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A low allele burden (i.e., <20%) of the CALR driver mutation is found in 10.8% of CALR-mutated MPNs, mostly in essential thrombocythemia, and correlates with a milder phenotype and a more indolent evolution compared to patients with an allele burden ≥20%.
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Trombocitemia Essencial , Humanos , Alelos , Calreticulina/genética , Janus Quinase 2/genética , Mutação , Fenótipo , Trombocitemia Essencial/genéticaAssuntos
Leucemia Linfocítica Granular Grande , Receptores de Antígenos de Linfócitos T gama-delta , Neoplasias Esplênicas , Idoso , Humanos , Genômica/métodos , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/patologia , Leucemia Linfocítica Granular Grande/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologiaRESUMO
The aim of this study was to evaluate how comorbidities and molecular landscape relate to outcome in patients with acute myeloid leukemia (AML) aged 60 years or older who received intensive induction therapy. In 91 patients, 323 mutations were identified in 77 genes by next-generation sequencing, with a median of four mutations per patient, with NPM1, FLT3, TET2, and DNMT3A being the most frequently mutated genes. A multistate model identified FLT3, IDH2, RUNX1, and TET2 mutations as associated with a higher likelihood of achieving complete remission while STAG2 mutations were associated with primary refractory disease, and DNMT3A, FLT3, IDH2, and TP53 mutations with mortality after relapse. Ferrara unfitness criteria and performance status were the best predictors of short-term outcome (area under the curve = 82 for 2-month survival for both parameters), whereas genomic classifications better predicted long-term outcome, with the Patel risk stratification performing the best over the 5-year follow-up period (C-index = 0.63 for event-free and overall survival). We show that most genomic prognostic classifications, mainly used in younger patients, are useful for classifying older patients, but to a lesser extent, because of different mutational profiles. Specific prognostic classifications, incorporating performance status, comorbidities, and cytogenetic/molecular data, should be specifically designed for patients over 60 years.
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Leucemia Mieloide Aguda , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Fatores de Risco , Mutação , PrognósticoRESUMO
In order to standardize cellular hematology practices, the French-speaking Cellular Hematology Group (Groupe Francophone d'Hématologie Cellulaire, GFHC) focused on Perls' stain. A national survey was carried out, leading to the proposal of recommendations on insoluble iron detection and quantification in bone marrow. The criteria presented here met with a "strong professional agreement" and follow the suggestions of the World Health Organization's classification of hematological malignancies.
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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.
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BACKGROUND: 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 LVR.
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Infarto do Miocárdio com Supradesnível do Segmento ST , Remodelação Ventricular , Humanos , Aprendizado de Máquina , Imagem Cinética por Ressonância Magnética , Valor Preditivo dos Testes , Estudos Prospectivos , Função Ventricular EsquerdaRESUMO
BACKGROUND: 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.
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Transplante de Células-Tronco Hematopoéticas/métodos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/terapia , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicas/terapia , Infecções Oportunistas/diagnóstico , Idoso , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Leucemia/imunologia , Leucemia/patologia , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Micoses/diagnóstico , Micoses/imunologia , Micoses/microbiologia , Agonistas Mieloablativos/uso terapêutico , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/microbiologia , Infecções Oportunistas/virologia , Prognóstico , Curva ROC , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Ativação Viral/efeitos dos fármacos , gama-Globulinas/metabolismoRESUMO
We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
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Mielofibrose Primária , Teorema de Bayes , Genômica , Humanos , Mutação , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Prognóstico , Proteínas Repressoras/genéticaAssuntos
Biomarcadores Tumorais/genética , Éxons , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/patologia , Policitemia Vera/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , França , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Policitemia Vera/genética , Prognóstico , Taxa de SobrevidaRESUMO
Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.
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Transtornos Mieloproliferativos , Policitemia Vera , Trombocitemia Essencial , Genômica , Humanos , Mutação , Policitemia Vera/genética , Trombocitemia Essencial/genéticaRESUMO
In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.
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Calreticulina/genética , Transtornos Mieloproliferativos/genética , Trombocitose/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Progressão da Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Adulto JovemRESUMO
Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient's DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p < 0.001). An increase in the percentage of recipient DNA in CD3-negative cells was associated with an increased risk of relapse (p < 0.001) but not with overall survival. Comparable performances between monitoring of CD3-negative cell chimerism and WT1 expression to predict relapse was observed up to more than 90 days before hematological relapse, with sensitivity of 82% and 78%, respectively, and specificity of 100% for both approaches. Quantitative specific chimerism of the CD3-negative mononuclear fraction, enriched in blastic cells, is a new and powerful tool for monitoring measurable residual disease and could be used for AML patients without available molecular markers.
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Biomarcadores Tumorais/metabolismo , Complexo CD3/metabolismo , Quimerismo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/patologia , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/metabolismo , Neoplasia Residual/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Proteínas WT1/metabolismo , Adulto JovemRESUMO
Classical 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 multivariate 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/104ABL1 enabled the diagnosis of PMF with a specificity of 95.8% (PMF vs ET; ROC AUCâ¯=â¯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.
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Transtornos Mieloproliferativos/diagnóstico , Mielofibrose Primária/diagnóstico , Proteínas WT1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Policitemia Vera , RNA Mensageiro/sangue , Curva ROC , Trombocitemia EssencialRESUMO
Philadelphia-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. © 2017 Wiley Periodicals, Inc.
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Biomarcadores Tumorais/genética , Mutação/genética , Policitemia Vera/genética , Policitemia Vera/patologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Estudos de Coortes , Progressão da Doença , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Janus Quinase 2/genética , PrognósticoRESUMO
An acute myeloid leukemia was diagnosed in a 53-year-old female patient. She received an allogeneic stem cell transplant. After this transplant, some neutrophils with hyposegmented nucleus and abnormal chromatin clumping appeared in the peripheral blood, and their number gradually increased. The hypothesis of early relapse after transplant was ruled out and drug-related anomaly was suspected. The authors discuss about morphological features of constitutional and acquired Pelger-Huët anomaly. In the patient reported here, ciclosporine seemed to be involved in the phenomenon, as the morphological anomaly of the neutrophils gradually decreased after the drug was discontinued.