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1.
J Infect ; 79(2): 95-100, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228471

RESUMO

OBJECTIVE: To describe and analyze the differences between infections in children with febrile neutropenia (FN) treated for solid tumor or blood cancer. METHODS: A prospective study included all episodes of FN in children from April 2007 to April 2016 in 2-pediatric cancer centers in France. Medical history, clinical and laboratory data available at admission and final microbiological data were collected. The proportion of FN, severe infection, categories of microorganisms and outcomes were compared between the two groups. The presumed gateway of the infection was a posteriori considered and evaluated. RESULTS: We analyzed 1197 FN episodes (mean age: 8 years). 66% of the FN episodes occurred in children with blood cancer. Severe infections were identified in 23.4% of episodes overall. The rate of severe infection (28.4% vs. 10.4%), types of microorganisms and the need for a management in intensive care unit (2.6% vs. 0.5%) was significantly different between children with blood cancer and solid tumor. Digestive or respiratory presumed gateway of the infections was less frequent for patients with solid tumor. CONCLUSION: Given these important microbiological and clinical differences, it may be appropriate to consider differently the risk of severe infection in these two populations and therefore the management of FN.

2.
Br J Haematol ; 186(5): 741-753, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31124581

RESUMO

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer - Children's Leukaemia Group trials (58881 and 58951), both based on the Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the latter trial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6 mg/m2 /day) versus prednisolone (60 mg/m2 /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100 × 109 /l and "good responders" to prephase. Medac E. coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P = 0·0015] and overall survival (HR 0·51, P = 0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100 × 109 /l, representing approximately 50% of T-ALL patients.

3.
BMC Pharmacol Toxicol ; 19(1): 81, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522521

RESUMO

BACKGROUND: The use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful. CASE PRESENTATION: We describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring. CONCLUSIONS: This case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B.

4.
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).

6.
Blood ; 132(12): 1318-1331, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

7.
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.

8.
Haematologica ; 102(10): 1727-1738, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28751566

RESUMO

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.


Assuntos
Asparaginase/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Quimioterapia de Consolidação , Proteínas de Escherichia coli/administração & dosagem , Proteínas de Escherichia coli/efeitos adversos , Proteínas de Escherichia coli/uso terapêutico , Feminino , Humanos , Quimioterapia de Indução , Lactente , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
9.
Pediatr Blood Cancer ; 64(7)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27905681

RESUMO

OBJECTIVES: Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months. PROCEDURE: Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months-18 years and diagnosed with primary ITP over a 5-year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI). RESULTS: One hundred thirty-seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0-4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1-6.0), and platelet counts ≥10 × 109 /l (OR = 3.2; 95% CI = 1.5-6.9). CONCLUSIONS: In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.


Assuntos
Púrpura Trombocitopênica Idiopática/patologia , Púrpura Trombocitopênica Idiopática/terapia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França , Humanos , Lactente , Masculino , Razão de Chances , Contagem de Plaquetas , Resultado do Tratamento
10.
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
11.
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
12.
Ann Hematol ; 95(1): 93-103, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26455579

RESUMO

Acute lymphoblastic leukemia of T cell lineage (T-ALL) is an aggressive malignant disease which accounts for 15 % of childhood ALL. T(11;14) is the more frequent chromosomal abnormality in childhood T-ALL, but its prognostic value remained controversial. Our aim was to analyze the outcome of childhood T-ALL with t(11;14) to know if the presence of this translocation is associated with a poor prognosis. We conducted a retrospective study from a series of 20 patients with t(11;14), treated in two consecutive trials from the European Organization for Research and Treatment of Cancer Children Leukemia Group over a 19-year period from 1989 to 2008. There were no significant differences between the 2 consecutive groups of patients with t(11;14) regarding the clinical and biological features at diagnosis. Among 19 patients who reached complete remission, 9 patients relapsed. We noticed 7 deaths all relapse- or failure-related. In the 58881 study, a presence of t(11;14) was associated with a poor outcome with an event-free survival at 5 years at 22.2 % versus 65.1 % for the non-t(11;14) T-ALL (p = 0.0004). In the more recent protocol, the outcome of T-ALL with t(11;14) reached that of non-t(11;14) T-ALL with an event-free survival at 5 years at 65.5 versus 74.9 % (p = 0.93). The presence of t(11;14) appeared as a poor prognostic feature in the 58881 trial whereas this abnormality no longer affected the outcome in the 58951 study. This difference is probably explained by the more intensive chemotherapy in the latest trial.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Translocação Genética/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do Tratamento
13.
J Pediatr Hematol Oncol ; 37(8): e468-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26479996

