Search

Purpose: Qualitative and quantitative analyses of retinal arteriolar tortuosity in patients with COL4A1 and COL4A2 mutations to identify a tortuosity index (TI) threshold for detecting increased retinal arteriolar tortuosity., Methods: Fifty-two eyes of 28 patients were included. Group 1 included eyes with a normal arteriolar pattern (n = 19, 37%), Group 2 included eyes with moderately increased arteriolar tortuosity (n = 13, 25%), and Group 3 included eyes with typical abnormal arteriolar tortuosity (n = 20, 38%). The TI was measured by calculating the arc-to-chord ratio of arterioles and venules in the posterior pole., Results: The mean arteriolar TI was significantly higher in all groups with a COL4A1/A2 mutation compared with controls: 1.19 ± 0.03, 1.24 ± 0.05, and 1.57 ± 0.23 in Groups 1, 2 and 3, respectively, versus 1.12 ± 0.01 (all P < 0.0001). The TI threshold was 1.13, with a sensitivity of 98.1% and a specificity of 100%. The area under the curve was 0.995., Conclusion: Measuring the arteriolar TI allowed diagnosing increased retinal arteriolar tortuosity in all eyes with a COL4A1 / A2 mutation, whereas the subjective assessment suspected or detected it in only 62% of eyes. In adult patients with cerebral microangiopathy, detecting increased retinal arteriolar tortuosity, even when mild, directs the diagnosis toward COL4A1/A2 -related cerebroretinal angiopathy.

Objective: Fetal intracranial hemorrhage (FICH) is a rare and potentially deleterious condition. Fetal alloimmune thrombocytopenia and pathogenic variations in COL4A1/A2 genes are well-recognized causes of FICH. However, pathogenic COL4A1/A2 variations are identified in only 20% of fetuses referred for FICH after excluding other known causes, leaving the majority unexplained and making genetic counseling difficult. Our main aim was to identify novel genes associated with FICH., Method: Exome sequencing was performed on 113 unrelated fetuses (35 trios, 3 families and 75 probands) after negative COL4A1/A2 testing and exclusion of known risk factors. Exome analysis incorporated several strategies including analyses of de novo and biallelic variants, and a collapsing gene-based burden test approach., Results: Nine individuals (8%) had a pathogenic or likely pathogenic variant identified. Additionally, 14 fetuses had a suspicious variant identified in a candidate gene. Causative genes involved platelet production, hemostasis (MPL, MECOM, PROC), endothelial cell adhesion (ESAM), and mitochondrial metabolism (ATP5PO, COQ2, PDHA1). These findings suggest that FICH may result from a broader range of genetic abnormalities beyond previously known COL4A1/A2 gene mutations., Conclusion: FICH is characterized by extreme genetic heterogeneity with various pathways involved, underscoring the importance of exome-wide analyses to fully understand its causes., (© 2025 John Wiley & Sons Ltd.)

