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  • 1
    Language: English
    In: World Neurosurgery, 2010, Vol.74(4), pp.532-537
    Description: A less favorable outcome is usually claimed for ETV in formerly shunted patients, and continuous bias exists on using endoscopy in cases with malfunctioning CSF shunts. A cohort of 60 patients with obstructive triventricular hydrocephalus (mean age 22 years, range 1–68) underwent an ETV instead of shunt revision. Fourteen patients had a history of multiple shunt-related surgeries (more than three times). Median follow-up lasted 2 years (range 1 month–8 years). Data on patients' preoperative condition and their history, including particularities of the surgery, were studied to define the impact of any given variable on the outcome. The Mann-Whitney test was used to assess differences among groups. Sixteen patients did not improve and needed permanent shunts anyway. The remaining 44 patients improved and became free of shunt (72%). No reliable correlation has been found regarding final outcome and data, characterizing patients' profile, for example, etiology of hydrocephalus, the history of intraventricular bleeding and/or CNS infection, age at onset and age at the first shunting, number of shunt surgeries, the origin of shunt malfunction, and complicated ventricular anatomy. There were no deaths, and overall cases with morbidity comprised 20% (12 cases); among them, serious complications with neurologic deficit were noted in three (5%) patients. Patients with obstructive hydrocephalus could benefit from ETV in case of their shunt malfunction and if carefully selected have about 70% probability to become shunt free. In formerly shunted patients, endoscopy has somewhat greater risk of serious complications; thus a wider experience is essential when offering them an ETV.
    Keywords: Cerebrospinal Fluid Shunts ; Endoscopic Third Ventriculostomy ; Obstructive Hydrocephalus ; Outcome
    ISSN: 1878-8750
    E-ISSN: 1878-8769
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  • 2
    In: Nature, 2012, Vol.482(7384), p.226
    Description: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases (1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX([alpha]-thalassaemia/mental retardation syndrome X-linked) (5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres (6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
    Keywords: Gene Mutation -- Research ; Dna -- Research ; Dna -- Physiological Aspects ; Glioblastomas -- Genetic Aspects ; Glioblastomas -- Research ; Tumor Proteins -- Physiological Aspects ; Tumor Proteins -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Cancer, 15 March 2004, Vol.100(6), pp.1230-1237
    Description: BACKGROUND: Ependymomas account for 3-5% of all intracranial malignancies and occur most often in children and young adults. These neoplasms continue to generate considerable controversy with regard to their rational clinical management. It has been shown that the histologic classification of ependymoma is a significant predictor of clinical outcome in patients with ependymoma.METHODS: Ependymomas from 258 patients who underwent microsurgery at a single institution were evaluated histologically to elucidate the prognostic utility of a recently proposed grading scheme. Pathologic and clinical data then were compared using univariate and multivariate analyses.RESULTS: Increasing grade of ependymoma malignancy was found to be associated strongly and independently with worse clinical outcomes in terms of both event-free survival and overall survival. The effect of radiotherapy also was found to be related to histologic grade and was more beneficial for patients who had anaplastic ependymomas and had undergone complete tumor removal.CONCLUSIONS: The application of a uniform diagnostic criteria for grading ependymomas highlighted the key role of tumor histology in clinical outcome in a cohort of patients who were treated in the microsurgical era. The recently proposed grading scheme is likely to be practically useful, reproducible, and clinically applicable.
