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BAG3-related myofibrillar myopathy: focus on its cardiac involvement
No full textInternational audienceMyofibrillar myopathy is a cause of rare and severe pediatric cardiomyopathies. Few descriptions of patients carrying the rare p. Pro209Leu variant in BAG3 and presenting with myofibrillar myopathy are reported in the literature. Most reports originate from neurological teams, while the cardiac phenotype remains poorly described, even though it is crucial for prognosis, as cardiac involvement can significantly influence patient outcomes. We focused on the cardiac phenotype associated with p. Pro209Leu variant in BAG3 and conducted a literature review. We report three patients with severe restrictive cardiomyopathy (RCM) including two with left ventricular hypertrophy. Cardiac symptoms appeared 7 [5–7.5] years after neurological onset and were predominantly right heart failure, with high NT-proBNP levels, and arrhythmic events (atrial flutter, ectopic atrial tachycardia). Cardiac MRI showed biatrial and left ventricular fibrosis. Prognosis was severe, with two deaths. In the reviewed cases, cardiac involvement was present in 76.9% and diagnosed at an early age of 11 [8.2–12.7]. Restrictive cardiomyopathy was the most prevalent phenotype (69.2%), followed by hypertrophic cardiomyopathy (5.1%) and rare long or borderline QT interval (7.7%). Arrhythmias were observed in only one patient. Heart transplantation was performed in 11 patients at 13 [10.5–13.5] years, with some developing secondary neurological symptoms. Most patients lost ambulation, required ventilation support, and exhibited orthopedic involvement. Overall mortality was 30.7%, with sudden death being the most reported cause. The p. Pro209Leu variant in BAG3 is associated with progressive neurological and cardiac involvement, leading to a poor prognosis. Repeated cardiac screening is recommended in these patients and conversely, neurological progression should be monitored after transplantation in patients initially presenting with isolated RCM
Influence des traits de personnalité sur la relation entre éco-anxiété et pensée future épisodique
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Impact des énergies renouvelables et non renouvelables sur le développement durable dans la corne de l’Afrique
No full textInternational audienceLa Corne de l’Afrique, qui comprend, Djibouti, l’Érythrée, l’Éthiopie et la Somalie, est confrontée à des défis majeurs en matière de développement durable. Bien que cette région possède un potentiel important en énergies renouvelables, elle reste largement dépendante des combustibles fossiles, entraînant des impacts environnementaux négatifs, la pauvreté énergétique et un retard dans la transition énergétique. Cette étude analyse l’impact des énergies renouvelables et non renouvelables sur le développement durable dans cette région, en tenant compte des dimensions économiques, sociales et environnementales. En utilisant une approche économétrique et des consultations avec les parties prenantes, ce travail vise à fournir des recommandations politiques pour promouvoir un mix énergétique durable et une meilleure résilience climatique. Cet article scientifique présente une analyse approfondie de l’impact des sources d'énergie dans la Corne de l'Afrique, avec une approche multidimensionnelle permettant d’éclairer les politiques futures dans la région
Reformas de infantería en la Beocia Helenística
No full textInternational audienceRecent research on Boeotia in the Hellenistic period has led to a betterunderstanding of its military organization. A rich epigraphic record provides insightinto the functioning and organization of the Boeotian federal army. Around 230 BC,the army was reorganized on the model of the Antigonid army, as evidenced by theappearance of a new type of infantry, the peltophoroi, replacing the hoplites andthyreophoroi attested previously. Two elite corps, the agema and the epilektoi, alsoappeared at this time, denoting a clear Macedonian inspiration. Compared to otherpowers of the period, this was an early adoption. This cultural transfer in turn allows usto date the introduction of peltasts in the Antigonid army more precisely: it must havetaken