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1.
Pancreatology ; 19(4): 566-568, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31130397

RESUMO

BACKGROUND: Perivascular epithelioid cell tumor, an extremely rare mesenchymal tumor, could be ubiquitous but rarely arises from pancreas. Surgery is considered the most appropriate treatment. Nevertheless, activation of mTOR pathway seems to be a common pathogenic event in PEComas paving the way to chemotherapy by mTOR inhibitor. METHOD: A 17 year-old man presented a hypervascular tumor of 55 mm, located in the head of pancreas without bile duct or pancreatic duct compression. RESULTS: Histopathology showed epithelioid cells with clear or focally granular eosinophilic cytoplasm with melanocytic (HMB-45, Melan-A) and myoid markers which confirmed diagnosis of PEComa. Given the absence of worrisome feature, we ruled out surgery and decided to initiate treatment with Sirolimus, an mTOR inhibitor. After 3.5 years, we showed a significant reduction in size of the tumor. CONCLUSION: This first case of pancreatic PEComa treated by mTOR inhibitor without surgery suggests a good efficiency of this therapy.

2.
Int J Cancer ; 145(10): 2781-2791, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31018240

RESUMO

In neuroblastoma (NB), genetic alterations in chromatin remodeling (CRGs) and epigenetic modifier genes (EMGs) have been described. We sought to determine their frequency and clinical impact. Whole exome (WES)/whole genome sequencing (WGS) data and targeted sequencing (TSCA®) of exonic regions of 33 CRGs/EMGs were analyzed in tumor samples from 283 NB patients, with constitutional material available for 55 patients. The frequency of CRG/EMG variations in NB cases was then compared to the Genome Aggregation Database (gnomAD). The sequencing revealed SNVs/small InDels or focal CNAs of CRGs/EMGs in 20% (56/283) of all cases, occurring at a somatic level in 4 (7.2%), at a germline level in 12 (22%) cases, whereas for the remaining cases, only tumor material could be analyzed. The most frequently altered genes were ATRX (5%), SMARCA4 (2.5%), MLL3 (2.5%) and ARID1B (2.5%). Double events (SNVs/small InDels/CNAs associated with LOH) were observed in SMARCA4 (n = 3), ATRX (n = 1) and PBRM1 (n = 1). Among the 60 variations, 24 (8.4%) targeted domains of functional importance for chromatin remodeling or highly conserved domains but of unknown function. Variations in SMARCA4 and ATRX occurred more frequently in the NB as compared to the gnomAD control cohort (OR = 4.49, 95%CI: 1.63-9.97, p = 0.038; OR 3.44, 95%CI: 1.46-6.91, p = 0.043, respectively). Cases with CRG/EMG variations showed a poorer overall survival compared to cases without variations. Genetic variations of CRGs/EMGs with likely functional impact were observed in 8.4% (24/283) of NB. Our case-control approach suggests a role of SMARCA4 as a player of NB oncogenesis.

4.
Bull Cancer ; 106(3): 189-200, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30771881

RESUMO

BACKGROUND: The use of complementary and alternative medicine (CAM) in children with cancer is commonly used. However, studies and data on this topic are still scarce in France. METHODS: Our aim was to investigate the prevalence of CAM usage in pediatric cancer patients and describe the modality of use. Our study population comprised children and young people treated from 2011 to 2012 in 2 French centers (Nantes, Paris). An anonymous self-administered questionnaire was addressed to families and data was collected from them and from the medical record. RESULTS: Out of the 202 patients selected for the study, 111 families answered the questionnaire (55%). Fifty-four (48.6%) of respondents reported CAM used. Forty-seven (87%) patients used CAM during initial therapy of cancer. Thirty-two (59.3%) of them talked about their CAM usage with health professionals, whose 25 (75.8%) with their oncologist. The three most common therapies used were homeopathy (75.8%), chiropractic (31.5%) and faith healing (42.6%). The main reason for the use of CAM was to control the side effects of conventional treatment (85.2%). Overall perceived satisfaction was rated 7.4/10. CONCLUSION: The prevalence of complementary and alternative medicines administration is high, even if scientific evidence is limited regarding the effects, mechanisms of action and security of CAM. Research is necessary to improve the communication and council quality to the family, optimize supportive cares and reinforce the pharmacovigilance.


