclear magnetic resonance and X-ray crystallography. The interaction is also studied by a combination of biophysical and proteomic techniques. Bcd1p interacts with a region that is distinct from the interaction interface between the histone chaperone and histone H3. Our results are evidence for a protein interaction interface for Rtt106p that controls its transcription-associated activity., Biogenesis of small nucleolar RNAs ribonucleoproteins (snoRNPs) requires dedicated assembly machinery. Here, the authors show that a subset of snoRNP assembly factors interacts, genetically or directly, with factors modulating chromatin architecture, suggesting a link between ribosome formation and chromatin functions.

International audience; Work-related asthma (WRA) is a very frequent condition in the occupational setting, and refers either to asthma induced (occupational asthma, OA) or worsened (work-exacerbated asthma, WEA) by exposure to allergens (or other sensitizing agents) or to irritant agents at work. Diagnosis of WRA is frequently missed and should take into account clinical features and objective evaluation of lung function. The aim of this overview on pulmonary function testing in the field of WRA is to summarize the different available tests that should be considered in order to accurately diagnose WRA. When WRA is suspected, initial assessment should be carried out with spirometry and bronchodilator responsiveness testing coupled with first-step bronchial provocation testing to assess non-specific bronchial hyper-responsiveness (NSBHR). Further investigations should then refer to specialists with specific functional respiratory tests aiming to consolidate WRA diagnosis and helping to differentiate OA from WEA. Serial peak expiratory flow (PEF) with calculation of the occupation asthma system (OASYS) score as well as serial NSBHR challenge during the working period compared to the off work period are highly informative in the management of WRA. Finally, specific inhalation challenge (SIC) is considered as the reference standard and represents the best way to confirm the specific cause of WRA. Overall, clinicians should be aware that all pulmonary function tests should be standardized in accordance with current guidelines.

International audience; Background: Detection of genomic rearrangements, like anaplastic lymphoma kinase (ALK) fusions, is a pivotal requirement in non-small cell lung cancer (NSCLC) for the initiation of a targeted treatment. While tissue testing remains the gold standard, detection of these alterations using liquid biopsies is an unmet need. To enable the detection of ALK rearrangements from circulating-free RNA (cfRNA) from NSCLC patients, we have evaluated a novel reverse transcription PCR (RT-PCR) based assay.Methods: Sixty-six patients with advanced stage NSCLC were included in the study. ALK status was determined by immunohistochemistry (IHC) and/or FISH on tissue sections. For the detection of ALK rearrangements from 2ml plasma collected in EDTA or Streck BCT DNA tubes, cfRNA was extracted using a prototype cfRNA sample preparation method and tested by a novel multiplex ALK/RET RT-PCR assay (Roche).Results: Of the forty-two patients with an ALK rearrangement, 30 (71%) were included at baseline. In 10 of the baseline patients, an ALK rearrangement was detected by RT-PCR [baseline sensitivity 33.33% (95% CI: 17.29–52.81%)]. All 24 negative ALK IHC/FISH-negative patients were negative using the RT-PCR based assay (specificity =100%).Conclusions: The prototype Roche ALK/RET RT-PCR assay was able to detect ALK fusion transcripts in the plasma of NSCLC patients at baseline as well as at disease progression with limited sensitivity but high specificity. Consequently, this assay could potentially be considered to select patients for an ALK-targeting therapy when tissue samples are lacking.

Background: Tobacco smoking is associated with more severe asthma symptoms, an accelerated decline in lung function, and reduced responses to corticosteroids. Our objective was to compare asthma outcomes in terms of disease control, exacerbation rates, and lung function in a population of asthmatic patients according to their smoking status. Methods: We compared patients&rsquo, demographics, disease characteristics, and lung-function parameters in current-smokers (CS, n = 48), former-smokers (FS, n = 38), and never-smokers (NS, n = 90), and identified predictive factors for asthma control. Results: CS had a higher prevalence of family asthma/atopy, a lower rate of controlled asthma, impaired perception of dyspnea, an increased number of exacerbations, and poorer lung function compared to NS. The mean asthma control questionnaire&rsquo, s (ACQ) score was higher in CS vs. NS and FS (1.9 vs. 1.2, p = 0.02). Compared to CS, FS had a lower rate of exacerbations, a better ACQ score (similar to NS), a higher prevalence of dyspnea, and greater lung-diffusion capacity. Non-smoking status, the absence of dyspnea and exacerbations, and a forced expiratory volume in one second &ge, 80% of predicted were associated with controlled asthma. Conclusions: CS with asthma exhibit worse clinical and functional respiratory outcomes compared to NS and FS, supporting the importance of smoking cessation in this population.

