HAL - RIIP
Not a member yet
17635 research outputs found
Sort by
Diagnostic relevance of SH2B3 mutations in suspected myeloid malignancies: Insights from a large-scale NGS-based screening study
No full textInternational audienceINTRODUCTION The SH2B3 gene encodes the cytoplasmic adaptor protein LNK that acts as a negative regulator of hematopoietic progenitor cell expansion and self-renewal, particularly through its interaction with JAK2 and regulation of the JAK-STAT pathway. In humans, SH2B3 alterations have been identified across a spectrum of hematologic malignancies, especially myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), MDS/MPN overlap syndromes including chronic myelomonocytic leukemia (CMML), and acute lymphoblastic leukemias (ALLs). Despite increasing recognition, their precise clinical relevance and pathogenic role remain incompletely understood. Here, we retrospectively investigated a cohort of 17 833 patients referred for suspicion of a myeloid neoplasm or acute leukemia. Through systematic assessment of SH2B3 as part of routine next-generation sequencing (NGS)-based diagnostic workflows, we aimed to delineate the mutational spectrum and clinical implications of SH2B3 variants. METHODS DNA was extracted from bone marrow or peripheral blood samples and analyzed using a custom targeted NGS panel covering the entire coding region of SH2B3, along with 125 other genes recurrently mutated in hematological malignancies.Clinical and biological data were retrospectively collected from medical records and communication with the referring physicians who ordered the molecular analyses. RESULTS Among the 17 833 individuals tested, 13 423 (75.3%) carried at least one SH2B3 variant. The vast majority (n = 11 589, 86.3%) harbored only the common p.W262R polymorphism (rs3184504).The remaining 1 830 individuals carried 415 unique SH2B3 variants, which were classified hierarchically into four tiers of pathogenicity based on variant type, minor allele frequency in gnomAD v4.1.0 and variant allele frequency in patient samples. This led to the following distribution: 169 individuals with Tier I variants, 86 with Tier II variants, 167 with Tier III variants and 1 451 individuals with Tier IV (other than p.W262R) variants. Overall, 246 unique individuals (~1.4% of the total 17 833) with Tier I and/or Tier II SH2B3 variants were identified, with notable enrichment in CMML (7.2%) and MPN cases (5.6%). Null variants were observed throughout the entire protein, without restriction to specific domains, suggesting they are loss-of-function alterations, likely through protein instability or complete loss of expression. By contrast, missense variants exhibited a non-random distribution, with clear enrichment in the PH and SH2 domains, which are essential for LNK's membrane localization and interaction with JAK2. In the cohort of 246 patients carrying Tier I/II SH2B3 variants, the retained diagnosis was as follow: AML (n=61), MDS (n=56), CMML (n=33), essential thrombocythemia or idiopathic thrombocytosis (n=31), myelofibrosis (n=17), polycythemia vera or idiopathic erythrocytosis (n=17), BCP-ALL (n=4), MDS/MPN with ring sideroblasts and thrombocytosis (n=4), T-cell ALL (n=4), and clonal cytopenia of undetermined significance (n=9). Diagnosis remained undetermined in 10 cases. The overall median age of this cohort was 72 years (IQR 61–78). Among them, 212 SH2B3-mutated patients (86.2%) harbored additional mutations, with a median of 3 co-mutations per patient. Mutations in TET2 (47%), TP53 (10%), and SF3B1 (17%) were associated with significantly lower hemoglobin levels, while RUNX1 (13%) and CBL (9%) mutations were associated with decreased platelet counts. Additionally, 54 patients (22%) carried canonical MPN driver mutations, including 40 with JAK2 V617F, 10 with CALR mutations, and 5 with MPL W515L. These included 15 patientswith AML (25% of SH2B3-mutated AML), suggesting an enrichment of secondary AML transformed from a previous MPN. By contrast, SH2B3 mutation as the sole aberration was associated with higher hemoglobin concentrations (β = 1.95; 95% CI: 0.87–3.02) and platelet counts (β = 0.23 log; 95% CI: 0.05–0.41). Individuals with isolated SH2B3 mutations were often younger and had higher SH2B3 variant allele frequencies. Familial co-segregation was confirmed in three families. CONCLUSION SH2B3 alterations are enriched in CMML and MPNs, including triple-negative cases. These findings underscore the biological and clinical relevance of SH2B3 in myeloid disorders and support its inclusion in diagnostic screening panels, particularly in cases of unexplained thrombocytosis or erythrocytosis
Sustained minimal residual disease (sMRD) negativity in transplant ineligible newly diagnosed multiple myeloma treated with isatuximab plus lenalidomide and dexamethasone with bortezomib (Isa-VRd) versus isa-rd: 12-24-month data from the phase 3 benefit trial (IFM 2020-05)