Assuntos
Institutos de Câncer/estatística & dados numéricos , Terapias Complementares/estatística & dados numéricos , Neoplasias/terapia , Adolescente , Criança , Feminino , França , Pesquisas sobre Serviços de Saúde/estatística & dados numéricos , Homeopatia/estatística & dados numéricos , Humanos , Terapia de Campo Magnético/estatística & dados numéricos , Masculino , Manipulação Osteopática/estatística & dados numéricos , Neoplasias/mortalidade , Satisfação do Paciente
5.
Cancer Causes Control ; 28(10): 1125-1132, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28840389

RESUMO

PURPOSE: Neuroblastoma (NB) is an embryonic tumor that occurs almost exclusively in infancy and early childhood. While considerable evidence suggests that it may be initiated during embryonic development, the etiology of NB is still unknown. The aim of this study was to explore whether there is an association between maternal use of household pesticides during pregnancy and the risk of NB in the offspring. METHODS: We conducted a pooled analysis of two French national-based case-control studies. The mothers of 357 NB cases and 1,783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on sociodemographic and perinatal characteristics, childhood environment, and life-style. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. RESULTS: After controlling for matching variables, study of origin, and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with NB (OR 1.5 [95% CI 1.2-1.9]). The most commonly used type of pesticides were insecticides and there was a positive association with their use alone (OR 1.4 [95% CI 1.1-1.9]) or with other pesticides (OR 2.0 [95% CI 1.1-3.4]). CONCLUSIONS: Although there is the potential for recall bias due to the study design, our findings add to the evidence of an association between the household use of pesticides and NB. Until a better study design can be found, our findings add yet another reason why to advise pregnant women to limit pesticide exposure during the periconceptional period.


Assuntos
Exposição Materna , Troca Materno-Fetal , Neuroblastoma/epidemiologia , Praguicidas , Adulto , Estudos de Casos e Controles , Pré-Escolar , Feminino , França/epidemiologia , Humanos , Lactente , Modelos Logísticos , Masculino , Razão de Chances , Gravidez , Fatores de Risco
6.
PLoS One ; 12(8): e0183841, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28841702

RESUMO

PURPOSE: The objective of this retrospective work was to evaluate the prognostic value on histological response and survival of quantitative indices derived from FDG-PET performed before and after chemotherapy (CHT), in a homogeneous pediatric Ewing sarcoma (EWS) and Osteosarcoma (OST) population. METHODS: Thirty-one patients with EWS and 31 with OST were included. All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had FDG-PET at diagnosis and after CHT, prior to surgery. Several parameters were evaluated: SUVmax, SUVpeak, SUVmean, metabolic tumor volume, total lesion glycolysis, 7 textural features and 3 shape features (SF). The segmentation was performed using an adaptive approach. Results were compared to histopathological regression of the resected tumor and to clinical follow-up for survival evaluation. RESULTS: For EWS, univariate analysis did not highlight any prognostic value on histological response, or survival regardless of all the considered metrics. For OST, only one of the SF, namely elongation, was significantly associated with PFS and OS on both univariate and multivariate analysis (PFS: p = 0.019, HR = 5.583; OS: p = 0.0062, HR = 7.113). CONCLUSION: Only elongation determined on initial FDG-PET has a potential interest as a prognostic factor of PFS and OS in pediatric OST patients. Unlike recent studies of the literature realized in adult population, all the metrics reveal limited additional prognostic value in pediatric EWS patients. This seems to reinforce the question of whether children experience different subtypes of the same pathologies than older patients, with different outcomes.


