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Secondary-type acute myeloid leukemia is associated with a higher risk of invasive fungal infection during intensive induction therapy. a correlative study on the ALFA 0702 trial.
No full textInternational audienceBackground. Invasive fungal infections (IFIs) represent a major cause of morbidity and mortality during intensive induction therapy for acute myeloid leukemia (AML). Although their incidence is increased in this setting, the associated risk factors remain poorly defined. In particular, the impact of somatic gene mutations on IFI risk during induction is not well understood. Secondary-type AML (sAML) gene mutations (ASXL1, BCOR, BCORL1, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2) define a distinct diagnostic and prognostic entity (PMID 35797463), and mutations in ≥2 genes amongst those (sAML2) may allow more robust identification of these patients (PMID 35941135) Objectives. We aimed to investigate whether recurrent AML gene mutations are associated with higher risk of invasive fungal infections during the first time-sequential induction therapy in the ALFA 0702 trial (NCT00932412). Methods. Main results of ALFA0702 were previously reported (PMID 28221862). IFIs were graded according to EORTC guidelines (PMID 34895843). Gene mutations were evaluated at diagnosis (PMID 32871585) and patients were classified as having secondary-type AML (sAML2) if ≥2 genes were mutated among the following: ASXL1, BCOR, BCORL1, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2. Cumulative incidence of IFI was evaluated considering death prior to start of the second course as a competing risk. Results. Of 713 patients (pts) with AML registered in the 0702 trial, 633 (M/F 340/293, median age 47y) had complete genetic and IFI data and did not have a preexisting IFI at inclusion. 447 (71%) pts received anti-fungal prophylaxis during the first intensive course (posaconazole n=360, other n=87). IFIs occurred in 96 (15%) patients during the first induction therapy. IFIs were more frequent in males (M 19%%, F 11%, p=0.007) and in the 21% of pts with baseline Absolute Neutrophil Count (ANC) < 500 x109/L (IFIs in 21% vs 12.5% in pts with ANC ≥ 500 x109/L, p=0.006) whereas time to neutrophil recovery (median 29 days) had no impact on occurrence of IFI (p=0.7). Of 38 genes recurrently mutated in at least 1% of pts, mutations in 4 genes were individually associated with increased risk of IFI when stratifying on receipt of antifungal prophylaxis (false-discovery rate [FDR] threshold 0.1), including SRSF2 (HR=2.36, FDR=0.03), BCOR (HR=1.97, FDR=0.089), CBL (HR=2.99, FDR=0.089) and SETBP1 (HR=3.30, FDR=0.089). Adjusting for sex, baseline ANC and time to neutrophil recovery led to similar results. Mutations in SRSF2 and BCOR contribute to the definition of secondary-type AML. Genetically-defined sAML2 was found in 77 pts (12%) and was associated with increased IFI risk in a similar analysis stratified on antifungal prophylaxis (sAML2: HR=2.2, p=0.001). Specifically, the cumulative incidence of emergent IFI at 60 days from first induction course onset was 21% in sAML2 vs 11% in non-sAML2 pts receiving antifungal prophylaxis, and 45% compared to 19% respectively when not receiving antifungal prophylaxis. The median time to neutrophil recovery was 32 days in sAML2 pts vs 28 days in other pts (p=0.0079). In a multivariable model also accounting for sex (M, HR=1.90, p=0.005), baseline neutropenia (ANC<500 x109/L, HR=1.67, p=0.02) and time to neutrophil recovery (days, as a continuous variable, HR=1.0, p=0.94), sAML2 was independently associated with an increased hazard of IFI (HR=1.96, p=0.01). Of note, the IFI profiles (Candida sp. vs Aspergillus sp. vs other) were similar between sAML2 and non-sAML2 pts (p=0.78). To explore the potential causal link between sAML2 genetic profile and incidence of IFI, we leveraged data from 177 patients treated in the ALFA0701 trial with detailed morphological and genetic annotations (PMID 34615986), including 21 (11.9%) with sAML2 profile. sAML2 was associated with a specific dysgranulopoiesis notable for persistent basophilia (28.3% of sAML2s versus 8.3% of non-sAML2 cases, p=0.018). Across 2 genetically annotated transcriptomic datasets (BEAT-AML2, n=428; ALFA0701, n=180), sAML2 status was robustly associated with increased expression of both type I and II IFN pathways (all FDR < 10-5), also possibly contributing to aberrant antifungal immunity. Conclusion. Genetically-defined secondary-type AML patients might be more susceptible to IFI during intensive AML induction therapy regardless of baseline ANC and duration of neutropenia. These findings may guide personalized IFI prevention policies in this population
Treatments and outcomes of adult patients with TP53-mutated acute myeloid leukemia (AML) in the real-life –Report of the prospective french observational ALFA-PPP study.
