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1.
Pediatr Blood Cancer ; 66(9): e27873, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31207026

RESUMO

INTRODUCTION: In order to describe relapsed B-cell non-Hodgkin lymphoma and mature acute leukemia in children/adolescents treated with the Lymphomes Malins B (LMB) regimen and their outcome in the rituximab era, relapses in the French LMB2001 study were reviewed. METHODS: Between February 2001 and December 2011, 33 patients out of 773 (4.3%) relapsed; 27 had Burkitt lymphoma and six large B-cell histology. Median age at diagnosis was 10.1 years. One patient was initially treated in risk group A, 21 in group B, and 11 in group C. RESULTS: Median time to relapse after diagnosis was 4.5 months (range 2.4-13.6). Thirty-two patients received salvage therapy. Twenty-seven received rituximab mainly in addition to high-dose cytarabine and etoposide (n = 18) and/or ifosfamide, carboplatin, and etoposide (n = 7). First-line salvage chemotherapy response rate was 66% with 47% being complete remission (CR). Twenty-one patients received high-dose chemotherapy (HDC) followed by autologous (n = 13) or allogeneic (n = 8) transplant. With a median follow-up of 6.8 years, the 5-year survival rate after relapse was 36.4% (95% confidence interval [CI] 22-53%). Twelve patients were still alive; all but one (group A) received consolidation treatment. Achieving CR before consolidation was significantly associated with better survival, with a 5-year survival rate of 75% (95% CI 46.8-91.1%) for patients in CR before HDC, 33% (95% CI 9.7-70%) for patients in partial remission, and 0% for nonresponders (P = .033). CONCLUSION: Survival of children/adolescents with mature B-cell lymphoma/leukemia remains poor after relapse with no apparent improvement with rituximab. Response rates to salvage chemo-immunotherapies are insufficient and new drugs are urgently needed to improve disease control.

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.

3.
Pediatr Blood Cancer ; 66 Suppl 3: e27670, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30828979

RESUMO

INTRODUCTION: Prognosis of dumbbell neuroblastoma (NBL) is mainly determined by the sequelae induced by the tumor itself and the neurosurgical approach. However, after primary chemotherapy, surgical management of the residual tumor, especially the spinal canal component, remains controversial. METHODS: We conducted a single-center retrospective cohort study over the last 15 years (2002-2017) including patients treated for NBL with spinal canal extension focusing on timing and type of surgery, complications, and functional and oncological follow-up. RESULTS: Thirty-two children (14 M, 18 F) were managed for NBL, with the majority (26) presenting with NBL stroma poor while four had ganglioneuroblastoma intermixed, one nodular, and one ganglioneuroma. All but two patients received neoadjuvant chemotherapy. Upfront laminotomy for spinal cord decompression was performed in two patients; nine patients had extraspinal surgery with a follow-up neurosurgical procedure in seven cases; eight patients had initial neurosurgery followed by an extraspinal procedure, while six patients underwent a combined multidisciplinary approach. With a median follow up of 3.6 years (0.1-14.9), 29 patients (90.6) are alive and two out of three (19, 65.5%) have functional sequelae. CONCLUSION: Patients with NBL with persistent spinal canal extension of the tumor after neoadjuvant chemotherapy treated at our center had outcomes that compare favorably with the literature. This is likely due to the multidisciplinary approach to optimal surgical strategy and continuous evaluation of the respective risks of tumor progression. Neurological disability results from initial spinal cord compression or the radicular sacrifice required for tumor resection.

