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1.
Neuro Oncol ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32025728

RESUMO

BACKGROUND: Considering that paediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). METHODS: We performed a multicentric retrospective study of 112 AYAs from adult and paediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyse their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25-years, histopathological HGG diagnosis, available clinical data, pre-operative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next generation sequencing, whole exome sequencing and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 WHO classification. RESULTS: Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of paediatric-subtypes (Histone H3-mutants, 40%) but also adult-subtypes (IDH-mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH-mutant and 1p/19q co-deleted and the relative high frequency of "rare adult IDH mutations" (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, the non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. CONCLUSIONS: HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from paediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

2.
Neurosurg Focus ; 48(1): E10, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31896084

RESUMO

Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.

3.
Clin Cancer Res ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924736

RESUMO

BACKGROUND: The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/Temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathological and molecular data. METHODS: Radiological, pathological and molecular data were correlated with trial clinical information to retrospectively re-evaluate event free and overall survival. RESULTS: One-hundred thirteen patients were randomized to the RT/TMZ arm (n =54) or the RT/TMZ+BEV (BEV arm; n =59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathological diagnosis was available in all cases and molecular data in 86/113. H3 K27M histone mutations were present in 23/32 Midline cases and H3 G34R/V mutations in 7/54 Cerebral cases. Total/near-total resection occurred in 44/68 (65%) Cerebral cases but only 5/45 (11%) Midline cases (p <0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than Cerebral tumors (10/68, p <0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (p <0.05). Pseudoprogression occurred in 8/111 (6.2%) cases. CONCLUSIONS: This study has shown that the poor outcome of midline tumors (compared to cerebral) may be related to 1) lesser surgical resection, 2) H3 K27M histone mutations, and 3) higher leptomeningeal dissemination.

4.
Acta Neuropathol ; 139(2): 287-303, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31677015

RESUMO

Pilocytic astrocytoma (PA) is the most common pediatric glioma, arising from a single driver MAPK pathway alteration. Classified as a grade I tumor according to the 2016 WHO classification, prognosis is excellent with a 10-year survival rate > 95% after surgery. However, rare cases present with anaplastic features, including an unexpected high mitotic/proliferative index, thus posing a diagnostic and therapeutic challenge. Based on small histomolecular series and case reports, such tumors arising at the time of diagnosis or recurrence have been designated by many names including pilocytic astrocytoma with anaplastic features (PAAF). Recent DNA methylation-profiling studies performed mainly on adult cases have revealed that PAAF exhibit a specific methylation signature, thus constituting a distinct methylation class from typical PA [methylation class anaplastic astrocytoma with piloid features-(MC-AAP)]. However, the diagnostic and prognostic significance of MC-AAP remains to be determined in children. We performed an integrative work on the largest pediatric cohort of PAAF, defined according to strict criteria: morphology compatible with the diagnosis of PA, with or without necrosis, ≥ 4 mitoses for 2.3 mm2, and MAPK pathway alteration. We subjected 31 tumors to clinical, imaging, morphological and molecular analyses, including DNA methylation profiling. We identified only one tumor belonging to the MC-AAP (3%), the others exhibiting a methylation profile typical for PA (77%), IDH-wild-type glioblastoma (7%), and diffuse leptomeningeal glioneuronal tumor (3%), while three cases (10%) did not match to a known DNA methylation class. No significant outcome differences were observed between PAAF with necrosis versus no necrosis (p = 0.07), or with 4-6 mitoses versus 7 or more mitoses (p = 0.857). Our findings argue that the diagnostic histomolecular criteria established for anaplasia in adult PA are not of diagnostic or prognostic value in a pediatric setting. Further extensive and comprehensive integrative studies are necessary to accurately define this exceptional entity in children.

5.
Neuro Oncol ; 22(1): 116-127, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31419298

RESUMO

BACKGROUND: The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG. METHODS: HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival. RESULTS: Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27-1.83; P < 0.0001). CONCLUSION: Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.