No full textInternational audienceIntroduction The prognosis of AML harboring TP53 mutations remains exceptionally poor. Clinical trials specifically designed for TP53-mutated AML are scarce and fail to represent real-world patient populations. Furthermore, most outcome data for TP53-mutated AML come from retrospective studies, where therapeutic decisions are frequently made without prior knowledge of molecular results. To address these gaps, we used data from the prospective ALFA-PPP registry (NCT04777916) to investigate the real-world management of patients with TP53-mutated AML. Methods We report the observations of the first 1,108 newly diagnosed adult AML patients (April 2022-August 2024) who had a centralized genomic profiling at diagnosis (50-gene NGS panel), focusing on the presence of TP53 mutation. Kaplan-Meier methodology was applied to estimate overall survival (OS). Multivariable analyses were performed using logistic regression or Cox regression, where appropriate. Results One hundred and sixty-five patients harbored at least one TP53 mutation at diagnosis. There were 89 males and 76 females (median age 72y [IQR, 64-77]; ECOG-PS 0-1/2/3-4, 98/42/21; median WBC 3.1 G/L [IQR, 1.7-7.3]; median marrow blast 31% [IQR, 22-54]). The numbers of patients with de novo, secondary and therapy-related AML (t-AML) were 90 (54%), 26 (16%) and 49 (30%), respectively. ELN-2022 cytogenetic risk was intermediate in 20 (12%), adverse in 137 (83%), and unclassifiable in 8 (5%). Median TP53 variant allele frequency was 44% (IQR 23-73), and 121 (74%) patients were classified as having bi-allelic TP53 mutations. In the full cohort, in multivariable analysis, older age (OR, 1.28 [95%CI, 1.09-1.52]; p=0.003), lower blast count (OR, 0.82 [95%CI, 0.75-0.90]; p<0.001), and adverse cytogenetic risk (OR, 30.98 [95%CI, 18.74-53.85]; p<0.001) were predictive of the presence of TP53 mutations. Secondary AML (OR, 0.88 [95%CI, 0.45-1.70]; p=0.714) or t-AML (OR, 1.39 [95%CI, 0.82-2.34]; p=0.217) were not significantly associated with TP53 mutation status. In the TP53-mutated cohort, treatment decision was intensive in 37 (22%) (median age, 63 years [56-66]; including 17 CPX-351), less intensive in 106 (64%) (median age, 75 years [68-79]; 78 AZA-VEN, 10 AZA, 18 unknown), and best supporting care in 16 (10%) patients, while the 5/6 remaining patients died before treatment decision. A total of 22/165 (13%) patients received an allogeneic stem cell transplant (HSCT) including 17 intensively and 5 less-intensively treated patients. With a median follow-up of 24 months (95% CI, 17-28), the median OS of intensively and less intensively treated patients was 11.7 (95% CI, 7.6-15.7) and 4.8 (95% CI, 3.6-6.2) months, respectively. The 12-month OS rates of intensively and less intensively treated patients were 48% (95%CI, 34-67%) and 19% (95% CI, 13-28%), respectively. The median OS of patients who underwent HSCT was 17.2 months (95% CI, 2.8-12.9). In these patients, multivariable Cox analysis evidenced older age (HR, 1.3 [95%CI 1.1-1.5]), higher ECOG (HR, 1.7 [95%CI, 1.2-2.5]; p=0.004), higher medullary blasts count (HR, 1.1 [95%CI, 1.01-1.2]; p= 0.03), t-AML (HR 1.7, [95%CI, 1.2-2.5]; p=0.006) and adverse ELN-2022 cytogenetic risk (HR, 2.5 [95%CI, 1.2-5.1]; p=0.02) as predictors of shorter OS. TP53 bi-allelic status had no impact on OS (HR 1.07, [95%CI, 0.66-1.7]; p=0.7). Finally, we assess the objective factors independently associated with the choice of a less intensive treatment option in the full cohort. Interestingly, the presence of TP53 mutations was strongly associated with a less intensive treatment option (OR, 6.5 [95%CI, 3.3-13.1]; p<0.001) while an adverse-risk cytogenetics was not (OR, 1.7 [95%CI, 0.98-2.8]; p=0.06), suggesting that the knowledge of the mutation may have influenced the treatment choice. The other factors associated with less intensive therapy were older age (OR, 8.2 [95%CI, 6.2-11.2]; p<0.001), higher ECOG (OR, 2.6 [95%CI 1.5-4.6]), AML type (OR, 2.5 [95%CI, 1-4-4.7]; p=0.003 for secondary AML, and OR, 2.6 [95%CI, 1.5-4.7]; p<0.001 for t-AML), and, unexpectedly, male sex (OR 1.8, [95%CI, 1.2-2.8]; p=0.004). Conclusion This prospective real-life AML patient cohort confirms that patients with TP53 mutations display distinct features and face a nearly incurable disease course, even when intensively treated. In absence of effective therapies, the knowledge of TP53 status at diagnosis appears to influence the decision to pursue less intensive treatment options
Exponential mixing of all orders and CLT for generic birational maps of .
