Distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome

VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is an inflammatory disorder with hematological and systemic features. A recent study demonstrated that the dermal infiltrate in neutrophilic dermatosis from VEXAS patients is derived from the pathological UBA1-mutated myeloid clone. Neutrophilic dermatosis is, however, only one of the various skin involvements observed in VEXAS syndrome. We analyzed 10 formalin-fixed paraffin-embedded skin biopsies from genetically confirmed VEXAS syndrome. UBA1 mutation was found in the biopsies related to neutrophilic dermatitis but in none of the other histological patterns (leukocytoclastic vasculitis and septal panniculitis). This could lead to a distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome, which could in turn improve therapeutic outcomes

No detection of atypical one-base deletion of CALR exon 9 with fragment analysis: A molecular trap to avoid

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Imatinib Treatment of Chronic Myeloid Leukemia Reveals a Preexisting CALR-mutated Essential Thrombocythemia

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Sequential analysis of 18 genes in polycythemia vera and essential thrombocythemia reveals an association between mutational status and clinical outcome

International audiencePhiladelphia-negative classical myeloproliferative neoplasms (MPN) are clonal diseases characterized by driver mutations of JAK2, MPL, or CALR. Additional mutations may occur in epigenetic regulators, signaling, or splicing genes that may be useful in the prognostic assessment of MPN patients. In primary myelofibrosis, molecular-based prognostic scoring systems have been recently proposed, but few data are available to date for polycythemia vera (PV) and essential thrombocythemia (ET). In this study, we used a next generation sequencing-based 18-gene panel in 50 JAK2V617F positive PV and JAK2V617F positive ET patients from an institutional cohort investigated at diagnosis and at 3-year follow-up (3y). Disease progression at 3y was defined by a composite criterion. Patients (28 PV and 22 ET) were included according to their clinical status, with or without disease progression. At diagnosis, we found 28 additional mutations in 21 of the 50 patients. Patients with disease progression were more likely to have at least one additional mutation. There was no difference between PV and ET. All patients with two or more additional mutations exhibited disease progression at 3y. No novel mutations appeared at 3y. The allele burden increase by at least one mutation at 3y was more frequent in patients with disease progression. Our data suggest that screening for additional mutations in PV and ET could identify patients at a higher risk of disease progression

Next generation sequencing redefines a triple negative essential thrombocythaemia as double‐positive with rare mutations on JAK 2 V617 and MPL W515 hotspots

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Post-infarct cardiac remodeling predictions with machine learning

International audienceBackground: We sought to improve the risk prediction of 3-month left ventricular remodeling (LVR) occurrence after myocardial infarction (MI), using a machine learning approach.Methods: Patients were included from a prospective cohort study analyzing the incidence of LVR in ST-elevation MI in 443 patients that were monitored at Angers University Hospital, France. Clinical, biological and cardiac magnetic resonance (CMR) imaging data from the first week post MI were collected, and LVR was assessed with CMR at 3 month. Data were processed with a machine learning pipeline using multiple feature selection algorithms to identify the most informative variables.Results: We retrieved 133 clinical, biological and CMR imaging variables, from 379 patients with ST-elevation MI. A baseline logistic regression model using previously known variables achieved an AUC of 0.71 on the test set, with 67% sensitivity and 64% specificity. In comparison, our best predictive model was a neural network using seven variables (in order of importance): creatine kinase, mean corpuscular volume, baseline left atrial surface, history of diabetes, history of hypertension, red blood cell distribution width, and creatinine. This model achieved an AUC of 0.78 on the test set, reaching a sensitivity of 92% and a specificity of 55%, outperforming the baseline model.Conclusion: These preliminary results show the value of using an unbiased data-driven machine learning approach. We reached a higher level of sensitivity compared to traditional methods for the prediction of a 3-month post-MI LV

Risk of infection according to the gamma globulin level in the 100 days following allogeneic stem cell transplantations

International audienceBackground: Immunoglobulin replacement therapy is recommended in case of severe hypogammaglobulinemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the supposed increased risk of infection in case of hypogammaglobulinemia has not been confirmed in allo-HSCT. In this study, we assessed the relationship between the gamma globulin level and the risk of infection during the 100 days following the allo-HSCT.Methods: We gathered the weekly laboratory tests from day 7 to day 100 of 76 allograft patients, giving a total of 1 044 tests. 130 infections were documented clinically, by imaging, or microbiologically.Results: Average gamma globulin levels between D-7 and D100 did not differ between patients with or without infection (642 ± 232 and 671 ± 246 mg/dL, respectively, P = .65). Gamma globulin level <400 mg/dl was not associated with the occurrence of infection between the test studied and the next one (aOR 1.33 [0.84-2.15], P = .24). The gamma globulin level was not predictive of bacterial or fungal infections (AUC 0.54 [95%CI: 0.47-0.61]) nor of viral reactivations (AUC 0.51 [95%CI: 0.43-0.60]).Conclusions: This confirmed that the humoral deficiency is a minor part of the immune deficiency in the 100 days post-transplant. This questions the relevance of the indications of immunoglobulin substitution during this period

Different number of circulating CD34 + cells in essential thrombocythemia, prefibrotic/early primary myelofibrosis, and overt primary myelofibrosis

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WT1 gene is overexpressed in myeloproliferative neoplasms, especially in myelofibrosis

International audienceClassical Philadelphia-negative myeloproliferative neoplasms include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are characterized by the presence of driver mutations of JAK2, CALR or MPL genes. Overexpression of WT1 is used as a marker of minimal residual disease in acute myeloid leukemia, especially after allogeneic stem cell transplantation (SCT). We investigated WT1 expression at diagnosis in 152 MPN patients and showed that the WT1 transcript was overexpressed in PMFs and PVs compared to controls. In particular, WT1 transcript levels were higher in PMF than in ET and PV. WT1 transcript levels were significantly increased during myelofibrotic transformation of ET or PV. Using multi-variate linear regression, high WT1 transcript levels in PMF were associated with age over 65, splenomegaly and thrombocytopenia. The ROC curve analysis showed that a level of WT1 transcript > 10 WT1 copies/10 4 ABL1 enabled the diagnosis of PMF with a specificity of 95.8% (PMF vs ET; ROC AUC = 0.91). In myelofibrosis, studying follow-ups of WT1 transcript showed that this marker is of interest after allogeneic SCT. These results demonstrate that WT1 overexpression is a simple marker of myelofibrosis in MPN and could be used during patient follow-up

Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms:a pragmatic study

International audienceA high number of circulating CD34+ cells has been advocated to distinguish primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms. We reevaluated the diagnostic interest of measuring circulating CD34+ cells in 26 healthy volunteers and 256 consecutive patients at diagnosis for whom a myeloproliferative neoplasm was suspected. The ROC curve analysis showed that a number of CD34+ <10/μl excludes the diagnosis of primary myelofibrosis with a sensitivity of 97%and a specificity of 90%(area under the curve: 0.93 [0.89–0.98]; p < 0.001). Patients with PMF harboring a CALR mutation had more circulating CD34+ cells than patients with either a JAK 2 or MPL mutation (p = 0.02 and p < 0.01, respectively). These results suggest that this fast, simple, non-invasive, and standardized test is of particular interest to exclude the diagnosis of primarymyelofibrosis