Introduction: BCG therapy is the standard treatment for bladder tumors that do not infiltrate smooth muscle. Fluoroquinolones for antibiotic prophylaxis are recommended to lessen the risk of BCG infection (BCGitis) with respiratory involvement., Case Report: This study describes five cases of BCGitis in males, with a median age of 71years [range: 66-77years] having undergone ofloxacin prophylaxis during their BCG therapy for a non-invasive bladder tumor (grade pT1a). Among these patients, four experienced fever within eight hours of the last instillation, as well as respiratory symptoms such as dyspnea and cough. Three of them exhibited substantial weight loss over the course of one month. Chest scans consistently revealed miliary patterns. While only in one patient was BCG identification confirmed, typical clinical and CT presentations prompted the initiation of treatment, predominantly employing a combination of isoniazid, rifampicin, and ethambutol in four patients, and isoniazid and rifampicin in the fifth. Treatment duration ranged from six to nine months. One-year follow-up indicated a favourable outcome for all patients., Conclusions: This study shows that ofloxacin prophylaxis may in some cases fail to prevent iatrogenic BCGitis., Competing Interests: Déclaration de liens d’intérêts Les auteurs déclarent ne pas avoir de liens d’intérêts., (Copyright © 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: COVID-19 started to spread early in 2020, the precise year that lung cancer (LC) patients were recruited into the prospective epidemiological cohort KBP-2020-CPHG in French hospitals. This provides a unique opportunity to study COVID-19 incidence, survival risk factors, and overall prognosis., Methods: COVID data was collected before vaccination was made available. Clinical characteristics were compared (COVID vs non-COVID), incidence rate ratios were calculated based on clinical characteristics, survival (1 and 3 months) was estimated and the impact of COVID-19 on the overall prognosis of the cohort was studied., Results: In 2020, 285 out of 8,999 lung cancer patients were diagnosed with COVID-19. Diagnosis was mainly based on PCR tests (86.3 %). The annual incidence was 8.3 % (95 % CI [7.4, 9.3]); it was higher in former smokers and patients with squamous cell carcinoma or small cell carcinoma than in those with adenocarcinoma, in those with a PS score ≥2 versus 0-1, and with stages III-IV versus stages I-II. The incidence was reduced in patients who received chemotherapy or immunotherapy. 64.9 % of patients were hospitalized due to COVID-19. Risk factors for death at 1 and 3 months in COVID-19 patients were age, LC stage, and PS score. Multivariate analysis showed a major prognostic impact of COVID-19 on mortality of LC patients (hazard ratio: 4.12, 95 % CI [3.42, 4.97], p < 0.001)., Conclusions: This prospective study demonstrated the high incidence of COVID-19 in LC patients and identified as risk factors for COVID-19: smoking status, histology, PS, and stage. The impact of COVID-19 on lung cancer mortality appears major., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have no financial or personal relationship with other people or organizations that could inappropriately bias this work. The scientific committee was fully independent from industrial sponsors., (Copyright © 2024 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: The KBP studies are real-life nationwide, prospective, multicenter cohort studies of patients diagnosed with primary lung cancer that have been conducted in French non-academic public hospitals each decade since 2000., Methods: Patients were analyzed in three prospective cohorts using the same methodology. In this study, we describe and compare the characteristics and outcomes of patients with small cell lung cancer (SCLC), with a focus on treatments in the 2020 cohort., Findings: 8999 patients with lung cancer were included in the 2020 cohort, of whom 1137 had SCLC. From 2000 to 2010 and 2020, the proportion of patients with SCLC decreased from 16.4 % to 13.5 % and 12.6 % respectively. Between 2000 and 2020, the proportion of women increased from 15.5 % to 35.7 %. 15.4 % of patients with SCLC had limited-stage (LS) disease and 84.6 % of patients had extensive-stage (ES) disease. The 1-year overall survival (OS) rate for all patients with SCLC increased from 34.4 % in 2000 to 38.4 % in 2020. For ES-SCLC, multivariate analysis weighted with "entropy balancing" by including age, sex, performance status, number of metastatic sites, and brain metastases indicated an improvement in median OS from 8.1 months in patients receiving chemotherapy only to 11.1 months in patients receiving chemotherapy plus immunotherapy (HR 0.62, p < 0.001)., Interpretation: The proportion with SCLC has decreased over time, but the proportion of women has increased. The 1-year OS rates have improved over 20 years. The KBP-2020 cohort suggests a benefit of immunotherapy on OS in patients with ES-SCLC in the real-life setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Management of stage-III-N2 non-small-cell lung cancer (NSCLC) based on a multimodal strategy (surgery or radiotherapycombined with systemic drugs) remains controversial. Patients are treated with a curative intent, and available data suggestprolonged survival after complete resection. However, no consensual definition of "tumor resectability" exists. This study aimed to analyze the concordanceamong French tumor board meeting (TBM)-emittedtherapeutic decisions forstage-III-N2 NSCLC., Methods: Six patients with stage-III-N2 NSCLC discussed at Saint-Etienne University Hospital'sthoracic TBMs were selected, anonymouslyreported, and submitted to the participating TBMs. The primary goal of this multicenter, prospective, observational study was to assess the consistency of TBMpanel decisions for each case. The secondary endpointwas identifying the demographic or technical factors that potentiallyaffected decision-making., Results: Twenty-seven TBMs from university hospitals, a cancer center, general hospitals, and a private hospitalparticipated in this study. None of their decisions for the six cases were unanimous.The decisions were homogenous for three cases (78%, 85%, and 88% TBMs opted for medical treatment, respectively),andmore ambivalent for the other three (medical versus surgical strategies were favored by 44%/56%, 46%/54%, and 58%/42% TBMs, respectively). Interestingly, decisions regarding chemoradiationand perioperative chemotherapyinthe medical and surgical strategies, respectively, were also discordant. Hospital type, specialist participation in TBMs, and activity volumes were not significantly associated with therapeutic decisions., Conclusion: The results of this study highlight substantial disparities amongFrench TBMs regarding therapeutic management of stage-III-N2 NSCLC. The decisions were not associated with local conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In an open-label multicenter non-randomized non-comparative phase II study in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC), oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine-kinase inhibitor and no prior chemotherapy (NCT04042558), atezolizumab, carboplatin, pemetrexed with or without bevacizumab showed some promising result. Beyond the clinical evaluation, we assessed safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in this population., Materials: Patients received platinum-pemetrexed-atezolizumab-bevacizumab (PPAB cohort) or, if not eligible, platinum-pemetrexed-atezolizumab (PPA cohort). The incidence, nature, and severity of adverse events (AEs) were assessed. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-Core 30 and EORTC QLQ-Lung Cancer 13)., Result: Overall, 68 (PPAB) and 72 (PPA) patients were evaluable for safety. Grade 3-4 AEs occurred in 83.8% (PPAB) and 63.9% (PPA). Grade 3-4 atezolizumab-related AEs occurred in 29.4% and 19.4%, respectively. Grade 3-4 bevacizumab-related AEs occurred in 36.8% (PPAB). Most frequent grade 3-4 AEs were neutropenia (19.1% in PPAB; 23.6% in PPA) and asthenia (16.2% in PPAB; 9.7% in PPA). In PPAB, we observed a global stability in global health security (GHS) score, fatigue and dyspnea with a constant tendency of improvement, and a significant improvement in cough. In PPA, we observed a significant improvement in GHS score with a significant improvement in fatigue, dyspnea and cough. At week 54, we observed an improvement from baseline in GHS score for 49.2% of patients. In both cohorts, patients reported on average no clinically significant worsening in their overall health or physical functioning scores., Conclusion: PPAB and PPA combinations seem tolerable and manageable in patients with stage IIIB/IV non-squamous NSCLC with oncogenic addiction (EGFR mutation or ALK/ROS1 fusion) after targeted therapies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.T report adviser and consultant for TAKEDA, BMS, ROCHE, JANSSENS, AMGEN and ASTRA ZENECA; support for attending meeting for TAKEDA, BMS, ASTRA ZENECA and JANSSENS. G.R-B report adviser and consultant for TAKEDA, ASTRA ZENECA,SANOFI, BMS ; support for attending meeting for LILLY, ASTRA ZENECA, PFIZER, SANOGI, TAKEDA, BOEHRINGER. L.B-G report adviser and consultant for BMS, MSD, ROCHE, JANSSEN, TAKEDA, VIATRIS, ASTRA-ZENECA, SANOFI and LEOPHARMA; support for attending meeting for JANSSEN, TAKEDA, ASTRA-ZENECA,MSD. D.A report support for attending meeting for MSD, TAKEDA, SANOFI. H.M report support for attending meeting for ARAIR, MSD, PFIZER, TAKEDA and BOEHRINGER. R.V report adviser and consultant for MSD, JANSSEN, ROCHE, BMS, PFIZER, SANOFI and TAKEDA; support for attending meeting for JANSSEN, TAKEDA and SANOFI. G.J report support for attending meeting for Sanofi. P.F report adviser and consultant for SANOFI, MSD and ASTRA ZENECA; support for attending meeting for TAKEDA. A.V report adviser and consultant for PIERRE FABRE, AMGEN and MSD; support for attending meeting for PIERRE FABRE, AMGEN; Participation on “Data Safety Monitoring Board or Advisory Board ” for MSD, ASTRAZENECA, SANOFI, AMGEN, PIERRE FABRE. A.B report support for attending meeting for Takeda, Sanofi and BMS. F.S report adviser and consultant for; support for attending meeting for report adviser and consultant for; support for attending meeting for C.D report adviser and consultant for BMS, MSD, TAKEDA, AMGEN, ROCHE, PFIZER, SANOFI, JANSSEN; support for attending meeting for ROCHE, AMGEN , MSD, TAKEDA. C.C reports research support from AstraZeneca, Boerhinger, GSK, Sanofi, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen; adviser and consultant for AstraZeneca, Boerhinger, GSK, Roche, Sanofi , BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen ; support for attending meeting for AstraZeneca, Boerhinger, GSK, Roche, Sanofi , BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer and Amgen; L.G. reports research support from BMS, MSD, Amgen, Lilly, Novartis, Pfizer, Roche, Sanofi and Takeda, adviser and consultant for Amgen, Janssens, BMS, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda; support for attending meeting for AstraZeneca, Amgen, MSD, Pfizer and Takeda. Participation on “Data Safety Monitoring Board or Advisory Board ” for Inhatarget Therapeutics; O.B reports adviser and consultant for BMS, AstraZeneca, Roche, MSD, Takeda, Janssens, support for attending meeting for AstraZeneca and MSD. All other authors (L.A,E.D, C.R, E.H, F.S, B.C) have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The impact of the most recent advances, including targeted therapies and immune checkpoint inhibitors, on early (3-month) mortality in lung cancer is unknown. The aims of this study were to evaluate the real-world rate of and risk factors for early mortality, as well as trends in early mortality over the last 20 years., Materials and Methods: The KBP prospective observational multicenter studies have been conducted every 10 years since 2000. These studies collect data on all newly diagnosed patients with lung cancer (all stages and histologies) over 1 year in non-academic public hospital pulmonology or oncology units in France. In this study, we analyzed data on patient and tumor characteristics from participants in the KBP-2020 cohort and compared the characteristics of patients who died within 3 months of diagnosis with those of all other patients within the cohort. We also carried out a comparative analysis with the KBP-2000 and KBP-2010 cohorts., Results: Overall, 8999 patients from 82 centers were included in the KBP-2020 cohort. Three-month survival data were available for 8827 patients, of whom 1792 (20.3%) had died. Risk factors for early mortality were: male sex, age >70 years, symptomatic disease at diagnosis, ever smoker, weight loss >10 kg, poor Eastern Cooperative Oncology Group performance status (≥1), large-cell carcinoma or not otherwise specified, and stage ≥IIIC disease. The overall 3-month mortality rate was found to have decreased significantly over the last 20 years, from 24.7% in KBP-2000 to 23.4% in KBP-2010 and 20.3% in KBP-2020 (P < 0.0001)., Conclusion: Early mortality among patients with lung cancer has significantly decreased over the last 20 years which may reflect recent improvements in treatments. However, early mortality remained extremely high in 2020, particularly when viewed in light of improvements in longer-term survival. Delays in lung cancer diagnosis and management could contribute to this finding., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes., Objective: To identify novel genes and mechanisms associated with familial CSVD., Design, Setting, and Participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset

Purpose: Severe asthma affects 5 to 10% of asthmatics and accounts for a large part of asthma-related morbidity and costs. The determinants of asthma severity are poorly understood. We tested the hypothesis that asthma severity was associated with 1) atopy and allergy and 2) markers associated with environmental exposure., Patients and Methods: Data from the FASE-CPHG study, a cross-sectional, observational, multicenter investigation, were analyzed to identify markers associated with asthma severity. Asthma severity was gauged using the ASSESS score, encompassing symptom control, exacerbations, FEV1 and therapeutic load. Bivariate and multivariate analyses were used to identify patient characteristics associated with the ASSESS score., Results: The analysis involved 948 patients, with 592 women, of which 447 patients (47%) had severe asthma. Among these, 491 patients (52%) had at least one positive aeroallergen skin prick test and 525 (55%) had at least one allergic disease among atopic dermatitis, chronic rhinitis and food allergy. The mean±SD ASSESS score was 11.2±3.4. Characteristics associated with a higher ASSESS score were female sex, secondary or lower education, unemployed occupational status, smoking, work-aggravated asthma and urban housing. There was no association between the ASSESS score and allergic diseases, aeroallergen-specific skin prick tests and IgEs, or blood eosinophil counts., Conclusion: While atopy and allergy were frequent among asthmatics, neither was associated with asthma severity. Modifiable environmental factors such as smoking, urban housing and work-aggravated asthma were independently associated with asthma severity., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Chevereau-Choquet et al.)

Background: Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib., Objective: This study aimed to describe the clinical characteristics of these long-term responders., Patients and Methods: This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint., Results: A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively., Conclusions: Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To refine the clinical spectrum of a very recently identified phenotype associated with LAMB1 end-truncating pathogenic variations., Methods: Detailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncating LAMB1 variations., Results: All patients harbored a LAMB1 end-truncating pathogenic variation. The specific association of a hippocampal type episodic memory dysfunction and a diffuse leukoencephalopathy was observed in all 4 patients aged older than 50 years, slightly worsening over time in 2 patients with several years of follow-up. Additional unspecific neurologic symptoms are reported, such as episodes of numbness, language troubles, or faintness in these 4 patients and the 2 younger ones., Discussion: The association of an extensive leukoencephalopathy with an episodic memory dysfunction of the hippocampal type is strongly suggestive of a LAMB1 end-truncating variation in adults older than 50 years. Early cognitive complaints and imaging abnormalities might exist decades before. Additional transient manifestations can be observed, and this association should lead to LAMB1 screening to avoid unnecessary invasive investigations., Competing Interests: H. Morel reports no disclosures relevant to the manuscript; L. Bailly reports no disclosures relevant to the manuscript; C. Urbanczyk reports no disclosures relevant to the manuscript; D. Hervé reports no disclosures relevant to the manuscript; S. Berroir reports no disclosures relevant to the manuscript; R. Le Bouc reports no disclosures relevant to the manuscript; R. Levy reports no disclosures relevant to the manuscript; M. Meyer reports no disclosures relevant to the manuscript; C. Aloui reports no disclosures relevant to the manuscript; E. Tournier-Lasserve reports no disclosures relevant to the manuscript; G. Mathey reports no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Even though COVID-19 clinical features, pathogenesis, complications, and therapeutic options have been largely described in the literature, long-term consequences in patients remain poorly known., Methods: The French, multicentre, non-interventional SISCOVID study evaluated lung impairment three (M3) and six months (M6) after hospital discharge in patients recovered from COVID-19. Evaluation was based on clinical examination, pulmonary function tests, and chest computed tomography (CT-scan)., Results: Of the 320 included patients (mean age: 61 years; men: 64.1%), 205 had had a severe form of COVID-19, being hospitalised in an intensive care unit (ICU), and requiring high flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation. At M6, 54.1% of included patients had persistent dyspnoea (mMRC score ≥1), 20.1% severe impairment in gas diffusing capacity (DL CO <60% pred.), 21.6% restrictive ventilatory pattern (total lung capacity <80% pred.), and 40% a fibrotic-like pattern at CT-scan. Fibrotic-like pattern and restrictive ventilatory pattern were significantly more frequent in patients recovered from severe than non-severe COVID-19. Improved functional and radiological outcomes were observed between M3 and M6. At M6, age was an independent risk factor for severe DLco impairment and fibrotic-like pattern and severe COVID-19 form was independent risk factor for restrictive ventilatory profile and fibrotic-like pattern., Conclusion: Six months after discharge, patients hospitalised for COVID-19, especially those recovered from a severe form of COVID-19, frequently presented persistent dyspnoea, lung function impairment, and persistent fibrotic-like pattern, confirming the need for long-term post-discharge follow-up in these patients and for further studies to better understand long-term COVID-19 lung impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 SPLF and Elsevier Masson SAS. All rights reserved.)

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown., Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS)., Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 <1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; Pinteraction = 0.036)., Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients., (©2022 American Association for Cancer Research.)