7.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

8.
Clin Cancer Res ; 25(22): 6788-6800, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31481512

RESUMO

PURPOSE: Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG. EXPERIMENTAL DESIGN: We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations. RESULTS: We uncover TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53MUT cells. CONCLUSIONS: Here, we demonstrate that TP53 mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.

9.
Oncogene ; 38(38): 6479-6490, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324890

RESUMO

Diffuse intrinsic pontine glioma (or DIPG) are pediatric high-grade gliomas associated with a dismal prognosis. They harbor specific substitution in histone H3 at position K27 that induces major epigenetic dysregulations. Most clinical trials failed so far to increase survival, and radiotherapy remains the most efficient treatment, despite only transient tumor control. We conducted the first lentiviral shRNA dropout screen in newly diagnosed DIPG to generate a cancer-lethal signature as a basis for the development of specific treatments with increased efficacy and reduced side effects compared to existing anticancer therapies. The analysis uncovered 41 DIPG essential genes among the 672 genes of human kinases tested, for which several distinct interfering RNAs impaired cell expansion of three different DIPG stem-cell cultures without deleterious effect on two control neural stem cells. Among them, PLK1, AURKB, CHEK1, EGFR, and GSK3A were previously identified by similar approach in adult GBM indicating common dependencies of these cancer cells and pediatric gliomas. As expected, we observed an enrichment of genes involved in proliferation and cell death processes with a significant number of candidates belonging to PTEN/PI3K/AKT and EGFR pathways already under scrutiny in clinical trials in this disease. We highlighted VRK3, a gene involved especially in cell cycle regulation, DNA repair, and neuronal differentiation, as a non-oncogenic addiction in DIPG. Its repression totally blocked DIPG cell growth in the four cellular models evaluated, and induced cell death in H3.3-K27M cells specifically but not in H3.1-K27M cells, supporting VRK3 as an interesting and promising target in DIPG.


Assuntos
Neoplasias do Tronco Encefálico/genética , Fosfotransferases/genética , Proteínas Serina-Treonina Quinases/fisiologia , RNA Interferente Pequeno/fisiologia , Análise de Sequência de RNA/métodos , Neoplasias do Tronco Encefálico/diagnóstico , Neoplasias do Tronco Encefálico/patologia , Sobrevivência Celular/genética , Células Cultivadas , /patologia , Genes Essenciais , Células HEK293 , Humanos , Fosfatidilinositol 3-Quinases/análise , Fosfatidilinositol 3-Quinases/genética , Fosfotransferases/análise , Prognóstico , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/análise
10.
Neurosurgery ; 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31342064

RESUMO

BACKGROUND: No link has been demonstrated between diffuse intrinsic pontine glioma and developmental venous anomaly in pediatric patients. OBJECTIVE: To determine the prevalence of developmental venous anomaly in a pediatric cohort of diffuse intrinsic pontine glioma. METHODS: We performed a retrospective cohort study (1998-2017) of consecutive pediatric patients harboring a diffuse intrinsic pontine glioma (experimental set, n = 162) or a craniopharyngioma (control set, n = 142) in a tertiary pediatric neurosurgical center. The inclusion criteria were the following: age <18 yr at diagnosis; histopathological diagnosis of diffuse intrinsic pontine glioma or craniopharyngioma according to the 2016 World Health Organization classification of tumors of the central nervous system; no previous oncological treatment; and available preoperative magnetic resonance imaging performed with similar acquisition protocol. RESULTS: We found a significantly higher prevalence of developmental venous anomaly in the experimental set of 162 diffuse intrinsic pontine gliomas (24.1%) than in the control set of 142 craniopharyngiomas (10.6%; P = .001). The prevalence of developmental venous anomalies was not significantly impacted by demographic data (sex, age at diagnosis, and underlying pathological condition), biomolecular analysis (H3-K27M-mutant subgroup, H3.1-K27M-mutant subgroup, and H3.3-K27M-mutant subgroup), or imaging findings (anatomic location, anatomic extension, side, and obstructive hydrocephalus) of the studied diffuse intrinsic pontine gliomas. CONCLUSION: We report a higher prevalence of developmental venous anomaly in pediatric diffuse intrinsic pontine glioma patients than in control patients, which suggests a potential underlying common predisposition or a causal relationship that will require deeper investigations.