4.
Acta Obstet Gynecol Scand ; 98(5): 630-637, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30919447

RESUMO

INTRODUCTION: The preservation of fertility is an integral part of care of children requiring gonadotoxic treatments for cancer or non-malignant diseases. In France, the cryopreservation of ovarian tissue has been considered and has been offered as a clinical treatment since its inception. The aim of this study is to review 20 years of activity in fertility preservation by ovarian tissue cryopreservation (OTC) for children and the feasibility of oocyte isolation and cryopreservation from the ovarian tissue at a single center. MATERIAL AND METHODS: Retrospective study including patients aged 15 years or younger who underwent OTC, combined for some with oocyte cryopreservation of isolated oocytes, before a highly gonadotoxic treatment for malignant or non-malignant disease was initiated. We describe the evolution of activities in our program for fertility preservation and patient characteristics at the time of OTC and follow up. RESULTS: From April 1998 to December 2018, 418 girls and adolescents younger than 15 years of age underwent OTC, representing 40.5% of all females who have had ovarian tissue cryopreserved at our center. In all, 313 patients had malignant diseases and 105 had benign conditions. Between November 2009 and July 2013, oocytes were isolated and also cryopreserved in 50 cases. The mean age of patients was 6.9 years (range 0.3-15). The most frequent diagnoses in this cohort included neuroblastoma, acute leukemia and hemoglobinopathies; neuroblastoma being the most common diagnosis in very young patients. During follow up, three patients requested the use of their cryopreserved ovarian tissue. All had undergone ovarian tissue transplantation, one for puberty induction and the two others for restoring fertility. So far, no pregnancies have been achieved. Eighty-four patients who had OTC died. CONCLUSIONS: Ovarian tissue cryopreservation is the only available technique for preserving fertility of girls. To our knowledge this is the largest series of girls and adolescents younger than 15 years so far reported on procedures of OTC before highly gonadotoxic treatment in a single center.

5.
Int J Cancer ; 144(1): 68-79, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29923174

RESUMO

Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms' tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations-CNAs, SNVs or both-in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Neoplasias Renais/genética , Tumor de Wilms/genética , Biomarcadores Tumorais/sangue , Criança , Pré-Escolar , DNA Tumoral Circulante/sangue , Variações do Número de Cópias de DNA , Feminino , Humanos , Lactente , Neoplasias Renais/diagnóstico , Neoplasias Renais/terapia , Masculino , Terapia Neoadjuvante , Nefrectomia , Estudos Retrospectivos , Sensibilidade e Especificidade , Sequenciamento Completo do Genoma/métodos , Tumor de Wilms/diagnóstico , Tumor de Wilms/terapia
6.
Lancet Oncol ; 19(12): 1617-1629, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30442501

RESUMO

BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.

7.
J Clin Oncol ; : JCO2018782516, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30188789

RESUMO

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

8.
Nat Commun ; 9(1): 3184, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093639

RESUMO

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

10.
Cancer Med ; 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29905027

RESUMO

The association between growth hormone (GH) treatment and cancer risk has not been thoroughly evaluated and there are questions about any increased risk of bone tumors. We examined cancer risk and especially bone tumor risk in a population-based cohort study of 6874 patients treated with recombinant GH in France for isolated GH deficiency, short stature associated with low birth weight or length or idiopathic short stature. Adult mortality and morbidity data obtained from national databases and from questionnaires. Case ascertainment completeness was estimated with capture-recapture methods. Standardized mortality and incidence ratios were calculated using national reference data. 111 875 person-years of observation were analyzed and patients were followed for an average of 17.4 ± 5.3 years to a mean age of 28.4 ± 6.2 years. For cancer overall, mortality and incidence were not different from expected figures. Five patients developed bone tumors (chondrosarcoma, 1, Ewing sarcoma, 1, osteosarcoma, 3) of whom 3 died (Ewing sarcoma, 1, osteosarcoma, 2), whereas only 1.4 case and 0.6 deaths were expected: standardized mortality ratio, 5.0 and standardized incidence ratio from 3.5 to 3.8 accounting or not accounting for missed cases. Most patients received conventional doses of GH, although one patient with osteosarcoma had received high dose GH (60 µg/kg/d). This study confirms an increased risk of bone tumors but not overall cancer risk in subjects treated with GH in childhood for isolated GH deficiency or childhood short stature. Further work is needed to elucidate the mechanisms involved.

11.
Eur J Hum Genet ; 26(8): 1217-1221, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29706636

RESUMO

Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.