Asthma assessment by spirometry is challenging in children as forced expiratory volume in 1 s (FEV1) is frequently normal at baseline. Bronchodilator (BD) reversibility testing may reinforce asthma diagnosis but FEV1 sensitivity in children is controversial. Ventilation inhomogeneity, an early sign of airway obstruction, is described by the upward concavity of the descending limb of the forced expiratory flow-volume loop (FVL), not detected by FEV1. The aim was to test the sensitivity and specificity of FVL shape indexes as β-angle and forced expiratory flow at 50% of the forced vital capacity (FEF50)/peak expiratory flow (PEF) ratio, to identify asthmatics from healthy children in comparison to "usual" spirometric parameters. Seventy-two school-aged asthmatic children and 29 controls were prospectively included. Children performed forced spirometry at baseline and after BD inhalation. Parameters were expressed at baseline as z-scores and BD reversibility as percentage of change reported to baseline value (Δ%). Receiver operating characteristic curves were generated and sensitivity and specificity at respective thresholds reported. Asthmatics presented significantly smaller zβ-angle, zFEF50/PEF and zFEV1 (p ≤ .04) and higher BD reversibility, significant for Δ%FEF50/PEF (p = .02) with no difference for Δ%FEV1. zβ-angle and zFEF50/PEF exhibited better sensitivity (0.58, respectively 0.60) than zFEV1 (0.50), and similar specificity (0.72). Δ%β-angle showed higher sensitivity compared to Δ%FEV1 (0.72 vs. 0.42), but low specificity (0.52 vs. 0.86). Quantitative and qualitative assessment of FVL by adding shape indexes to spirometry interpretation may improve the ability to detect an airway obstruction, FEV1 reflecting more proximal while shape indexes peripheral bronchial obstruction.

Occupational asthma (OA) represents one of the major public health problems due to its high prevalence, important social and economic burden. The aim of this review is to summarize current data about clinical phenotypes, biomarkers, diagnosis and management of OA, a subtype of work-related asthma. Most studies have identified two phenotypes of OA. One is sensitizer-induced asthma, occuring after a latency period and caused by hypersensitivity to high- or low-molecular weight agents. The other is irritant-induced asthma, which can occur after one or more exposures to high concentrations of irritants without latency period. More than 400 agents causing OA have been identified and its list is growing fast. The best diagnostic approach for OA is a combination of clinical history and objective tests. An important tool is a specific inhalation challenge. Additional tests include assessments of bronchial hyperresponsiveness to methacholine/histamine in patients without airflow limitations, monitoring peak expiratory flow at- and off-work, sputum eosinophil count, exhaled nitric oxide measurement, skin prick tests with occupational allergens and serum specific IgE. Treatment of OA implies avoidance of exposure, pharmacotherapy and education. OA is a heterogeneous disease. Mechanisms of its different phenotypes, their diagnosis, role of new biomarkers and treatment require further investigation.

Resume Introduction Les evenements osseux (EO) sont frequents chez les patients atteints de cancer bronchique (CB) metastatique au niveau osseux et ont un impact negatif sur la qualite de vie et la survie. L’objectif de cette etude est d’identifier les facteurs predictifs de survenue d’EO dans cette population. Methodes Une analyse retrospective sur 3 ans a ete realisee incluant 100 patients avec un CB metastatique au niveau osseux. Resultats Quatre-vingt-deux patients presentaient au moins un EO (69,5 % au diagnostic). La mediane de survenue d’un EO etait de 4,5 mois et les douleurs osseuses severes etaient l’EO le plus frequent (56 %). Les facteurs predictifs identifies pour la survenue d’EO etaient un taux serique de phosphatases alcalines (PAL) > 120 UI/L (risque relatif [RRs] = 2,8 ; intervalle de confiance (IC) 95 % [1,5–5,4] ; p = 0,002) et une calcemie > 2,6 mmol/L ([RRs] = 9,7 ; IC 95 % [5,1–18,4] ; p Conclusion Le taux eleve de PAL seriques et l’hypercalcemie sont des facteurs predictifs d’EO chez les patients ayant un CB metastatique au niveau osseux et devraient etre utilises dans la pratique courante comme biomarqueurs pour adapter la prise en charge de ces patients.