No full textInternational audienceIntroduction: Sustained minimal residual disease (sMRD) negativity has shown a stronger correlation with survival outcomes than MRD negativity at a single time point or at best response. We evaluated MRD negativity between 12 and 24 months in newly diagnosed multiple myeloma (NDMM) transplant-ineligible (TI) patients enrolled in the BENEFIT study.Methods: BENEFIT is a multicenter, phase 3 randomized trial comparing isatuximab-lenalidomide-dexamethasone with or without bortezomib (Isa-Rd ± V) in NDMM TI patients. In the Isa-VRd arm, bortezomib (V) was administered weekly for up to 18 months, dexamethasone was permanently discontinued after 12 months, and isatuximab-lenalidomide (Isa-R) was continued until progression. Data are presented in the intention-to-treat (ITT) population.Results: With a median follow-up of 33.4 months (95% CI, 33.0–34.0), 78 patients (29%) discontinued treatment, primarily due to progressive disease. At 24 months, the MRD negativity rate at 10⁻⁵ was significantly higher in the Isa-VRd arm (odds ratio [OR] 2.26; 95% CI, 1.35–3.79; p=0.002). Sustained MRD negativity at 10⁻⁵ was also more frequent in the Isa-VRd arm (OR 2.73; 95% CI, 1.50–4.80; p=0.0007). Similar results were observed for sMRD at the 10⁻⁶ threshold. Importantly, MRD negativity at both 10⁻⁵ and 10⁻⁶ was evaluated in the t(11;14) NDMM TI subgroup. In this subgroup, MRD negativity rates were consistently lower at all time points up to 24 months, consistent with recent observations from the MIDAS study. Due to the small number of patients per group, no subgroup-specific analysis was feasible. Larger cohorts are required to determine whether t(11;14) MM in TI patients achieves delayed or less frequent MRD negativity, potentially reflecting a MGUS-like phenotype. No new safety signals were observed in either treatment arm, including in high-risk multiple myeloma (HRMM) patients.Conclusion: The BENEFIT study continues to support the efficacy of the quadruplet Isa-VRd regimen in NDMM TI patients, notably through improved sustained MRD negativity rates. These data support Isa-VRd as a new standard of care (SOC) for NDMM TI patients aged 65–79 years, including those with HRMM.ClinicalTrials.gov Identifier: NCT0475187
Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice
No full textInternational audienceAbstract STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice. We found a terminally exhausted T cell phenotype, established early in life upon entry into the periphery, independent of type I interferons and intrinsic STING activation in T cells or stromal cells. Mechanistically, naive T cells in the lymphopenic periphery experienced heightened stimulation of the IL-7 receptor and TCR, including NFAT pathway, a key factor in T cell exhaustion. Transplantation of STING GOF hematopoietic stem cells with wild-type bone marrow prevented exhaustion in this non-lymphopenic context, placing lymphopenia as a key driver. T cell exhaustion was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results highlight T cell exhaustion induced by lymphopenia and could have important implications for the management of patients with severe immune deficiencies
The Impact of COVID-19 on HIV Care Disruption and Return to Treatment in Mauritius: Findings from the COVIH-OI Qualitative Study
No full textInternational audienc
A CRISPR-based diagnostic tool to survey drug resistance in human African trypanosomiasis
No full textInternational audienceThe World Health Organization aims to eliminate human African trypanosomiasis caused by Trypanosoma brucei gambiense (gHAT) by 2030. With the decline of reported cases, maintaining active surveillance is essential, including for the potential emergence of drug-resistant parasites. We have developed new highly specific diagnostic tools, using the Cas13a-based Specific High-Sensitivity Reporter Enzymatic UnLOCKing (SHERLOCK) technology, for the detection of drug-resistant genotypes that (i) are already circulating, such as the AQP2/3 (814) chimera providing resistance to pentamidine and melarsoprol or (ii) could emerge, such as the Tb CPSF3 (N 232 H) mutation, associated with acoziborole resistance under laboratory conditions. The AQP2/3 (814) SHERLOCK assay detected RNA from both cultured parasites and field strains isolated from gHAT patients who relapsed following melarsoprol or pentamidine treatment. The CPSF3 (SNV) SHERLOCK assay discriminated between wild-type CPSF3 RNA and CPSF3 bearing a single A-C mutation that confers resistance to acoziborole in vitro . These SHERLOCK assays are amenable for use as a high-throughput screening method to monitor for drug-resistant-associated mutations in Trypanosoma brucei , providing a new molecular tool for epidemiological surveillance during the gHAT elimination phase
Sustained excess all-cause mortality post COVID-19 in 21 countries: an ecological investigation
No full textInternational audienceAbstract Background Despite widespread vaccination efforts, significant excess mortality continued in various countries following the COVID-19 pandemic. This study aims to estimate excess mortality during 2022 in 21 countries and regions, and to examine the relationship of governmental control measures and vaccination rates with excess mortality during 2021–2 at an ecological level. Methods Excess mortality for 2022 was estimated by analysing weekly mortality data from January 2020 to December 2022 across 21 countries and regions participating in the C-MOR consortium. This was achieved by comparing the observed age-standardized mortality rates per 100 000 population to a baseline derived from historical data (2015–19). Governmental control measures and vaccination efforts were investigated for their association with weekly excess mortality during 2021–2 in multilevel models with country as a random effect. Results All 21 countries experienced excess mortality in 2022, ranging from 8.6 (Peru) to 116.2 (Georgia) per 100 000 population, noting that rates were not directly comparable across countries. Many countries had higher excess mortality in 2022 compared with previous years. Mauritius showed a significant excess mortality for the first time in 2022. The proportion of COVID-19 deaths relative to total deaths decreased in 2022 for most countries, except Australia. Governmental control measures and vaccinations were associated with reduced excess mortality in 2021 and 2022, respectively. Conclusion The study reveals sustained excess mortality throughout 2022. Excess deaths were mainly non-COVID-19-related, likely due to displaced mortality or to broader long-term impacts of the pandemic response. Governmental control policies and vaccination efforts were associated with lower excess mortality. These findings provide critical insights into pandemic mortality dynamics and emphasize the need for continued vigilance and adaptive public health strategies
