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Impact of midostaurin in younger AML patients intensively treated with high-dose anthracycline
No full textInternational audienceIntroduction: Midostaurin (MIDO) was approved by the FDA in 04/2017 for the treatment of FLT3 mutated AML patients in combination with intensive chemotherapy (ICT) with daunorubicin (DAUNO) administered at 60 mg/m² for 3 days based on the findings of the RATIFY trial (Stone, NEJM 2017). Moreover, the UK NCRI AML17 trial (Burnett, Blood 2016) demonstrated that higher DAUNO exposure at 90 mg/m² (without MIDO) provided a particular benefit for patients with FLT3 mutated AML. The aim of this post-hoc study was to assess the impact of MIDO in combination with higher-dose anthracyclines (DAUNO or idarubicin) in the BIG-1 trial (Hunault, NEJM Ev 2025). Methods: Between 01/2015 and 07/2021, the BIG-1 trial (NCT02416388) included patients (pts) aged 18-60 years with newly diagnosed AML treated with ICT (CBF-AML and APL excluded). DNA fragment analysis (FA) detected FLT3-ITD (AR≥0.05 for positivity) and FLT3-TKD mutations were detected depending on each center's usual procedures. The protocol planned single and first induction cycle containing anthracycline. Pts may receive either DAUNO (90 mg/m², d1-3) or idarubicin (9 mg/m², d1-5), combined with cytarabine 200 mg/m² (d1-7). After its approval, MIDO has been introduced in 07/2018 during the course of the trial and provided by Novartis. This offered the opportunity to assess the role of MIDO in this context using an internal control group. Of note, MIDO was omitted during the post-induction cycles in the few pts who entered nested randomized studies evaluating dexamethasone (N=46) or vosaroxin (N=13) in combination with HDAC or IDAC, respectively. Results: Overall, 382 (84.7%) pts had FLT3-ITD, 83 (18.4%) had a TKD mutation and 14 had both, leading to the inclusion of 451 pts in this analysis. 282 (62.5%) pts received ICT without MIDO (ICT group: internal control) and 169 (37.4%) received ICT with MIDO (ICT+MIDO group). Median age was 50.1y and 263 pts were female. ELN-2022 genetic risk was favorable, intermediate and adverse in 49 (10.9%), 319 (70.7%) and 77 (17.1%) pts. 302 (67%) pts carried also a NPM1 mutation without significant differences between the two groups. Following induction, the rate of CR/CRi was 77.3% vs 88.7% in ICT vs ICT+MIDO groups (p=0.002), respectively. Early death rate at d30 was 4.3% vs 1.2% (p=0.006). After adjustment on confounding factors including allo-HSCT in CR1 as a time-dependent variable in multivariate analysis, MIDO was significantly and independently associated with a decreased risk of relapse (sHR 0.63 [0.46-0.85]; P=0.003). At 2 and 5 years, cumulative incidence of relapse (CIR) was 43.6% vs 35% and 48.1% vs 40.9%, in the ICT and ICT+MIDO group respectively. The two other independent predictive factors for relapse were ELN-2022 genetic risk and allo-SCT in CR1 as protective factor. Anthracycline, gender, age and WBC did not significantly influence CIR. MIDO was also significantly and independently associated with a decreased risk of death or relapse (aHR 0.74 [0.55-0.98]; P=0.036), as well as ELN-2022 genetic risk and allo-SCT in CR1. At 2 and 5 years, RFS was 49.7% vs 55.4% and 42.5% vs 46.4%, in the ICT and ICT+MIDO group respectively. Again, anthracycline, gender, age and WBC did not significantly influence RFS. MIDO was significantly and independently associated with a decreased risk of death, relapse or failure (aHR: 0.65 [0.50-0.84]; P=0.001), as well as WBC, ELN-2022 genetic risk and allo-SCT in CR1. At 2 and 5 years, EFS was 43.3% vs 54.2% and 37.6% vs 44%, in ICT and ICT+MIDO groups respectively. Anthracycline, gender and age did not significantly influence EFS. Finally, MIDO was significantly and independently associated with a decreased risk of death (aHR: 0.70 [0.50-0.96]; P=0.02), as well as WBC, age and ELN-2022 genetic risk but neither allo-HSCT in CR1, nor sex, nor the type of anthracycline was associated with OS. At 2 and 5 years, OS was 62.8% vs 73.2% and 52.8% vs 62%, in ICT and ICT+MIDO group respectively. Conclusion: Subject to the limitations of this non-randomized study, adding MIDO to high-dose anthracycline-based chemotherapy improves CIR, RFS, EFS and OS independently of other factors, resulting in notable 5-year cure rates
