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1.
Am J Med Genet A ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471951

RESUMO

In this study, we describe the biological immune profiles and clinical dysimmune manifestations (infections, autoimmune diseases, and allergies) of patients with 22q11.2 deletion syndrome with the aim of determining risk factors for clinical events. This retrospective study concerned all the patients with 22q11 deletion syndrome attending the Montpellier University Hospital from January 1, 1992, to December 31, 2014 who had at least one immune investigation before the age of 18. We analyzed the clinical features, biological tests and the course of infections, autoimmunity, and allergy of 86 children. Among these 86 children, 48 (59%) had a low T lymphocyte level. Twenty-nine patients (34%) had a severe infection. The only risk factor for severe infection was the low level of CD4+ T-cells (OR: 3.3; 95% confidence interval (CI) [1.020-11.108]). Eleven patients (13%) developed an autoimmune disease; the only risk factor was an antecedent of severe infection (OR: 4.1; 95% CI [1.099-15.573]). Twenty-three patients (27%) had allergic episodes. A low level of CD8+ T-cells (OR: 3.2; 95% CI [1.07-9.409]) was significantly associated with allergy manifestations. Patients with 22q11 deletion syndrome have a high rate of dysimmune manifestations. We found statistic correlations among CD4+ T-cell count, infectious manifestations, and autoimmunity.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31378693

RESUMO

INTRODUCTION: Acute bronchiolitis epidemics are known to destabilize healthcare structures and stand as a major public health issue. Our tertiary care regional university hospital designed an organizational infrastructure paediatric plan (OIPP) to adapt to bronchiolitis epidemics. This study aimed to assess the impact of the OIPP on the length of stay and quality of care of children hospitalized for bronchiolitis. METHODS: This epidemiological study analyzed data from 2 epidemic seasons before and after the OIPP implementation. The OIPP used a standardized algorithm of patient orientation and a 4-level stratification of care. RESULTS: A total of 1636 children were included in the study, with 718 children before and 918 children after the OIPP implementation. The length of stay significantly decreased after the OIPP implementation, from 5.1±6.8 days to 3.9±3 days (P<0.001). The 30-day readmission for bronchiolitis remained stable (4.6% vs. 3.4%, P=0.2). The net annual patient service revenue increased from 1,292,532 € to 1,545,720 €. CONCLUSION: The implementation of the OIPP resulted in a significant decrease in the average hospital length of stay. This plan improved patients' quality of care while maintained a balanced budget. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03663660.

3.
J Clin Immunol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401750

RESUMO

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

4.
Blood ; 134(1): 9-21, 2019 Jul 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.

5.
Br J Haematol ; 183(4): 608-617, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30421536

RESUMO

Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV 600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV 600E mutation was present compared to 2·9% if it was absent (P = 0·002).

7.
J Crohns Colitis ; 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29788237

RESUMO

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases (VEO-IBD). The present study aimed at defining how next-generation sequencing (NGS) methods can be used to improve identification of known molecular diagnosis and adapt treatment. Methods: 207 children were recruited in 45 Paediatric centres through an international collaborative network (ESPGHAN GENIUS working group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesis suggestive of a monogenic disorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing (WES) of parents-child trios. Genetic findings were validated clinically and/or functionally. Results: Molecular diagnosis was achieved in 66/207 children (32%): 61% with small bowel inflammation, 39% with colitis and perianal lesions and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variations previously missed by WES. Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.

8.
World J Pediatr ; 14(1): 35-43, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29442252

RESUMO

BACKGROUND: In children, surveys on Staphylococcus aureus have focused on specific infections, situations or strains but no study has so far given an overview on S. aureus isolation without any selection. Here, we describe the overall bacteriological and clinical characteristics of S. aureus isolation in children, with a special focus on isolates harbouring tst, sea, and/or luk-PV genes, respectively, encoding the three clinically relevant toxins: toxic shock syndrome toxin-1, enterotoxin A and Panton-Valentine leukocidin. METHODS: Data associated with S. aureus isolation were reviewed: isolation site, infection status, tst, sea and luk-PV genes, antimicrobial susceptibility pattern, agr typing. RESULTS: Three hundred and seventy-seven isolates retrieved from 328 children during S. aureus infection (55.2%) or colonisation (44.8%) were included. tst, sea and luk-PV genes were amplified in 14.3, 9.5 and 5.8% of the isolates, respectively. These isolates were significantly more frequently retrieved during infection (69.1%) than colonisation but differences were observed according to isolation site. Methicillin-resistance was found in 7.2% of the isolates, 78% of which harboured ≥ 1 of the targeted toxin-encoding genes. CONCLUSIONS: This first comprehensive study of S. aureus in children showed S. aureus to be mainly retrieved during infection and a high rate of colonisation, not limited to the nasopharynx. Predominant infections were skin and soft tissue infections where tst was most frequently detected. luk-PV was most commonly detected during bone and joint infections. Isolates harbouring targeted toxin-encoding genes were significantly associated with infections but a quarter of children were asymptomatic carriers representing a reservoir for dissemination of isolates with virulence potency.