Mast cells (MCs) are granular cells of the innate immune system which develop from CD34+/CD117+ progenitors and play a role in orchestrating adaptive immune responses. They have a well-known role in allergic reactions following immunoglobulin (Ig)E-mediated activation of the cell-surface expressed IgE high-affinity receptor (FcεRI). MCs can also respond to various other stimuli due to the expression of a variety of receptors including toll-like receptors (TLRs), immunoglobulin (IgG) receptors (FcγR), complement receptors such as C5a (CD88) expressed by skin MCs, neuropeptides receptors including nerve growth factor receptor, (NGFR), cytokines receptors such as (IL)-1R and IL-3R, and chemokines receptors including CCR-1 and CCR-3. MCs release three groups of mediators upon degranulation differentiated according to their chemical composition, storage, and time to release. These include preformed mediators (mainly histamine, tryptase, and chymase), de novo synthesized mediators such as prostaglandin (PG)D2, leukotriene (LT)B4 and LTD4, and cytokines including IL-1β, IL-3, tumor necrosis factor (TNF)α, and transforming growth factor(TGF)-β. Emerging evidence indicates a role for IgE-independent MC activation in the late-stage asthmatic response as well as in non-allergic airway diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. MC infiltration/activation has been reported in some, but not all, studies of lung cancer. MC-derived TNF-α possesses tumor-suppressive activity while IL-1β supports tumor progression and metastasis. In IPF lungs, an increase in density of tryptase- and chymase-positive MCs (MCTC) and overexpression of TGF-β support the fibrosis progression. MC-derived chymase activates latent TGF-β that induces the differentiation of fibroblasts to matrix-producing myofibroblasts. In summary, increasing evidence highlights a critical role of MCs in non-allergic diseases that may indicate new approaches for therapy.

Introduction Obesity-associated asthma (OA) is frequently severe, with an increased rate of hospitalizations, numerous comorbidities and low response to corticosteroids. Despite progress in applying for personalized medicine in asthma, no specific recommendations exist for the management of OA. Areas covered The aim of this review is to summarize recent data about the relationship obesity-asthma, describe clinical characteristics, potential mechanisms involved and possible therapeutic interventions to improve OA outcomes. Extensive research in the PubMed was performed using the following terms: "asthma and obesity" and "obese asthma" in combination with "phenotypes", "airway inflammation", "biomarkers", "lung function", "weight loss", "lifestyle interventions", "therapies" Currently two phenotypes are described. Early-onset atopic asthma is conventional allergic asthma aggravated by the pro-inflammatory properties of adipose tissue in excess, while late-onset non-atopic asthma is due to airway dysfunction as a consequence of the chronic lung compression caused by the obese chest walls. Previous data showed that different therapeutic strategies used in weight loss have a positive impact on OA outcomes. Expert opinion The presence of a multidisciplinary team (chest physician, nutritionist, exercise physiologist, physiotherapist, psychologist, bariatric surgeon) and the collaboration between different specialists are mandatory to optimize the management and to apply the personalized medicine in OA.

Purpose of review Target therapy is the necessary step towards personalized medicine. The definition of asthma phenotypes and underlying mechanisms (endotypes) represent a key point in the development of new asthma treatments. Big data analysis, biomarker research and the availability of monoclonal antibodies, targeting specific cytokines is leading to the rapid evolution of knowledge. In this review, we sought to outline many of the recent advances in the field. Recent findings Several attempts have been made to identify asthma phenotypes, sometimes with contrasting results. More success has been obtained concerning the pathogenetic mechanism of specific asthma patterns with the consequent identification of biomarkers and development of effective ad hoc treatment. Summary We are in the middle of an extraordinary revolution of our mode of thinking about and approaching asthma. All the effort in the identification of clusters of patients with different disease clinical patterns, prognosis and response to treatment is closely linked to the identification of endotypes (Th2-low and Th2-high). This approach has allowed the development of the specific treatments (anti IgE, Anti IL5 and IL5R) that are now available and is leading to new ones.

