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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: 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.)

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: Despite the well-established role of lateral extra-articular procedures (LEAPs) in reducing failure rates after anterior cruciate ligament (ACL) reconstruction (ACLR) in the adult population, similar in-depth research for the adolescent and pediatric population remains lacking., Purpose: To examine the effect of the LEAP augmentation on the rerupture rate after ACLR in patients aged <18 years., Study Design: Cohort study; Level of evidence, 3., Methods: This was a retrospective analysis of prospectively collected data from October 2012 to June 2020, involving adolescents <18 years old undergoing primary ACLR with a minimum follow-up of 2 years. Two groups, matched for age, sex, Tegner activity scale, and presence of meniscal injury, were established: ACLR alone and ACLR+LEAP augmentation. The primary outcome measure was the rate of rerupture after ACLR. The secondary outcome measures were the rate of non-graft rupture related reoperation after ACLR; rate of return to sport (RTS) rate, timing, and level compared with preinjury status; and functional scores including the International Knee Documentation Committee (IKDC) score, Knee injury and Osteoarthritis Outcome Score (KOOS) (Pain, Symptoms, Activities of Daily Living, Sport and Recreation, and Quality of Life), Tegner activity scale score, ACL Return to Sport after Injury (ACL-RSI) score, and Lysholm score., Results: After accounting for follow-up losses, we analyzed 132 patients who underwent ACLR alone and 121 patients who underwent ACLR+LEAP from the initial 147 per group. The mean age of the patients in both groups was 16.1 years (SD, 1.1 and 1.0 years, respectively), with similar patient and injury characteristics across both groups ( P > .05). Both groups also showed comparable preoperative functional scores. A significantly lower preoperative ACL-RSI score was observed in the ACLR-alone group compared with the ACLR+LEAP group ( P = .0044). Graft rupture was significantly less common in the ACLR+LEAP group (2.5%) than in the ACLR-alone group (13.6%) ( P = .002). The attributable risk reduction for ACLR+LEAP was 11.1%, and the calculated number needed to treat was 9. Kaplan-Meier analysis showed significantly better rerupture-free survival at 5 years for the ACLR+LEAP group ( P = .001). Cox regression confirmed a 6-fold increased rerupture risk in the ACLR-alone group ( P = .004). At the final follow-up, despite similar IKDC, KOOS, Lysholm, and ACL-RSI values across both groups, the ACLR+LEAP group had a significantly higher Tegner score (7.2 vs 6.3; P = .0042). No significant differences were observed in RTS rates or sport level compared with preinjury states between the groups., Conclusion: ACLR+LEAP augmentation significantly reduced rerupture risk and facilitated higher postoperative activity levels in adolescents., Registration: NCT02511158 (ClinicalTrials.gov identifier)., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: N.L. has received consulting fees from Websurvey Society. A.H. has received consulting fees from Arthrex and DePuy. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable., Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm., Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis., Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score., Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation., Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5., Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups., Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Objectives: The aim of this postmarket clinical study was to assess the safety and efficacy of the latest generation polymer-free sirolimus-eluting stents (PF-SES) in an all-comers population comparing outcomes in stable coronary artery disease (CAD) versus acute coronary syndrome (ACS) in France., Background: The efficacy and safety of the first-generation PF-SES have already been demonstrated by randomized controlled trials and "all-comers" observational studies., Methods: For this all-comers observational, prospective, multicenter study, 1456 patients were recruited in 22 French centers. The primary endpoint was target lesion revascularization (TLR) rate at 12 months and secondary endpoints included major adverse cardiac events (MACE) and bleeding., Results: 895 patients had stable CAD and 561 had ACS. At 12 months, 2% of patients had a TLR, with similar rates between stable CAD and ACS (1.9% vs 2.2%, p  = 0.7). The overall MACE rate was 5.2% with an expected higher rate in patients with ACS as compared to those with stable CAD (7.3% vs 3.9%, p  = 0.007). The overall bleeding event rate was 4.5%, with similar rates in stable CAD as compared to ACS patients (3.8% vs 5.6%, p  = 0.3). Dual antiplatelet therapy (DAPT) interruptions prior to the recommended duration occurred in 41.7% of patients with no increase in MACE rates as compared to patients who did not prematurely interrupt DAPT (3.9% vs 6.1%, p  = 0.073)., Conclusions: The latest generation PF-SES is associated with low clinical event rates in these all-comers patients. There was a high rate of prematurely terminated DAPT, without any effect on MACE at 12 months. This trial is registered with NCT03809715., Competing Interests: Quentin Landolff, Marine Quillot, Fabien Picard, Georgios Sideris, Raphael Lasserre, and René Koning report consulting fees from B. Braun. The other authors have no conflicts of interest to declare., (Copyright © 2023 Quentin Landolff et al.)