Assuntos
Fluordesoxiglucose F18/administração & dosagem , Osteossarcoma/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Quimioterapia Adjuvante , Criança , Feminino , Humanos , Masculino , Metástase Neoplásica , Osteossarcoma/patologia , Prognóstico , Sarcoma de Ewing/patologia , Resultado do Tratamento
7.
Bull Cancer ; 104(7-8): 625-635, 2017 Jul - Aug.
Artigo em Francês | MEDLINE | ID: mdl-28687117

RESUMO

SUBJECT: Prognostic values of an early detection of a relapse after treatment of a localized rhabdomyosarcoma and the interest of performing systematic radiologic assessment after treatment have not yet been evaluated in Europe. MATERIAL AND METHODS: Modalities of relapse of 99 patients under 20 years of age, after an initially localized rhabdomyosarcoma, treated in 9 French centers ("Société française des cancers de l'enfant" consortium) have been analyzed. Prognostic value of the protocol compliance during the observation period after therapy has been evaluated. RESULTS: Relapses have been diagnosed in 59 cases by a "symptom" the child was complaining of, in 12 cases because of "physical signs" detected during the clinical examination of a systematic consultation and in 27 cases thanks to "systematic follow-up imaging" (missing data: 1 case). Survival after relapse at 3 years was 47.5 % (IC95 %: 37.1 %-57.1 %). Diagnosis of the relapse is established earlier in the group "systematic imaging" rather than with other methods of detection ("symptom", "physical signs"), (P= 0.025), with detection of smaller tumors (≤ 5 cm ; 100.0 % vs. 60.9 % vs. 77.8 %, P= 0.007) but without possibility of reaching a second remission (70.4 % vs. 50.8 % vs. 50.0 % P= 0.37), nor significant impact on 5-year overall survival (47.1 % vs. 47.1 % vs. 48.6 % P= 0.94). CONCLUSION: Current methods of systematic surveillance after a first-line treatment of an initially localized rhabdomyosarcoma seem to improve the earliness of the diagnosis, but not the prognosis of the relapse.


Assuntos
Detecção Precoce de Câncer/métodos , Recidiva Local de Neoplasia/diagnóstico , Rabdomiossarcoma/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico por Imagem/métodos , Detecção Precoce de Câncer/mortalidade , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Avaliação de Sintomas/métodos , Carga Tumoral , Adulto Jovem
8.
J Pediatr Hematol Oncol ; 39(5): 388-394, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28375941

RESUMO

BACKGROUND: Germ cell tumors with somatic malignant transformation (GCT with SMT) are rare in children and poorly described. Data are missing to determine if therapies should target the GCT, the SMT compound, or both simultaneously. PATIENTS AND METHODS: A retrospective national study was conducted in the Société Française des cancers de l'Enfant (SFCE) Centers. Medical records from patients aged 0 to 18 years diagnosed with GCT with SMT between 2000 and 2015 were analyzed. Any stages and primary sites were considered as well as synchronous and metachronous cases. RESULTS: Fifteen patients were identified. Thirteen patients had synchronous GCT with SMT. In the latter cases, primaries were ovary (5), mediastinum (3), pineal gland (3), sacrococcyx (1), and parametrium (1). SMT histologies were central primitive neuroectodermal tumor (5), embryonal rhabdomyosarcomas (3) or thyroid papillary adenocarcinoma, leukemia, poorly differentiated carcinoma, mixed sarcomas, and miscellaneous histology (1 case each). Chemotherapy was targeted against the GCT (3), the SMT (6), or both components (3). The last patient received surgery exclusively. Partial or complete response to chemotherapy was observed in 5/10 assessable cases: 2/3 patients treated with GCT-dedicated chemotherapy, 3/6 patients treated with SMT-dedicated therapy, and 0/1 treated with combined therapy. In addition, 2 patients with mediastinal GCT primary had metachronous SMT, with acute myeloid leukemia and thyroid papillary adenocarcinoma, 8 months and 8 years, respectively, after the diagnoses of GCT. Two patients (1 synchronous and 1 metachronous) were cured with surgery exclusively. At the end of follow-up, 6 patients died of their disease including all 4 with postsurgical macroscopic residue. CONCLUSIONS: GCT with SMT constitutes a very rare entity in children and adolescents. Surgical removal of the tumor is the cornerstone of the treatment and might be sufficient in selected cases. In the remaining cases, the best management is still unknown and should take into account both components and their respective chemosensitivity. Long-term surveillance is advised for patient with unresected teratoma as late transformation can occur.