11.
J Neuroradiol ; 46(3): 207-213, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30731145

RESUMO

INTRODUCTION: Medulloblastoma is the most common malignant cerebral tumor during childhood, arising in the posterior fossa. Children treated for medulloblastoma often experience working memory (WM) deficits, affecting their quality of life and school performance. The aim of the present study undertaken to describe the cerebellar involvement in WM deficits observed in these children. MATERIAL AND METHODS: 23 healthy children and 11 children treated for medulloblastoma were included into study. All subjects performed a detailed neuropsychological examination, an anatomical and functional MRI. Stimuli were presented to the participants with alternating sensory modality and nature of communication in a block design during functional magnetic resonance imaging acquisitions. Non-parametric tests were used for analyzing neuropsychological and behavioral data. SPM8 and SUIT (Spatially Unbiased Atlas Template) were used for anatomical and functional MRI data analyses. RESULTS: Patients had cerebellar resections mainly located in the left posterior lobe. Patients had significantly reduced intelligence quotient, central executive and visuospatial WM. In healthy children group, fMRI showed activations for non-verbal and visuospatial WM in the left posterior cerebellar lobe. CONCLUSION: This study provides further evidence that left posterior cerebellar lobe plays a critical role in WM. Indeed, lesions of left posterior cerebellar lobe were associated with WM impairment in children treated for cerebellar medulloblastoma. Additionally, fMRI using WM tasks showed activation in the left posterior cerebellar lobe in healthy children. Taken together, these findings may help for improving treatment and rehabilitation of children referred for cerebellar tumor.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/psicologia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/psicologia , Imagem por Ressonância Magnética/métodos , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/psicologia , Memória de Curto Prazo , Adolescente , Mapeamento Encefálico , Neoplasias Encefálicas/cirurgia , Criança , Feminino , França , Humanos , Deficiência Intelectual/etiologia , Masculino , Meduloblastoma/cirurgia , Testes Neuropsicológicos , Procedimentos Neurocirúrgicos , Qualidade de Vida , Fatores de Risco
12.
J Neurooncol ; 141(2): 253-263, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30446898

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. METHODS: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. RESULTS: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). CONCLUSION: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.


Assuntos
Neoplasias do Tronco Encefálico/fisiopatologia , Neoplasias do Tronco Encefálico/terapia , Glioma/fisiopatologia , Glioma/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Neoplasias do Tronco Encefálico/genética , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Glioma/genética , Histonas/genética , Humanos , Camundongos , Mutação , Estudos Retrospectivos
13.
J Neurooncol ; 141(2): 265, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30484110

RESUMO

There are two errors and one omission in the original article. Author Gottardo's correct name is Nicholas G. Gottardo, author Hulleman's correct affiliation is no. 3 (VUMC, Amsterdam), and the Acknowledgements should include the following sentence: "We would like to thank Dr Angel Montero Carcaboso (Hospital Sant Joan de Deu, Barcelona, Spain) for generously supplying the HSJD-DIPG007 cells."

