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1.
Acta Neuropathol ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781912

RESUMO

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

2.
Cell Death Dis ; 10(10): 696, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541075

RESUMO

Medulloblastoma, an embryonal tumor of the cerebellum/fourth ventricle, is one of the most frequent malignant brain tumors in children. Although genetic variants are increasingly used in treatment stratification, survival of high-risk patients, characterized by leptomeningeal dissemination, TP53 mutation or MYC amplification, is still poor. FOXM1, a proliferation-specific oncogenic transcription factor, is deregulated in various solid tumors, including medulloblastoma, and triggers cellular proliferation, migration and genomic instability. In tissue samples obtained from medulloblastoma patients, the significant upregulation of FOXM1 was associated with a loss of its putative regulating microRNA, miR-4521. To understand the underlying mechanism, we investigated the effect of miR-4521 on the expression of the transcription factor FOXM1 in medulloblastoma cell lines. Transfection of this microRNA reduced proliferation and invasion of several medulloblastoma cell lines and induced programmed cell death through activation of caspase 3/7. Further, downstream targets of FOXM1 such as PLK1 and cyclin B1 were significantly reduced thus affecting the cell cycle progression in medulloblastoma cell lines. In conclusion, a restoration of miRNA-4521 may selectively suppress the pathophysiological effect of aberrant FOXM1 expression and serve as a targeted approach for medulloblastoma therapy.

3.
J Neurosurg ; : 1-9, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31561218

RESUMO

OBJECTIVE: CSF dynamics after transcallosal resection of intraventricular lesions can be altered, and the need for shunt implantation complicates the management of these patients. Because the pathophysiological mechanism and contributing factors are poorly understood and the incidence has largely not been described, the authors conducted a study to elucidate these factors. METHODS: The authors retrospectively reviewed data from patients who had been operated on at their institution via a transcallosal approach between March 2002 and December 2016. They evaluated the need for a shunt implantation up to 3 months after surgery by assessing clinical variables. These variables were age at surgery, the need for perioperative external CSF drainage, histology of the lesion, and the following radiological parameters: pre- and postoperative Evans index, maximal postoperative extension of subdural effusions (SDEs) measured on axial images, and maximal interhemispheric fissure (IHF) width measured on coronal images assessed at 4 different points in time (preoperatively, day 1, days 2-4, and days 4-8 after surgery). To identify potential risk factors, univariate and multivariate regression models were constructed. Receiver operating characteristic (ROC) curves for significant predictors, as well as the area under the curve (AUC), were calculated. RESULTS: Seventy-four patients (40 female and 34 male) were identified; their median age at surgery was 17.6 years (range 4 months to 76 years). Shunt implantation was necessary in 13 patients (ventriculoperitoneal [VP] shunt, n = 7; subdural peritoneal [SDP] shunt, n = 6) after a median interval of 24 days (range 10 days to 3 months). Univariate logistic regression models revealed a significant effect of IHF width on days 4-8 (OR 1.31, 95% CI 1.03-1.66; p = 0.027), extension of SDE on days 2-4 (OR 1.33, 95% CI 1.11-1 0.60; p = 0.003), and age (OR 0.932, 95% CI 0.88-0.99; p = 0.02). In the multiple regression model, the effect of the independent variable extension of the SDE remained significant. ROC curves for the predictors IHF width on days 4-8 and extension of SDE on days 2-4 revealed an AUC equal to 0.732 and 0.752, respectively. Before shunt implantation, the ventricles were smaller compared to the preoperative size in 9 of the 13 patients (SDP shunt, n = 5; VP shunt, n = 4). CONCLUSIONS: The rate of shunt-dependent hydrocephalus 3 months after surgery in this heterogeneous group of patients was 17.6% (95% CI 9.7%-28.2%). The authors identified as predictive factors the variables extension of the convexity space, IHF 1 week after surgery, and younger age.

4.
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.

5.
Acta Neuropathol Commun ; 7(1): 128, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391125

RESUMO

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAFV600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAFV600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG. In vitro, BRAFV600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.