The prognostic value of exon 19 and 21 EGFR mutations in stage IV non-small cell lung cancer (NSCLC) is well established. We aimed to evaluate the prognostic value of the mutations in surgically resected NSCLC. We retrospectively reviewed data from 1798 surgically resected NSCLC adenocarcinomas between 2007 and 2017 in three departments of thoracic surgery (Nancy/Strasbourg, France, and Torino, Italy) for whom mutational status was known. Overall survival (OS) was evaluated using log-rank and Cox proportional hazard models. EGFR exon 19 deletion was observed in 108 patients (55.1%) and exon 21 L858R mutations were observed in 88 patients (44.9%). In stage I, the median OS was not significantly different between exons 19 and 21 (p = 0.54), while, in stage II, the median OS reached 65 months [95% confidence interval (CI) 41.67–88.33] for exon 19 mutations and decreased to 48 months for exon 21 mutations (95% CI 44.21–51.79; p = 0.027). In multivariate analysis, exon 19 deletion remained a favorable prognostic factor [hazard ratio (HR) 0.314, 95% CI 0.098–0.997; p = 0.05]. In stage III, the median OS reached 66 months (95% CI 44.67–87.32) for exon 19 mutations and decreased to 32 months for exon 21 mutations (95% CI 29.86–34.14; p = 0.03). In multivariate analysis, exon 19 deletion remained a significantly favorable prognostic factor (HR 0.165, 95% CI 0.027–0.999; p = 0.05). The prognostic value of EGFR exon 19 and 21 mutations appears to be different according to disease stage in surgically resected NSCLC.

PURPOSE Prophylactic radiotherapy to prevent procedure-tracts metastases from malignant pleural mesothelioma remains controversial and clinical practice varies. The purpose was to assess the efficacy of local radiotherapy in a single fraction of 10Gy in preventing malignant seeding at intervention pleural site in patients with malignant pleural mesothelioma. MATERIAL AND METHODS This is a retrospective cohort study, including patients with histological confirmed malignant pleural mesothelioma treated by prophylactic irradiation to prevent interventional site metastases with a unique fraction of 10Gy with 6 to 18MeV, from January 1990 to December 2013 in the institut de cancerologie de Lorraine (Nancy, France). RESULTS Ninety-one patients were treated by irradiation in intervention site, involving 120 intervention pleural sites, 91 thoracoscopies, 17 thoracotomies with chest drain and 12 CT or ultrasound guided needle biopsies. The median follow-up was 7 months (interquartile between 3 and 15 months). The overall survival was 43.5% at 12 months. The local progression free survival was 43.7% at 12 month. The incidence of local recurrence was 8% at 12 months. The median interval from radiotherapy to local recurrence was 4 months (2; 32). No grade II or higher toxicity was observed. CONCLUSION Irradiation of pleural intervention sites with a single fraction of 10Gy is effective, well tolerated, simple, fast and cost effective.

Approximately 5%-10% of asthmatics suffer from severe asthma. New biological treatments represent a great opportunity to reduce asthma burden and to improve asthma patients' lives. Reslizumab will soon be available in several European countries. This anti-IL-5 IgG4/kappa monoclonal antibody, administered intravenously at a dose of 3 mg/kg over 20-50 minutes every 4 weeks, has been shown to be safe and effective in patients with 400 eosinophils/mu L or more in their peripheral blood. The clinical effects in reducing asthma exacerbations and in improving the quality of life and lung function are clear, but further research is needed to determine the best biological compound for a specific cluster of patients. Research data have shown that in patients who were expressing other clinical features of eosinophilic inflammation over asthma (rhinosinusitis and nasal polyposis), the clinical benefit of reslizumab was greater. Furthermore, it has also been observed that in patients with unsatisfactory response to mepolizumab, reslizumab is able to significantly improve the clinical and biological parameters. The aim of personalized medicine is to provide the right drug to the right patient at the right dose at the right moment. The biological treatments that were developed to modify specific pathological pathways not only provide us with the tools for the management of asthma patients but also clarify the biological mechanisms involved in its pathogenesis.