The ten-year cancer control strategy launched in 2021 highlights the structuring of supportive care as a strong axis to limit the side effects of treatments and simplify the patient's journeys. On the other hand, the "Gradation instruction" published in 2020, introduced new invoicing rules for outpatient hospital wards, which facilitates the coordinated interventions of several health professionals (medical, paramedical, or socio-educational) around patients. Among these professionals, the pharmacist has a particular role, inside the multidisciplinary oncology teams, since cancer oral therapies require therapeutic adherence and a continuum of care with retail pharmacists. Until now, these clinical pharmaceutical activities, which include carrying out medication reviews, developing personalized pharmaceutical plans and conducting pharmaceutical interviews with patients, have struggled to develop in a sustainable manner due to a lack of funding in hospitals. Finally, the "gradation instruction" represents a real opportunity to support clinical pharmacy actions, particularly in outpatient hospital wards. In order to save time for hospital teams wishing to initiate or consolidate these activities, we should consider points of vigilance and facilitating factors., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Neurogenesis in the developing human cerebral cortex occurs at a particularly slow rate owing in part to cortical neural progenitors preserving their progenitor state for a relatively long time, while generating neurons. How this balance between the progenitor and neurogenic state is regulated, and whether it contributes to species-specific brain temporal patterning, is poorly understood. Here, we show that the characteristic potential of human neural progenitor cells (NPCs) to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the amyloid precursor protein (APP). In contrast, APP is dispensable in mouse NPCs, which undergo neurogenesis at a much faster rate. Mechanistically, APP cell-autonomously contributes to protracted neurogenesis through suppression of the proneurogenic activator protein-1 transcription factor and facilitation of canonical WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.

Background: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear., Methods: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days., Results: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment., Conclusions: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: The extent of the consequences of an episode of severe acute kidney injury (AKI) on long-term outcome of critically ill patients remain debated. We conducted a prospective follow-up of patients included in a large multicenter clinical trial of renal replacement therapy (RRT) initiation strategy during severe AKI (the Artificial Kidney Initiation in Kidney Injury, AKIKI) to investigate long-term survival, renal outcome and health related quality of life (HRQOL). We also assessed the influence of RRT initiation strategy on these outcomes., Results: Follow-up of patients extended from 60 days to a median of 3.35 years [interquartile range (IQR), 1.89 to 4.09] after the end of initial study. Of the 619 patients included in the AKIKI trial, 316 survived after 60 days. The overall survival rate at 3 years from inclusion was 39.4% (95% CI 35.4 to 43.4). A total of 46 patients (on the 175 with available data on long-term kidney function) experienced worsening of renal function (WRF) at the time of follow-up [overall incidence of 26%, cumulative incidence at 4 years: 20.6% (CI 95% 13.0 to 28.3)]. Fifteen patients required chronic dialysis (5% of patients who survived after day 90). Among the 226 long-term survivors, 80 (35%) answered the EQ-5D questionnaire. The median index value reported was 0.67 (IQR 0.40 to 1.00) indicating a noticeable alteration of quality of life. Initiation strategy for RRT had no effect on any long-term outcome., Conclusion: Severe AKI in critically ill patients was associated with a high proportion of death within the first 2 months but less so during long-term follow-up. A quarter of long-term survivors experienced a WRF and suffered from a noticeable impairment of quality of life. Renal replacement therapy initiation strategy was not associated with mortality outcome., (© 2023. The Author(s).)

Background and Aim: The efficacy and safety profiles of elbasvir-grazoprevir (EBR/GZR) has been established in more than 10 clinical trials. However, the characteristics of patients treated in routine clinical practice may differ. The present study was therefore designed to assess the real-life effectiveness of EBR/GZR therapy in the general population and among subgroups with a high hepatitis C virus (HCV) prevalence in France., Methods: The Zephyr study was designed as a French, multicentre, prospective, observational study on EBR/GZR use and effectiveness in current practice in chronic hepatitis C patients. These results are based on data regarding the adult patients who received at least one dose of EBR/GZR between December 2017 and June 2019 in 67 French hospitals and clinics., Results: Overall, 478 patients were included. The Full Analysis Set corresponded to the 467 patients who met all the inclusion criteria and none of the exclusion criteria. Gender was balanced and the mean age was 55.7 ± 13.3 years. The patients were mainly treatment-naive (89.5%) and infected with Genotype 1b (70.4%). Among the 75 patients with HCV Gt1a genotype, 56% had HCV RNA ≥ 800,000 IU/ml. F3-F4 fibrosis stage involved 24.2% of our population. Our subgroups were distributed among 110 migrants (23.6%), 58 (15.3%) using opioid agonist treatment, including people who inject drugs, 30 (6.8%) with chronic kidney disease Stages 3-5, 9 (1.9%) with an inherited blood disorder, and 4 (0.9%) coinfected with HIV. The remaining 269 (58.7%) were included in the general population subgroup. Overall, sustained virologic response 12 weeks after the end of treatment reached 98.0% and remained consistent among genotype, HCV RNA values, fibrosis stage, and the subgroup of interest. The rate of Alcohol Use Disorders Identification Test-Consumption​​​ and Life Habit questionnaire completion was high at each visit, with data suggesting alcohol consumption decrease and an improvement in quality of life., Conclusions: Using real-world evidence data on a French population representative of HCV patients, we confirmed the results obtained during EBR/GZR development program., Competing Interests: All the authors reviewed the manuscript and gave their approval for its publication. Jean‐Pierre Bronowicki, Patrick Miailhes, Bertrand Hanslik, Stéphanie Perot, Jérémy Skrzypski, Astrid de Hauteclocque, Axelle Spampinato, Philippe Mariot, Philippe Sogni had full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis. Jean‐Pierre Bronowicki reported links of interest with MSD, Gilead, Abbvie; Patrick Miailhes reported links of interest with MSD; Bertrand Hanslik has given some lectures and has participated in the advisory board for MSD; Denis Ouzan reported links of interest with Abbvie and Gilead; Dominique Larrey was invited to participate in the congress and participate as clinicians in registry study for Gilead and Abbvie; Ghassan Riachi was invited to participate in the congress by MSD, Gilead and Abbvie; Régine Truchi has given some lecture and participated in the clinical study for Abbvie, Gilead et Merck; Armand Abergel was invited to participate in the congress and to give some lectures during Post‐University Training session for MSD, Gilead, AbbVie and Ipsen, and has also participated in the advisory board for MSD, Gilead and AbbVie; Xavier Causse reported links of interest with AbbVie, Gilead, Mylan and MYR Pharmaceuticals; Stéphanie Perot and Jérémy Skrzypski worked as contracted CRO staff members for MSD France on the Zephyr Study. Astrid de Hauteclocque, Axelle Spampinato, and Philippe Mariot are employees of MSD France. Philippe Sognia reported links of interest with AbbVie, Galmed, Genfit, Gilead, Intercept Pharma, Janssen, MSD, Novo‐Nordisk, and Roche. Vincent Jouannaud and Dan Pospait reported no conflicts of interest., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background: During the COVID-19 pandemic, intensive care units (ICU) introduced restrictions to in-person family visiting to safeguard patients, healthcare personnel, and visitors., Methods: We conducted a web-based survey (March-July 2021) investigating ICU visiting practices before the pandemic, at peak COVID-19 ICU admissions, and at the time of survey response. We sought data on visiting policies and communication modes including use of virtual visiting (videoconferencing)., Results: We obtained 667 valid responses representing ICUs in all continents. Before the pandemic, 20% (106/525) had unrestricted visiting hours; 6% (30/525) did not allow in-person visiting. At peak, 84% (558/667) did not allow in-person visiting for patients with COVID-19; 66% for patients without COVID-19. This proportion had decreased to 55% (369/667) at time of survey reporting. A government mandate to restrict hospital visiting was reported by 53% (354/646). Most ICUs (55%, 353/615) used regular telephone updates; 50% (306/667) used telephone for formal meetings and discussions regarding prognosis or end-of-life. Virtual visiting was available in 63% (418/667) at time of survey., Conclusions: Highly restrictive visiting policies were introduced at the initial pandemic peaks, were subsequently liberalized, but without returning to pre-pandemic practices. Telephone became the primary communication mode in most ICUs, supplemented with virtual visits., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)