Background: Long-term changes in lung cancer (LC) patients are difficult to evaluate. We report results from the French KBP-2020 real-life cohort., Methods: KBP-2020 was a prospective cohort that included all patients diagnosed with LC in 2020, in nonacademic public hospital in France. Patient and tumour characteristics were described and compared with similarly designed cohorts in 2000 and 2010., Findings: In 2020, 82 centers included 8,999 patients diagnosed with LC. The proportion of women increased: 34·6% (3114/8999) compared to, 24·3% (1711/7051) and 16·0% (904/5667) in 2010 and 2000 ( p< 0·0001). The proportion of non-smokers was higher in 2020 (12·6%, 1129/8983) than in previous cohorts (10·9% (762/7008) in 2010; 7·2% (402/5586) in 2000, p< 0·0001). In 2020, at diagnosis, 57·6% (4405/7648) of patients had a metastatic/disseminated stage non-small-cell lung cancer (NSCLC) (58·3% (3522/6046) in 2010; 42·6% (1879/4411) in 2000, p< 0·0001). Compared with 2000 and 2010 data, early survival improved slightly. In 2020, 3-month mortality of NSCLC varied from 3·0% [2·2 - 3·8] for localized to 9·6% [8·1 - 11·0] for locally advanced to 29·2% [27·8 - 30·6] for metastatic and was 24·8% [22·3 - 27·3] for SCLC., Interpretation: To our knowledge KBP cohorts have been the largest, prospective, real-world cohort studies involving LC patients conducted in worldwide. The trend found in our study shows an increase in LC in women and still a large proportion of patients diagnosed at metastatic or disseminated stage., Funding: The study was promoted by the French College of General Hospital Pulmonologists with financial support of industrials laboratories., Competing Interests: The authors have no financial and personal relationship with other people or organization that could inappropriately bias this work. The scientific committee was fully independent from industrial sponsors., (© 2022 The Authors.)

Competing Interests: Conflicts of Interest None.

Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes., Methods: We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized., Results: We showed that LAMB1 truncating variants escaping nonsense-mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 × 10 -8 ). Using 2 antibodies recognizing the N- and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy., Interpretation: These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962-975., (© 2021 American Neurological Association.)

Purpose: We studied the quality differences between the different hypo-osmotic swelling test (HOST) classes, as measured by criteria of DNA fragmentation, DNA decondensation, and nuclear architecture. The aim was to find particular HOST classes associated with good-quality metrics, which may be potentially used in ICSI (intra-cytoplasmic sperm injection)., Methods: Ten patients from the Department of Reproductive Medicine at Tenon Hospital (Paris, France) were included. Their semen samples were collected and divided into two fractions: one was incubated in a hypo-osmotic solution as per HOST protocol and sorted by sperm morphology, and a second was incubated without undergoing the HOST protocol to serve as an unsorted baseline. Three parameters were assessed: DNA fragmentation (TUNEL assay), DNA decondensation (chromomycin A3 assay), and nuclear architecture (FISH, with telomeric and whole chromosome painting probes). The different HOST classes were evaluated for these three parameters, and statistical analysis was performed for each class versus the unsorted non-HOST-treated sperm. Results with p<0.05 were considered statistically significant., Results: For each of the parameters evaluated, we found significant differences between HOST-selected spermatozoa and non-selected spermatozoa. Overall, spermatozoa of HOST classes B and B+ exhibited the highest quality based on four metrics (low DNA fragmentation, low DNA decondensation, short inter-telomeric distance, and small chromosome 1 territory area), while spermatozoa of HOST classes A and G exhibited the poorest quality by these metrics., Conclusion: In addition to their pathophysiological interest, our results open possibilities of sperm selection prior to ICSI, which may allow for optimization of reproductive outcomes in heretofore unstudied patient populations., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non-small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR -mutant NSCLC., Patients and Methods: In this phase II, randomized, open-label study, patients with stage III/IV EGFR -positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed., Results: Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5-14.1) and 12.9 (9.2-14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received., Conclusions: These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR -mutant NSCLC., (©2021 American Association for Cancer Research.)

Purpose: Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands., Methods: Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene., Results: These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations., Conclusion: This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is the most common and severe interstitial lung disease (ILD). It is a progressive disease that requires a regular follow-up: clinical examination, pulmonary function testing (PFT) and CT scan, which is performed yearly in France. These exams have two major disadvantages: patients with severe dyspnoea have difficulties to perform PFT and repeated CT scans expose to high dose of radiations. Considering these limits, it would be relevant to develop new tools to monitor the progression of IPF lesions. Three main signs have been described in ILD with lung ultrasound (LUS): the number of B lines, the irregularity and the thickening of the pleural line. Cross-sectional studies already correlated the intensity of these signs with the severity of fibrosis lesions on CT scan in patients with IPF, but no prospective study described the evolution of the three main LUS signs, nor the correlation between clinical evaluation, PFT and CT scan. Our hypothesis is that LUS is a relevant tool to highlight the evolution of pulmonary lesions in IPF. The main objective of our study is to show an increase in one or more of the three main LUS signs (total number of B lines, pleural line irregularity score and pleural line thickness) during the follow-up., Methods: ThOracic Ultrasound in Idiopathic Pulmonary Fibrosis Evolution is a French prospective, multicentric and non-interventional study. Every 3 months, patients with IPF will have a clinical examination, PFT and LUS. CT data will be collected if the CT scan is performed within 3 months before the inclusion; the second CT scan will be performed from 9 to 12 months after the inclusion. The presence, location and severity of LUS signs will be recorded for each patient, and their correlation with clinical, functional and CT scan evolution will be evaluated. 30 patients will be enrolled., Ethics and Dissemination: The protocol was approved by the French Research Ethics Committee (Comité de Protection des Personnes SUD OUEST ET OUTRE MER II, reference RIPH3-RNI19-TOUPIE) on 11 April 2019. Results will be disseminated via peer-reviewed publication and presentation at international conferences., Trial Registration Number: NCT03944928;Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Missense variants ABI3&#95;rs616338-T and PLCG2&#95;rs72824905-G were previously associated with elevated or reduced risk of Alzheimer's disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3&#95;rs616338-T and PLCG2&#95;rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (n Total  = 2008, n PSP  = 1037, n LBD-NP  = 971) and Thal phase amyloid plaque scores (n Total  = 1786, n PSP  = 1018, n LBD-NP  = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3&#95;rs616338-T (OR = 2.65, 95% CI 1.46-4.83, p = 0.001). PLCG2&#95;rs72824905-G was associated with lower Braak stage (ß = - 0.822, 95% CI - 1.439 to - 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = - 0.995, 95% CI - 1.773 to - 0.218, p = 0.012) than LBD-NP patients (ß = - 0.292, 95% CI - 1.283 to 0.698, p = 0.563). PLCG2&#95;rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = - 0.638, 95% CI - 1.139 to - 0.136, p = 0.013). These findings support a role for PLCG2&#95;rs72824905-G in suppressing tau neuropathology. ABI3&#95;rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.

