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1.
Am J Hematol ; 98(7): 1058-1069, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37115038

RESUMO

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.


Assuntos
Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Humanos , Criança , Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Doença de Erdheim-Chester/genética , Mutação , Éxons
4.
Lancet Child Adolesc Health ; 6(4): 260-268, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34871572

RESUMO

BACKGROUND: In 2017, international guidelines proposed new management of febrile neutropenia in children with cancer, adapted to the risk of severe infection by clinical decision rules (CDRs). Until now, none of the proposed CDRs has performed well enough in high-income countries for use in clinical practice. Our study aimed to build and validate a new CDR (DISCERN-FN) to predict the risk of severe infection in children with febrile neutropenia. METHODS: We did two prospective studies. First, a prospective derivation study included all episodes of febrile neutropenia in children (aged <18 years) with a cancer diagnosis and receiving treatment for it who were admitted for an episode of febrile neutropenia, excluding patients already treated with antibiotics for this episode, febrile neutropenia not induced by chemotherapy, those receiving palliative care, and those with a stem cell allograft for less than 1 year, from April 1, 2007, to Dec 31, 2011 from two paediatric cancer centres in France. We collected the children's medical history, and clinical and laboratory data, and analysed their associations with severe infection. Sipina software was used to derive the CDR as a decision tree. Second, a prospective, national, external validation study was done in 23 centres from Jan 1, 2012, to May 31, 2016. The primary outcome was severe infection, defined by bacteraemia, a positive bacterial culture from a usually sterile site, a local infection with a high potential for extension, or an invasive fungal infection. The CDR was applied a posteriori to all episodes to evaluate its sensitivity, specificity, and negative likelihood ratio. FINDINGS: The derivation set included 539 febrile neutropenia episodes (270 episodes in patients with blood cancer [median age 7·5 years, IQR 3·7-11·2; 158 (59 %) boys and 112 (41%) girls] and 269 in patients with solid tumours [median age 6·6 years, IQR 2·9-14·2; 140 (52 %) boys and 129 (48%) girls]). Significant variables introduced into the decision tree were cancer type (solid tumour vs blood cancer), age, high-risk chemotherapy, level of fever, C-reactive protein concentration (at 24-48 h after admission), and leucocyte and platelet counts and procalcitonin (at admission and at 24-48 h after admission). For the derivation set, the CDR sensitivity was 98% (95% CI 93-100), its specificity 56% (51-61), and the negative likelihood ratio 0·04 (0·01-0·15). 1806 febrile neutropenia episodes were analysed in the validation set (mean age 8·1 years [SD 4·8], 1014 (56%) boys and 792 (44%) girls), of which 332 (18%, 95% CI 17-20) were linked with severe infection. For the validation set, the CDR had a sensitivity of 95% (95% CI 91-97), a specificity of 38% (36-41), and a negative likelihood ratio of 0·13 (0·08-0·21). Our CDR reduced the risk of severe infection to a post-test probability of 0·8% (95% CI 0·2-2·9) in the derivation set and 2·4% (1·5-3·9) in the validation set. The validation study is registered at ClinicalTrials.gov, NCT03434795. INTERPRETATION: The use of our CDR substantially reduced the risk of severe infection after testing in both the derivation and validation groups, which suggests that this CDR would improve clinical practice enough to be introduced in appropriate settings. FUNDING: Ligue Nationale Contre le Cancer.


Assuntos
Neutropenia Febril , Infecções , Neoplasias , Criança , Regras de Decisão Clínica , Árvores de Decisões , Neutropenia Febril/complicações , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Infecções/epidemiologia , Masculino , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença
5.
BMC Infect Dis ; 21(1): 1143, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749667

RESUMO

BACKGROUND: Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. CASE PRESENTATION: We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0-12 h was measured at 51 µg h/mL, which was within the therapeutic range (40-60 µg h/mL). Afterward, viral load decreased and became undetectable. CONCLUSIONS: This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.


Assuntos
Infecções por Citomegalovirus , Ganciclovir , Antivirais/uso terapêutico , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Monitoramento de Medicamentos , Ganciclovir/uso terapêutico , Humanos , Masculino , Carga Viral
7.
Pediatr Hematol Oncol ; 37(3): 259-268, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32028812

RESUMO

Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.


Assuntos
Ciclosporina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunomodulação , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Doadores de Tecidos , Quimeras de Transplante/sangue , Aloenxertos , Criança , Ciclosporina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/prevenção & controle , Masculino , Estudos Prospectivos , Recidiva
8.
Bull Cancer ; 107(1S): S62-S67, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31000319

RESUMO

Recommendations for visits or environment restrictions, and sometimes for food are usually well described for inpatient within HSCT unit procedures where those measures are less precise and detailed for outpatient from the discharge to the immune reconstitution achievement. The present paper main objective is to define risk patient groups depending on time, immune-suppressive drugs as well as graft-versus-host disease and immune reconstitution. We define here 3 risk patient groups and propose measures about house cleaning, pets, schools, social activities, hygiene, foods, sexual life and siblings.


Assuntos
Assistência ao Convalescente/normas , Transplante de Células-Tronco Hematopoéticas , Alta do Paciente/normas , Adolescente , Aloenxertos , Animais , Criança , Dieta , Suscetibilidade a Doenças , Exposição Ambiental , Relações Familiares , Feminino , Doença Enxerto-Hospedeiro/etiologia , Habitação , Humanos , Higiene , Hospedeiro Imunocomprometido , Terapia de Imunossupressão , Controle de Infecções/métodos , Controle de Infecções/normas , Relações Interpessoais , Masculino , Animais de Estimação , Medição de Risco , Instituições Acadêmicas , Comportamento Sexual
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