Introduction: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF., Methods and Analysis: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients., Ethics and Dissemination: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings., Trial Registration Number: NCT03098706., Competing Interests: Competing interests: EC received fees for lectures and conference talks and had travel and accommodation expenses related to attending scientific meetings covered by Gilead, Baxter and Sanofi-Genzyme., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: FRESC reanalyzed extensive-stage small-cell lung cancer (ES-SCLC) patient data from the French KBP-2010 cohort to describe the characteristics and therapeutic management of ES-SCLC and provide real-world estimates of survival., Methods: A target population of first line (1L) ES-SCLC was identified at initial diagnosis in KBP-2010 (KBP population, N = 796). A KBP-2010 subpopulation was defined as patients who also met the IMpower133 clinicaltrial PS ≤ 1 inclusion criteria (KBP-PS&#95;0/1 population, N = 394). Subgroups were defined according to the 1L ES-SCLC chemotherapy regimens: carboplatin or cisplatin with etoposide (Carb-E or Cisp-E subgroups)., Results: The vast majority of KBP populations exhibited stage IV ES-SCLC (84.9%) at initial diagnosis. Median age was 66 years; patients were mostly male and smokers. Patients receiving Cisp + Eto were younger (median age 61 years [55.0-67.0]) and fitter (25.5% had PS ≥ 2) than those receiving Carb + Eto (71 years [62.5-77.5]; 44.1%had PS ≥ 2). Median overall survival (OS) of chemotherapy-treated 1L ES-SCLC patients varied from 7.0 months [95% CI, 6.1; 7.8] in the KBPCarb-Esubgroups to 9.6 months [95% CI, 8.4;10.8] in the KBP Cisp-E subgroup. KBP-PS&#95;0/1 population showed better median OS, especially for the Cisp-E subgroup (10 months [95% CI, 8.7; 11.3])., Conclusion: In the KBP-PS&#95;0/1 population, median OS was close to the one that was found in the IMpower133 control arm. Although this needs to be confirmed by further research, it suggests the transposability of the IMpower133 results to real-life conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Studies describing the clinical features and short-term prognosis of patients admitted to the intensive care unit (ICU) for menstrual toxic shock syndrome (m-TSS) are lacking., Methods: This was a multicenter retrospective cohort study of patients with a clinical diagnosis of m-TSS admitted between 1 January 2005 and 31 December 2020 in 43 French pediatric (n = 7) or adult (n = 36) ICUs. The aim of the study was to describe the clinical features and short-term prognosis, as well as to assess the 2011 Centers for Disease and Control (CDC) diagnostic criteria, in critically ill patients with m-TSS., Results: In total, 102 patients with m-TSS (median age, 18 years; interquartile range, 16-24 years) were admitted to 1 of the participating ICUs. All blood cultures (n = 102) were sterile. Methicillin-sensitive Staphylococcus aureus grew from 92 of 96 vaginal samples. Screening for superantigenic toxin gene sequences was performed for 76 of the 92 vaginal samples positive for S. aureus (83%), and toxic shock syndrome toxin 1 was isolated from 66 strains (87%). At ICU admission, no patient met the 2011 CDC criteria for confirmed m-TSS, and only 53 (52%) fulfilled the criteria for probable m-TSS. Eighty-one patients (79%) were treated with antitoxin antibiotic therapy, and 8 (8%) received intravenous immunoglobulins. Eighty-six (84%) patients required vasopressors, and 21 (21%) tracheal intubation. No patient required limb amputation or died in the ICU., Conclusions: In this large multicenter series of patients included in ICUs for m-TSS, none died or required limb amputation. The CDC criteria should not be used for the clinical diagnosis of m-TSS at ICU admission., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The presence of bacteraemia in pneumococcal pneumonia in critically ill patients does not appear to be a strong independent prognostic factor in the existing literature. However, there may be a specific pattern of factors associated with mortality for ICU patients with bacteraemic pneumococcal community-acquired pneumonia (CAP). We aimed to compare the factors associated with mortality, according to the presence of bacteraemia or not on admission, for patients hospitalised in intensive care for severe pneumococcal CAP., Methods: This was a post hoc analysis of data from the prospective, observational, multicentre STREPTOGENE study in immunocompetent Caucasian adults admitted to intensive care in France between 2008 and 2012 for pneumococcal CAP. Patients were divided into two groups based on initial blood culture (positive vs. negative) for Streptococcus pneumoniae. The primary outcome was hospital mortality, which was compared between the two groups using odds ratios according to predefined variables to search for a prognostic interaction present in bacterial patients but not non-bacteraemic patients. Potential differences in the distribution of serotypes between the two groups were assessed. The prognostic consequences of the presence or not of initial bi-antibiotic therapy were assessed, specifically in bacteraemic patients., Results: Among 614 included patients, 274 had a blood culture positive for S. pneumoniae at admission and 340 did not. The baseline difference between the groups was more frequent leukopaenia (26% vs. 14%, p = 0.0002) and less frequent pre-hospital antibiotic therapy (10% vs. 16.3%, p = 0.024) for the bacteraemic patients. Hospital mortality was not significantly different between the two groups (p = 0.11). We did not observe any prognostic factors specific to the bacteraemic patient population, as the statistical comparison of the odds ratios, as an indication of the association between the predefined prognostic parameters and mortality, showed them to be similar for the two groups. Bacteraemic patients more often had invasive serotypes but less often serotypes associated with high case fatality rates (p = 0.003). The antibiotic regimens were similar for the two groups. There was no difference in mortality for patients in either group given a beta-lactam alone vs. a beta-lactam combined with a macrolide or fluoroquinolone., Conclusion: Bacteraemia had no influence on the mortality of immunocompetent Caucasian adults admitted to intensive care for severe pneumococcal CAP, regardless of the profile of the associated prognostic factors., (© 2021. The Author(s).)