14.
Brain Pathol ; 29(3): 325-335, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30325077

RESUMO

Ependymoma with RELA fusion has been defined as a novel entity of the revised World Health Organization 2016 classification of tumors of the central nervous system (CNS), characterized by fusion transcripts of the RELA gene and consequent pathological activation of the NFkB pathway. These tumors represent the majority of supratentorial ependymomas in children. The validation of diagnostic tools to identify this clinically relevant ependymoma entity is essential. Here, we have used interphase fluorescent in situ hybridization (FISH) for C11orf95 and RELA, immunohistochemistry (IHC) for p65-RelA and the recently developed DNA methylation-based classification besides conventional histopathology, and compared the precision of the methods in 40 supratentorial pediatric brain tumors diagnosed as ependymomas in the past years. Reverse transcription PCR (RT-PCR) and RNA sequencing were performed to explore discordant cases. Furthermore, we integrated imaging and clinical features as additional layers of information. The concordance between nuclear RelA expression by IHC and RELA FISH was 100%. Concordance between IHC and DNA methylation profiling, and between FISH and DNA methylation profiling was also high (96.4% and 95.2%, respectively). Thirty-four out of 40 (85%) cases were confirmed by integrated diagnoses as ependymal tumors, including 22 RELA-fused ependymomas (71% of ependymal tumors), two YAP1-fused ependymomas (6%), six non-RELA/non-YAP1 ependymomas (18%) and four ependymal/subependymal mixed tumors (12%). Ependymal/subependymal mixed tumors had an excellent clinical outcome despite the presence of histopathological signs of malignancy, suggesting that these tumors should not be diagnosed as classic ependymomas. DNA methylation profiling helped in the differential diagnosis of RELA-fused ependymomas. IHC and FISH, which are available in the majority of pathology laboratories, are valuable tools to identify RELA-fused ependymomas.


Assuntos
Metilação de DNA , Ependimoma/diagnóstico , Ependimoma/genética , Neoplasias Supratentoriais/diagnóstico , Neoplasias Supratentoriais/genética , Fator de Transcrição RelA/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Ependimoma/metabolismo , Ependimoma/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente/métodos , Lactente , Masculino , NF-kappa B/metabolismo , Proteínas/genética , Proteínas/metabolismo , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/patologia , Fator de Transcrição RelA/metabolismo
15.
Brain Pathol ; 29(2): 205-216, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30246434

RESUMO

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.


Assuntos
Ependimoma/genética , Ependimoma/patologia , Neoplasias Supratentoriais/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Dev Neurorehabil ; 22(1): 19-26, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29336639

RESUMO

PURPOSE: To investigate intellectual and situation-based social outcome and educational achievement in adult survivors of childhood medulloblastoma and analyse factors influencing outcome Methods: We collected demographic, medical and cognitive data, and social and educational outcome at a mean time since the end of treatments of 14.9 years in 58 adults, aged 19-35 years, consecutively treated in a single cancer center between 1989 and 2005. RESULTS: Ten survivors had severe intellectual disability, 12 were still studying, 23 had a regular employment and 13 were unemployed. Full Scale Intellectual Quotient, assessed 6.6 years after the end of treatments, ranged from 46 to 131. It was strongly associated with educational achievement and significantly lower in patients who experienced postoperative cerebellar mutism, and when parental education level was low. CONCLUSION: These factors should be systematically considered at diagnosis in order to offer adequate and timely assessments and interventions.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/estatística & dados numéricos , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Cerebelares/epidemiologia , Meduloblastoma/epidemiologia , Desempenho Acadêmico , Adolescente , Adulto , Neoplasias Cerebelares/reabilitação , Criança , Pré-Escolar , Cognição , Emprego , Feminino , Humanos , Masculino , Meduloblastoma/reabilitação , Pessoa de Meia-Idade , Ajustamento Social
17.
Pediatr Blood Cancer ; 66(2): e27487, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30378286