Assuntos
Antibacterianos/farmacologia , Toxinas Bacterianas/genética , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/isolamento & purificação , Distribuição por Idade , Toxinas Bacterianas/metabolismo , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Resistência Microbiana a Medicamentos , Feminino , França/epidemiologia , Inquéritos Epidemiológicos , Hospitais Universitários , Humanos , Incidência , Lactente , Pacientes Internados/estatística & dados numéricos , Masculino , Testes de Sensibilidade Microbiana , Pacientes Ambulatoriais/estatística & dados numéricos , Medição de Risco , Distribuição por Sexo , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Estatísticas não Paramétricas
9.
Clin Immunol ; 188: 52-57, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29330115

RESUMO

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C>T; c.109+1092_568-512del; c.110-2A>G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450+1C>T), STAT3 gain-of-function (c.2147C>T; c.2144C>T) and KRAS (c.37G>T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.

10.
J Pediatr ; 194: 211-217.e5, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29198545

RESUMO

OBJECTIVE: To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life. STUDY DESIGN: The French Reference Center for PIDs conducted a prospective multicenter cohort that enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms. RESULTS: Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions. CONCLUSIONS: Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35.

11.
Br J Haematol ; 177(5): 751-758, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28444729

RESUMO

Childhood autoimmune haemolytic anaemia (AIHA) requires second-line immunosuppressive therapy in 30-50% of cases. It appears that rituximab is indicated in such circumstances. This prospective national study reports the practice, efficacy and tolerance of rituximab in children with isolated AIHA and AIHA in the setting of Evans syndrome (ES). Sixty-one children were given rituximab between 2000 and 2014. The median interval from diagnosis to rituximab was 9·9 [interquartile range (IQR) 1·6-28·5] months. Forty-six patients responded (75%) and the 6-year relapse-free survival (RFS) was 48%. Twenty patients relapsed at a median interval of 10·8 (IQR 3·9-18·7) months, rituximab allowed steroid withdrawal in 44/61 (72%) of children. In isolated AIHA, complete response and 6-year RFS were significantly higher than in ES (P < 0·05). Ten out of 61 patients were infants, seven of who responded with a 6-year RFS of 71%. Among patients without immunoglobulin substitution before rituximab, 4 are still receiving substitutions. Five patients died, including one potentially attributable to rituximab. This large observational series of childhood AIHA established the rituximab benefit-risk ratio, allowing steroid withdrawal, with 37% of long-term responders, mainly in isolated AIHA. All subgroups of patients drew benefit. Our long-term results indicate the baseline to be challenged by new treatment approaches.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Hematínicos/uso terapêutico , Rituximab/uso terapêutico , Adolescente , Transfusão de Sangue/estatística & dados numéricos , Criança , Pré-Escolar , Substituição de Medicamentos , Feminino , França , Humanos , Masculino , Estudos Prospectivos , Esteroides/uso terapêutico , Resultado do Tratamento
12.
Br J Haematol ; 178(3): 457-467, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28444728

RESUMO

The BRAFV600E mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAFV600E allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAFV600E -mutated LCH were investigated to detect ccf BRAFV600E at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAFV600E was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0·001, Fisher's exact test). The positive BRAFV600E load was higher for RO+ patients (mean, 2·90%; range, 0·04-11·4%) than for RO- patients (mean, 0·16%; range, 0·01-0·39) (P = 0·003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAFV600E compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0·002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAFV600E load at day 15. Thus, ccf BRAFV600E is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Proteínas Proto-Oncogênicas B-raf/sangue , Adolescente , Alelos , Biomarcadores/sangue , Sistema Livre de Células/metabolismo , Criança , Pré-Escolar , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Humanos , Indóis/uso terapêutico , Lactente , Masculino , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/uso terapêutico , Vemurafenib , Vimblastina/uso terapêutico
13.
J Allergy Clin Immunol ; 139(4): 1275-1281.e7, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27697497

RESUMO

BACKGROUND: Most children with primary immunodeficiencies (PIDs) now reach adulthood. However, few studies have evaluated their health status and health-related quality of life (HRQoL). OBJECTIVE: To investigate long-term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the French Childhood Immune Deficiency Long-term Cohort. The data collected were used to assess the physical health condition of patients who reached adulthood and the effect on their quality of life. METHODS: Patients were asked to complete health status questionnaires. A severity score (grade 1 [mild] to grade 4 [life-threatening]) was assigned to each health condition. The HRQoL of patients was compared with age- and sex-matched French normal values by using the 36-item Short-Form Survey (SF-36) HRQoL questionnaire. RESULTS: Among 329 participants, the mean age at evaluation was 27.6 years, with a 21-year mean follow-up after diagnosis; 43% reported at least 1 grade 4 health condition, and 86% reported at least 1 grade 3 (severe) or 4 health condition. Twenty-five (7.6%) patients had been treated for cancer. Compared with the French normal values, adults with PIDs scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3-4 health conditions was highly significant for all physical and mental domains. CONCLUSION: Adults with PIDs diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population.