Introduction: Streptozocin can impair renal function. The purpose of this study was to evaluate the evolution of renal function in patients receiving this anti-mitotic for the treatment of locally advanced/metastatic digestive well differentiated neuroendocrine tumours., Methods: A prospective and a retrospective cohort of patients with normal baseline renal function were analysed. The primary endpoint was the incidence of a decrease in the estimated glomerular filtration rate ≥ 25% during treatment. Secondary endpoints were the evaluation of glomerular filtration rate changes, the impact of combined nephrotoxic treatments, other toxicities, compliance, and the objective response rate., Results: After screening 142 patients, 27 were included in the prospective and 84 in the retrospective cohort. A decrease in estimated glomerular filtration rate ≥ 25% was observed in 32 patients (30%): respectively four (15.4%) and 28 patients (34.1%) among respectively 26 and 82 patients with numerous measures (P = 0.0097). Altogether, 39 patients (35%) experienced grade 1-2 renal toxicity, while no grade 3-4 occurred in the prospective and 1 occurred in the retrospective cohort. Renal toxicity was more frequent in the retrospective cohort with a less careful follow up. As best responses, objective response was achieved in 27% of patients with pancreatic primary tumours, disease control in 78.9% of patients with pancreatic primary tumours, in 87% of those with small bowel tumours and in 72.7% of patients with other primary locations., Conclusions: Strongly recommended for pancreatic NET, streptozocin is associated with frequent mild renal toxicity but low occurrence of renal impairment in patients with baseline normal renal function and under adequate hydration., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: International guidelines include early nutritional support (≤48 hour after admission), 20-25 kcal/kg/day, and 1.2-2 g/kg/day protein at the acute phase of critical illness. Recent data challenge the appropriateness of providing standard amounts of calories and protein during acute critical illness. Restricting calorie and protein intakes seemed beneficial, suggesting a role for metabolic pathways such as autophagy, a potential key mechanism in safeguarding cellular integrity, notably in the muscle, during critical illness. However, the optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding. We hypothesised that nutritional support with calorie and protein restriction during acute critical illness decreased day 90 mortality and/or dependency on intensive care unit (ICU) management in mechanically ventilated patients receiving vasoactive amine therapy for shock, compared with standard calorie and protein targets., Methods and Analysis: NUTRIREA-3 is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients receiving invasive mechanical ventilation and vasoactive amine therapy for shock and given early nutritional support according to one of two strategies: early calorie-protein restriction (6 kcal/kg/day-0.2-0.4 g/kg/day) or standard calorie-protein targets (25 kcal/kg/day, 1.0-1.3 g/kg/day) at the acute phase defined as the first 7 days in the ICU. We will include 3044 patients in 61 French ICUs. Two primary end-points will be evaluated: day 90 mortality and time to ICU discharge readiness. The trial will be considered positive if significant between-group differences are found for one or both alternative primary endpoints. Secondary outcomes include hospital-acquired infections and nutritional, clinical and functional outcomes., Ethics and Dissemination: The NUTRIREA-3 study has been approved by the appropriate ethics committee. Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT03573739., Competing Interests: Competing interests: JR had travel and accommodation expenses to attend scientific meetings covered by Baxter and Fresenius., (© 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.)