6.
Cell ; 178(4): 835-849.e21, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31327527

RESUMO

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.

7.
Nature ; 572(7767): 74-79, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341285

RESUMO

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.


Assuntos
Genômica , Meduloblastoma/genética , Meduloblastoma/patologia , Análise de Célula Única , Transcriptoma , Adolescente , Adulto , Animais , Linhagem da Célula , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Lactente , Meduloblastoma/classificação , Camundongos , Neurônios/metabolismo , Neurônios/patologia
8.
Neurosurgery ; 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31065705

RESUMO

BACKGROUND: Primary intratumoral hemorrhage as a presenting sign is rare in children with medulloblastomas but may result in severe complications. Given the distinct properties of molecular medulloblastoma subgroups, the impact on neurosurgical practice has still to be defined. OBJECTIVE: To investigate both clinical and radiological presentation of intratumoral hemorrhage in medulloblastoma patients in the context of molecular subgroups. METHODS: Data of all consecutive medulloblastoma patients treated at our institution between 1993 and 2018 (n = 104) were retrospectively reviewed in respect of clinical and radiological presentation as well as molecular subgroups. For cases with available tumor tissue (n = 86), subgroups were assigned by either 450 K methylation array or immunohistochemistry and CTNNB1 sequencing. Available imaging at diagnosis (n = 62) was reviewed by an experienced neuroradiologist. RESULTS: Within the entire cohort, 4 patients (4%) presented with massive spontaneous hemorrhage. Although no patient died as a direct consequence of hemorrhage, all suffered from serious sequelae. Moreover, 3 additional patients displayed radiological evidence of significant hemorrhage. Interestingly, all 7 cases belonged to the wingless (WNT) subgroup (n = 13), resulting in intratumoral hemorrhage in 54% (7/13) of pediatric WNT medulloblastomas. In contrast, significant hemorrhage was absent in all other molecular subgroups. CONCLUSION: Our results suggest that a substantial proportion of pediatric WNT medulloblastomas display significant intratumoral hemorrhage at the time of diagnosis. Consequently, the presence of significant hemorrhage in fourth ventricle childhood tumors is suggestive of WNT medulloblastoma and should lead to a less aggressive attempt for total resection in this prognostically favorable tumor type.

9.
Acta Neurochir (Wien) ; 161(4): 745-754, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30783805

RESUMO

BACKGROUND: Choroid plexus tumors are rare entities. Resection is the mainstay of treatment in grade I and grade II tumors and adjuvant treatment is usually reserved for the less frequent choroid plexus carcinoma (CPC). Outcome is not only related to their histological grade but also dependent on their size, location, and presence of often multifactorial disturbances of cerebrospinal fluid (CSF) circulation. METHODS: Retrospective analysis of 36 consecutive patients operated on a choroid plexus tumor at our institution in a mixed pediatric and adult population between 1991 and 2016. RESULTS: Twenty-one CPP, 11 atypical choroid plexus papillomas (aCPP), and four CPC were encountered in 17 children and 19 adults. Regardless of histological grading, gross-total resection (GTR) could be achieved in 91.7% of patients. Tumor recurrence (25.0%) was significantly associated with histological grading (p = 0.004), subtotal resection (p = 0.002), and intraoperatively evident zones of tumor infiltration (p = 0.001). Adjuvant therapy was performed in 19.4% of patients, mainly diagnosed with CPC. The 5-year overall survival rate was 95.2% for CPP and 100.0% for both aCPP and CPC. Survival was related to the extent of resection (p = 0.001), tumor progression (p = 0.04), and the presence of leptomeningeal metastases (p = 0.002). Even after resection, either ventricular or subdural shunting was required in 25.0% of patients. CONCLUSIONS: We could confirm that GTR is crucial for treatment of choroid plexus tumors. Parenchymal tumor infiltration as detected intraoperatively was associated with the extent of resection and not limited to CPC. CSF disturbances mandating treatment may persist after resection.