Assuntos
Transformação Celular Neoplásica , Neoplasias Embrionárias de Células Germinativas , Adolescente , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , França , Humanos , Lactente , Masculino , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Estudos Retrospectivos , Procedimentos Cirúrgicos Operatórios , Taxa de Sobrevida , Resultado do Tratamento
9.
Pediatr Blood Cancer ; 64(6)2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27896933

RESUMO

BACKGROUND: The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. PROCEDURE: We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. RESULTS: Mean age was 12 ± 5.7 years (range 0.1-21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). CONCLUSIONS: Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors.


Assuntos
Glioma/genética , Glioma/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Glioma/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Neuroblastoma/terapia , Sarcoma/terapia
10.
Clin Cancer Res ; 22(22): 5564-5573, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27440268

RESUMO

PURPOSE: The tumor genomic copy number profile is of prognostic significance in neuroblastoma patients. We have studied the genomic copy number profile of cell-free DNA (cfDNA) and compared this with primary tumor arrayCGH (aCGH) at diagnosis. EXPERIMENTAL DESIGN: In 70 patients, cfDNA genomic copy number profiling was performed using the OncoScan platform. The profiles were classified according to the overall pattern, including numerical chromosome alterations (NCA), segmental chromosome alterations (SCA), and MYCN amplification (MNA). RESULTS: Interpretable and dynamic cfDNA profiles were obtained in 66 of 70 and 52 of 70 cases, respectively. An overall identical genomic profile between tumor aCGH and cfDNA was observed in 47 cases (3 NCAs, 22 SCAs, 22 MNAs). In one case, cfDNA showed an additional SCA not detected by tumor aCGH. In 4 of 8 cases with a silent tumor aCGH profile, cfDNA analysis revealed a dynamic profile (3 SCAs, 1 NCA). In 14 cases, cfDNA analysis did not reveal any copy number changes. A total of 378 breakpoints common to the primary tumor and cfDNA of any given patient were identified, 27 breakpoints were seen by tumor aCGH, and 54 breakpoints were seen in cfDNA only, including two cases with interstitial IGFR1 gains and two alterations targeting TERT CONCLUSIONS: These results demonstrate the feasibility of cfDNA copy number profiling in neuroblastoma patients, with a concordance of the overall genomic profile in aCGH and cfDNA dynamic cases of 97% and a sensitivity of 77%, respectively. Furthermore, neuroblastoma heterogeneity is highlighted, suggesting that cfDNA might reflect genetic alterations of more aggressive cell clones. Clin Cancer Res; 22(22); 5564-73. ©2016 AACRSee related commentary by Janku and Kurzrock, p. 5400.


Assuntos
DNA Tumoral Circulante/genética , Dosagem de Genes/genética , Neuroblastoma/sangue , Neuroblastoma/genética , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , Feminino , Amplificação de Genes/genética , Genômica/métodos , Humanos , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico , Estudos Prospectivos
11.
Int J Cancer ; 139(9): 1936-48, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27342419

RESUMO

Neuroblastoma (NB), an embryonic tumour arising from neural crest cells, is the most common malignancy among infants. The aetiology of NB is largely unknown. We conducted a pooled analysis to explore whether there is an association between NB and preconception and perinatal factors using data from two French national population-based case-control studies. The mothers of 357 NB cases and 1783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on demographic, socioeconomic and perinatal characteristics, childhood environment, life-style and maternal reproductive history. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. After controlling for matching variables, study of origin and potential confounders, being born either small (OR 1.4 95% CI 1.0-2.0) or large (OR 1.5 95% CI 1.1-2.2) for gestational age and, among children younger than 18 months, having congenital malformations (OR 3.6 95% CI 1.3-8.9), were significantly associated with NB. Inverse associations were observed with breastfeeding (OR 0.7 95% CI 0.5-1.0) and maternal use of any supplements containing folic acid, vitamins or minerals (OR 0.5 95% CI 0.3-0.9) during the preconception period. Our findings reinforce the hypothesis that fetal growth anomalies and congenital malformations may be associated with an increased risk of NB. Further investigations are needed in order to clarify the role of folic acid supplementation and breastfeeding, given their potential importance in NB prevention.