Study Question: Is there an added diagnosis value of buccal cell FISH analysis compared with blood lymphocyte chromosomal investigations in patients with Turner syndrome (TS)?, Summary Answer: Buccal cell FISH analysis, a non-invasive technique, modified the chromosomal results obtained with the blood karyotype in 17 patients (12%) of our cohort., What Is Known Already: Few studies have evaluated buccal cell FISH analysis and compared them with blood karyotype in patients with TS., Study Design, Size, Duration: A prospective, monocentric cohort study was conducted in a rare diseases centre (CMERC) between July 2017 and August 2019., Participants/materials, Setting, Methods: In total, 142 adult patients with TS, and at least 5% 45,X cells in a previous blood karyotype, were recruited. All the patients' files were included in the CEMARA database. This national database has been declared to the French data protection agency (CNIL approval number 1187326). In compliance with French law, consent regarding non-opposition to collect and use the data was obtained from each patient. A FISH analysis on a buccal smear was performed., Main Results and the Role of Chance: The percentage of 45,X cells was identical between the two tissues in only 32.4% of cases. The discrepancy was higher than 41% for 12% of the cohort. The percentage of 45,X cells was higher in blood in 53 (37.3%) patients, and higher in buccal cells in 43 (30.3%) of cases. In 17 (12%) cases, the blood karyotype had to be reconsidered in regard to the buccal cell analysis., Limitations, Reasons for Caution: It would have been interesting to evaluate karyotypes in cells from other tissues such as cells from skin biopsy or from the urinary tract and even from blood vessels or gonads in case of surgery and to compare them with each patient's phenotype. However, most of the time, these tissues are not available., Wider Implications of the Findings: Although blood lymphocyte karyotype remains the gold standard for the diagnosis of TS, buccal cell FISH analysis is an efficient tool to evaluate the global chromosomal constitution in these patients, thus allowing them to have better care and follow-up. For instance, identifying a Y chromosome can prevent the occurrence of a gonadoblastoma, as gonadectomy should be discussed. On the other hand, finding normal XX cells in a patient with a previous diagnosis of homogenous 45,X TS, may be psychologically helpful and relevant for gynaecological care., Study Funding/competing Interest(s): No specific funding was sought for the study. The authors declare no competing interests., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Wilson disease is an autosomal recessive metabolic disorder resulting from accumulation of excess copper especially in the liver and brain. This disease is mainly characterized by hepatic disorders and less frequently by neuro-psychiatric disturbances. This recessive disease is due to mutation in ATP7B, which codes for an ATPase involved in copper-transport across the plasma membrane. Molecular diagnosis of WD is positive in approximately 98% of cases. Also, in few cases, WD patients present a single deleterious mutation (heterozygous) or no mutation after sanger and NGS standard sequencing analysis of ATP7B. Therefore, in these problematic WD cases, we hypothesized that deleterious mutations reside in intronic regions of ATP7B., Methods: Complete ATP7B gene was sequenced by Next Generation Sequencing including its promoter., Results: Five unrelated families with Wilson disease shared the same novel, deep intronic NG&#95;008806.1 (ATP7B&#95;v001):c.2866-1521G>A variant in ATP7B. Analysis of RNA transcripts from primary fibroblasts of one patient confirmed the deleterious impact of the intronic variant on splicing and its likely pathologic effect in this compound heterozygote., Conclusion: This discovery of a novel intronic mutation in ATP7B has improved the molecular diagnosis of WD in the French patient cohort to greater than 98%. Thus, we recommend complete sequencing of ATP7B gene, including introns, as a molecular diagnostic approach in cases of clinically confirmed WD which lack pathogenic exon or promoter variants in one or both alleles., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

The usefulness and feasibility of a global allergens avoidance method with counselors visiting patients' home for allergens measures and adapted advices were prospectively evaluated through asthma control and environment evaluation. Twenty seven patients were prospectively included and compared to a cohort of 30 control patients. The level of control of asthma at inclusion and after 1 year was evaluated by the clinical signs, the evolution of the FEV1, and the healthcare use. Environmental measurements included the fungal load of 5 surfaces of the dwellings and the evaluation of moisture. A significant clinical improvement in the population that benefited from the home counselors visit was observed compared to the baseline (p < 0.0001), as well as a decreased number of hospitalizations for asthma and of the consumption of anti-asthma drugs (p < 0.01). Dampness markers slightly improved with an improvement of the fungal loads in two-third of the dwellings.

Although the leaf economic spectrum has deepened our understanding of leaf trait variability, little is known about how leaf traits scale with leaf area. This uncertainty has resulted in the assumption that leaf traits should vary by keeping the same pace of variation with increases in leaf area across the leaf size range. We evaluated the scaling of morphological, tissue-surface and vascular traits with overall leaf area, and the functional significance of such scaling. We examined 1,271 leaves for morphological traits, and 124 leaves for anatomical and hydraulic traits, from 38 trees of Cecropia obtusa Trécul (Urticaceae) in French Guiana. Cecropia is a Neotropical genus of pioneer trees that can exhibit large laminas (0.4 m2 for C. obtusa), with leaf size ranging by two orders of magnitude. We measured (i) tissue fractions within petioles and their second moment of area, (ii) theoretical xylem hydraulic efficiency of petioles and (iii) the extent of leaf vessel widening within the hydraulic path. We found that different scaling of morphological trait variability allows for optimisation of lamina display among larger leaves, especially the positive allometric relationship between lamina area and petiole cross-sectional area. Increasing the fraction of pith is a key factor that increases the geometrical effect of supportive tissues on mechanical rigidity and thereby increases carbon-use efficiency. We found that increasing xylem hydraulic efficiency with vessel size results in lower leaf lamina area: xylem ratios, which also results in potential carbon savings for large leaves. We found that the vessel widening is consistent with hydraulic optimisation models. Leaf size variability modifies scaling of leaf traits in this large-leaved species., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permission@oup.com.)