RESUMO

To distinguish children with chemotherapy-induced febrile neutropenia (FN) at low risk of severe infection, the variables that are significant risk factors must be identified. Our objective was to identify them by applying evidence-based standards. This retrospective 2-center cohort study included all episodes of chemotherapy-induced FN in children in 2005 and 2006. The medical history, clinical, and laboratory data available at admission were collected. Severe infection was defined by bacteremia, a positive culture of a normally sterile body fluid, invasive fungal infection, or localized infection at high risk of extension. Univariate analysis identified potential predictive variables. A generalized mixed model was used to determine the adjusted variables that predict severe infection. We analyzed 372 FN episodes. Severe infections occurred in 16.1% of them. Variables predictive of severe infection at admission were: disease with high risk of prolonged neutropenia (adjusted odds ratio [aOR]=2.5), blood cancer (aOR=1.9), fever ≥38.5°C (aOR=3.7), and C-reactive protein level ≥90 mg/L (aOR=4.5). Now that we have identified these variables significantly associated with the risk of severe infection, they must be validated prospectively before combining the best predictive variables in a decision rule that can be used to distinguish children at low risk.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Neutropenia Febril/complicações , Infecção/epidemiologia , Adolescente , Antineoplásicos/efeitos adversos , Biomarcadores , Proteína C-Reativa/análise , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Conjuntos de Dados como Assunto/estatística & dados numéricos , Medicina Baseada em Evidências/normas , Neutropenia Febril/sangue , Neutropenia Febril/induzido quimicamente , Feminino , França/epidemiologia , Unidades Hospitalares/estatística & dados numéricos , Hospitais Universitários/estatística & dados numéricos , Humanos , Lactente , Infecção/sangue , Infecção/etiologia , Masculino , Análise Multivariada , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Curva ROC , Estudos Retrospectivos , Risco , Estatísticas não Paramétricas , Centros de Atenção Terciária/estatística & dados numéricos
14.
Front Pediatr ; 3: 79, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26484337

RESUMO

Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2-17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1-16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1-28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7-28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies.

15.
Haematologica ; 100(10): 1311-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26137961

RESUMO

DNA copy number analysis has been instrumental for the identification of genetic alterations in B-cell precursor acute lymphoblastic leukemia. Notably, some of these genetic defects have been associated with poor treatment outcome and might be relevant for future risk stratification. In this study, we characterized recurrent deletions of CD200 and BTLA genes, mediated by recombination-activating genes, and used breakpoint-specific polymerase chain reaction assay to screen a cohort of 1154 cases of B-cell precursor acute lymphoblastic leukemia uniformly treated according to the EORTC-CLG 58951 protocol. CD200/BTLA deletions were identified in 56 of the patients (4.8%) and were associated with an inferior 8-year event free survival in this treatment protocol [70.2% ± 1.2% for patients with deletions versus 83.5% ± 6.4% for non-deleted cases (hazard ratio 2.02; 95% confidence interval 1.23-3.32; P=0.005)]. Genetically, CD200/BTLA deletions were strongly associated with ETV6-RUNX1-positive leukemias (P<0.0001), but were also identified in patients who did not have any genetic abnormality that is currently used for risk stratification. Within the latter population of patients, the presence of CD200/BTLA deletions was associated with inferior event-free survival and overall survival. Moreover, the multivariate Cox model indicated that these deletions had independent prognostic impact on event-free survival when adjusting for conventional risk criteria. All together, these findings further underscore the rationale for copy number profiling as an important tool for risk stratification in human B-cell precursor acute lymphoblastic leukemia. This trial was registered at www.ClinicalTrials.gov as #NCT00003728.


Assuntos
Antígenos CD/genética , Deleção de Genes , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores Imunológicos/genética , Adolescente , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Ensaios Clínicos como Assunto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Recidiva
16.
Eur J Cancer ; 50(18): 3206-11, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25459396

RESUMO

PURPOSE: The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. METHODS: Retrospective data from 81 children less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). RESULTS: A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall (p < 10(-4)) irrespective of gender and pubertal age. The height SDS was significantly (p < 10(-4)) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. CONCLUSION: Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents.