Resume Le syndrome de Doege-Potter associe une hypoglycemie paraneoplasique a une tumeur fibreuse solitaire. Les tumeurs fibreuses solitaires sont rares et le plus souvent asymptomatiques. L’apparition de signes cliniques ou de syndromes paraneoplasiques est le fait de tumeurs volumineuses avec un index mitotique eleve. Le diagnostic est evoque par l’imagerie mais la confirmation diagnostique est apportee par la chirurgie qui reste le traitement de choix. L’hypoglycemie resulte de la secretion par la tumeur de formes incompletes d’un facteur de croissance apparente a l’insuline appele « big »-IGF-2 ( insulin-like growth factor ). Plusieurs tests biologiques permettent de demontrer l’augmentation du taux plasmatique du « big »-IGF-2 confirmant le diagnostic de « non islet cell tumour induced hypoglyceamia ». L’exerese tumorale conduit a la resolution de l’hypoglycemie. Ces tumeurs ont un potentiel de malignite intermediaire. Malgre l’analyse histologique et immunohistochimique, leur pronostic et leur agressivite restent difficiles a etablir. Des recidives et des transformations malignes sont possibles tardivement, ce qui impose un suivi radiologique au long terme. Nous rapportons un cas de syndrome de Doege-Potter concernant une tumeur fibreuse solitaire pleurale a recidive maligne tardive dont l’interet est de documenter la physiopathologie de l’hypoglycemie paraneoplasique.

Background The most emblematic members of Urticaceae at allergic risk level are wall pellitories ( Parietaria ), whereas nettle ( Urtica ) pollen is considered as poorly allergenic. No allergen from nettle pollen has yet been characterized, whereas 4 are listed for Parietaria pollen by the International Union of Immunological Societies. Clinical and biological profiles of 2 adult men who developed symptoms against nettle pollen and/or leaves were studied. Objective To characterize the allergic reaction and identify the potential nettle pollen sensitizing allergens. Methods IgE-mediated reaction to nettle pollen extract was evaluated by skin prick test, immunoassay, nasal provocation, and basophil activation test. To characterize specific nettle pollen allergens, an allergomic (IgE immunoproteomic) analysis was performed combining 1- and 2-dimensional electrophoresis, IgE immunoblots of nettle pollen extract, identification of allergens by mass spectrometry, and database queries. Results The results of biological and immunochemical analyses revealed that the allergic rhinitis was due to Urtica dioica pollen in both patients. The allergomic analysis of nettle pollen extract allowed the characterization of 4 basic protein allergens: a thaumatin-like protein (osmotin) with a relative molecular mass of 27 to 29 kDa, a pectinesterase (relative molecular mass, 40 kDa), and 2 other basic proteins with relative molecular masses of 14 to 16 kDa and 43 kDa. There is no or only very weak allergen associations between pellitory and nettle pollen. Conclusion Exposure to nettle pollen can be responsible of allergic symptoms, and several allergens were characterized. Unravelling the allergens of this underestimated allergy might help to improve diagnosis and care for patients, to predict cross-reactivities and design adapted specific immunotherapy.

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Background and objective Omalizumab is a human anti-IgE antibody approved for the treatment of severe allergic asthma (SAA). However, its effectiveness in SAA associated with chronic rhinosinusitis with nasal polyposis (CRSNP+) is less well documented. Objective: The aim of this study was to evaluate the real-life effectiveness of omalizumab in patients with SAA and CRSNP+ who tolerated and did not tolerate aspirin. Methods We performed a retrospective, observational, multicenter, real-life study of patients with SAA and CRSNP+ treated with omalizumab for 6 months. Asthma outcome parameters (symptoms, number of salbutamol rescues/wk, number of moderate/severe exacerbations, Asthma Control Test score, and lung function), sinonasal outcome parameters (symptoms, number of episodes of acute rhinosinusitis, sinus computed tomography images, nasal polyps endoscopy score), and serum eosinophil levels were analyzed 6 months before and after treatment with omalizumab. Results Twenty-four adult patients were included (9 with documented aspirin intolerance). All respiratory parameters were significantly improved by the treatment. In parallel, a significant improvement was observed in sinonasal clinical outcomes and sinus computed tomography images, with no major effect on the nasal polyps endoscopy score. The serum eosinophil count decreased significantly after 6 months of treatment with omalizumab. Conclusion Treatment of SAA with omalizumab improves the outcome of associated CRSNP+, thus supporting the concept of a "one airway disease".

