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1.
Blood Adv ; 3(13): 1981-1988, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31270080

RESUMO

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αß lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% (P = .177).

2.
Int J Cancer ; 145(11): 2907-2916, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30697705

RESUMO

Neuroblastoma (NB) is the most common extra-cranial tumour in children. Little is known about the aetiology of NB. The early age at onset and the embryonic nature suggest a role for perinatal exposures. We conducted a pooled analysis of two French national population-based case-control studies to explore whether there was an association between parental smoking and alcohol consumption and the risk of NB. The mothers of 357 NB cases and 1,783 controls from general population, frequency matched by age and sex, were interviewed on demographic, socioeconomic and perinatal characteristics, maternal reproductive story, and life-style and childhood environment. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. A meta-analysis of our findings with those of previous studies was also conducted. Maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 [95% CI 0.9-1.7]; summary OR from meta-analysis 1.1 [95% CI 1.0-1.3]. Paternal smoking in the year before child's birth were not associated with NB as independent exposure (OR 1.1 [95% CI 0.9-1.4] but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 [95% CI 1.1-2.1]. No association was observed with maternal alcohol intake during pregnancy (OR 1.0 [95% CI 0.8-1.4], summary OR from meta-analysis 1.0 [95% CI 0.9-1.2]. Our findings provide some evidence of an association between maternal smoking during pregnancy and NB and add another reason to recommend that women refrain from smoking during pregnancy.

3.
Leukemia ; 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089916

RESUMO

Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64-6.82), P < 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38-8.92), P = 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63-7.16), P = 0.001; OS HR = 3.02 (95%CI = 1.16-7.85), P = 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.

5.
Aesthetic Plast Surg ; 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29750320

RESUMO

BACKGROUND: Brachioplasties often culminate in unsightly scars that are a source of disappointment to patients. We aimed to evaluate the results of M-Y axilloplasty following massive weight loss. PATIENTS: We performed a retrospective assessment of our technique for brachioplasty with an M-Y axilloplasty in 159 female patients after massive weight loss. This retrospective study covered a study period of 10 years. METHOD: After substantial lipoaspiration, the incision is placed on the internal side of the arm, with an M-shaped axilloplasty. RESULTS: The satisfaction rate was 154/159 (97%) and 120/159 (75.5%) being happy with their esthetic results. Nineteen percent (30/159) of the patients had complications and 12/159 (7.5%) underwent a surgical revision. CONCLUSION: M-Y axilloplasty for brachioplasty is an effective procedure for treating women who are unhappy with their upper arms after massive weight loss. The satisfaction rate is high, and the result leaves no excess skin on the chest. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

6.
Blood ; 132(2): 187-196, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29692343

RESUMO

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (KIT, NRAS, KRAS, FLT3, JAK2, CBL). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age (P = .004) and inv(16) subtype (P = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference (P = .14). The repertoire of KIT, FLT3, and NRAS/KRAS variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival (P < 10-4), whereas the presence of a single signaling clone did not (P = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.

7.
Oncotarget ; 9(5): 6478-6489, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464086

RESUMO

Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. ZBTB7A mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. FOXP1 focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried FOXP1 truncating mutations. Finally, CCDC26 disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.

8.
EMBO Mol Med ; 10(2): 188-199, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29282224

RESUMO

Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild-type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27-dependent proliferation toward CD70-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes.

9.
J Pediatr Hematol Oncol ; 40(1): 43-47, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29189507

RESUMO

Central nervous system (CNS) involvement at diagnosis of pediatric acute myeloid leukemia (AML) is not considered as an independent prognostic factor. This study describes the prognostic value of pediatric AML with CNS involvement at diagnosis. Pediatric patients were treated for de novo AML in the French multicenter trial ELAM02. Lumbar puncture was carried out in the first week, and the treatment was adapted to the CNS status. No patient received CNS radiotherapy. The patients were classified into 2 groups: CNS+ and CNS-. Of the 438 patients, 16% (n=70) had CNS involvement at diagnosis, and 29% showed clinical signs. The patients with CNS disease were younger (40% were below 2 y old), had a higher white blood cell count (median of 45 vs. 13 G/L), and had M4 and M5 morphologies. The complete remission rate was similar at 92.8% for CNS+ and 88.5% for CNS-. There was no significant difference between the CNS+ and the CNS- group in overall survival (76% and 71%, respectively) and event-free survival (57% and 52%, respectively). Regarding the occurrence of first relapse, the CNS+ group had a higher combined relapse rate of 26.1% compared with 10% for the CNS- group. The results indicate that CNS involvement at diagnosis of pediatric AML is not an independent prognostic factor. Triple intrathecal chemotherapy combined with high-dose intravenous cytarabine should be the first-line treatment for CNS disease.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Prognóstico , Adolescente , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , Citarabina/administração & dosagem , França , Humanos , Lactente , Leucemia Monocítica Aguda , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Aguda , Contagem de Leucócitos , Recidiva , Análise de Sobrevida
10.
Blood ; 131(7): 717-732, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29146883

RESUMO

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

11.
Blood ; 131(3): 289-300, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29051182

RESUMO

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10-4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10-4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/L, gLoR classifier, and MRD <10-4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.