Assuntos
Anormalidades Congênitas/epidemiologia , Suplementos Nutricionais/estatística & dados numéricos , Neuroblastoma/epidemiologia , Complicações na Gravidez/epidemiologia , Adolescente , Adulto , Peso ao Nascer , Aleitamento Materno , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , França/epidemiologia , Humanos , Lactente , Recém-Nascido , Entrevistas como Assunto , Modelos Logísticos , Masculino , Gravidez , Complicações na Gravidez/etiologia , Adulto Jovem
12.
Int J Radiat Oncol Biol Phys ; 94(3): 450-60, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26867874

RESUMO

PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Núcleo Celular/metabolismo , Quebras de DNA de Cadeia Dupla , Histonas/metabolismo , Lesões por Radiação/classificação , Tolerância a Radiação/fisiologia , Pele/efeitos da radiação , Análise de Variância , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biópsia , Linhagem Celular , Reparo do DNA , Fibroblastos/efeitos da radiação , Humanos , Testes para Micronúcleos/métodos , Fosforilação , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Tolerância a Radiação/genética , Pele/patologia , Fatores de Tempo
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.
Clin Cancer Res ; 21(21): 4913-21, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26059187

RESUMO

PURPOSE: In neuroblastoma, activating ALK receptor tyrosine kinase point mutations play a major role in oncogenesis. We explored the potential occurrence of ALK mutations at a subclonal level using targeted deep sequencing. EXPERIMENTAL DESIGN: In a clinically representative series of 276 diagnostic neuroblastoma samples, exons 23 and 25 of the ALK gene, containing the F1174 and R1275 mutation hotspots, respectively, were resequenced with an extremely high depth of coverage. RESULTS: At the F1174 hotspot (exon 23), mutations were observed in 15 of 277 samples (range of fraction of mutated allele per sample: 0.562%-40.409%). At the R1275 hotspot (exon 25), ALK mutations were detected in 12 of 276 samples (range of fraction of mutated allele: 0.811%-73.001%). Altogether, subclonal events with a mutated allele fraction below 20% were observed in 15/27 ALK-mutated samples. The presence of an ALK mutation was associated with poorer 5-year overall survival (OS: 75% vs. 57%, P = 0.0212 log-rank test), with a strong correlation between F1174 ALK mutations and MYCN amplification being observed. CONCLUSIONS: In this series, deep sequencing allows the detection of F1174 and R1275 ALK mutational events at diagnosis in 10% of cases, with subclonal events in more than half of these, which would have gone undetected by Sanger sequencing. These findings are of clinical importance given the potential role of ALK mutations in clonal evolution and relapse. These findings also demonstrate the importance of deep sequencing techniques for the identification of patients especially when considering targeted therapy.


Assuntos
Evolução Clonal/genética , Mutação , Neuroblastoma/genética , Receptores Proteína Tirosina Quinases/genética , Adolescente , Adulto , Alelos , Quinase do Linfoma Anaplásico , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Amplificação de Genes , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico , Neuroblastoma/mortalidade , Prognóstico , Adulto Jovem
15.
Bull Cancer ; 102(6): 550-8, 2015 Jun.
Artigo em Francês | MEDLINE | ID: mdl-26028491