Intravenous thrombolysis use in the late time-window before interhospital transfer for thrombectomy: Association with efficacy and safety outcomes
No full textInternational audiencemportance: In patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO), the benefit of intravenous thrombolysis (IVT) administered beyond 4.5 hours from the last time known well before endovascular therapy (EVT) is uncertain. Recently, the TIMELESS trial failed to demonstrate a benefit of IVT in this setting, but this trial focused on patients directly admitted to comprehensive stroke centers (CSCs) with fast access to EVT.Objective: To assess the efficacy and safety of IVT initiated beyond 4.5 hours in patients with AIS-LVO initially admitted to primary stroke centers (PSCs) and subsequently transferred to a CSC for EVT, allowing substantial time for the IVT to take effect.Design, setting, and participants: This multicenter retrospective cohort study was conducted between January 2020 and December 2024, with 3-month follow-up, at 20 French PSCs. All consecutive patients with AIS-LVO admitted beyond 4.5 hours from the last time they were known well in the PSC and subsequently transferred to a CSC for EVT, with or without IVT administered prior to transfer, were eligible for inclusion. Data analysis was performed between May 2025 and July 2025.Main outcomes and measures: The primary outcome was the 3-month modified Rankin Scale score, analyzed in the ordinal approach. Propensity score with overlap weighting (PSOW) balanced covariates between patients treated with IVT vs those without.Results: A total of 584 patients were included, among whom 309 patients (52.9%) were female. Median (IQR) age was 71 (61-81) years, median (IQR) baseline National Institutes of Health Stroke scale score was 15 (10-19), median (IQR) time from last known well to PSC imaging was 10.5 (6.9-14.0) hours, and 232 patients (39.7%) received IVT before transfer. Advanced brain imaging (magnetic resonance imaging or computed tomography [CT] with CT-perfusion) was performed at the PSC in 544 patients (93.2%). IVT use before transfer was independently associated with a shift toward better 3-month outcomes (PSOW-common odds ratio [OR], 1.97; 95% CI, 1.33-2.92; P = .001) and higher odds of recanalization during transfer (PSOW-OR, 8.69; 95% CI, 3.16-23.87; P < .001) compared with those without. The rate of any intracerebral hemorrhage and symptomatic intracerebral hemorrhage were similar between groups.Conclusions and relevance: In this multicenter cohort study, IVT initiated beyond 4.5 hours prior to interhospital transfer for EVT was associated with higher rates of recanalization during transfer and improved 3-month functional outcomes, without safety concerns. These findings offer encouraging support for clinical trials evaluating IVT in the late time window before interhospital transfer
Evaluation of a pro-recovery training intervention (REFOCUS-RETAFORM) in specialist mental health services across France: stepped-wedge cluster randomised controlled trial protocol