Background The hyperventilation syndrome (HVS) is characterized by somatic/ psychological symptoms due to sustained hypocapnia and respiratory alkalosis without any organic disease. Objective The purpose of this study was to compare ventilatory parameters and symptoms reproducibility during the hyperventilation provocation test (HVPT) and cardiopulmonary exercise test (CPET) as diagnostic tools in patients with HVS, and to identify the most frequent etiologies of the HVS by a systematic assessment. Methods After exclusion of organic causes, 59 patients with HVS according to Nijmegen’s questionnaire (NQ) score ≥23 with associated hypocapnia (PaCO2/PETCO2 Results The most frequent comorbidities of HVS were anxiety and asthma (respectively 95% and 73% of patients). All patients described ≥3 symptoms of NQ during the HVPT vs 14% of patients during the CPET (p Conclusions In term of symptoms reproducibility, HVPT is a better diagnostic tool than CPET for HVS. An important proportion of patients with HVS has an atypical asthma previously misdiagnosed. The exercise-induced hyperventilation did not induce abnormal reduction in PETCO2, suggesting that the exercise could be a therapeutic tool in HVS.

Introduction La recente decouverte des addictions oncogeniques a radicalement modifie la prise en charge du cancer bronchopulmonaire avance via le developpement des therapies ciblees par inhibiteurs de tyrosine kinase. Notre etude avait pour objectifs l’estimation de la repartition des principales addictions oncogeniques et l’etude de leur impact pronostique chez les patients suivis au CHRU de Nancy pour un adenocarcinome bronchopulmonaire d’emblee metastatique. Methodes Une analyse retrospective incluant 114 patients qui presentaient un adenocarcinome bronchopulmonaire metastatique diagnostique au CHRU de Nancy entre 2012 est 2014 a ete realisee afin d’etudier la survie a 5 ans. Resultats La repartition des addictions oncogeniques dans notre population, comparable a celle obtenue sur le plan national [1] , etait la suivante : KRAS (27,2%), puis EGFR (13,2%), et enfin BRAF (4,4%) et ALK (1,8%) ( Tableau 1 ). Le pronostic de l’adenocarcinome bronchopulmonaire metastatique restait sombre avec une survie a 5 ans Conclusion La repartition des addictions oncogeniques dans l’adenocarcinome bronchopulmonaire au CHRU de Nancy, comprenant une majorite de patients mutes KRAS, semble superposable aux donnees de la litterature pour les populations d’Europe Occidentale. La mutation EGFR semble conferer un avantage pronostique, en grande partie explique par l’efficacite des therapies ciblant cette alteration moleculaire.

Asthma is a chronic respiratory disease characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Evidence suggests that air pollution has a negative impact on asthma outcomes in both adult and pediatric populations. The aim of this review is to summarize the current knowledge on the effect of various outdoor and indoor pollutants on asthma outcomes, their burden on its management, as well as to highlight the measures that could result in improved asthma outcomes. Traffic-related air pollution, nitrogen dioxide and second-hand smoking (SHS) exposures represent significant risk factors for asthma development in children. Nevertheless, a causal relation between air pollution and development of adult asthma is not clearly established. Exposure to outdoor pollutants can induce asthma symptoms, exacerbations and decreases in lung function. Active tobacco smoking is associated with poorer asthma control, while exposure to SHS increases the risk of asthma exacerbations, respiratory symptoms and healthcare utilization. Other indoor pollutants such as heating sources and molds can also negatively impact the course of asthma. Global measures, that aim to reduce exposure to air pollutants, are highly needed in order to improve the outcomes and management of adult and pediatric asthma in addition to the existing guidelines.

Biogenesis of eukaryotic box C/D small nucleolar ribonucleoproteins (C/D snoRNPs) is guided by conservedtrans-acting factors that act collectively to assemble the core proteins SNU13/Snu13, NOP58/Nop58, NOP56/Nop56, FBL/Nop1, and box C/D small nucleolar RNAs (C/D snoRNAs), in human and in yeast, respectively. This finely elaborated process involves the sequential interplay of snoRNP-related proteins and RNA through the formation of transient pre-RNP complexes. BCD1/Bcd1 protein is essential for yeast cell growth and for the specific accumulation of box C/D snoRNAs. In this work, chromatin, RNA, and protein immunoprecipitation assays revealed the ordered loading of several snoRNP-related proteins on immature and mature snoRNA species. Our results identify Bcd1p as an assembly factor of C/D snoRNP biogenesis that is likely recruited cotranscriptionally and that directs the loading of the core protein Nop58 on RNA.