Assuntos
Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Transtornos do Crescimento/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Adolescente , Estatura/efeitos dos fármacos , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Mesilato de Imatinib , Lactente , Masculino , Estudos Retrospectivos
17.
Blood ; 124(15): 2408-10, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25170123

RESUMO

Studies in adults have shown that an early molecular response to imatinib predicts clinical outcome in chronic myeloid leukemia (CML). We investigated the impact of the BCR-ABL1 transcript level measured 3 months after starting imatinib in a cohort of 40 children with CML. Children with a BCR-ABL1/ABL ratio higher than 10% at 3 months after the start of imatinib had a larger spleen size and a higher white blood cell count compared with those with BCR-ABL1/ABL ≤10%. Children with BCR-ABL1/ABL ≤10% 3 months after starting imatinib had higher rates of complete cytogenetic response and major molecular response at 12 months compared with those with BCR-ABL1/ABL >10%. With a median follow-up of 71 months (range, 22-96 months), BCR-ABL1/ABL ≤10% correlated with better progression-free survival. Thus, early molecular response at 3 months predicts outcome in children treated with imatinib for CML. This trial was registered at www.clinicaltrials.gov as #NCT00845221.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Benzamidas/uso terapêutico , Criança , Pré-Escolar , Análise Citogenética , Intervalo Livre de Doença , França , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Lactente , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico
18.
Pediatr Blood Cancer ; 61(10): 1786-91, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24975886

RESUMO

BACKGROUND: Clinical decision rules (CDRs) have sought to identify the few children with chemotherapy-induced febrile neutropenia (FN) really at risk of severe infection to reduce the invasive procedures and costs for those at low risk. Several reports have shown that most rules do not perform well enough to be clinically useful. Our objective was to analyze the derivation methods and validation procedures of these CDRs. PROCEDURE: A systematic review using Medline, Ovid, Refdoc, and the Cochrane Library through December 2012 searched for all CDRs predicting the risk of severe infection and/or complications in children with chemotherapy-induced FN. Their methodological quality was analyzed by 17 criteria for deriving and validating a CDR identified in the literature. The criteria published by the Evidence Based Medicine Working Group were applied to the published validations of each CDR to assess their level of evidence. RESULTS: The systematic research identified 612 articles and retained 12 that derived CDRs. Overall, the CDRs met a median of 65% of the methodological criteria. The criteria met least often were that the rule made clinical sense, or described the course of action, or that the variables and the CDR were reproducible. Only one CDR, developed in South America, met all methodological criteria and provided the highest level of evidence; unfortunately it was not reproducible in Europe. CONCLUSION: Only one CDR developed for children with FN met all methodological standards and reached the highest level of evidence.


Assuntos
Técnicas de Apoio para a Decisão , Neutropenia Febril/terapia , Oncologia/normas , Pediatria/normas , Antineoplásicos/efeitos adversos , Criança , Neutropenia Febril/induzido quimicamente , Humanos
19.
Haematologica ; 99(7): 1220-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24727815

RESUMO

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Feminino , Humanos , Imunofenotipagem , Quimioterapia de Indução , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisolona/administração & dosagem , Fatores de Risco , Resultado do Tratamento
20.
Pediatr Infect Dis J ; 32(9): 962-4, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23629023

RESUMO

The study through Monte Carlo simulation of ß-lactam pharmacokinetic/pharmacodynamic target attainment and determination of subsequent serum concentrations of piperacillin-tazobactam administered through continuous infusion to children treated for fever and neutropenia shows that 400 mg/kg/day has the highest probability of target attainment against Pseudomonas aeurginosa in our oncology ward compared with the standard regimen of 300 mg/kg/day.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Febre de Causa Desconhecida/tratamento farmacológico , Neutropenia/tratamento farmacológico , Ácido Penicilânico/análogos & derivados , Infecções por Pseudomonas/tratamento farmacológico , Adolescente , Antibacterianos/farmacologia , Criança , Feminino , Febre de Causa Desconhecida/complicações , Humanos , Infusões Intravenosas/métodos , Masculino , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/administração & dosagem , Piperacilina/farmacocinética , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Resultado do Tratamento
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