Phenotypic clustering analysis of patients rejected for mitral valve interventions: implications for future transcatheter technologies
No full textInternational audienceAims Although several treatment options are available for patients with severe mitral regurgitation (MR), a significant proportion of patients remain ineligible for any mitral valve (MV) intervention. We aimed to analyse the phenotypic characteristics of surgical high-risk patients ineligible for MV interventions using an unsupervised phenotypic clustering approach. Methods and results Between 2014 and 2022, the CHOICE-MI registry included 984 patients with MR undergoing screening for transcatheter MV replacement at 33 international sites. For this study, only patients with screening failure receiving medical therapy alone were included. Patients receiving transcatheter or surgical treatment were excluded. A cluster analysis using K-means was performed on baseline clinical, demographic, and imaging variables to identify different patient phenotypes. Among 284 patients with MR (77.4 ± 8.82 years, 56.0% female, EuroSCORE II: 6.6 ± 5.8%) considered ineligible for any MV intervention, two clinically distinct phenogroups (PGs) were identified using unsupervised hierarchical clustering of principal components: PG1, elderly women with primary MR, preserved left ventricular function, and annular calcification; and PG2, patients with secondary MR, advanced heart failure, and high prevalence of comorbidities. One-year all-cause mortality did not differ between the PGs (PG1: 21.4%, PG2: 23.4%, P = 0.89). Predictors of mortality were albumin, renal function, and extracardiac arteriopathy for PG1 and albumin, coronary artery disease, and prior myocardial infarction for PG2. Conclusion This study identified two major subgroups among patients ineligible for mitral interventions showing profound differences in clinical and anatomical profiles. Identifying these factors may drive technological evolution to address the unmet clinical need for therapeutic options in MR patients. ClinicalTrials.gov identifier NCT04688190 (CHOICE-MI Registry
Indications and contraindications to platelet‐rich plasma injections in musculoskeletal diseases in case of infectious, oncological and haematological comorbidities: A 2025 formal consensus from the GRIIP (International Research Group on Platelet Injections)
No full textInternational audiencePurpose Platelet‐rich plasma (PRP) could be a vector for certain diseases, and its composition may vary by pathologic condition. The main comorbidities that could affect PRP composition are infectious, oncologic and haematologic. In addition to potential alteration of clinical response, these pathologies could have a significant impact on the local tolerance of PRP as well as a risk of disease dissemination to the injection site. To date, there are few specific recommendations related to these comorbidities to guide clinicians. Therefore, the International Research Group on Platelet Injections (GRIIP) supported a consensus project to develop these recommendations. Methods Following the ‘recommendations by formal consensus’ methodology, a steering committee performed a literature review and drafted an initial set of recommendations. They were evaluated by an international rating group (15 specialists in musculoskeletal [MSK] diseases, five haematologists, four oncologists, three infectiologists and four scientists specialising in platelet physiology). From this rating, the first set of recommendations was discussed in a plenary meeting and then modified by the steering committee. Finally, four overarching principles and 23 recommendations were re‐evaluated by the rating group. Recommendations were classified as appropriate or not, with strong or relative agreement, or uncertain. Results From the 23 recommendations, 10 concerned infectious diseases (viral and bacterial infections; dialysis; immunosuppressive drugs; dental care…), five oncologic diseases (local tumour; cured, active or in remission cancer…) and eight haematologic diseases (cytopenia; cured, active or stabilised cured hemopathy; monoclonal gammopathy…). All were considered appropriate by the experts (median = 9; range = 8–9), with strong or relative agreement. Due to the paucity of literature data, the recommendations are mainly based on expert opinion (Grade D). Conclusion This consensus project provides four overarching principles and 23 recommendations related to contraindications of PRP injections in case of infectious, oncologic or hematologic diseases, validated by an international expert group. Level of Evidence Level I
Safety profile of JAK inhibitors in inflammatory or autoimmune diseases.