RESUMO

Sex-cord stromal tumors (SCT) are rare pediatric tumors accounting for less than 5% of gonadal tumors in children and adolescents. They differ from those diagnosed in adults by their presentation, histology, evolution and treatment modalities. Testicular SCT occur mostly in infants less than 6 months. Testicular swelling is often the only symptom, but signs of hormonal secretion with gynecomastia may be present. Juvenile granulosa SCT is the main histologic subtype. Sertoli SCTs are much less frequent while Leydig tumors occurred in older children and adolescents. Prognosis is excellent after inguinal orchiectomy. Testis sparing surgery could be performed but indications and modalities have to be strongly defined. Ovarian SCT are diagnosed in older children and adolescents and present with abdominal symptoms and/or signs of hormonal secretion: estrogenic manifestations (isosexual pseudoprecocity, menometrorrhagia) or virilization (hirsutism, amenorrhea). Main histologic subtype is juvenile granulosa (rarely Sertoli-Leydig). If oophorectomy (or salpingo-oophorectomy) may be curative for localized disease, adjuvant cisplatin-containing chemotherapy is mandatory in case of tumor rupture or peritoneal dissemination to prevent recurrences. Because of the rarity of these pediatric tumors, concerted multidisciplinary cares are required to best adapt therapeutic strategy before any surgical intervention.


Assuntos
Tumor de Células da Granulosa , Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Adolescente , Quimioterapia Adjuvante , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Tumor de Células da Granulosa/complicações , Tumor de Células da Granulosa/diagnóstico por imagem , Tumor de Células da Granulosa/patologia , Tumor de Células da Granulosa/terapia , Humanos , Lactente , Masculino , Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Cirurgia de Second-Look , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico por imagem , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia , Neoplasias Testiculares/complicações , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/cirurgia , Ultrassonografia
16.
J Pediatr Hematol Oncol ; 37(6): 474-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25851554

RESUMO

Neuroendocrine tumors are rare, preferentially located in the gastrointestinal tract or in the lungs. We present the case of a 9-year-old child, presenting with a tissue mass involving the nasopharynx and associated with multiple pulmonary and bone metastases. The immunohistochemical analysis showed a proliferation of large tumor cells stained with Chromogranin A and Synaptophysin. The diagnosis of multimetastatic large cell neuroendocrine carcinoma was made. This tumor is infrequent in this location and particularly in children. This case describes the pathologic aspects and immunohistochemical results and presents a discussion of the differential diagnoses.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/secundário , Carcinoma de Células Grandes/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias Pulmonares/secundário , Neoplasias Nasofaríngeas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/terapia , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/terapia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/terapia , Quimiorradioterapia , Criança , Evolução Fatal , Feminino , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/terapia
17.
PLoS One ; 9(7): e101990, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25013904

RESUMO

BACKGROUND: Somatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN. METHODS: Genomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected. RESULTS: In total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%±11% vs 34.9%±7%, log-rank p<0.05). CONCLUSION: NBs harbouring regional amplification(s) without MNA are rare and seem to show atypical features in clinical presentation and genomic profile. Further high resolution genetic explorations are justified in this heterogeneous group, especially when considering these alterations as predictive markers for targeted therapy.


Assuntos
Amplificação de Genes/genética , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Humanos , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc , Estudos Retrospectivos
18.
Pediatr Blood Cancer ; 61(2): 253-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23940114

RESUMO

PURPOSE: Some children with extracranial germ cell tumors (GCT) relapse after or do not respond to first-line treatment combining chemotherapy and surgery, of whom very few experience long-term survival despite multimodal salvage treatment. METHODS: This prospective study, part of the French TGM95 Protocol for non-seminomatous GCT (NSGCT), included 19 (7%) children with malignant refractory or recurrent extracranial NSGCT who were studied to identify prognostic factors and determine the best salvage treatment. RESULTS: At the end of the first-line treatment, 10 and 9 children were in complete and incomplete remission, respectively. Events occurred within 2 years (5-23 months) after initial diagnosis. A progression was observed in 13 patients at least in one site initially involved. Two patients had a purely biological relapse (increase in isolated markers), and four patients had a purely metastatic relapse (brain location in three cases). After salvage treatment combining surgery and various types of chemotherapy (including high-dose chemotherapy (HDCT) in 10 cases), the 5-year event-free survival and overall survival rates were of 26% (95%CI: 9.6-46.8%) and 32% (95%CI: 12.9-52.2%), respectively. Patients who underwent complete surgery (or without any detectable tumor) had higher survival rate than patients who underwent partial surgery or for whom surgery was not feasible (P = 0.0003) at first relapse while this rate was similar between patients treated or not with HDCT. CONCLUSION: In pediatric recurrent or refractory NSGCT, complete excision of the tumor appears essential. The role of HDCT remains debated.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Bleomicina/administração & dosagem , Criança , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Lactente , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Neoplasias Testiculares , Vimblastina/administração & dosagem , Adulto Jovem
19.
Bull Cancer ; 99(6): 715-22, 2012 Jun.
Artigo em Francês | MEDLINE | ID: mdl-22640917