Assuntos
Nível de Saúde , Síndromes de Imunodeficiência/complicações , Qualidade de Vida , Adulto , Idade de Início , Criança , Estudos de Coortes , Feminino , França , Humanos , Masculino , Inquéritos e Questionários , Tempo
14.
Ann Rheum Dis ; 76(7): 1191-1198, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27965258

RESUMO

OBJECTIVES: Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. METHODS: To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. RESULTS: We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. CONCLUSIONS: We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. TRIAL REGISTRATION NUMBER: NCT02067962; Results.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Artrite Juvenil/genética , Doenças Autoimunes/genética , Doenças Hereditárias Autoinflamatórias/genética , Dermatopatias/genética , Adolescente , Grupo com Ancestrais do Continente Africano , Argélia , Artrite Juvenil/complicações , Artrite Juvenil/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Caspase 1/imunologia , Criança , Consanguinidade , Grupo com Ancestrais do Continente Europeu , Feminino , Doenças Hereditárias Autoinflamatórias/complicações , Doenças Hereditárias Autoinflamatórias/imunologia , Homozigoto , Humanos , Interleucina-18/imunologia , Masculino , Mutação , Países Baixos , Células Precursoras de Linfócitos B/imunologia , Dermatopatias/complicações , Dermatopatias/imunologia , Síndrome
15.
Blood Adv ; 1(21): 1815-1826, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-29296828

RESUMO

Thrombopoietin (Tpo) and its receptor (Mpl) are the principal regulators of early and late thrombopoiesis and hematopoietic stem cell maintenance. Mutations in MPL can drastically impair its function and be a contributing factor in multiple hematologic malignancies, including congenital amegakaryocytic thrombocytopenia (CAMT). CAMT is characterized by severe thrombocytopenia at birth, which progresses to bone marrow failure and pancytopenia. Here we report unique familial cases of CAMT that presented with a previously unreported MPL mutation: T814C (W272R) in the background of the activating MPL G117T (K39N or Baltimore) mutation. Confocal microscopy, proliferation and surface biotinylation assays, co-immunoprecipitation, and western blotting analysis were used to elucidate the function and trafficking of Mpl mutants. Results showed that Mpl protein bearing the W272R mutation, alone or together with the K39N mutation, lacks detectable surface expression while being strongly colocalized with the endoplasmic reticulum (ER) marker calreticulin. Both WT and K39N-mutated Mpl were found to be signaling competent, but single or double mutants bearing W272R were unresponsive to Tpo. Function of the deficient Mpl receptor could be rescued by using 2 separate approaches: (1) GRASP55 overexpression, which partially restored Tpo-induced signaling of mutant Mpl by activating an autophagy-dependent secretory pathway and thus forcing ER-trapped immature receptors to traffic to the cell surface; and (2) CRISPR-Cas9 gene editing used to repair MPL T814C mutation in transfected cell lines and primary umbilical cord blood-derived CD34+ cells. We demonstrate proof of principle for rescue of mutant Mpl function by using gene editing of primary hematopoietic stem cells, which indicates direct therapeutic applications for CAMT patients.

17.
J Clin Oncol ; 34(25): 3023-30, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27382093

RESUMO

PURPOSE: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS: BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. RESULTS: Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). CONCLUSION: In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Corticosteroides/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , França/epidemiologia , Histiocitose de Células de Langerhans/enzimologia , Histiocitose de Células de Langerhans/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sistema de Registros , Vimblastina/administração & dosagem
18.
Br J Haematol ; 174(6): 887-98, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27273725

RESUMO

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.


Assuntos
Histiocitose de Células de Langerhans/epidemiologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , França/epidemiologia , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Vigilância da População , Padrão de Cuidado , Análise de Sobrevida , Resultado do Tratamento
19.
Viruses ; 8(3): 86, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-27102168

RESUMO

Mammalian retroviruses cause a variety of diseases in their hosts, including hematological and immunodeficiency disorders. Both human T-cell leukemia (HTLV) and human immunodeficiency (HIV) viruses originated from several independent zoonotic transmissions, indicating that cross-species transmissions from animal to humans may still occur. Thus, as the risk for retroviral transmissions from animals to humans increase, we investigated whether mammalian retroviruses are involved in selected pediatric idiopathic diseases whose symptoms evoke retroviral infections. Blood samples, sera, and synovial fluids, or bone marrow cells were collected from pediatric patients under 18 years of age with different autoimmune idiopathic diseases. Overall, we screened clinical samples from 110 children using sensitive nested and semi-nested PCR strategies targeting env genes, and a C-type retrovirus reverse transcriptase (RT) activity kit. All clinical samples were free of retroviral signatures, indicating the unlikelihood of an etiological role of the retroviruses we assessed in the pediatric diseases we tested.


Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/patologia , Infecções por Retroviridae/patologia , Infecções por Retroviridae/virologia , Retroviridae/isolamento & purificação , Adolescente , Criança , Pré-Escolar , Produtos do Gene env/genética , Humanos , Lactente , Reação em Cadeia da Polimerase , DNA Polimerase Dirigida por RNA/análise , Retroviridae/genética
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