12.
J Pediatr Hematol Oncol ; 40(6): 426-432, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29642099

RESUMO

High-risk neuroblastoma is characterized by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). The benefits of a tandem high-dose therapy and hematologic stem cell reinfusion (HSCR) have been shown in these patients. Further dose escalation will be limited by toxicity. It is thus important to evaluate the efficacy and tolerability of the addition of new agents such as I-MIBG (131Iode metaiodobenzylguanidine) to be combined with high-dose therapy in the consolidation phase. We report the feasibility of busulfan/melphalan (BuMel) after I-MIBG therapy with HSCR in patients with refractory or relapsed metastatic neuroblastoma. From November 2008 to March 2015, 9 patients received BuMel after I-MIBG therapy and topotecan. The main toxicity was digestive with only 1 patient developing grade 4 sinusoidal obstructive syndrome. Seven patients are alive at a median follow-up of 25 months. Among them, 2 are in ongoing complete remission and 1 in ongoing stable disease. These results suggest that BuMel with HSCR can be administered safely 2 months after I-MIBG therapy associated with topotecan for VHR patients. This strategy will be compared with tandem high-dose chemotherapy (thiotepa and busulfan-melphalan), followed by HSCR in the upcoming SIOPEN VHR Neuroblastoma Protocol.

13.
Artigo em Inglês | MEDLINE | ID: mdl-29409315

RESUMO

BACKGROUND: The aim of this study was to assess the prognostic value of postoperative 123I-MIBG scintigraphy, including systematic SPECT/CT and semiquantification of the uptake at the surgical site, in a prospective series of NB patients. METHODS: Patients operated for neuroblastoma and who had benefited from postoperative 123I-MIBG scintigraphy were prospectively and consecutively included. Completeness of surgery was assessed on operative report. One month postoperative 123I-MIBG scintigraphy included planar acquisition and SPECT/CT. Semi-quantification of the 123I-MIBG SPECT/CT uptake at the surgical site was performed and ratios to reference (liver and mediastinum) areas were calculated. RESULTS: Thirty patients were included between August 2012 and July 2015. Median follow-up was 36 months (range 10-98). Surgery was considered as complete in 23 patients and incomplete in 7 patients. Eight patients (26.7%) presented progressive disease (1 progression and 7 recurrences). Seven patients died (23.3%), all from NB. Six (20%) patients had positive 123I-MIBG scintigraphy (3 on planar acquisitions and 6 on SPECT/CT) and 24 patients had negative 123I-MIBG scintigraphy. Five of the 6 patients (83%) with positive 123I-MIBG scintigraphy presented progressive disease. Ratio of the uptake at the surgical site to mediastinum was strongly and independently correlated with disease-free interval and overall survival (p=0.02 and 0.01 respectively). The amplified MYCN status was also confirmed as correlated with poorer outcomes. CONCLUSIONS: Postoperative 123I-MIBG scintigraphy including SPECT/CT and semiquantification of the uptake at the surgical site appeared to be a valuable prognostic tool in neuroblastoma.

14.
Pediatr Blood Cancer ; 65(5): e26916, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29334194

RESUMO

BACKGROUND: The European Paediatric Regulation was introduced in 2007 to facilitate access to new medicines for children. Our study explored accessibility of early-phase trials in pediatric oncology, in line with the European Paediatric Regulation, to identify the reasons for not inviting patients to participate, parents' refusal, or inclusion failure. PROCEDURE: We conducted a retrospective chart review at Institut Curie, Paris, for all pediatric patients whose cancer progressed despite known effective treatments between July 2010 and December 2013. RESULTS: Out of 100 patients in the palliative phase, 52 received one or more invitations to participate in early-phase trials. Twenty parents declined the invitation, mainly prioritizing quality of life or fearing constraints. Fourteen inclusions failed despite parental approval, mostly due to rapid clinical deterioration. Five patients received no invitations because no early-phase trials were available. Major reasons for noninclusion in the 43 remaining patients were presence of exclusion criteria or other physical factors, preference for conventional treatment, constraints, psychological factors, and follow-up in another hospital after moving. CONCLUSIONS: The Paediatric Regulation has led to increased availability of early-phase trials. Better timing of the proposal, designing less constraining early-phase trials, reducing waiting lists, and improving information for parents and children would facilitate pediatric access to new medicines.

15.
Clin Cancer Res ; 24(4): 939-949, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29191970

RESUMO

Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression.Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients.Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. Clin Cancer Res; 24(4); 939-49. ©2017 AACR.