place during the reign of Demetrios II or at the very beginning of the reign ofAntigonos Doson.Investigaciones recientes sobre Beocia en el período helenístico han permitido comprender mejor su organización militar. Un rico registro epigráfico proporciona información sobre el funcionamiento y la organización del ejército federal beocio. Alrededor del 230 a. C., el ejército se reorganizó siguiendo el modelo del ejército antigónida, como lo demuestra la aparición de un nuevo tipo de infantería, los peltóforos, que reemplazaron a los hoplitas y tiroforos previamente documentados. Dos cuerpos de élite, los agema y los epilectos, también aparecieron en esta época, lo que denota una clara inspiración macedonia. En comparación con otras potencias de la época, esta fue una adopción temprana. Esta transferencia cultural, a su vez, nos permite fechar con mayor precisión la introducción de los peltastas en el ejército antigónida: debió de tener lugar durante el reinado de Demetrio II o a principios del reinado de Antígono Doson
Optimization of heat transfer in water-NePCM filled cavities through cylinder rotation and size variation
No full textInternational audienceMixed convection heat transfer within a square cavity filled with nano-encapsulated phase change material (NEPCM), uniformly dispersed in water and containing a rotating heated cylinder centrally located is studied numerically. The combined effect of natural and forced convection on heat transfer released by the heated cylinder and evacuated through the walls of the cavity is investigated. The main control parameters of the problem are the Richardson number (0.1 ≤ Ri ≤ ∞), the dimensionless fusion temperature (0.05 <= theta(f) <= 0.95), the volume fraction of NEPCM (0% ≤ φ ≤ 5%), the Reynolds number (0 < Re < 401.61), the Stephan number (0.313 ≤ Ste ≤ 1), and the radius of the inner cylinder (0.1 ≤ R ≤ 0.4). The remaining parameters are the Rayleigh number (Ra = 10(5)) and Prandtl number (Pr-f = 6.2). The results obtained show that mixed convection is dominant within the Ri range from 10 to 10 x 10(2) for R <= 0.3; whereas forced convection is the dominant regime for R = 0.4 irrespective of the Ri. The maximum improvement of ~ 14.92% was recorded when the NEPCM suspension volume fraction (φ) was increased from 0% to 5%. Moreover, for Ri = 100 and R = 0.2, the NEPCM fusion temperature of 0.45 yields the best heat transfer performance
Chapter 4 Portrait Painting, Photography, and the Subliminal Testimony of the Environing Life‐World
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Comprehensive mutational profiling and clinical outcome of adults AML with NUP98 rearrangement
No full textInternational audienceAcute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r) is recognized as a distinct entity in the 2022 WHO classification; however, it is not as a prognostic factor within the ELN 2022 classification. We report a large cohort of 95 adult patients with NUP98r AML. Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×109/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41y vs 61y), had more de novo AML (94% vs 64%), higher rates of normal karyotypes (56% vs 4.5%), FLT3-ITD (76% vs 18%) and WT1 mutations (50% vs 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 14.8 months (95% CI, 11.9–20.8) and event-free survival was 3.3 months (2-7.5). Among patients treated intensively (n=73), age (HR = 1.04) and FLT3 inhibitor therapy (HR = 0.45) influenced OS in univariate analysis, while leukocytosis, partner type, ELN classification, presence of a FLT3-ITD or WT1 mutation or hematopoietic stem cell transplant did not. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with OS approaching that of intermediate-risk AML patients (33.3 months [11.9–not reached])
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
Real life study of ivosidenib in either monotherapy or combined with azacytidine for first line mutant IDH1 AML: A study from the french AML intergroup ALFA/filo