No full textInternational audienceBackground: While recovery orientation is national policy in many countries, evidence remains limited for the effectiveness at a service level. This paper describes the protocol for implementing a pro-recovery training intervention (REFOCUS-RETAFORM) in specialist mental health services across France. The aim is to evaluate whether REFOCUS-RETAFORM plus usual care leads to improved outcomes for adolescent and adult mental health service users compared with usual care alone.Methods: A two-step stepped wedge cluster randomised controlled trial will be conducted, with a nested qualitative sub-study exploring stakeholders' views on changes in staff-user relationships and implementation influences. The REFOCUS-RETAFORM intervention is a training intervention for mental health staff, to develop recovery-promoting relationships and pro-recovery working practices. Clusters are services, which transition sequentially from control to intervention condition in a randomised order. Eight clusters are randomised to deliver REFOCUS-RETAFORM in year one and eight clusters in year two. Each cluster delivers REFOCUS-RETAFORM to two teams from their organisation (32 teams in total). Participants are a) service users aged 13-65 years attending services implementing REFOCUS-RETAFORM, and b) staff receiving the intervention. The primary outcome is the Questionnaire about the Process of Recovery. Secondary outcomes include perceived stigma and coercion, self-stigma and wellbeing for service users, and recovery-orientation for staff. Data will be collected from 540 service users (180 at baseline, 180 at month 12, 180 at month 24) and 220 staff. We will use multilevel mixed-effects models, adjusting for secular trends and thematic analysis for the qualitative interview data.Discussion: Findings will inform the continued transformation of French specialist mental health services toward a recovery orientation.Trial registration: Clinical Trials NCT05824234, registered 21 April 2023
Temporal stability of inflammatory subphenotypes of acute respiratory distress syndrome: 28-day insights from the ICAR trial
No full textInternational audienceBackgroundInternational guidelines have emphasized the necessity of evaluating the temporal stability of acute respiratory distress syndrome (ARDS) subphenotypes. This study aimed to assess the temporal stability of subphenotypes of ARDS over 28 days.MethodsA reanalysis of a randomized trial was conducted, including patients with COVID-19-related moderate-to-severe ARDS across 43 centers. A K-means clustering was conducted to identify subphenotypes at 7-day intervals from inclusion to day 28. A Bayesian discrete-time Markov model was constructed to assess the temporal stability of subphenotypes.ResultsTwo subphenotypes were identified among 146 patients. At inclusion, 121 (83%) patients were in the hypoinflammatory subphenotype and 25 (17%) in the hyperinflammatory subphenotype. The hyperinflammatory subphenotype was associated with higher rates of organ failure, higher plasma levels of cytokines, chemokines, adhesion molecules, and proangiogenic factors, and lower endothelial stability than the hypoinflammatory subphenotype. The hyperinflammatory subphenotype was associated with higher 28-day mortality (13/25, 52% vs. 30/121, 25%, p = 0.001) and fewer ventilatory-free-days through day 28 (p < 0.01) than the hypoinflammatory subphenotype. In the Bayesian Markov model, over 7-day intervals, patients in the hypoinflammatory subphenotype had a higher probability of remaining hypoinflammatory (70%) or being extubated (17%) than of progressing to the hyperinflammatory subphenotype (7%). Inversely, patients in the hyperinflammatory subphenotype had a higher probability of remaining in the hyperinflammatory subphenotype (52%) or dying (23%) than of transitioning to the hypoinflammatory subphenotype (20%) or being extubated (5%).ConclusionsInflammatory subphenotypes were stable in COVID-19-related ARDS, with few transitions over 28 days. Monitoring these subphenotypes could be valuable for assessing patient trajectories and treatment responses
Anti-interleukines 17 : taux de maintien, efficacité, et tolérance dans le psoriasis de l’enfant. Cohorte internationale rétrospective en vie courante