No full textInternational audienceOver the past decade, Janus kinase inhibitors (JAKi) have emerged as a promising treatment for inflammatory and autoimmune diseases. Concurrently, there has been increasing attention to their potential side effects, particularly infectious and cardiovascular risks. In this review, we outline the various adverse effects of these treatments and emphasize the importance of their prevention. First, we examine the risk of infection and the preventive measures through screening, vaccination, and prophylaxis. Subsequently, we explore the risk of developing malignant tumors, venous thromboembolism, and major cardiovascular events. Although the data are sometimes inconsistent, they indicate the existence of a subpopulation at increased risk of JAKi side effects, including patients over 65 years of age, those with cardiovascular and malignancy risk factors, and smokers. Finally, we discuss the risk and prevention strategies for gastrointestinal perforation, as well as the risk of biological abnormalities, such as cytopenias, cytolysis, dyslipidemia, and elevated CPK levels.Au cours de la dernière décennie, les inhibiteurs de Janus kinase (JAKi) sont apparus comme un traitement prometteur des maladies inflammatoires et auto-immunes. Parallèlement, leurs effets secondaires potentiels, en particulier les risques infectieux et cardiovasculaires, ont fait l’objet d’une précaution croissante. Dans cette revue, nous décrivons les différents effets indésirables de ces traitements et soulignons l’importance de leur prévention. Dans un premier temps, nous examinons le risque infectieux et les mesures préventives par le dépistage, la vaccination et la prophylaxie. Ensuite, nous explorons le risque de développer des tumeurs malignes, ainsi que des événements thromboemboliques veineuses et cardiovasculaires majeurs. Bien que les données soient parfois incohérentes, elles indiquent l’existence d’une sous-population présentant un risque accru d’effets secondaires des JAKi, notamment des patients âgés de plus de 65 ans, ceux qui présentent des facteurs de risque cardiovasculaire et de malignité, ainsi que les fumeurs. Enfin, nous discutons du risque et des stratégies de prévention des perforations gastro-intestinales et des anomalies biologiques, telles que les cytopénies, la cytolyse hépatique, les dyslipidémie et l’élévation des CPK
Toward Semiautomated Analysis of Cerebrovascular Reserve: Enhancing Objective Comparisons Using 99mTc-HMPAO SPECT With Acetazolamide in Moyamoya.
No full textInternational audienceBACKGROUND AND OBJECTIVES: Cerebrovascular reserve (CVR) is a key physiological mechanism allowing the brain to adapt to fluctuating perfusion, particularly relevant in the management of neurovascular disorders such as idiopathic (iMM) and syndromic moyamoya (sMM). Although 99mTc-HMPAO SPECT with acetazolamide is commonly used for CVR assessment, it faces limitations including low spatial resolution, artifacts, and variability in interpretation. This study primarily aims to evaluate a novel, semiautomated, and more objective method for interpreting HMPAO SPECT in CVR assessment. As a secondary objective, the method is applied to a cohort of patients who underwent revascularization surgery for iMM or sMM.METHODS: A retrospective analysis was performed on prospectively collected data from a tertiary neuroscience center, including 20 adult patients with iMM (n = 9) or sMM (n = 11). Clinical and imaging data were reviewed. 99mTc-HMPAO SPECT images were assessed independently by 2 nuclear medicine physicians blinded to clinical details. Images were registered to T1-weighted MRI and overlaid with an arterial territory atlas. Territories classified as healthy by experts were defined as true negatives; all others as altered. Statistical comparisons were made using Student's t-tests with false discovery rate correction.RESULTS: Among the 20 patients (12 females), patients with sMM were older and had more cardiovascular risk factors. The proposed method significantly discriminated between altered and healthy perfusion territories. Compared with expert interpretation, the method demonstrated specificities of 93% (iMM) and 92% (sMM), with negative predictive values of 80% and 75%%, respectively.CONCLUSION: Although 99mTc-HMPAO remains a validated modality for CVR assessment, its interpretation is operator-dependent. The proposed semiautomated method offers high specificity and greater objectivity, supporting its integration into clinical workflows. Further multicenter validation is warranted