    Keywords: Ependymoma ; Histology ; Malignancy Grade ; Prognosis ; Radiotherapy
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 4
    Language: English
    In: International Journal of Cancer, 01 November 2011, Vol.129(9), pp.2297-2303
    Description: Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated Ras/Raf/MEK/ERK signaling. Common genetic lesions observed in PA, which are linked to aberrant ERK pathway activity, include either inactivation, or gain‐of‐function mutations. To investigate the mutation spectrum within the proto‐oncogene encoding the Ser/Thr‐kinase B‐Raf in more detail, we analyzed 64 primary tumor samples from children with PA including two patients with neurofibromatosis type 1 (NF1). The well‐known mutation was found in 6/64 (9.38%) of our samples. For the first time, we report concomitant presence of a somatic mutation in an NF1 patient indicating that more than one Ras/ERK pathway component can be affected in PA. Furthermore, 2/64 (3.13%) of our samples carried a 3‐bp insertion in resulting in the duplication of threonine 599. This conserved residue is located within the activation segment and, if phosphorylated in a Ras‐dependent manner, plays a key role in Raf activation. Here, we demonstrate that this mutant (B‐Raf) and another B‐Raf mutant, which carries two additional threonine residues at this position, display an kinase activity and cellular MEK/ERK activation potential comparable to those of B‐Raf. Notably, replacement of threonines by valine residues had similar effects on B‐Raf activity, suggesting that the distortion of the peptide backbone by additional amino acids rather than the insertion of additional, potential phosphorylation sites destabilizes the inactive conformation of the kinase domain. We also demonstrate that B‐Raf and B‐Raf, but not B‐Raf, provoke drastic morphological alterations in human astrocytes.
    Keywords: Pilocytic Astrocytoma ; Neurofibromatosis Type 1 ; B‐Raf ; Insertion Mutagenesis ; Mapk Pathway
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 5
    Language: English
    In: Zhurnal voprosy neirokhirurgii imeni N. N. Burdenko, 2016, Vol.80(4), pp.13-20
    Description: The study objective was to develop a rational approach for defining the extent of posterior decompression in children with Chiari 1 malformation. Posterior decompression was performed in 76 children with Chiari 1 malformation, under 18 years of age, in the period between 2001 and 2015. Fifty two (68%) children had syringomyelia. Extradural decompression (EDD) was performed in 14 (18%) cases, extra-arachnoid duraplasty (EAD) in 21 (28%) cases, intra-arachnoid dissection and duraplasty in 21 (28%) cases, and foramen of Magendie stenting and duraplasty in 20 (26%) cases. Complications occurred in 15 (20%) patients, with one of them being fatal (case fatality rate, 1.3%). The complication rate was higher after (1) intra-arachnoid dissection (p=0.0009) and stenting (p=0.02). Re-operation was required in 8 (11%) patients. The overall rate of complications and re-operations was lowest after EAD (10%). EAD is the method of choice for Chiari 1 malformation in children. EDD can be adopted as a primary option, but it requires selection of relevant patients. Intra-arachnoid dissection, with/without stenting, is not advisable as a primary intervention, but may be inevitable in the re-operation case.
    Keywords: Arnold-Chiari Malformation -- Surgery ; Decompression, Surgical -- Methods ; Syringomyelia -- Surgery
    ISSN: 0042-8817
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(6), p.e0178351
    Description: Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths.This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed.Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group.Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 8
    In: Nature, 2012, Vol.488(7409), p.100
    Description: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
    Keywords: Cerebellar Neoplasms -- Genetics ; Genome, Human -- Genetics ; Medulloblastoma -- Genetics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 9
    Language: English
    In: Nature medicine, November 2018, Vol.24(11), pp.1752-1761
    Description: Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.
    Keywords: Biological Specimen Banks ; Immunohistochemistry ; Brain Neoplasms -- Pathology ; Xenograft Model Antitumor Assays -- Methods
    ISSN: 10788956
    E-ISSN: 1546-170X
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  • 10
    Language: English
    In: Acta neuropathologica, September 2017, Vol.134(3), pp.507-516
    Description: Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.
    Keywords: Brain Tumor ; Egfr ; Glioblastoma ; Mycn ; Methylation ; Pdgfra ; Pediatric ; Prognostic ; Rtk ; Subgroup ; Survival ; Mutation ; Brain Neoplasms -- Genetics ; Glioblastoma -- Genetics ; Histones -- Genetics ; Isocitrate Dehydrogenase -- Genetics
    ISSN: 00016322
    E-ISSN: 1432-0533
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