Background: Vascular access for renal replacement therapy (RRT) is routine question in the intensive care unit. Randomized trials comparing jugular and femoral sites have shown similar rate of nosocomial events and catheter dysfunction. However, recent prospective observational data on RRT catheters use are scarce. We aimed to assess the site of RRT catheter, the reasons for catheter replacement, and the complications according to site in a large population of critically ill patients with acute kidney injury., Patients and Methods: We performed an ancillary study of the AKIKI study, a pragmatic randomized controlled trial, in which patients with severe acute kidney injury (KDIGO 3 classification) with invasive mechanical ventilation, catecholamine infusion or both were randomly assigned to either an early or a delayed RRT initiation strategy. The present study involved all patients who underwent at least one RRT session. Number of RRT catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected., Results: Among the 619 patients included in AKIKI, 462 received RRT and 459 were finally included, with 598 RRT catheters. Femoral site was chosen preferentially (n = 319, 53%), followed by jugular (n = 256, 43%) and subclavian (n = 23, 4%). In multivariate analysis, continuous RRT modality was significantly associated with femoral site (OR = 2.33 (95% CI (1.34-4.07), p = 0.003) and higher weight with jugular site [88.9 vs 83.2 kg, OR = 0.99 (95% CI 0.98-1.00), p = 0.03]. Investigator site was also significantly associated with the choice of insertion site (p = 0.03). Cumulative incidence of catheter replacement did not differ between jugular and femoral site [sHR 0.90 (95% CI 0.64-1.25), p = 0.67]. Catheter dysfunction was the main reason for replacement (n = 47), followed by suspected infection (n = 29) which was actually seldom proven (n = 4). No mechanical complication (pneumothorax or hemothorax) occurred., Conclusion: Femoral site was preferentially used in this prospective study of RRT catheters in 31 French intensive care units. The choice of insertion site depended on investigating center habits, weight, RRT modality. A high incidence of catheter infection suspicion led to undue replacement.

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of hepatocellular carcinoma (HCC) published in March 2019., Method: It is a collaborative work under the auspices of most of the French medical societies involved in the management of HCC. It is based on the previous guidelines published in 2017. Recommendations are graded in 3 categories according to the level of evidence of data found in the literature., Results: The diagnosis and staging of HCC is essentially based on clinical, biological and imaging features. A pathological analysis obtained by a biopsy of tumoral and non-tumoral liver is recommended. HCCs can be divided into 2 groups, taking into account not only the tumor stage, but also liver function. HCCs accessible to curative treatments are tumors that are in Milan criteria or with an AFP score ≤ 2, mainly treated by surgical resection, local ablation or liver transplantation. Intermediate and advanced HCCs with no liver insufficiency, accessible only to palliative treatments, benefit from TACE, SIRT or systemic therapy according to the presence or absence of macrovascular invasion or extrahepatic spread., Conclusion: Such recommendations are in permanent optimization and each individual case must be discussed in a multidisciplinary expert board., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction: In intensive care unit (ICU), the decision of extubation is a critical time because mortality is particularly high in case of reintubation. To reduce that risk, guidelines recommend to systematically perform a spontaneous breathing trial (SBT) before extubation in order to mimic the postextubation physiological conditions. SBT is usually performed with a T-piece disconnecting the patient from the ventilator or with low levels of pressure-support ventilation (PSV). However, work of breathing is lower during PSV than during T-piece. Consequently, while PSV trial may hasten extubation, it may also increase the risk of reintubation. We hypothesise that, compared with T-piece, SBT performed using PSV may hasten extubation without increasing the risk of reintubation., Methods and Analysis: This study is an investigator-initiated, multicentre randomised controlled trial comparing T-piece vs PSV for SBTs in patients at high risk of reintubation in ICUs. Nine hundred patients will be randomised with a 1:1 ratio in two groups according to the type of SBT. The primary outcome is the number of ventilator-free days at day 28, defined as the number of days alive and without invasive mechanical ventilation between the initial SBT (day 1) and day 28. Secondary outcomes include the number of days between the initial SBT and the first extubation attempt, weaning difficulty, the number of patients extubated after the initial SBT and not reintubated within the following 72 hours, the number of patients extubated within the 7 days following the initial SBT, the number of patients reintubated within the 7 days following extubation, in-ICU length of stay and mortality in ICU, at day 28 and at day 90., Ethics and Dissemination: The study has been approved by the central ethics committee 'Ile de France V' (2019-A02151-56) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT04227639., Competing Interests: Competing interests: AWT reports financial support (payment for lectures and travel expenses coverage to attend scientific meetings) by Fisher & Paykel, Covidien, Maquet—Getinge, GE Healthcare. J-PF reports consulting fees from Fisher & Paykel and SOS oxygène., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report the case of a 13-year-old young lady with a one year reccuring bullous dermatitis history for which the diagnostic hypothesis of dermatitis arterfacta was made. This hypothesis was made by the pathologist, without it being suggested by the dermatologist, after observing singular histological lesions coresponding to a cutaneous blister associated with epidermic necrosis with multinucleated keratinocytes. When dermatitis artefacta is suspected, a biopsy is usually conducted to rule out differential diagnosis such as auto-immmune dermatitis when there is a blister. Confession from patients is rarely obtained. Therefore, having positive histogical clues for dermatitis artefacta would be of a great use to help making the diagnosis in difficult cases., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: Immunoglobulin replacement therapy (IgRT) is increasingly used in secondary immunodeficiency (SID) related to hematological malignancies (HM) to prevent infections. Study's objective was to document prospectively the efficacy and safety of IgRT in patients with HM-associated SID., Methods: Non-interventional, prospective French longitudinal study., Results: One-hundred and sixty patients starting IgRT for HM-associated SID (myeloma: 54 cases, chronic lymphoid leukemia: 54, aggressive non-Hodgkin B-cell lymphoma: 19, indolent non-Hodgkin B-cell lymphoma: 29, and Hodgkin disease: 4. entered an observational, prospective, longitudinal study and were followed-up for 8.7 ± 4.0 months. Seventeen patients died (five within the context of sepsis). Compared to baseline, IgRT increased serum immunoglobulin levels by 3.4 ± 2.4 g/L and decreased frequency and severity of infections. Treatment was discontinued in 9% of patients, stopped for futility in 31%, temporally interrupted in 8%, suspended during summertime in 14% and pursued without interruption in 38% of patients., Conclusion: Our data confirm the efficacy of IgRT in reducing the risk of infections in HM-associated SID therefore fulfilling physicians' main expectations. They also illustrate the heterogeneity of management policies within the community setting.