International audience; IntroductionCough is a major symptom of asthma frequently experienced during exercise but little is known about interactions between cough and exercise. The goal of our study was to clarify the potential modulation of the cough reflex (CR) by exercise in a spontaneously breathing anaesthetized animal model of airway eosinophilic inflammation.Materials & methodsTen ovalbumin (OVA) sensitized adult rabbits and 8 controls were studied. The ventilatory response to direct tracheal stimulation, performed both at rest and during exercise was determined to quantify the incidence and the sensitivity of the CR.Broncho-alveolar lavages (BAL) and cell counts were performed to assess the level of the airway inflammation following OVA-induced sensitization. Exercise was mimicked by Electrically induced hindlimb Muscular Contractions (EMC).ResultsAmong 494 tracheal stimulations, 261 were performed at rest and 233 at exercise. OVA challenges in sensitized rabbits caused a significant increase in the percentage of eosinophils (p = 0.008) in BAL. EMC increased minute ventilation by 36% and 35% in OVA and control rabbits respectively, compared to rest values. The sensitivity of the CR decreased during exercise compared to baseline in control rabbits (p = 0.0313) while it remained unchanged in OVA rabbits.ConclusionThe desensitization of the CR during exercise in control rabbits was abolished in OVA rabbits. The precise role of airway inflammation in this lack of CR desensitization needs to be further investigated but it might contribute to the exercise-induced cough in asthmatics.

Box C/D small nucleolar ribonucleoparticles (snoRNPs) support 2'-O-methylation of several target RNAs. They share a common set of four core proteins (SNU13, NOP58, NOP56, and FBL) that are assembled on different guide small nucleolar RNAs. Assembly of these entities involves additional protein factors that are absent in the mature active particle. In this context, the platform protein NUFIP1/Rsa1 establishes direct and simultaneous contacts with core proteins and with the components of the assembly machinery. Here, we solve the nuclear magnetic resonance (NMR) structure of a complex resulting from interaction between protein fragments of human NUFIP1 and its cofactor ZNHIT3, and emphasize their imbrication. Using yeast two-hybrid and complementation assays, protein co-expression, isothermal titration calorimetry, and NMR, we demonstrate that yeast and human complexes involving NUFIP1/Rsa1p, ZNHIT3/Hit1p, and SNU13/Snu13p share strong structural similarities, suggesting that the initial steps of the box C/D snoRNP assembly process are conserved among species.

In asthmatics patients, tabacco smoking is associated with accelerated decline in pulmonary function, poor disease control and reduced responsiveness to corticosteroids. Our objective was to compare asthma control efficiency in a population of asthmatic patients according to smoking status. We compared 3 equal groups of 30 asthmatics patients: group 1 never smokers, group 2 former smokers and group 3 current smokers. We collected demographic, clinical data, hospital anxiety/depression (HAD) score, functional respiratory data and asthma control scores (ACQ6) for all patients. The three groups were identical in terms of demographical data (mean age 42 vs 46 vs 44.5 years) and lung function: FEV1=80.6%, FVC=94.07%, FEV1/FVC=0.72 in group 1, FEV1=80.9%, FVC=99.16%, FEV1/FVC=0.68 in group 2 and FEV1=79.21%, FVC=96.04%, FEV1/FVC=0.69 in group 3 (p=0.457). Anxiety defined by an HAD ≥8 was present in 46.67% patients in group 1, 53.33% in group 2 and 23.33% in group 3. Mean ACQ6 score was significantly higher in group 3 vs group 2 (1.73 vs 1.23, p=0.003), and vs group 1 (1.17; p=0.003), without significant difference between group 1 and 2 (p=0.416). According to ACQ6, 9 patients in group 1 had an uncontrolled asthma, 11 in group 2 and 15 in group 3. Dyspnea sensation was significantly lower in group 3 vs group 1 (p=0.047). In conclusion, current smokers had underestimated dyspnea, lower anxiety, and poorer asthma control than nonsmokers or former smokers. These observations stress the importance of smoking cessation to help achieve asthma control.