10.
J Med Genet ; 56(2): 53-62, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30415209

RESUMO

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

11.
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
12.
Mol Genet Metab ; 124(3): 184-188, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29793829

RESUMO

For decades, intracerebroventricular (ICV), or intraventricular, devices have been used in the treatment of a broad range of pediatric and adult central nervous system (CNS) disorders. Due to the limited permeability of the blood brain barrier, diseases with CNS involvement may require direct administration of drugs into the brain to achieve full therapeutic effect. A recent comprehensive literature review on the clinical use and complications of ICV drug delivery revealed that device-associated complication rates are variable, and may be as high as 33% for non-infectious complications and 27% for infectious complications. The variability in reported safety outcomes may be driven by a lack of consensus on best practices of device use. Numerous studies have demonstrated that employing strict aseptic techniques and following stringent protocols can dramatically reduce complications. Key practices to be considered in facilitating the safe, long-term use of these devices are presented.


Assuntos
Fármacos do Sistema Nervoso Central/administração & dosagem , Doenças do Sistema Nervoso Central/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Injeções Intraventriculares/instrumentação , Guias de Prática Clínica como Assunto/normas , Humanos
13.
Science ; 360(6386): 331-335, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29674595

RESUMO

Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.


Assuntos
Neoplasias Encefálicas/patologia , Carcinogênese/genética , Glioma/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Oncogenes , Neoplasias Encefálicas/genética , Proliferação de Células , Glioma/genética , Histonas/metabolismo , Humanos , Proteína Quinase 7 Ativada por Mitógeno/genética , Mutação , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos
15.
Strahlenther Onkol ; 194(6): 552-559, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29349602

RESUMO

PURPOSE: Paediatric high grade glioma (pHGG) are rare. Following maximum safe resection, children >3 years with HGG receive radiotherapy as standard of care. Whether the interval from tumour surgery to radiotherapy (ISRT) influences survival is disputed in adults with glioblastoma, data for children are lacking. This retrospective single-centre analysis investigates a possible impact of ISRT on survival in paediatric patients with HGG. METHODS: Survival was analysed in patients aged 3-19 years with non-pontine HGG. RESULTS: Thirty-eight patients were included (female:male 19:19) with a median age of 11.0 years (3.4-17.7). Seventeen patients had grade 3 and 21 grade 4 glioma. Gross total resection was achieved in 26.3%, partial resection in 36.8% and 36.8% underwent biopsy only. All patients received concomitant and adjuvant chemotherapy. Fifty percent (n = 19) started irradiation ≤17 days (median interval 12 days [range 5-17]), 50% thereafter (median 28 days [range 19-78]). More patients with grade 4 tumours were irradiated shortly after surgery. ISRT (as a continuous variable and dichotomised into two groups by the median ISRT of 18 days) did not significantly influence overall survival (OS) or progression-free survival (PFS). Higher extent of resection (EOR), lower tumour grade as well as chemotherapy with temozolomide had a significant positive impact on OS and PFS in univariate analysis and (except for the effect of temozolomide on PFS) also in multivariable analysis. CONCLUSIONS: ISRT did not influence survival in pHGG. In view of upcoming targeted treatment options in pHGG the present data suggest that it is safe to perform molecular analyses within a 4-week timeframe before radiotherapy.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Craniotomia , Glioma/radioterapia , Glioma/cirurgia , Radioterapia Adjuvante , Adolescente , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Feminino , Glioma/mortalidade , Humanos , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
16.
Dev Neurorehabil ; 21(6): 415-422, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28968151

RESUMO

OBJECTIVE: Previous studies differ regarding the long-term effects of surgically removed pediatric cerebellar pilocytic astrocytomas (CPA). Thus, the aim of this study was to investigate the long-term impact on neurocognitive and functional outcome and to analyze age as an influencing factor. METHODS: Fourteen CPA patients were compared to the age norm and to a group of 14 high-achieving peers regarding cognitive functioning, health-related quality of life (HRQoL), and stress regulation. Mean follow-up time after diagnosis was 13.29 years (range: 3-21 years). RESULTS: Patients showed satisfactory academic achievement and did not differ from the norm except for the bodily dimension of HRQoL. However, there were marked differences in specific neurocognitive functions between patients and high achievers. Age at diagnosis did not influence neurocognitive outcome. CONCLUSION: CPA patients treated with surgery only seem to have a favorable long-term outcome, yet, in comparison with high achievers specific cognitive impairments become apparent.