Objective: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC)., Methods: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here., Results: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed., Conclusion: Although pazopanib prolonged PFS, this was not associated with improvement in median OS., Clinical Trial Information: ClinicalTrials.gov: NCT00866697., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

SUMOylation is a highly conserved and dynamic post-translational mechanism primarily affecting nuclear programs for adapting organisms to stressful challenges. Alteration of SUMOylation cycles leads to severe developmental and homeostatic defects and malignancy, but signals coordinating SUMOylation are still unidentified. The adrenal cortex is a zonated endocrine gland that controls body homeostasis and stress response. Here, we show that in human and in mouse adrenals, SUMOylation follows a decreasing centripetal gradient that mirrors cortical differentiation flow and delimits highly and weakly SUMOylated steroidogenic compartments, overlapping glomerulosa, and fasciculata zones. Activation of PKA signaling by acute hormonal treatment, mouse genetic engineering, or in Carney complex results in repression of small ubiquitin-like modifier (SUMO) conjugation in the inner cortex by coordinating expression of SUMO pathway inducers and repressors. Conversely, genetic activation of canonical wingless-related integration site signaling maintains high SUMOylation potential in the outer neoplastic cortex. Thus, SUMOylation is tightly regulated by signaling pathways that orchestrate adrenal zonation and diseases.-Dumontet, T., Sahut-Barnola, I., Dufour, D., Lefrançois-Martinez, A.-M., Berthon, A., Montanier, N., Ragazzon, B., Djari, C., Pointud, J.-C., Roucher-Boulez, F., Batisse-Lignier, M., Tauveron, I., Bertherat, J., Val, P., Martinez, A. Hormonal and spatial control of SUMOylation in the human and mouse adrenal cortex.

Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: To assess glomerular filtration rate in the early phase of acute circulatory failure by measuring iohexol plasma clearance., Design: Interventional prospective multicentric study., Setting: Three French ICUs in tertiary teaching hospitals., Patients: Patients with acute circulatory failure within 12 hours after ICU admission., Interventions: IV administration of a nontoxic 5-mL dose of iohexol. Collection of nine arterial blood samples over 24 hours for iohexol plasma concentration measurements. Iohexol clearance calculation with a population pharmacokinetic model. Iohexol clearance was an estimation of the mean glomerular filtration rate over 24 hours., Measurements and Main Results: Among 99 included patients, we could calculate iohexol clearance for 85. The median iohexol clearance was 31 mL/min (interquartile range, 16-44). According to iohexol clearance, 41 patients (48%) had severe hypofiltration (clearance, < 30 mL/min), 29 (34%) had moderate hypofiltration, and 10 (12%) had mild hypofiltration (clearance, 30-60 and 60-90 mL/min, respectively). Four patients (5%) had normal glomerular filtration rate, and only one (1%) showed hyperfiltration (clearance, > 130 mL/min). Urinary creatinine clearance underestimated renal impairment in one patient out of two; the bias of iohexol clearance toward 24-hour urinary creatinine clearance over the same period was -18.1 mL/min (limits of agreement, -73.5 to 37.4)., Conclusions: We demonstrated the feasibility of iohexol clearance measurement in unstable critically ill patients. Normal kidney function is exceptional during the early phase of acute circulatory failure. Glomerular filtration rate estimation by urinary creatinine clearance frequently fails to detect renal impairment. Hyperfiltration is very infrequent.

Background: Although nebulizing beta 2-agonists during noninvasive ventilation (NIV) could prove helpful, this administration route has to date never been studied in unstable chronic obstructive pulmonary disease (COPD) patients. We sought to demonstrate that salbutamol could be nebulized through an NIV circuit in COPD exacerbation and improve forced expiratory volume in 1 second (FEV1) as compared with placebo. Patient and Methods: This is a bench study to determine the optimal pattern of nebulization followed by a randomized double-blind parallel-group trial comparing salbutamol and placebo aerosols delivered during NIV to 43 intensive care unit patients. Aerosols were generated by a vibrating mesh nebulizer positioned just after the Y-piece. Spirometry was performed immediately before and at several predetermined time points after nebulization. Clinical and biological safety parameters were recorded. Results: We failed to demonstrate a difference between salbutamol and placebo when changes in FEV1 were assessed immediately after nebulization (-20 vs. -35 mL, p  = 0.66). However, FEV1 increased significantly from baseline to 40 minutes after the end of salbutamol nebulization, as compared with placebo (+30 vs. -50 mL, p  = 0.04). Nebulization was well tolerated. Conclusion: When assessing FEV1 changes 40 minutes after the end of 5 mg salbutamol nebulization in patients undergoing NIV, we observed a slight improvement that was statistically significant compared with the changes observed with an equivalent saline volume.