No full textFor Hénon maps, Bianchi and Dinh recently proved the exponential mixing of all orders for the measure of maximal entropy and, as a consequence of the recent work of Björklund and Gorodnik, the CLT for Hölder observables. We extend their results to generic birational maps of . Because of the indeterminacy set, Hölder maps are not stable under iteration, so we need to work with a suitable space of test functions
First genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia
No full textInternational audienceBackground Idiopathic achalasia (IA) is characterised by the degeneration of neurons in the myenteric plexus leading to an irreversible impaired oesophageal function. Although immune-mediated mechanisms have been proposed, the underlying aetiopathology of IA remains poorly understood. Objective This study aimed to uncover the genetic risk architecture of IA. Design We carried out the first genome-wide association study (GWAS) on 4602 European patients with IA and 10 766 ethnically-matched controls. Results A single nucleotide polymorphism (SNP) in HLA-DQB1 leading to an 8-amino acid insertion on the protein level conferred strongest IA risk (PQGPPPAG: p=3.27×10 –68 , OR=2.45). Conditional analyses within the HLA locus revealed a complex genetic risk architecture. Three additional amino acid positions showed independent IA association (Omnibus p<5×10 −8 ). These refer to positions 41 and 130 in HLA-DQα1, position 45 in HLA-DQβ1 and position 86 in HLA-DRβ1. Together, these findings highlight the pivotal role of class II HLA genetic variation in IA pathogenesis. Outside HLA, three independent variants showed IA association (p<5×10 −8 ). One leads to an amino acid substitution with functional effect in PTPN22. Another risk variant leads to a downregulated expression of TNFSF8 , TNFSF15 and TNC in immune cells. The third risk SNP is located near ZNF365 , but the exact underlying cellular mechanism remains unknown. Beyond the single marker level, polygenic risk scores revealed that patients with IA can be stratified based on their genetic risk. In addition, IA shows a shared aetiopathology with Crohn’s disease (r g =0.335). Integrating GWAS and single-cell RNA-sequencing data from the myenteric plexus showed that the memory T-cell type FOS + Tc4 + CD8 + plays a central role in IA development (p=2.50×10 −19 ). Conclusion This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology
Demonstration and frequency noise characterization of a 17 μm quantum cascade laser
No full textInternational audienceWe evaluate the spectral performance of a novel continuous-wave room-temperature distributed feedback quantum cascade laser operating at the longwavelength of 17 μm. By demonstrating broadband laser absorption spectroscopy of the ν2 fundamental vibrational mode of N2O molecules, we havedetermined the spectral range and established the spectroscopic potential of this laser. We have characterized the frequency noise and measured theline width of this new device, uncovering a discrepancy with the current consensus on the theoretical modeling of quantum cascade lasers. Our resultsconfirm the potential of such novel narrow-line-width sources for vibrational spectroscopy. Extending laser spectroscopy to longer wavelength is afascinating prospect that paves the way for a wide range of opportunities from chemical detection, to frequency metrology as well as for exploringlight-matter interaction with an extended variety of molecules, from ultra-cold diatomic species to increasingly complex molecular systems
"Hacer teatro documento y político o cómo los dramaturgos españoles proponen reflexionar sobre pasado y presente".