Assuntos
Astrocitoma/cirurgia , Neoplasias Cerebelares/cirurgia , Transtornos Cognitivos/epidemiologia , Cognição , Complicações Pós-Operatórias/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Transtornos Cognitivos/etiologia , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/etiologia
17.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28771999

RESUMO

PURPOSE: About 10% of patients with neurofibromatosis type 1 (NF-1) develop malignant peripheral nerve sheath tumours (MPNST) mostly arising in plexiform neurofibroma (PN); 15% of MPNST arise in children and adolescents. 2-[18 F]fluoro-2-deoxy-d-glucose ([18 F]FDG)-PET (where PET is positron emission tomography) is a sensitive method in differentiating PN and MPNST in symptomatic patients with NF-1. This study assesses the value of [18 F]FDG-PET imaging in detecting malignant transformation in symptomatic and asymptomatic children with PN. METHODS: Forty-one patients with NF-1 and extensive PN underwent prospective [18 F]FDG imaging from 2003 to 2014. Thirty-two of the patients were asymptomatic. PET data, together with histological results and clinical course were re-evaluated retrospectively. Maximum standardised uptake values (SUVmax) and lesion-to-liver ratio were assessed. RESULTS: A total of 104 examinations were performed. Mean age at first PET was 13.5 years (2.6-22.6). Eight patients had at least one malignant lesion; four of these patients were asymptomatic. Two of four symptomatic patients died, while all patients with asymptomatic malignant lesions are alive. All malignant tumours could be identified by PET imaging in both symptomatic and asymptomatic patients. All lesions judged as benign by [18 F]FDG imaging and clinical judgment were either histologically benign if removed or remained clinically silent during follow-up. SUVmax of malignant and benign lesions overlapped, but no malignant lesion showed FDG uptake ≤3.15. Asymptomatic malignant lesions were detected with a sensitivity of 100%, a negative predictive value of 100% and a specificity of 45.1%. CONCLUSION: Malignant transformation of PN also occurs in asymptomatic children and adolescents. Detection of MPNST at early stages could increase the possibility of oncologically curative resections.


Assuntos
Fluordesoxiglucose F18/administração & dosagem , Neurofibroma Plexiforme/diagnóstico por imagem , Neurofibromatose 1/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino
18.
Pediatr Neurol ; 76: 27-36, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28935367

RESUMO

BACKGROUND: Children with central nervous system (CNS) tumours may present with a multitude of symptoms, ranging from elevated intracranial pressure to focal neurological deficit. In everyday practice, some signs may be misleading, thereby causing prolonged prediagnostic symptomatic intervals. Prediagnostic symptomatic intervals are longer for pediatric brain tumors than for other childhood malignancies. This study evaluated prediagnostic symptomatic intervals and parental and diagnostic intervals for pediatric patients with CNS tumours in Austria. It also considered socioeconomic factors. METHODS: Patients ≤ 19 years of age treated at the Medical University of Vienna and diagnosed during the years 2008 to 2013 were included. Patients diagnosed incidentally or by screening were excluded. RESULTS: Two hundred twelve consecutive patients were included in the study. They reflected the expected spectrum of CNS tumors. Patients presented with a median of five symptoms at diagnosis, most frequently with signs of elevated intracranial pressure. The median prediagnostic symptomatic interval was 60 days (0 days to seven years), the median parental interval was 30 days (0 days to 6.7 years), and the median diagnostic interval was three days (0 days to 6.5 years). In spinal tumors alone (n = 7), the median prediagnostic symptomatic interval was 70 days (ten days to seven years), and three of seven patients had a prediagnostic symptomatic interval longer than 320 days. Young age, higher tumor grade, and ataxia were associated with a shorter prediagnostic symptomatic interval. Localization in the supratentorial midline, histology of craniopharyngioma, and endocrine symptoms prolonged the prediagnostic symptomatic interval. There was a clear trend for longer prediagnostic symptomatic interval in non-native speakers. CONCLUSIONS: Results are comparable to other industrialized countries. However, long delays in diagnosis of central nervous system tumors still occur, urging increased awareness.