No full textInternational audienceIntroductionLe psoriasis sévère, justifiant un traitement systémique, touche 10 à 20 % des enfants souffrant d’un psoriasis. Les biothérapies, utilisées le plus souvent après échec d’un traitement systémique conventionnel, ont transformé leur prise en charge. L’efficacité de ces biothérapies a été évaluée dans des essais thérapeutiques sur de faibles effectifs, souvent moins de 50 enfants. Les données en vie courante sur de plus grands effectifs sont nécessaires pour mieux appréhender leur place dans l’arsenal thérapeutique. Le taux de maintien comparatif, l‘efficacité, la tolérance ont été évalués pour l’étanercept, l’adalumimab et l’ustékinumab dans les cohortes BiPe, réalisées avant l’arrivée des anti-interleukines 17 (Il17), sécukinumab (SECU) et ixékizumab (IXE).La cohorte Secu-Ped est une cohorte rétrospective visant à évaluer les anti-Il17 en vie courante dans le psoriasis de l’enfant : taux de maintien, efficacité, et tolérance.Matériel et méthodesCohorte rétrospective internationale (France, Italie, Portugal, Espagne, Pays-Bas, Argentine, et Maroc) dans laquelle étaient inclus tous les enfants (<18 ans) recevant un anti-Il17 pour un psoriasis cutané en dehors d’essais thérapeutiques. Inclusions de janvier à mai 2025. L’efficacité était évaluée sur le taux de Physician Global Assessment (PGA) 0–1 et la réduction du Psoriasis Area and Severity Index (PASI) de 75 et 90 % (PASI75 et 90) au troisième mois (M3). Seuls les évènements indésirables (EI) imputés par l’investigateur au traitement étaient retenus.RésultatsAu total, 152 enfants (âge moyen : 12,9 ± 3,4 ans ; filles : 54 % ; psoriasis en plaques : 58 % ; rhumatisme psoriasique : 9,9 %) ont été inclus dans 36 centres. Ils ont reçu 160 traitements : SECU : n = 139 ; IXE : n = 21. Le taux de maintien à 2 ans était supérieur pour le SECU (75 %) vs IXE (50 %) (p = 0,036) ; une tendance se dessinait pour un meilleur maintien chez les enfants bionaïfs avant introduction d’une 1ère cure de SECU (p = 0,10), mais il n’y avait pas de différences en fonction des groupes de poids.Le taux de PGA0-1 à M3 était de 58 % et 92 % pour le SECU et l’IXE respectivement, de PASI75 : 45 vs 70 %, et de PASI90 : 32 % et 60%.Les principaux EI étaient pour le SECU : eczéma (n = 5), candidose, exacerbation de psoriasis, bronchite, et rhinite (n = 3), et pour l’IXE : douleur au point d’injection (n = 4), rhinite, asthénie, nausées, et eczéma (n = 2)DiscussionCette cohorte internationale en vie courante d’enfants psoriasiques montre un taux de maintien supérieur pour le SECU que pour l’IXE et un niveau d’efficacité (PGA, PASI75/90) inférieur à celui rapporté dans les essais publiés. La fréquence des EI était très faible avec notamment des eczémas, rhinites sous anti-Il17, des douleurs aux points d’injection pour l’IXE, et des candidoses et exacerbation du psoriasis pour le SECU.ConclusionCes cohortes en vie courante sont indispensables afin de mieux apprécier la place respective des différents traitements dans le psoriasis de l’enfant
Cold Agglutinin Syndrome Secondary to Mycoplasma pneumoniae Infection in Adults: Results From a Large French Observational Study (MyCOLD Study)
No full textInternational audienceMycoplasma pneumoniae (MP), primarily a respiratory pathogen, can cause extra-pulmonary manifestations including cold agglutinin syndrome (CAS). We conducted a national, multicenter, observational, ambispective study to describe the characteristics, risk factors, and outcomes of MP-associated CAS. Adult patients hospitalized for a MP-infection with CAS (hemolytic anemia with hemoglobin < 10 g/dL and C3 positive direct anti-globulin test) were included. Recovery was defined as hemoglobin > 10 g/dL off therapy. We also compared MP-infected patients with or without CAS. Sixty patients (51.7% of females; median age of 48.5 years) were included. CAS was diagnosed a median of 10 days after MP-infection symptoms onset. At diagnosis, the median hemoglobin level was 6.9 g/dL, and 71.7% of patients received red blood cell transfusions. Intensive care unit (ICU) admission was required in 45% of patients, and 16.7% experienced a venous thromboembolic event (VTE). Seventeen patients (28.3%) received glucocorticoids alone, while 40 (66.7%) did not receive any specific treatment for CAS. After a median follow-up of 56 (30–83) days, 90% of patients achieved recovery, while 2 patients (3.3%) died from sepsis and pulmonary embolism. Glucocorticoid use did not significantly impact the rate or timing of recovery. Compared with MP-infected patients from the MYCADO cohort study (n = 1267), CAS patients had significantly more VTE (p < 0.0001) and ICU admissions (p = 0.03). MP-associated CAS typically occurs 10 days after the first symptoms of MP infection and is associated with ICU admissions and VTE. Overall, the prognosis of CAS is good, and glucocorticoids do not appear to influence outcomes