Purpose: To assess the relative importance of host and bacterial factors associated with hospital mortality in patients admitted to the intensive care unit (ICU) for pneumococcal community-acquired pneumonia (PCAP)., Methods: Immunocompetent Caucasian ICU patients with PCAP documented by cultures and/or pneumococcal urinary antigen (UAg Sp) test were included in this multicenter prospective study between 2008 and 2012. All pneumococcal strains were serotyped. Logistic regression analyses were performed to identify risk factors for hospital mortality., Results: Of the 614 patients, 278 (45%) had septic shock, 270 (44%) had bacteremia, 307 (50%) required mechanical ventilation at admission, and 161 (26%) had a diagnosis based only on the UAg Sp test. No strains were penicillin-resistant, but 23% had decreased susceptibility. Of the 36 serotypes identified, 7 accounted for 72% of the isolates, with different distributions according to age. Although antibiotics were consistently appropriate and were started within 6 h after admission in 454 (74%) patients, 116 (18.9%) patients died. Independent predictors of hospital mortality in the adjusted analysis were platelets ≤ 100 × 10 9 /L (OR, 7.7; 95% CI, 2.8-21.1), McCabe score ≥ 2 (4.58; 1.61-13), age > 65 years (2.92; 1.49-5.74), lactates > 4 mmol/L (2.41; 1.27-4.56), male gender and septic shock (2.23; 1.30-3.83 for each), invasive mechanical ventilation (1.78; 1-3.19), and bilateral pneumonia (1.59; 1.02-2.47). Women with platelets ≤ 100 × 10 9 /L had the highest mortality risk (adjusted OR, 7.7; 2.8-21)., Conclusions: In critically ill patients with PCAP, age, gender, and organ failures at ICU admission were more strongly associated with hospital mortality than were comorbidities. Neither pneumococcal serotype nor antibiotic regimen was associated with hospital mortality.

Purpose: The aim of the study was to investigate the management and prognosis of Pure primary squamous cell carcinoma (PPSCC) of the breast., Materials and Methods: This study is a multicentre retrospective cohort from three French tertiary referral hospitals (Rennes, Orléans and Tours) including all women treated for a PPSCC of the breast defined by squamous cells that could contain a minority of sarcomatoid component. We excluded carcinomas with a ductual component. Clinicopathologic, radiological and therapeutic patterns were described. Demographic, histological and therapeutic characteristics were compared to a population of women with triple negative invasive breast carcinomas., Results: Twelve patients were included, with a mean age of 71.6 years. All lesions were unifocal, with a cystic complex ultrasound mass in 50% of cases. Mean tumor size was 43mm, with axillary lymph node metastasis in 25% of patients. The comparison with a population of women with triple negative breast carcinomas revealed that women with PPSCC were older (71 versus 57 years, p=0.003), tumor size was larger (43mm versus 25mm, p=0.032) and local recurrence occurred earlier (three months versus 38 months, p=0.014)., Conclusion: PPSCC is a rare entity with a worse prognosis in comparison with triple negative invasive carcinoma., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: To describe the characteristics of patients suffering from secondary immunodeficiencies (SID) associated with hematological malignancies (HM), who started immunoglobulin replacement therapy (IgRT), physicians' expectations regarding IgRT, and IgRT modalities., Methods: Non-interventional, prospective French cross-sectional study., Results: The analysis included 231 patients (66 ± 12 years old) suffering from multiple myeloma (MM) (N = 64), chronic lymphoid leukemia (CLL) (N = 84), aggressive non-Hodgkin B-cell lymphoma (aNHL) (N = 32), indolent NHL (N = 39), acute leukemia (N = 6), and Hodgkin disease (N = 6). Of the HM, 47% were currently treated, 42% were relapsing or refractory, 23% of patients had received an autologous hematopoietic stem-cell transplant, and 1% had received an allograft. Serum immunoglobulin trough levels in 195 individuals were less than 5 g/L in 68.7% of cases. Most patients had a history of recurrent infections. Immunoglobulin dose was about 400 mg/kg/mo. Half of patients started with subcutaneous infusion. When starting IgRT, physicians mainly expected to prevent severe and moderate infections. They also anticipated improvement in quality of life and survival which is beyond evidence-based medicine., Conclusion: NHL is a frequent condition motivating IgRT besides well-recognized indications. Physicians mainly based the decision of starting IgRT on hypogammaglobulinemia and recurrence of infections but, irrespective of current recommendations, were also prepared to start IgRT prophylactically even in the absence of a history of infections., (© 2018 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.)

