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1.
J Pediatr ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33340549

RESUMO

OBJECTIVE: To describe 4 subgroups of pediatric patients treated with splenectomy, hydroxychloroquine, azathioprine, or rituximab as the first-option, second-line treatment for chronic immune thrombocytopenia. STUDY DESIGN: Selection of patients with chronic immune thrombocytopenia from the French national prospective cohort of pediatric autoimmune cytopenia OBS'CEREVANCE and VIGICAIRE study, treated by splenectomy, hydroxychloroquine, azathioprine, or rituximab as a first second-line treatment. RESULTS: For 137 patients, treated between 1989 and 2016, the median follow-up after diagnosis and after treatment initiation was 8.5 (2.8-26.4) years and 4.7 (1.1-25.1) years, respectively. Median age at diagnosis and at initiation of treatment were 9 (0.7; 16) and 12 (2; 18.1) years, respectively without significant difference between subgroups. For the whole cohort, 24-month event-free survival was 62% (95% CI 55; 71). It was 85% (95% CI 77; 95) for the 56 patients treated with splenectomy, 60% (95% CI 44; 84) for the 23 patients treated with rituximab, 46% (95% CI 30; 71) for the 24 patients treated with azathioprine, and 37% (95% CI 24; 59) for the 34 patients treated with hydroxychloroquine (log-rank P < .0001). For the splenectomy subgroup, being older than 10 years at splenectomy tended to improve event-free survival (P = .05). Female teenagers with antinuclear antibody positivity benefited from hydroxychloroquine therapy. CONCLUSIONS: This national study, limiting pitfalls in the analysis of the effects of second-line therapies, showed that splenectomy remains the treatment associated with the better response at 24 months.

2.
Science ; 369(6500): 202-207, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32647003

RESUMO

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.


Assuntos
Actinas/metabolismo , Citocinas/biossíntese , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas de Membrana/fisiologia , Fator 1 de Ribosilação do ADP/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Humanos , Síndromes de Imunodeficiência/imunologia , Transtornos Linfoproliferativos/imunologia , Proteínas de Membrana/genética , Linhagem , Fosforilação , Família de Proteínas da Síndrome de Wiskott-Aldrich/química , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo
4.
J Clin Immunol ; 40(5): 752-762, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32562208

RESUMO

BACKGROUND: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. METHODS: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. RESULTS: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. CONCLUSION: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.

6.
Blood ; 134(1): 9-21, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-30940614

RESUMO

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.


Assuntos
Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Trombocitopenia/genética , Trombocitopenia/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mutação , Adulto Jovem
7.
Sci Rep ; 8(1): 7714, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769547

RESUMO

The large number of drugs administered simultaneously to neonates and children in hospital results in the formation of particles that are potentially infused. We have investigated the ability of IV in-line filters to eliminate particulate matter from multidrug infusion lines and so prevent contamination. The impact on particle occurrence of the internal volume of the IV line below the in-line filter was then evaluated. The multidrug therapy given to children was reproduced with and without in-line filtration. Three combinations with a filter were tested to vary the internal volume (V) between the filter and the catheter egress. The catheter was then connected to a dynamic particle count to evaluate the particulate matter potentially administered to children during infusion. The introduction of in-line filters led to a significant reduction in overall particulate matter, from 416,974 [208,479-880,229] to 7,551 [1,985-11,287] particles (p < 0.001). Larger particles of ≥10 and 25 µm were also significantly reduced. Adding an extension set to the egress of the in-line filter (V = 1.7 mL) caused a significant increase in particulate contamination for both. This study showed that in-line filtration is an effective tool in preventing particle administration to patients. Their position in the infusion in-line is therefore important because of its impact on internal volume and drug particle formation.


Assuntos
Contaminação de Medicamentos/prevenção & controle , Filtração/métodos , Leucemia/tratamento farmacológico , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/química , Criança , Quimioterapia Combinada , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Tamanho da Partícula , Material Particulado/química , Preparações Farmacêuticas/administração & dosagem
8.
Eur J Haematol ; 100(1): 104-107, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29034503

RESUMO

ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia (ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH-ALL, we screened 81 unrelated subjects with HeH-ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adolescente , Análise Mutacional de DNA , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico
10.
Clin Case Rep ; 3(10): 814-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26509013

RESUMO

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.

12.
Pediatr Radiol ; 45(8): 1253-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25875633

RESUMO

Chédiak-Higashi syndrome is a rare inherited metabolic disorder characterized by partial oculocutaneous albinism, immunodeficiency, and neurological dysfunction. We present the brain magnetic resonance imaging (MRI) and MR spectroscopy (MRS) findings obtained during the accelerated phase of the disorder in an 8-year-old. The brain MRI manifestations at recurrences 15 months and 24 months later are reported as well.


Assuntos
Encéfalo/patologia , Síndrome de Chediak-Higashi/patologia , Imagem por Ressonância Magnética , Síndrome de Chediak-Higashi/tratamento farmacológico , Criança , Meios de Contraste , Ciclosporina/uso terapêutico , Dexametasona/uso terapêutico , Imagem de Difusão por Ressonância Magnética , Imagem Ecoplanar , Seguimentos , Gadolínio , Humanos , Aumento da Imagem , Imunossupressores/uso terapêutico , Espectroscopia de Ressonância Magnética , Masculino , Metotrexato/uso terapêutico , Recidiva , Resultado do Tratamento
13.
Pediatr Blood Cancer ; 62(6): 1042-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25755136

RESUMO

BACKGROUND: Drug incompatibilities, recognizable through precipitate, may have clinical consequences for patients, especially during multidrug IV therapies, where vancomycin and piperacillin are present. Drug concentration and infusion set influence the overall particulate contamination of pediatric infusion protocols. The use of multi-lumen infusion sets could prevent such incompatibilities. Our goal was to define and assess a new way to infuse these drugs during leukemia treatment in children. PROCEDURES: This in vitro study focused on a pediatric multidrug protocol for patients diagnosed with lymphoblastic leukemia and receiving allogeneic transplantation. Different vancomycin concentrations were tested to infuse incompatible drugs simultaneously without any particle formation (optimized multidrug protocol). A dynamic particle count test was used over 24 hr to evaluate the overall particulate contamination of our standard and optimized multidrug protocols, using both a standard and a multi-lumen infusion set. RESULTS: No visible particles were detected on a decreased vancomycin concentration compared to the standard dose. For the optimized multidrug protocol, the use of a multi-lumen infusion set reduced overall particulate contamination by 68%, compared to the standard infusion set (P = 0.002). Large-sized particles were significantly reduced when using the multi-lumen infusion set approximately 60% (P = 0.027) and 90% (P = 0.009) for particle sizes ≥10 µm and 25 µm, respectively. CONCLUSIONS: This study demonstrates that a large number of particles can be administered during parenteral multidrug infusion. The choice of drug concentration and/or the type of infusion set may reduce this. Further studies are required to evaluate adverse clinical effects.


Assuntos
Contaminação de Medicamentos , Incompatibilidade de Medicamentos , Humanos , Infusões Intravenosas , Tamanho da Partícula , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
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