No full textInternational audienceThe article considers how certain playwrights echo social and political concerns in their productions and create plays that are integrated into what is often called “document theater” as defined by Peter Weiss. Based on the study of four plays that were performed at the Teatro del Barrio, El pan y la sal and Flores de España (2015) by Rafael Quirós, Ruz-Bárcenas (2014) by Jordi Casanovas, and Masacre (2017) by Alberto San Juan, we analyze the discourses that construct these plays and the means used by the playwrights to achieve their goal, either to show the injustice suffered by the victims of the civil war and post-war period and their relatives, or to expose how certain unethical power structures act
Temps et vie quotidienne en établissement d'accueil des jeunes enfants (EAJE): Étude ethnographique au sein de quatre crèches
No full textL'accueil collectif des tout petits s'effectue dans des structures très diverses tant du point de vue de leur statut (municipal, privé, associatif...) que de leur fonctionnement. Cette diversité interroge les formes de travail qui y sont développées et les manières dont sont pensés les processus de socialisation des enfants. En effet, si le travail des professionnels1 est globalement connu dans le sens où chacun a une représentation des principales activités effectuées au sein d'un établissement d'accueil des jeunes enfants (EAJE), il reste en fait largement méconnu sur les manières de s'y prendre avec un enfant comme avec des groupes d'enfants. Que font concrètement les professionnels pour faciliter et développer leur socialisation ? Comment s'y prennent- ils pour s'assurer que chaque enfant est à son aise et profite pleinement d'une garde collective ? Comment s'organisent-ils pour établir une équité de traitement entre tous les enfants tout en considérant les situations particulières (handicap, précarité...) ?... [premières lignes
Conception d’un modèle de simulateur de pose de trocarts de coelioscopie à partir de données « in vivo » de patiente au bloc opératoire et de modélisation du chirurgien : le bon geste au bon endroit
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Le débat sur l’oralité africaine, lieu d’une politique des savoirs
No full textInternational audienceThis article looks at the debates on African orality in Francophone research from an epistemo-political perspective. It defends the idea that orality is a place structured by the coloniality of knowledge and that discussions on its existence or its coefficient in African societies are therefore linked to epistemo-political positions. We show that orality is a stereotypical evidence about Africa and a heterogeneous category, with three different meanings depending on the author (oral production in the linguistic sense, a corpus of texts, a social relationship), structuring a major French academic field with pedagogical, scientific and editorial boundaries. We then take up the criticisms levelled at the proponents of African orality, focusing on the inventionist arguments and proposing a response to the criticism of Mamoussé Diagne's thesis (2005, 2022) by Ba 2020, focused on the oral/written divide.L'article porte sur les débats sur l'oralité africaine dans la recherche francophone, dans une perspective épistémo-politique : on y défend l'idée que l'oralité est un lieu structuré par la colonialité du savoir et que les discussions sur son existence ou son coefficient dans les sociétés africaines sont donc articulées avec des positions épistémo-politiques. On montre que l'oralité constitue une évidence stéréotypée sur l'Afrique et une catégorie hétérogène, recevant selon les auteurs trois acceptions différentes (la production orale au sens linguistique, un corpus de textes, un rapport social), structurant un important champ académique français balisé sur les plans pédagogique, scientifique et éditorial. On reprend ensuite les critiques adressées aux tenants de l'oralité africaine, en insistant sur les arguments inventionnistes et en proposant une réponse à la critique de la thèse de Mamoussé Diagne (2005, 2022) par Ba 2020, centrée sur la division oral/écrit
The Effects of Burst Steroid Therapy on Short-term Decongestion in Acute Heart Failure Patients With Pro-inflammatory Activation: A Post Hoc Analysis of the CORTAHF Randomized, Open-label, Pilot Trial
No full textInternational audienceBackground: The effect of steroids on congestion in patients with acute heart failure (AHF) is not known.Methods and results: Patients with AHF, NT-proBNP levels > 1500 pg/mL and high-sensitivity C-reactive protein (hsCRP) levels > 20 mg/L were randomized to once-daily oral 40 mg prednisone for 7 days or usual care. In this post hoc analysis, congestion score was calculated on the basis of orthopnea, edema and rales (0 reflecting lack of congestion, and 9 maximal congestion) at each time point. Among 100 eligible patients randomized, those assigned to prednisone had a greater improvement in congestion score at day 31 (win odds for the prednisone group compared to usual care at day 31 was 1.77 (95% CI 1.17-2.84; P = 0.0066) in all patients and 2.41 (95% CI 1.37-5.05; P = 0.0016) in patients with IL-6 > 13 pg/mL at baseline. In patients with congestion scores ≥ 7 at baseline, the effects of prednisone therapy on the EQ-5D visual analog scale score were 4.30 (95% CI 0.77-7.83) points at day 7 and 5.40 (0.51-10.29) points at day 31, accompanied by lower heart rate and respiratory rate and higher oxygen saturation compared to usual care.Conclusions: In patients with AHF and inflammatory activation, 7-day steroid therapy was associated with reduction in signs of congestion up to day 31. These results need confirmation in larger studies examining potential effects of steroids on congestion, diuresis, fluid redistribution and vascular permeability as well as clinical effects in AHF