12.
Rev Prat ; 68(4): 426-430, 2018 Apr.
Artigo em Francês | MEDLINE | ID: mdl-30869394

RESUMO

Pediatric lumbar puncture : indications, execution and complications. Lumbar puncture (LP) is a commonly performed procedure with specific indications and technical considerations in pediatrics. The principal indication is for the diagnosis of central nervous system infection, but in case of meningitis in infants, nuchal rigidity may be absent and the clinical picture is more likely to be marked by axial hypotonia associated with abnormal behavior and/or a bulging fontanel. Pharmacological agents and non-pharmacological techniques (reassuring approach, distraction, presence of a parent) should be used whenever possible, to create successful environmental conditions for the completion of the LP procedure in childhood. During the procedure, the LP needle should be moved forward slightly and perpendicularly to the patient's back, and the stylet should be removed regularly to check CSF reflux, as resistance related to the spinal ligaments and dura mere are often absent in young children. In children, post-LP headaches may be prevented by the use of atraumatic and/or the smallest LP needle, and the replacement of the stylet prior to needle removal.


Assuntos
Punção Espinal , Criança , Pré-Escolar , Humanos , Lactente , Agulhas
14.
J Pediatr Hematol Oncol ; 39(5): 365-369, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28486259

RESUMO

To study the management of acute appendicitis in neutropenic patients, we retrospectively reviewed cases of acute appendicitis in neutropenic children treated for cancer. The patients' demographics, medical records, and outcomes were tracked. We compared nonoperative treatment versus emergency or delayed surgery. The cases of 30 patients with a mean age of 8.8 years in 12 French departments of Pediatric Hematology/Oncology between 1995 and 2013 were studied. Most patients (90%) were treated for hematological malignancies. Seven of the 30 children were successfully treated with exclusive medical treatment. Early surgery was performed in 6 patients, and the remaining 17 underwent combined management with a first-line antibiotic treatment and delayed appendectomy. Treatments were successful in all cases with transitory complications in only 3 patients. No death linked to infection was reported. Surgery was well tolerated even in the neutropenic period. Appendix perforation was a major risk factor of prolonged hospitalization. Histologic as well as bacteriologic and mycologic/parasitologic analyses were required in case of surgery. Analysis of diagnostic assessments showed the major importance of imaging (ultrasonography and tomography) on diagnosis confirmation. We could not come to a conclusion in the few numbers of reviewed cases because of a significant difference in management strategies, but we can conclude that early surgery after adequate supportive care is an acceptable modality of treatment and must be chosen in the face of life-threatening conditions.


Assuntos
Apendicite/complicações , Apendicite/terapia , Neutropenia/complicações , Adolescente , Apendicite/cirurgia , Criança , Pré-Escolar , Diagnóstico por Imagem , Feminino , Humanos , Lactente , Tempo de Internação , Masculino , Estudos Retrospectivos , Tempo para o Tratamento , Resultado do Tratamento
15.
Cancer Cell ; 31(3): 452-465, 2017 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-28292442

RESUMO

Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.


Assuntos
Leucemia Megacarioblástica Aguda/patologia , Proteínas de Fusão Oncogênica/fisiologia , Ativação Transcricional , Animais , Diferenciação Celular , Criança , Elementos Facilitadores Genéticos , Fator de Transcrição GATA1/genética , Humanos , Camundongos , Proteínas de Fusão Oncogênica/química , Regulador Transcricional ERG/fisiologia
16.
Pediatr Crit Care Med ; 18(2): 120-127, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28165347

RESUMO

OBJECTIVES: To determine whether real-time video communication between the first responder and a remote intensivist via Google Glass improves the management of a simulated in-hospital pediatric cardiopulmonary arrest before the arrival of the ICU team. DESIGN: Randomized controlled study. SETTING: Children's hospital at a tertiary care academic medical center. SUBJECTS: Forty-two first-year pediatric residents. INTERVENTIONS: Pediatric residents were evaluated during two consecutive simulated pediatric cardiopulmonary arrests with a high-fidelity manikin. During the second evaluation, the residents in the Google Glass group were allowed to seek help from a remote intensivist at any time by activating real-time video communication. The residents in the control group were asked to provide usual care. MEASUREMENTS AND MAIN RESULTS: The main outcome measures were the proportion of time for which the manikin received no ventilation (no-blow fraction) or no compression (no-flow fraction). In the first evaluation, overall no-blow and no-flow fractions were 74% and 95%, respectively. During the second evaluation, no-blow and no-flow fractions were similar between the two groups. Insufflations were more effective (p = 0.04), and the technique (p = 0.02) and rate (p < 0.001) of chest compression were more appropriate in the Google Glass group than in the control group. CONCLUSIONS: Real-time video communication between the first responder and a remote intensivist through Google Glass did not decrease no-blow and no-flow fractions during the first 5 minutes of a simulated pediatric cardiopulmonary arrest but improved the quality of the insufflations and chest compressions provided.