The burden of antibiotic-resistant infections among Gram-negative bacteria is increasing. Resistance to third-generation cephalosporins (3GCs) in Enterobacteriaceae is mainly conferred by the acquisition of β-lactamases or by deregulation of natural genetically-encoded β-lactamase enzymes. Enterobacteriaceae such as Enterobacter spp., Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (ESCPM group) possess chromosomally-encoded inducible AmpC β-lactamases. AmpC can be overproduced as a response to β-lactam antibiotic exposure or by constitutive dysfunction of the AmpC regulation system. This overproduction can lead to the inactivation of 3GCs. Based on small clinical studies, international guidelines and expert recommendations suggest that 3GCs should be avoided as definitive therapy for infections caused by ESCPM group organisms. In this narrative review, we discuss the published literature and evaluate the risk related to 3GC use in the case of documented ESCPM infection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have been approved as second-line therapy for advanced non-small cell lung cancers (NSCLCs) progressing after platinum-based chemotherapy. However, some patients' disease progressed rapidly and sometimes exhibited explosive tumor progression. This descriptive, prospective study aimed to assess the characteristics of nonresponders with rapid progression (RP), defined as progression-free survival (PFS) ≤2 or 2-4 months under ICIs., Methods: This analysis included all consecutive ICI-treated (second-or-more line) patients with RP ≤4 months from 1 September 2016 to 31 August 2017 and compared the clinical characteristics, treatments, and outcomes (overall survival [OS]; responses; PFS, according to treatment line) of NSCLCs that progressed after ≤2 vs 2-4 months on ICIs., Results: Comparisons of the 224 (70.2%) patients with ≤2-month and 95 (29.8%) with 2- to 4-month RP revealed the former had less frequent nonsmokers and ECOG PS = 0, more frequent stage IV disease and higher neutrophil/lymphocyte ratio. Their respective ICI PFS rates were: 1.6 [95% CI: 0.1-2] and 2.7 [2.0-4.2] months, with 16.5% and 11.6% having partial responses to first- and second-line therapies post-ICI chemotherapy. Their respective median OS rates were 6.0 and 9.0 months (P ≤ .009). Multivariate analysis retained only PFS of the first-line therapy pre-ICI and neutrophil/lymphocyte ratio at ICI onset as being significantly associated with ≤2-month RP., Conclusion: In the real-life setting, NSCLC RP on ICI remains a challenge. New descriptive and analytic studies are needed to identify factors predictive of RP., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia [skeletal muscle mass (SMM) loss], inflammation, and anorexia. The aim of this study was to stage CAX in non-small-cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters., Methods: This was a cross-sectional and non-interventional multicentre study. SMM was assessed by analysing L3 computed tomography-scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ-C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ)., Results: Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0-1, and the tumour stage was mainly IIIB-IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre-CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K-RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre-CAX patients. Overall, 43.8% of pre-CAX patients had only sarcopenia with limited weight loss (≤2%) and no anorexia., Conclusions: This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX., (© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

The increasingly female face of chronic obstructive pulmonary disease (COPD) prevalence among women has equalled that of men since 2008, due in part to increased tobacco use among women worldwide and exposure to biomass fuels. This finding is supported by a number of characteristics. There is evidence of susceptibility to smoking and other airborne contaminants, along with epidemiological and phenotypic manifestations. COPD has thus become the leading cause of death in women in the USA. The clinical presentation is characterised by increasingly pronounced dyspnoea with a marked tendency towards anxiety and depression, undernutrition, nonsmall cell lung cancer (especially adenocarcinoma) and osteoporosis. Quality of life is also more significantly impacted. The theories advanced to explain these differences involve the role played by oestrogens, impaired gas exchange in the lungs and smoking habits. While these differences require appropriate therapeutic responses (smoking cessation, pulmonary rehabilitation, long-term oxygen therapy), barriers to the treatment of women with COPD include greater under-diagnosis than in men, fewer spirometry tests and medical consultations. Faced with this serious public health problem, we need to update and adapt our knowledge to the epidemiological changes., Competing Interests: Conflict of interest: C. Gut-Gobert reports personal fees from Novartis, Chiesi and GSK, outside the submitted work. Conflict of interest: A. Cavailles has nothing to disclose. Conflict of interest: A. Dixmier reports non-financial support from Novartis, outside the submitted work. Conflict of interest: S. Guillot has nothing to disclose. Conflict of interest: S. Jouneau reports grants and personal fees (fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups and research projects) from Actelion, AIRB, AstraZeneca, BMS, Boehringer, Chiesi, Gilead, GSK, LVL, Mundipharma, Novartis, Pfizer, Roche and Savara-Serendex, outside the submitted work. Conflict of interest: C. Leroyer has nothing to disclose. Conflict of interest: S. Marchand-Adam reports personal fees from Novartis, Roche and Boehringer, outside the submitted work. Conflict of interest: D. Marquette has nothing to disclose. Conflict of interest: J-C. Meurice reports grants, personal fees and nonfinancial support from ResMed, grants from Philips, personal fees from Fisher Paykel, and personal fees and nonfinancial support from Novartis and Orkyn, outside the submitted work. Conflict of interest: N. Desvigne reports other fees from Novartis, outside the submitted work. Conflict of interest: H. Morel has nothing to disclose. Conflict of interest: C. Person-Tacnet has nothing to disclose. Conflict of interest: C. Raherison reports personal fees from Novartis, AstraZeneca, Chiesi, GSK and Boeringher Ingelheim, outside the submitted work., (Copyright ©ERS 2019.)

Tetragametic chimeras are due to the fusion of 2 different zygotes after fertilization. When occurring between embryos of different chromosomal sex, the phenotype ranges from fertile individuals to infertile patients and even to patients with variations in sex development. Here, we report 3 new cases of XX/XY chimeras, one in a young boy carrying an abnormal gonad which turned out to be an ovary and 2 in phenotypically normal infertile men, one of whom had been diagnosed previously as a XX-SRY negative male. These cases highlight the importance of combining several cytogenetic and molecular techniques on different tissues for a proper diagnosis and an appropriate prognosis., (© 2020 S. Karger AG, Basel.)

Objectives: To assess how physicians and surgeons carried out malnutrition screening and follow-up for patients with lung cancer. Materials and methods: We carried out an expert opinion survey in France using an anonymous self-administered online questionnaire. Results: In 2017, 206 practitioners responded, of which 60.7% were pulmonologists, 17.4% thoracic surgeons, 11.2% oncologists, and 10.7% radiotherapists. At initial diagnosis, 79.3% of practitioners recorded patients' percentage of weight loss. During follow-up examinations, 67.5% recorded this data for patients at risk of malnutrition and 70.4 % for malnourished patients. Food intake was evaluated by 21.7% of practitioners at initial diagnosis. Surgeons assessed percentage of weight loss and food intake significantly less often than pulmonologists did, they were less likely to request serum albumin tests and waited for a greater percentage of weight loss before referring patients to a nutrition professional. All practitioners were well aware of the prevalence of malnutrition among lung cancer patients and its consequences. The main factors preventing optimal nutritional assessment reported by practitioners were a lack of time and limited specialized knowledge. Conclusion: Nutritional assessment remained suboptimal, especially for surgical patients. The importance granted to malnutrition needs to be increased for patients with lung cancer, especially in surgical departments. Highlights Physicians and thoracic surgeons are well aware of the prevalence and consequences in lung cancer patients. Thoracic surgeons seemed to be less sensitized to malnutrition screening than pulmonologists. Lack of time and limited specialized knowledge were reported as the main factors preventing optimal nutritional assessment.