Assuntos
Neoplasias do Sistema Nervoso Central , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Adolescente , Distribuição por Idade , Áustria/epidemiologia , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Pressão Intracraniana/fisiologia , Masculino , Estudos Retrospectivos , Adulto Jovem
19.
J Neurooncol ; 135(2): 361-369, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28779461

RESUMO

Over the past decades, many studies used global outcome measures like the IQ when reporting cognitive outcome of pediatric brain tumor patients, assuming that intelligence is a singular and homogeneous construct. In contrast, especially in clinical neuropsychology, the assessment and interpretation of distinct neurocognitive domains emerged as standard. By definition, the full scale IQ (FIQ) is a score attempting to measure intelligence. It is established by calculating the average performance of a number of subtests. Therefore, FIQ depends on the subtests that are used and the influence neurocognitive functions have on these performances. Consequently, the present study investigated the impact of neuropsychological domains on the singular "g-factor" concept and analysed the consequences for interpretation of clinical outcome. The sample consisted of 37 pediatric patients with medulloblastoma, assessed 0-3 years after diagnosis with the Wechsler Intelligence Scales. Information processing speed and visuomotor function were measured by the Trailmaking Test, Form A. Our findings indicate that FIQ was considerably impacted by processing speed and visuomotor coordination, which leaded to an underestimation of the general cognitive performance of many patients. One year after diagnosis, when patients showed the largest norm-deviation, this effect seemed to be at its peak. As already recommended in international guidelines, a comprehensive neuropsychological test battery is necessary to fully understand cognitive outcome. If IQ-tests are used, a detailed subtest analysis with respect to the impact of processing speed seems essential. Otherwise patients may be at risk for wrong decision making, especially in educational guidance.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/psicologia , Inteligência , Meduloblastoma/diagnóstico , Meduloblastoma/psicologia , Testes Neuropsicológicos , Adolescente , Criança , Pré-Escolar , Cognição , Estudos Transversais , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto Jovem
20.
PLoS One ; 12(7): e0180200, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28692686

RESUMO

While it has been shown that cerebellar tumor lesions have an impact on cognitive functions, the extent to which they shape distant neuronal pathways is still largely undescribed. Thus, the present neuroimaging study was designed to investigate different aspects of cognitive function and their neuronal correlates in patients after childhood cerebellar tumor surgery. An alertness task, a working memory task and an incompatibility task were performed by 11 patients after childhood cerebellar tumor surgery and 17 healthy controls. Neuronal correlates as reflected by alterations in functional networks during tasks were assessed using group independent component analysis. We were able to identify eight networks involved during task performance: default mode network, precuneus, anterior salience network, executive control network, visual network, auditory and sensorimotor network and a cerebellar network. For the most 'basic' cognitive tasks, a weaker task-modulation of default mode network, left executive control network and the cerebellar network was observed in patients compared to controls. Results for higher-order tasks are in line with a partial restoration of networks responsible for higher-order task execution. Our results provide tentative evidence that the synchronicity of brain activity in patients was at least partially restored in the course of neuroplastic reorganization, particularly for networks related to higher-order cognitive processes. The complex activation patterns underline the importance of testing several cognitive functions to assess the specificity of cognitive deficits and neuronal reorganization processes after brain lesions.


Assuntos
Neoplasias Cerebelares/fisiopatologia , Cognição , Neurônios/patologia , Adolescente , Adulto , Comportamento , Encéfalo/patologia , Encéfalo/fisiopatologia , Neoplasias Cerebelares/cirurgia , Criança , Feminino , Humanos , Modelos Lineares , Masculino , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Análise e Desempenho de Tarefas , Adulto Jovem
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