Rationale: The optimal strategy for initiation of renal replacement therapy (RRT) in patients with severe acute kidney injury in the context of septic shock and acute respiratory distress syndrome (ARDS) is unknown., Objectives: To examine the effect of an early compared with a delayed RRT initiation strategy on 60-day mortality according to baseline sepsis status, ARDS status, and severity., Methods: Post hoc analysis of the AKIKI (Artificial Kidney Initiation in Kidney Injury) trial., Measurements and Main Results: Subgroups were defined according to baseline characteristics: sepsis status (Sepsis-3 definition), ARDS status (Berlin definition), Simplified Acute Physiology Score 3 (SAPS 3), and Sepsis-related Organ Failure Assessment (SOFA). Of 619 patients, 348 (56%) had septic shock and 207 (33%) had ARDS. We found no significant influence of the baseline sepsis status (P = 0.28), baseline ARDS status (P = 0.94), and baseline severity scores (P = 0.77 and P = 0.46 for SAPS 3 and SOFA, respectively) on the comparison of 60-day mortality according to RRT initiation strategy. A delayed RRT initiation strategy allowed 45% of patients with septic shock and 46% of patients with ARDS to escape RRT. Urine output was higher in the delayed group. Renal function recovery occurred earlier with the delayed RRT strategy in patients with septic shock or ARDS (P < 0.001 and P = 0.003, respectively). Time to successful extubation in patients with ARDS was not affected by RRT strategy (P = 0.43)., Conclusions: Early RRT initiation strategy was not associated with any improvement of 60-day mortality in patients with severe acute kidney injury and septic shock or ARDS. Unnecessary and potentially risky procedures might often be avoided in these fragile populations. Clinical trial registered with www.clinicaltrials.gov (NCT 01932190).

Background: The aim of ESCAP-2011-CPHG, promoted by the French College of General Hospital Respiratory Physicians, was to describe therapeutic strategies in lung cancer in the first 2 years after diagnosis, in a real-life setting. This article focuses on patients undergoing surgical management of a non-small cell lung cancer (NSCLC)., Methods: A prospective multicentre study was conducted in 53 French general hospitals. For each patient with lung cancer diagnosed in 2010, a standardised form was completed following each change in treatment strategy up to 2 years after diagnosis., Results: Overall, 3418 of the 3943 included patients had NSCLC. 741 patients (21.7%) underwent curative surgery (stage 0-II, IIIA, IIIB, and IV: 65%, 27%, 3% and 5%, respectively). The therapeutic strategy changed less often in surgical than non-surgical patients and average follow-up time was longer: 23.3 months (SD: 9.3) versus 10.4 months (SD: 9.5) for non-surgical patients. Among patients with a surgical first strategy (92.6% of surgical patients as a whole), 56.9% did not receive any other treatment, 34.7% received chemotherapy, 5.9% radio-chemotherapy, 2.6% radiotherapy. At the end of follow-up, 55.8% were still alive without any other strategy, 13.1% had died, and 31.1% had received at least one more strategy. Among patients with a surgical second strategy, 63% had received chemotherapy alone during the first strategy., Conclusions: ESCAP -2011- CPHG assessed everyday professional practice in the surgical management of NSCLC in general hospitals. It pointed out the discrepancies between current guidelines and the therapeutic strategies applied in real life conditions., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Koebner phenomenon (KP) affects from a quarter to a third of the patients with psoriasis and can occur on tattoos MATERIAL AND METHODS: We retrospectively reviewed a case series of seven tattooed patients with an isomorphic response on their tattoos or partial psoriasis patches on their tattoos. We collected the demographic data, the past history of psoriasis, the clinical presentation, and the outcomes. We also performed a review of the literature. We tried to classify the different clinical profile of KP/psoriasis on tattoos accordingly., Results: Six men and one woman with a median age of 36 ± 6.4 years old were included. Five disclosed a KP in a recent tattoo within days to 1 month after its completion. Fifteen additional cases were collected from the literature (8 men, median age 22 ± 8.2 years old). The delay of psoriasis flare-up after tattooing was rather short, from a few weeks to several months. We found a high variability in the clinical presentation with five clinical subtypes/profiles of psoriasis on tattoos. A possible confusion between "genuine" KP on tattoos and the coincidental occurrence of psoriasis patches on tattoos is possible in some cases of the literature. Patients were mainly managed locally, rarely by systemic treatments or biologics., Conclusion: Koebner phenomenon on tattoos may occur in patients with psoriasis under various forms. The evolution is benign, and psoriasis is not a contraindication for tattooing, but patients need proper counseling before getting tattooed., (© 2017 The International Society of Dermatology.)

Background: Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC., Patients and Methods: All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded., Results: 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72)., Conclusions: We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization., Methods: We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria., Results: There were 143 patients randomized: 71 to the AFIS group, and 72 to the placebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo., Conclusions: In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden., Trial Registry: ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy., Methods: In this randomised, controlled, open-label trial, we enrolled patients aged 18-75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (< or ≥2·25 log 10 IU/mL) to allocate patients (1:1) to receive a 48 week course of subcutaneous injections of 180 μg per week of pegylated interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392., Findings: Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] to pegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analogues group from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI -2·6 to 12·5]; p=0·15). 85 (94%) of 90 patients started pegylated interferon, three (4%) of whom had a dose reduction and 17 (20%) had an early discontinuation of pegylated interferon (seven [41%] for serious adverse events). Grade 3 and 4 adverse events were more frequent in the pegylated interferon plus nucleos(t)ide analogues group (26 [29%] grade 3 adverse events; 19 [21%] grade 4 adverse events) than in the nucleos(t)ide analogues-alone group (three [3%] grade 3; six [6%] grade 4)., Interpretation: Addition of a 48 week course of pegylated interferon to nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B with undetectable HBV DNA for a least 1 year was poorly tolerated and did not result in a significant increase of HBsAg clearance., Funding: Institut national de la santé et de la recherche médicale-Agence nationale de recherches sur le sida et les hépatites virales (France Recherche Nord&sud Sida-vih Hepatites)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)