Sensory plasticity of dorsal horn silent neurons: a critical mechanism for neuropathic pain
No full textInternational audienceThe spinal cord dorsal horn (DH) integrates and modulates sensory processing but undergoes critical plasticity following nerve injury, leading to pain hypersensitivity. Mechanical allodynia, or touch-evoked pain, is a highly prevalent and debilitating symptom of neuropathic pain. It has been proposed that, after nerve injury, innocuous sensory neurons gain access to nociceptive-specific (NS) circuits in the DH due to altered spinal inhibitory controls, thereby converting touch into pain. It is however unclear how sensory processing is reorganized in these conditions across the different laminae of the DH to generate this symptom. In this study, we developed a novel ex vivo somatosensory preparation to selectively analyze excitatory neuronal activity across all DH laminae simultaneously, following physiological stimulations of the skin. Using two-photon calcium (Ca2+) imaging, we studied the DH activity under physiological conditions, after spinal disinhibition or nerve injury, and generated a computational model to reveal the sensory plasticity of individual DH neurons that leads to neuropathic pain. We demonstrate that spinal disinhibition, whether pharmacologically induced or resulting from nerve injury, converts most DH excitatory neurons into highly polymodal cells. We further show that such disinhibition unmasks an unprecedented number of previously silent neurons in both superficial and deep DH laminae, responding to a wide dynamic range (WDR) of sensory modalities. The computational model pinpoints that neuropathic pain does not result primarily from the transformation of excitatory NS neurons into WDR neurons, but rather from the activation of a previously dormant excitatory circuit. This newly active circuit spans both superficial and deep DH laminae and is predominantly composed of WDR excitatory neurons The identification of this extensive silent neuronal network provides critical insights into DH plasticity mechanisms underlying neuropathic pain, and should guide future therapeutic strategies
What is the lower limb length discrepancy after arthroplasty for proximal femoral fracture? A prospective, multicenter observational study of 590 hips
No full textInternational audienceIntroductionLower limb length discrepancy (LLD) following hip arthroplasty after proximal femoral fracture (PFFA) is little studied. The aim of this work was to answer the following questions: 1) What are the incidence and mean values of LLD after PFFA? 2) What are the clinical consequences (tolerance) of LLD after PFFA? 3) Can we identify risk factors for LLD after PFFA? 4) Is there a significant difference in terms of LLD after PFFA to treat intra- versus extra-capsular fractures?HypothesisLLD after proximal femoral fracture arthroplasty is rare but has good clinical tolerance, given the low functional demands of the patients.Patients and methodsThis is a multicenter prospective observational cohort study (15 centers), including 590 patients, operated on for hip arthroplasty for proximal femur fracture between May 2022 and June 2023. The mean age was 81.74 years (±10.72). The clinical and radiological measurement of LLD was carried out between the 6th week and the 6th month postoperatively. A positive LLD meant that the operated side was lengthened, a negative LLD meant that