Objectives: Recent studies have demonstrated that elevated BMI is associated with improved survival in patients with lung cancer. According to the authors, this "obesity paradox" could be a true benefit or a spurious relationship. In this context, data from the French KBP-2010-CPHG cohort (7,051 patients followed up for primary lung cancer diagnosed in 2010 in the respiratory medicine departments of 104 nonacademic hospitals) were analyzed., Methods: Patients were stratified according to BMI at diagnosis using the definition of the French-Speaking Society of Clinical Nutrition and Metabolism (Société Francophone de Nutrition Clinique et Métabolisme). Survival was analyzed using log-rank and a univariate Cox model. Prognostic factors were identified using a multivariate Cox model with backward elimination procedure, and with or without inclusion of prediagnosis weight loss in the model., Results: Patients were followed for a median 20.2 months. At diagnosis, respectively 12%, 28%, 45%, and 15% of the 6,595 patients with BMI data were obese, overweight, normal-weight, and underweight; 35%, 43%, 57%, and 75% reported prediagnosis weight loss (i.e., weight loss within the 3 months prior to diagnosis). One-year survival (% [95% CI]) was 53% [50%-57%], 50%, [48%-52%], 43%, [42%-45%], and 32% [29%-35%] in obese, overweight, normal-weight, and underweight patients, respectively (p < 0.001). It was particularly low in underweight patients with prediagnosis weight loss: 27% [24-30%]. BMI did not remain an independent prognostic factor associated with survival when prediagnosis weight loss was introduced in the Cox model. Risk of death was increased by 17%, 23%, and 46% in patients with <5 kg, 5-10 kg, or ≥10 kg prediagnosis weight loss, respectively (p < 0.001)., Conclusion: BMI is an easy but crude assessment tool. Other variables should be used to improve management of patients, and understanding of how prediagnosis body size and nutritional status are associated with cancer survival., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Osteochondroplastic tracheobronchopathy (OCTB) is a rare disorder of unknown cause that affects the tracheobronchial tree. It is characterized by multiple cartilaginous formations or bone nodules projecting into the tracheal or proximal bronchial lumen. It is usually asymptomatic because of the slow progression of the nodules. However, chronic cough, recurrent hemoptysis or recurrent respiratory infections have been reported., Observations: We describe the cases of three patients with symptomatic OCTB: two men and one woman consulting for bronchial infections or pneumonia with sputum difficulties (2 cases) or simply for chronic cough (1 case). In all three cases, the diagnosis was suspected because of irregularities of the tracheal or bronchial wall with calcification seen on imaging and confirmed at bronchoscopy with biopsy specimens. No specific therapy was initiated in these patients except for the treatment of associated complications or comorbidities., Conclusion: OCTB is a benign pathology which can lead to bronchial symptoms ranging from mild cough to severe airway obstruction due to tracheobronchial stenosis. A key to diagnosis, limiting non-essential examinations and biopsies, is to consider OCTB based on CT scan or bronchoscopy based on irregularities of the tracheal or bronchial wall with calcification., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Wilson's disease (WD) is a rare autosomal recessive metabolic disease caused by ATP7B gene mutations tat cause excessively high copper levels, particularly in the liver and brain. The WD phenotype varies in terms of its clinical presentation and intensity. Diagnosing this metabolic disorder is important as a lifelong treatment, based on the use of copper chelating agents or zinc salts, is more effective if it's started early. Worldwide prevalence of WD is variable, with an average of 1/30,000. In France, a recent study based on French health insurance data estimated the clinical prevalence of the disease to be around 3/200,000., Methods: To estimate the genetic prevalence of WD in France, we analysed the ATP7B gene by Next Generation Sequencing from a large French cohort of indiscriminate subjects., Results: We observed a high heterozygous carrier frequency of ATP7B in France. Among the 697 subjects studied, 18 variants classified as pathogenic or probably pathogenic were found at heterozygous level in 22 subjects (22 alleles/1394 alleles), yielding a prevalence of 0.032 or 1/31 subjects., Conclusions: This considerable and unexplained discrepancy between the heterozygous carrier frequency and the clinical prevalence of WD may be explained by the clinical variability, the incomplete penetrance and the existence of modifiers genes. It suggests that the molecular analysis of ATP7B should be interpreted with caution, always alongside copper assays (ceruloplasmin, relative exchangeable copper, 24 h-urinary copper excretion) with particular respect to exome sequencing.

Multidrug-resistant Candida auris has emerged as a cause of insidious hospital outbreaks and complicated infections. We present the analysis of an ongoing C. auris outbreak including the largest published series of C. auris bloodstream infection. All C. auris-positive patients from April-2016 to January-2017 were included. Environmental, clinical and microbiological data were recorded. Definitive isolate identification was performed by ITS-rDNA sequencing, and typing by amplified fragment length polymorphism fingerprinting. One hundred and forty patients were colonised by C. auris during the studied period (68% from surgical intensive care). Although control measures were implemented, we were not able to control the outbreak. Forty-one invasive bloodstream infections (87.8% from surgical intensive care) were included. Clinical management included prompt intravascular catheter removal and antifungal therapy with echinocandins. All isolates were fluconazole- and voriconazole-resistant, but echinocandin- and amphotericin B-susceptible. Thirty-day mortality rate was 41.4%, and severe septic metastasis as spondylodiscitis and endocarditis were observed in 5 patients (12%). C. auris was also recovered from inanimate patient surroundings and medical equipment. Despite antifungal treatment, high mortality and late complication rates were recorded. Molecular typing suggested a clonal outbreak different from those previously published., (© 2018 Blackwell Verlag GmbH.)

Introduction: Benign metastasizing leiomyoma (BML) is a rare cause of pulmonary nodules. They can occur in women of reproductive age who have undergone hysterectomy for uterine leiomyoma., Observation: We report the case of a 46-year-old women, who was incidentally found to have bilateral pulmonary cavitating nodules. Pathology exam was consistent with BML., Conclusion: Although BML is a rare cause of pulmonary nodules, it should be considered as one of the possibilities especially in young women with a history of hysterectomy for leiomyoma., (Copyright © 2018 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To determine the prevalence of Adverse Events related to Medication (AEM) in hospitals of the Valencian Community in the 2005-2013 study period, and to describe the associated risk factors and their impact., Methods: This study is based on data and methodology of the Study of Prevalence of Adverse Events in hospitals (EPIDEA), since its inception in 2005 until 2013. AEM produced in each year were analyzed., Results: We identified 344 AEM that occurred in 337 patients, among 35,103 patients studied, giving a prevalence of patients with AEM of 0.96% (IC95% 0.89-1.07). The most prevalent intrinsic risk factors for AEM were hypertension, diabetes and cancer. The most prevalent extrinsic risk factors were peripheral venous catheter, urinary catheter and central venous catheter. Therapeutic groups most frequently involved were systemic antibiotics, cardiovascular drugs and antineoplastics. The 61.17% of AEM was classified as moderate, followed by 27.18% as mild and 11.65% as severe. The 33.99% of EAM caused increase of the patient's stay and 39.90% of EAM caused the re-entry of patient. The 58.5% of AEM were avoidable. Mild AEM were avoidable in 46.3%, moderate AEM were avoidable in 60.3% and severe AEM were in 75% (p = 0.013)., Conclusions: The prevalence of patients with AEM in hospitals of the Community of Valencia for the period 2005- 2013 was 0.96%. More than half of AEM were preventable, and preventability increases significantly with the severity of the event.