Assuntos
Reanimação Cardiopulmonar/educação , Parada Cardíaca/terapia , Internato e Residência/métodos , Pediatria/educação , Treinamento por Simulação/métodos , Telemedicina/métodos , Videoconferência , Centros Médicos Acadêmicos , Reanimação Cardiopulmonar/métodos , Competência Clínica , Sistemas de Computação , Feminino , Hospitais Pediátricos , Humanos , Lactente , Masculino , Manequins , Paris
17.
Blood Adv ; 1(20): 1760-1772, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29296822

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) expands in various bone marrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surface marker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tail-derived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL from tail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle-related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle-dependent chemotherapy.

18.
Pediatr Hematol Oncol ; 34(8): 425-427, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29303660

RESUMO

We report the outcome of 27 children with de novo acute megakaryoblastic leukemia (AMKL) (excluding Down syndrome) enrolled in the French multicenter prospective study ELAM02 (2005-2011). There was no difference in gender, initial leukocyte count, CNS involvement, and complete remission rate (88.9%), as compared to other acute myeloid leukemia (AML) subtypes. AMKL patients had a significantly poorer outcome (5-year overall survival 54% [CI 95% 33%-71%] than children with other AML subtypes (5-year overall survival 73% [CI 95% 68%-77%] p = 0.02). Gender, age, CNS leukemia, hyperleukocytosis, complete remission or cytogenetic subgroups were not significant prognostic factors of disease-free survival. AMKL (excluding Down syndrom) remains an AML subgroup with inferior outcome.


Assuntos
Leucemia Megacarioblástica Aguda/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Síndrome de Down , Feminino , França/epidemiologia , Humanos , Lactente , Leucemia Megacarioblástica Aguda/sangue , Leucemia Megacarioblástica Aguda/terapia , Masculino , Estudos Prospectivos , Taxa de Sobrevida
19.
Blood ; 127(20): 2451-9, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-26980726

RESUMO

Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years). Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Fatores de Ligação ao Core/genética , DNA de Neoplasias/genética , Leucemia Mieloide Aguda/genética , Mutação , Translocação Genética , Adolescente , Adulto , Alelos , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Cromatina/genética , Cromatina/ultraestrutura , Proteínas Cromossômicas não Histona/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Adulto Jovem
20.
Eur J Pediatr ; 175(6): 767-74, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26847430

RESUMO

UNLABELLED: Compliance by residents in pediatrics to pediatric resuscitation guidelines is low. In many French faculties, a 1-h traditional lecture is still used to educate medical students about pediatric cardiopulmonary arrest (CPA). We developed an innovative pedagogic course combining a 23-min video and 3-h simulation exercises to improve knowledge and skills of medical students. A prospective controlled study was conducted. Medical student knowledge was tested before, just after, and 6-12 months after the innovative course and compared to that of a cohort who attended the traditional lecture. A high-fidelity mannequin simulator simulating cardiopulmonary arrest was used to assess and compare the skills of the study and control groups. Costs of the courses were evaluated; 809 of 860 (94 %) medical students were assessed for knowledge. Six to 12 months after the courses, the median score was significantly higher for the innovative group than that for the traditional lecture group (p < 0.001). In terms of skills, student in the innovative group scored higher on the performance score than the control group (p < 0.01). The innovative course was 24 times more expensive. CONCLUSION: Combination of video and simulation allows better retention of knowledge than a traditional lecture and leads to better compliance to resuscitation guidelines. WHAT IS KNOWN: • Compliance by residents to pediatric resuscitation guidelines is low. • We developed an innovative pedagogic course combining an educational video and simulation. What is new: • Knowledge retention after the innovative course was better than after a traditional lecture. • Sixty-six students tested on their skills demonstrated better compliance to resuscitation guidelines.


Assuntos
Reanimação Cardiopulmonar/educação , Parada Cardíaca , Pediatria/educação , Desenvolvimento de Programas/métodos , Treinamento por Simulação/métodos , Estudantes de Medicina , Criança , Competência Clínica/estatística & dados numéricos , Humanos , Manequins , Guias de Prática Clínica como Assunto , Desenvolvimento de Programas/economia , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Treinamento por Simulação/economia , Gravação em Vídeo
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