No full textInternational audienceBackground: IDH1 mutations are found in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (IVO), an oral mIDH1 inhibitor, is approved for newly diagnosed mIDH1 AML in patients (pts) aged ≥75 years or unfit for intensive chemotherapy as monotherapy (US), based on the results of the AG120-C-001 study (Roboz, Blood, 2020, median overall survival (mOS) 12.6 months) or with azacitidine (AZA) (US and Europe) based on the results of the AGILE study (Montesinos, NEJM, 2022, mOS 29.3 months). However, data available on IVO+/-AZA in real-life are limited. Method: This retrospective study (IVOOBS, NCT06377579)included pts treated in France between 01/2017 and 02/2024 through a compassionate use program with IVO+/-AZA for mIDH1 AML, front-line or at time of relapse or for a refractory disease. Here we focused only on newly diagnosed pts. The primary objective was OS and secondary objectives included response rate (ELN-2022 criteria) and toxicity. Results: 49 pts from 17 centers were included; 16 (33%) received IVO alone (IVO-mono cohort) and 33 (67%) the combination (IVO+AZA cohort). IVO-mono cohort (n=16) : The median age was 72 yo (IQR: 60 - 83.25), 62.5% were male. Most of the pts were unfit (PS > 2 in 92%) with high-risk disease (secondary AML n=14, including 8 pts who have already received AZA for prior hematologic disease; adverse (adv)-risk according to ELN-2022 classification n=7, 43%, intermediate (int)-risk n= 9, 57%). The median white blood count (WBC) was 2.67 Giga/L. The majority of pts started IVO at the recommended dose of 500 mg/day (d) (n=13, 81%), while 3 started at 250 mg/d (concomitant prescription of azole). Median duration of IVO treatment was short (3.25 months, IQR: 1.6-7.07) as 77% % (n=10) of IVO discontinuations occurred within 4 months (3 allo-HCT, 3 progressions, 2 differentiation syndrome (DS), 1 QT prolongation (QTp), 1 death). Any grades of DS and QTp were reported in 25% (n=4) and 7% (n=1) of pts, respectively, while grade 3-4 hepatic, infection and hematologic adverse events (AE) occurred in 0, 4 and 3 pts, respectively. Two deaths were linked to IVO (DS). Mortality at D30 and D60 was 6% and 25%, respectively. Composite complete remission (CCR) (CR/CRh/CRi) rate was 37% (31%/6%/0%), with no MLFS and 44% of non-responders (19% of pts not assessed (NA)). For pts receiving IVO at 500mg/d, CCR was 46% (38%/8%/0%). At 250mg/d, 2 pts did not respond and 1 was NA. Four pts (3 in CR, 1 in no response) received an allo-HCT after IVO. Among responders (n=6), 1 pt relapsed at 10.8 months. With a median follow-up (mFU) of 4.5 months, mOS was 4.5 months (95% CI: 2.07-not reached (NR)) and 2y OS 31.25% (95% CI: 15.11-64.64). IVO+AZA cohort (n=33): The median age was 78 yo (IQR: 75 – 80), 60% were male. The majority of pts were unfit (PS > 2 in 93%) and classified as int-risk (83%) according to ELN-2022 classification (adv-risk 17%). However, according to ELN-2024 classification, most pts had favourable-risk (n=22, 67%) (adv-risk n=2, NA n=9). The median WBC was 2.15 Giga/L. Nine pts (27%) had a secondary AML. The majority of pts started IVO at the dose of 500 mg/d (n=27, 82%), while 6 pts started at 250 mg/d (concomitant prescription of azole (n=5), previous cardiac history (n=1)). Median number of AZA cycles was 6 (range: 1; 28). Median duration of IVO treatment was 13.1 months (IQR: 8.4-18.4) and 26% (n=5) of IVO discontinuations occurred within 4 months (3 progressions, 2 deaths). Mortality at D30 and D60 was 3% and 9%, respectively. DS was reported in 3 pts (9%) and QTp in 2 (7%), any grades, while grade 3-4 hepatic, infection and hematologic AE occurred in 0, 5 and 8 pts, respectively. No death was linked to IVO. CCR was 73% (55%/12%/6%), 3% showed MLFS, 21% were non-responders and 3% NA. CCR was 78% (56%/15%/7%) and 50% (50%/0%/0%) for those receiving IVO at 500 mg/d and 250mg/d, respectively. Among responders (n=24), only 1 pt was consolidated with an allo-HCT and 8 (33%) relapsed at a median of 11.4 months. At relapse, 4 were treated with AZA+BCL2 inhibitor and 1 obtained CR. With a mFU of 16.6 months, mOS was NR (95% CI: 16.62-NR) and 2y OS 52% (95% CI: 35.55-76.56). Conclusion: This retrospective real-life study shows the reproducibility of the results of the AGILE study (IVO+AZA). Pts receiving IVO mono had poorer outcome compared to those of the AG120-C-001 study, likely because pts were at higher risk. The dose of 500 mg/d should also be preferred questioning the role of azole prophylaxis