RESUMO

Fibrosarcomas (FS) are rare malignant tumors in pediatrics, classified in the heterogeneous non-rhabdomyosarcomas group of malignant mesenchymal tumors. Infantile FS are found typically in children less than 2 years of age, and include congenital FS usually occurring in infants in the first 3 months of life. Histological diagnosis can be difficult; and confirmed with detection by molecular biology of the ETV6-NTRK3 fusion protein. FS is most often a localized disease at diagnosis, with involvement of an extremity. The management of these patients must be multidisciplinary, to define the different phases of treatment and avoid mutilating surgery. Cellular or atypical mesoblastic nephroma (MN) is a subtype of malignant pediatric renal tumors, most often present in children of less than 3 months. Histopathological characteristics of the cellular MN are very close to the congenital FS due to a fusion transcript common to both diseases. Treatment schedule is defined by initial local stage of the disease. FS called "adult-type" found exceptionally in childhood occur most often after 10 years old. Adult FS differ from infantile FS in their clinical presentation because of a strong local aggressiveness and problematic appearance of metastasis in 50% of cases, sometimes late. These three diseases present therefore histological similarities. Both have a common name but different clinical presentation and outcome: infantile FS and adult FS. Two have different names and initial location but similar histology, chromosomal rearrangement, sensitivity to chemotherapy and outcome: the congenital FS and cellular mesoblatic nephroma. Authors present a review of the literature of these entities.


Assuntos
Fibrossarcoma , Doenças Raras , Adolescente , Fatores Etários , Criança , Pré-Escolar , Fibrossarcoma/classificação , Fibrossarcoma/congênito , Fibrossarcoma/diagnóstico , Fibrossarcoma/terapia , Humanos , Lactente , Neoplasias Renais/congênito , Neoplasias Renais/patologia , Nefroma Mesoblástico/congênito , Nefroma Mesoblástico/patologia , Doenças Raras/classificação , Doenças Raras/congênito , Doenças Raras/diagnóstico , Doenças Raras/terapia
20.
Pediatr Blood Cancer ; 59(1): 34-8, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22287258

RESUMO

BACKGROUND: Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, has proven efficacy in some adult tumors; it is now proposed as a new therapeutic strategy for refractory or recurrent brain tumors in some children, either alone or combinated. PROCEDURE: We retrospectively analyzed 28 children who received bevacizumab on a compassionate basis for refractory or recurrent brain tumors between June 2007 and August 2010 in 7 French centers. Among them, 12 had high-grade gliomas, 7 low-grade gliomas, 4 ependymomas, 2 primitive neurectodermal tumors, 3 neuroglial tumors. The median age at start of bevacizumab was 11.0 years. Bevacizumab was administered at 5-10 mg/kg every 2 weeks, with concomitant chemotherapy for 27 patients. RESULTS: Bevacizumab was used in combination with irinotecan in 27 patients. Bevacizumab-related toxicity was mild. Toxicities reported were grade I-II hypertension (n = 4), proteinuria (n = 1), lymphopenia (n = 2), wound healing delay (n = 2). Whereas tumor reduction could be observed in 6:7 patients with low-grade gliomas, no efficacy could be documented in patients with high-grade glioma, nor PNET nor ependymoma. CONCLUSION: Bevacizumab-related acute toxicity appears to be low in children, even in combination with irinotecan. Further prospective trials are required to confirm the hypothetical efficacy of bevacizumab and to assess the risk of long-term toxicity especially in the youngest children.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Irinotecano , Masculino , Estudos Retrospectivos
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