it was shortened. Clinical tolerance was measured using objective (Merle d’Aubigné (PMA) and Harris (HHS)) and subjective (Oxford-12 and Forgotten Joint Score (FJS)) functional scores as well as autonomy measured using the Parker score.ResultsClinical and radiological measurements of LLD were highly correlated (p < 0.001), and showed an overall shortening trend of −0.03 mm (±4.99). In total, 265/590 patients (45%) had a LLD greater than 3 mm, 131/590 (22%) had an LLD greater than 5 mm, and 24/590 (4%) had a LLD greater than 10 mm. A LLD beyond ±3 mm significantly worsened all functional scores compared to an LLD below this threshold (PMA: 12.2 ± 3.2 vs. 12.9 ± 3.6 (p = 0.020); HHS: 62.7 ± 20.3 vs. 66.5 ± 19.3 (p = 0.027); FJS: 61.5 ± 28.8 vs. 72.5 ± 25.6 (p < 0.001); and the Oxford-12 score: 29.2 ± 9.7 vs. 26 ± 9.4 (p < 0.001)). However, no significant difference was observed for the autonomy (Parker score 4.7 ± 2.5 versus 4.8 ± 2.7 (p = 0.58)). Female gender (+0.43 mm ± 4.71 (p < 0.001)) and cementing of the femoral implant (+0.42 mm ± 4.57 (p = 0.014)) were associated to lengthening. Cementless stems (−0.41 mm ± 5.29 (p = 0.014)), general anesthesia without curare (−1.8 mm ± 5.96 (p = 0.007)), and the Röttinger and Watson-Jones approaches (−1.34 mm ± 4.57 (p = 0.04)) were associated to shortening. There was no difference between LLD after intracapsular fracture (−0.06 mm ± 5) and extracapsular fracture (+0.9 mm ± 3 (p = 0.45)).DiscussionOur results are consistent with the literature data which is sparse on the subject, with 78% of LLD in our series ranging between +5 and −5 mm. Functional consequences were observed as soon as the 3 mm threshold was exceeded but without effect on autonomy. Only 4% of patients had a centimeter inequality.Level of evidenceIV; prospective study without control group
OXYTOCIN ADMINISTRATION DURING SPONTANEOUS LABOUR AND POSTPARTUM BLOOD LOSS: A FRENCH MULTICENTRE COHORT
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The type of sport, but not sex, impacts body composition and metabolic response to a complete weight loss–weight regain episode in weight cycling athletes: results from the WAVE study
No full textInternational audienceAthletes may engage in weight cycling—successive episodes of weight loss and weight (re)gain—for performance reasons, but risk metabolic adaptations and regaining more fat that was lost (fat overshoot). This study aimed to assess the influence of a complete weight cycling episode on body composition, thermoregulation, and metabolism in athletes, considering sex and the type of sport practiced. Forty-eight athletes (28 males, 20 females) engaged in combat ( n = 23), strength (n = 12), or endurance ( n = 13) sports were examined under three experimental conditions (weight maintenance, weight loss, weight (re)gain) during a weight cycling episode using their habitual strategies. Body composition (dual-energy X-ray absorptiometry), core body temperature (telemetric temperature sensor), energy expenditure and substrate oxidation at rest and during moderate exercise (indirect calorimetry), and energy intake (48 h food record) were assessed. Overall, athletes lost 4.4 ± 2.3% body weight, 12.2 ± 10.6% fat mass, and 2.6 ± 2.3% fat-free mass ( p < 0.001). All variables returned to baseline values during the regain period, and a higher fat mass regain was observed in endurance than combat athletes ( p < 0.01). During weight loss, a transient increase in lipid and decrease in carbohydrate oxidation occurred at rest and during exercise ( p < 0.001). Energy expenditure and core body temperature remained unchanged across the three experimental conditions, and no specific sex effect was observed. Overall, no apparent body weight nor fat overshoot was observed in athletes after a complete weight cycling episode. Nonetheless, the greater fat mass gain in endurance, compared with combat athletes, highlights a need for further specific long-term studies in this population. Clinical Trial registration: NCT04107545