EO2463 (EO) peptide immunotherapy combined with rituximab (R) for first-line treatment of low-tumor burden follicular lymphoma (FL): A feasibility evaluation in Study EONHL1-20/sidney (NCT04669171)
No full textInternational audienceBackground Single-agent R is a common 1st-line therapy for patients (pts) with FL, especially those with low-tumor burden advanced stage disease or comorbidities. EO is a therapeutic vaccine generated from non-self-protein sequences from gut bacteria, including 4 HLA-A2 CD8 T cell epitopes that mimic B cell-specific markers: CD20, CD22, CD37 and BAFF-receptor. EO also contains a CD4 helper epitope UCP2. EO expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which can cross-react with B cell antigens on tumor cells. The aim adding EO to R is to safely increase the depth and duration of responses. Methods Cohort 3 (C3) of trial EONHL1-20/SIDNEY includes pts with HLA-A2 and previously untreated low-tumor burden (GELF) FL grade 1-3A in need of treatment (per pt/treating physician). Pts receive EO (300μg/peptide) SC with adjuvant Montanide, q2 weeks (w) x 4, then q4w for a total of 12 doses, combined with R starting at w7 (375 mg/m2 IV q1w x4, then q8w x4). For immune responses blood mononuclear cells were assayed by flow cytometry and EO-mimic or B cell peptide specific tetramers without in vitro stimulation. The primary objective is to assess safety; secondary objectives include EO immunogenicity and preliminary efficacy. Results As of July 2025, the 6 planned pts had started EO. Median age was 66 years (range 46-73); 5 ECOG 0/1 ECOG 1; 1 Ann Arbor stage III/5 stage IV; FLIPI low risk 2/intermediate 2/high 2; FLIPI-2 low risk 2/intermediate 4. At median follow-up 10.6 months (mo) 4 pts completed and 2 are ongoing on EO. Median treatment duration was 43 w (range 2-43). Best response by Lugano in the 6 pts included 4 complete (CR) and 2 partial responses (PR). Median time to PR/CR was 17.1 w (range 6.0-18.0). Currently there is only 1 (not yet confirmed) progression at 20.5 mo. All 5 immune response evaluable pts had expansion of CD8 T cells specific for EO mimic and B cell target peptides during treatment; 4 of 5 had detectable expansions at w5 (1st testing time). Currently, the longest tested immune response is at w65 and positive for both EO mimic and B cell target peptides. Expanded specific CD8 T cells had a memory phenotype predominantly composed of effector memory (TEM) cells but also including central memory (TCM) and terminally differentiated effector memory CD8 T (TEMRA) cells. Across the 5 pts, the medians of max % (sum of specific CD8 T cells targeting either the 4 EO mimic peptides or the 4 B cell antigen epitopes at a specific timepoint) among all peripheral CD8 T cells were 0.71% (range 0.19-3.97) for EO mimic and 0.33% (0.20-1.30) for B cell target peptides. The most common EO-related adverse events (AEs) were local administration site reactions (erythema, pain, induration). These included Gr (Grade) 1 reactions in 3 pts, Gr 2 in 1 pt, and Gr 3 in 1 pt; latter being ulceration with EO-interruption at w10.1, and in context of a strong immune response against EO mimic [3.97% of all peripheral CD8 T cells at w5] and B cell target [1.30%] peptides, and CR from w16.7. Other EO related AEs were Gr 1 lymph node pain (1 pt), and related to both EO and R were Gr 2 urticaria (1 pt) and Gr 1 fatigue (1 pt). Only R related were Gr 2 infusion related reaction (3 pts), Gr 2 enterocolitis infection (1 pt), and in 1 pt each Gr 1 flushing, anemia, headache and diarrhea. There were no further Gr 3-4 AE and no death on treatment/follow-up. Complete B cell depletion was seen in 5 pts tested at w18 (R added w7); no recovery in the range of w30-65. Only 3 infections were reported, per above enterocolitis, and 2 cases of COVID-19 both resolved without sequalae. ConclusionsThe combination of EO with R has a predictable and manageable safety profile, with EO only adding local administration site reactions to the well-known R safety profile. In this feasibility cohort all evaluable pts developed a specific immune response against EO and B cell targets, and a Lugano objective response. The combination of EO and R is feasible and can be evaluated in further trials. Updated results will be presented at the meeting