International audience; Zf-HIT family members share the zf-HIT domain (ZHD), which is characterized by a fold in ``treble-clef' through interleaved CCCC and CCHC ZnF motifs that both bind a zinc atom. Six proteins containing ZHD are present in human and three in yeast proteome, all belonging to multimodular RNA/protein complexes involved in gene regulation, chromatin remodeling, and snoRNP assembly. An interesting characteristic of the cellular complexes that ensure these functions is the presence of the RuvBL1/2/Rvb1/2 ATPases closely linked with zf-HIT proteins. Human ZNHIT6/BCD1 and its counterpart in yeast Bcd1p were previously characterized as assembly factors of the box C/D snoRNPs. Our data reveal that the ZHD of Bcd1p is necessary but not sufficient for yeast growth and that the motif has no direct RNA-binding capacity but helps Bcd1p maintain the box C/D snoRNAs level in steady state. However, we demonstrated that Bcd1p interacts nonspecifically with RNAs depending on their length. Interestingly, the ZHD of Bcd1p is functionally interchangeable with that of Hit1p, another box C/D snoRNP assembly factor belonging to the zf-HIT family. This prompted us to use NMR to solve the 3D structures of ZHD from yeast Bcd1p and Hit1p to highlight the structural similarity in the zf-HIT family. We identified structural features associated with the requirement of Hit1p and Bcd1p ZHD for cell growth and box C/D snoRNA stability under heat stress. Altogether, our data suggest an important role of ZHD could be to maintain functional folding to the rest of the protein, especially under heat stress conditions. (C) 2016 Elsevier Ltd. All rights reserved.

On behalf of the CNR MyRMA and the Tuberculosis Consilium of the CNR MyRMA; International audience; Bedaquiline (BDQ) has demonstrated potent clinical activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis complex strains [1–3]. It has now been used in >50 countries, and it is estimated that ∼2500 patients had been treated with BDQ by the end of 2015. In spite of its recent clinical use, there are few reports of BDQ-resistant strains [4, 5]. Mutations in the rv0678 gene encoding the MmpL5 efflux pump repressor generate low-level BDQ resistance and clofazimine (CFZ) cross-resistance [6]. To our knowledge, this is the sole mechanism of BDQ resistance described in clinical strains [4, 5]. Despite its introduction in France in 2011 for XDR- and MDR-tuberculosis (TB) treatment, we report herein four BDQ-resistant cases, and discuss strategies to avoid a surge of BDQ resistance.

Objectif de l’etude Le recours a la radiotherapie prophylactique afin de prevenir les metastases des sites d’intervention pleurale dans le mesotheliome pleural malin demeure controverse et les pratiques cliniques variees. L’objectif etait d’evaluer l’efficacite de la radiotherapie externe en une seance unique de 10 Gy en prevention de l’ensemencement des sites d’intervention pleurale des patients atteints de mesotheliome pleural malin. Materiel et methode Il s’agit d’une etude epidemiologique descriptive retrospective de cohorte, incluant les patients atteints d’un mesotheliome pleural malin histologiquement prouve irradies en regard des sites d’intervention pleurale en une seance unique de 10 Gy par des electrons de 6 a 18 MeV, entre janvier 1990 et decembre 2013 a l’institut de cancerologie de Lorraine. Resultats Quatre-vingt-onze patients ont ete traites par irradiation prophylactique des sites d’intervention pleurale a l’institut de cancerologie de Lorraine, soit 120 sites d’intervention pleurale : 91 thoracoscopies, 17 thoracotomies avec drainage pleural, 12 ponctions–biopsies guidees par scanographie ou echographie. Le suivi median etait de 7 mois (intervalle interquartile entre 3 et 15 mois). La probabilite de survie globale etait de 43,5 % a 12 mois, celle de survie sans progression locale de 43,7 %. L’incidence de la progression locale etait de 8 % a 12 mois. Le temps median ecoule entre l’irradiation et la progression locale etait de 4 mois (extremes : 2–32 mois). Il n’y avait pas d’effet secondaire precoce ou tardif de grade superieur ou egal a deux. Conclusion L’irradiation des sites d’intervention pleurale en une seance unique de 10 Gy est efficace, bien toleree, simple, rapide et peu couteuse.