RESUMO

BACKGROUND: We conducted an integrated analysis of clinical data to describe long-term effects of bevacizumab on growth and bone development in pediatric and adolescent patients with solid tumors. PROCEDURE: Clinical data were pooled from five phase I/II trials of bevacizumab versus chemotherapy: BERNIE, HERBY, and AVF4117s enrolled newly diagnosed patients, AVF3842s and AVF2771s enrolled patients with relapsed/refractory disease. Height, weight, body mass index (BMI), and bone-age data were pooled by treatment group. Growth charts were used to track and monitor growth in relation to a reference population of healthy children. Bone age was measured based on X-ray of the left hand and wrist. Analyses were exploratory/descriptive. RESULTS: Overall, 268 patients received bevacizumab ± chemotherapy and 135 received chemotherapy alone. Baseline characteristics were generally balanced. Median duration of long-term follow-up was 41.8 months (range, 2.4-75.1) with bevacizumab and 22.9 months (range, 2.8-69.2) with chemotherapy alone. Patients had age-appropriate baseline height and weight. Mean height and weight percentiles decreased over time in both treatment groups, but remained within the normal range (height: mean standard deviation score [SDS] range -2 to +3; weight: mean SDS range -2 to +1). Similar trends were seen in BMI. A tendency for reduced growth velocity relative to the reference population was observed at 6 months and 1 year in both groups, but there was no additional decrease for patients receiving bevacizumab. CONCLUSION: Bevacizumab did not appear to have additional negative effects on growth or development of pediatric and adolescent patients with solid tumors.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Bevacizumab/efeitos adversos , Desenvolvimento Ósseo/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Adolescente , Estatura/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
18.
J Psychosoc Oncol ; 37(1): 96-109, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30592250

RESUMO

BACKGROUND: Despite evidence that pediatric cancer induces a trajectory of parental stress, studies including mothers of children with malignant brain tumors remain scarce. The present work aims to add to the scientific literature by evaluating maternal stress with a French translation of the Pediatric Inventory for Parents (PIP) in a population of mothers whose children have been diagnosed with a brain tumor. PROCEDURE: The mothers of 35 children with malignant brain tumors completed the Pediatric Inventory for Parents (PIP), the State-Trait Anxiety Inventory (STAI) and the Family Assessment Device (FAD) at a mean time since diagnosis of 2.3 years. RESULTS: The PIP showed good internal consistency and correlated significantly with the STAI and the FAD. Maternal stress scores were higher in younger mothers and in mothers of younger children. Emotional functioning was the most affected domain. CONCLUSIONS: Emotional stress as assessed by the PIP in mothers of children with malignant brain tumors is considerable, and should be routinely assessed, in order to implement appropriate specific psychosocial interventions when needed.

19.
Acta Neuropathol Commun ; 6(1): 117, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30396367

RESUMO

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.


Assuntos
Neoplasias Encefálicas/genética , Epigenômica , Glioma/genética , Histonas/genética , Mutação/genética , Transcriptoma/fisiologia , Adolescente , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Lisina/genética , Masculino , Metionina/genética , Análise de Componente Principal , Células Tumorais Cultivadas
20.
Brain Inj ; 32(13-14): 1780-1786, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30296189

RESUMO

OBJECTIVE: Studies on parental stress following childhood acquired brain injury (ABI-including brain tumours (BT) and other brain injuries) are scarce. The aim of this study was to assess maternal stress in a sample of children and adolescents diagnosed with severe paediatric ABI. METHODS: Seventy-eight French-speaking mothers of 37 with BT and 41 with other ABIs completed the Paediatric Inventory for Parents (PIP), the State-Trait Anxiety Inventory (STAI) and the Family Assessment Device (FAD) at a mean time since diagnosis of 1.5 years. RESULTS: The PIP correlated significantly with the STAI and the FAD. Socio-demographic factors, such as the age of mother and child, and the mother's educational level, were correlated with both maternal stress and anxiety. Maternal stress scores were comparable between groups. Emotional functioning was the most markedly affected domain, followed by parental role. CONCLUSIONS: Emotional stress as assessed by the PIP in mothers of children with ABI is significant and should motivate specific psychosocial interventions.


Assuntos
Lesões Encefálicas/epidemiologia , Relações Mãe-Filho/psicologia , Mães/psicologia , Estresse Psicológico/etiologia , Adolescente , Adulto , Lesões Encefálicas/psicologia , Lesões Encefálicas/reabilitação , Criança , Correlação de Dados , Família , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Fatores Socioeconômicos , Estresse Psicológico/epidemiologia , Inquéritos e Questionários
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