16.
J Pediatr Hematol Oncol ; 40(2): 93-98, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29135842

RESUMO

Opsoclonus myoclonus syndrome (OMS), often called "dancing eyed syndrome," is a rare neurological condition associated with neuroblastoma in the majority of all childhood cases. Genomic copy number profiles have shown to be of prognostic significance for neuroblastoma patients. The aim of this retrospective multicenter study was to analyze the genomic copy number profiles of tumors from children with neuroblastoma presenting with OMS at diagnosis. In 44 cases of neuroblastoma associated with OMS, overall genomic profiling by either array-comparative genomic hybridization or single nucleotide polymorphism array proved successful in 91% of the cases, distinguishing tumors harboring segmental chromosome alterations from those with numerical chromosome alterations only. A total of 23/44 (52%) tumors showed an segmental chromosome alterations genomic profile, 16/44 (36%) an numerical chromosome alterations genomic profile, and 1 case displayed an atypical profile (12q amplicon). No recurrently small interstitial copy number alterations were identified. With no tumor relapse nor disease-related deaths, the overall genomic profile was not of prognostic impact with regard to the oncological outcome in this series of patients. Thus, the observation of an excellent oncological outcome, even for those with an unfavorable genomic profile of neuroblastoma, supports the hypothesis that an immune response might be involved in tumor control in these patients with OMS.

17.
Bull Cancer ; 105 Suppl 1: S68-S79, 2018 Dec.
Artigo em Francês | MEDLINE | ID: mdl-30595201

RESUMO

NEW PERSPECTIVES IN IMMUNOTHERAPIES FOR PEDIATRIC MALIGNANCIES: New therapeutic paradigms are needed to improve the survival of children and adolescents with high-risk malignancies, and to reduce the sequelae associated with treatment. Immunotherapies, targeting tumor cells and/or the immune system to enhance existing anti-tumor immunity or induce novel anti-tumor immune responses, are becoming increasingly successful in adult oncology. Based on the results obtained with anti-ganglioside2 antibodies in neuroblastoma, rituximab in mature B malignancies, immune checkpoint inhibitors in lymphoma and especially in Hodgkin lymphoma, blinatumomab and CAR-T CD19 cells for B-cell acute lymphoblastic leukemia, immunotherapy has demonstrated irrefutable benefits in pediatric patients. However, these results are currently limited to a minority of patients and histologies. Current and ongoing trials tend to focus on a single type of immunotherapy, but it is likely that combinations of immunotherapies with different mechanisms of action or combination with other classes of anti-cancer treatments will be additives or even synergistic. The development of this new class of drugs in the treatment of pediatric cancers has multiple challenges: to better evaluate the response to treatment, to define the optimal doses and schedules, to manage immuno-mediated toxicities, to identify its specific sequelae, and, finally, to better understand the strategies of immune evasion of pediatric cancers in order to develop efficient immunotherapies.


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Criança , Terapia Combinada , Humanos , Ipilimumab/uso terapêutico , Neoplasias/imunologia , Nivolumabe/uso terapêutico , Microambiente Tumoral
18.
PLoS One ; 12(9): e0185190, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28945781

RESUMO

PURPOSE: This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome. PATIENTS AND METHODS: This IRB-approved retrospective observational study included 133 NB patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses. RESULTS: A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001). CONCLUSION: Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome.


Assuntos
Neuroblastoma/diagnóstico por imagem , Neuroblastoma/genética , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Feminino , França/epidemiologia , Genômica , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Neuroblastoma/mortalidade , Fenótipo , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Transcriptoma
19.
J Pediatr Oncol Nurs ; 34(6): 406-413, 2017 Nov/Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28845730

RESUMO

The purpose of this study was to examine the relationships between nurses' organizational and managerial resources (ie, perceived organizational support and transformational leadership) and their quality of patient care, and second, the mediating role of job satisfaction in these relationships. Participants were 510 nurses from 25 out of 29 French pediatric oncology units. Structural equation modeling results revealed that perceived organizational support and transformational leadership were related to nurses' perceived quality of care and that job satisfaction acted as a mediator between these 2 antecedents (ie, organizational and managerial determinants) and this outcome (ie, quality of care). Based on these findings, practical suggestions and directions for future research are discussed.


Assuntos
Satisfação no Emprego , Recursos Humanos de Enfermagem no Hospital/psicologia , Enfermagem Oncológica/organização & administração , Enfermagem Pediátrica/organização & administração , Qualidade da Assistência à Saúde/organização & administração , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , França , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade
20.
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
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