Background: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase., Patients and Methods: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival., Results: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001)., Conclusion: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Chronic obstructive pulmonary disease (COPD) is the chronic respiratory disease with the most important burden on public health in terms of morbidity, mortality and health costs. For patients, COPD is a major source of disability because of dyspnea, restriction in daily activities, exacerbation, risk of chronic respiratory failure and extra-respiratory systemic organ disorders. The previous French Language Respiratory Society (SPLF) guidelines on COPD exacerbations were published in 2003. Using the GRADE methodology, the present document reviews the current knowledge on COPD exacerbation through 4 specific outlines: (1) epidemiology, (2) clinical evaluation, (3) therapeutic management and (4) prevention. Specific aspects of outpatients and inpatients care are discussed, especially regarding assessment of exacerbation severity and pharmacological approach., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The objective of this study was to assess the effectiveness of a catheter-related bloodstream infection (CR BSI) reduction programme and healthcare workers' compliance with recommendations. A 3-year surveillance programme of CR BSIs in all hospital settings was implemented. As part of the programme, there was a direct observation of insertion and maintenance of central venous catheters (CVCs) to determine performance. A total of 38 education courses were held over the study period and feedback reports with the results of surveillance and recommendations were delivered to healthcare workers every 6 months. A total of 6722 short-term CVCs were inserted in 4982 patients for 58 763 catheter-days. Improvements of compliance with hand hygiene was verified at the insertion (87·1-100%, P < 0·001) and maintenance (51·1-72·1%, P = 0·029) of CVCs; and the use of chlorhexidine for skin disinfection was implemented at insertion (35·7-65·4%, P < 0·001) and maintenance (33·3-45·9%, P < 0·197) of CVCs. There were 266 CR BSI incidents recorded with an annual incidence density of 5·75/1000 catheter-days in the first year, 4·38 in the second year [rate ratio (RR) 0·76, 95% confidence interval (CI) 0·57-1·01] and 3·46 in the third year (RR 0·60, 95% CI 0·44-0·81). The education programme clearly improved compliance with recommendations for CVC handling, and was effective in reducing the burden of CR BSIs.

COPD is a slowly progressive chronic respiratory disease causing an irreversible decrease in air flow. The main cause is smoking, which provokes inflammatory phenomena in the respiratory tract. COPD is a serious public health issue, causing high morbidity, mortality and disability. Related comorbidities are linked to ageing, common risk factors and genetic predispositions. A combination of comorbidities increases healthcare costs. For instance, patients with more than two comorbidities represent a quarter of all COPD sufferers but account for half the related health costs. Our review describes different comorbidities and their impact on the COPD prognosis. The comorbidities include: cardiovascular diseases, osteoporosis, denutrition, obesity, ageing, anemia, sleeping disorders, diabetes, metabolic syndrome, anxiety-depression and lung cancer. The prognosis worsens with one or more comorbidities. Clinicians are faced with the challenge of finding practical and appropriate ways of treating these comorbidities, and there is increasing interest in developing a global, multidisciplinary approach to management. Managing this chronic disease should be based on a holistic, patient-centred approach and smoking cessation remains the key factor in the care of COPD patients., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Surveillance programmes have become the most effective tool for controlling catheter-related bloodstream infections (CRBSI). However, few studies have investigated programmes covering all hospital settings., Aim: To describe the results of a control and prevention programme for CRBSI based on compliance with recommendations for insertion and maintenance, using annual burden of disease in a tertiary level hospital., Methods: A CRBSI control and prevention programme involving all hospital settings was implemented. The programme consisted of CRBSI surveillance, direct observation of insertion and maintenance of catheters to determine performance, and education for healthcare workers., Findings: In total, 2043 short-term catheters were inserted in 1546 patients for 18,570 catheter-days, and 279 long-term catheters were inserted in 243 patients for 40,440 catheter-days. The annual incidence density was 5.98 (first semester 6.40, second semester 5.64) CRBSI per 1000 catheter-days for short-term catheters, and 0.57 (first semester 0.66, second semester 0.43) CRBSI per 1000 catheter-days for long-term catheters. One hundred and forty insertion procedures were observed, with an average insertion time of 13 (standard deviation 7) min. Compliance with recommendations was as follows: hand hygiene, 86.8%; use of alcoholic chlorhexidine solution for skin disinfection, 35.5%; use of mask, 93.4%; use of gloves, 98.7%; use of gown, 75.0%; use of sterile cloth, 93.8%; use of cap, 92.2%; bandage application, 62.7%; and use of aseptic technique, 89.5%. Forty-five maintenance procedures were observed, and compliance rates were as follows: hand hygiene, 42.1%; use of gloves, 78.1%; and port disinfection with alcoholic chlorhexidine solution, 32.5%., Conclusion: The CRBSI control and prevention programme implemented at the study hospital has decreased the rate of CRBSI, provided important information about the total burden of disease, and revealed possible ways to improve interventions in the future., (Copyright © 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

By 2020, chronic obstructive pulmonary disease (COPD) will be the third cause of mortality. Extrapulmonary comorbidities influence the prognosis of patients with COPD. Tobacco smoking is a common risk factor for many comorbidities, including coronary heart disease, heart failure and lung cancer. Comorbidities such as pulmonary artery disease and malnutrition are directly caused by COPD, whereas others, such as systemic venous thromboembolism, anxiety, depression, osteoporosis, obesity, metabolic syndrome, diabetes, sleep disturbance and anaemia, have no evident physiopathological relationship with COPD. The common ground between most of these extrapulmonary manifestations is chronic systemic inflammation. All of these diseases potentiate the morbidity of COPD, leading to increased hospitalisations and healthcare costs. They can frequently cause death, independently of respiratory failure. Comorbidities make the management of COPD difficult and need to be evaluated and treated adequately.

Objectives: To compare bicarbonate kinetics and acid base status in HD and HDF for the same patient; and to investigate the effect of patient physiologic parameters on these kinetics., Methods: In order to monitor HCO3- kinetics during dialysis, acid-base parameters, pH, blood gases partial pressures, and HCO3- concentrations were recorded during 3 regular dialysis (HD) and 3 on-line post-dilution HDF sessions performed on 12 patients, using same dialysis fluid with a 38 mmol/l HCO3- concentration. HCO3- mass transfers through the hemodialyzers membranes and into the patients were continuously calculated during the sessions from HCO3- concentrations, together with HCO3-dialysance. The"apparent" HCO3-gain was calculated by integrating over time the instantaneous mass transfer from dialyzer and re-infusion fluid to the patient. A second method consisted in calculating the patient apparent bicarbonate space (ABS) and HCO3- mass (ABS times plasma concentration) at beginning and end of session., Results: No significant differences were observed between acid base parameters at the end of HD and HDF sessions. In contrast to urea clearances, HCO3- dialysances decayed with time during sessions from 110 to 140 ml/min to about 40 ml/min after one hour. The net HCO3- gain was taken as the difference between final and initial HCO3-masses. This net gain was in average 63% of apparent gain in HD and 74% in HDF., Conclusions: Uremic acidosis was well corrected without risk of alkalosis. An unexpected result was the continuous decay of bicarbonate dialysance both in HD and HDF during runs.