Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion–Positive Supratentorial Ependymomas

Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histological features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors

MAPK pathway activation in pilocytic astrocytoma

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions

Executive function deficits in pediatric cerebellar tumor survivors

Development Psychopathology in context: clinical setting

Transatlantic progress in measurement of cognitive outcomes in paediatric oncology trials

The importance of measuring quality of survival within paediatric oncology trials is increasingly recognised. However, capturing neuropsychological outcomes and other aspects of quality of survival in the context of large or multinational trials can be challenging. We provide examples of protocols designed to address this challenge recently employed in clinical trials in the USA and Europe. We discuss their respective strengths and challenges, obstacles encountered and future opportunities for transatlantic collaboration

c-myc expression in medulloblastoma and its prognostic value

To identify prognostic factors in medulloblastoma, a common malignant brain tumor of childhood, expression of the oncogene c-myc was examined at the mRNA level by in situ hybridization. c-myc mRNA expression was observed in 30 of 72 tumors (42%), The c-myc gene copy number was determined by quantitative PCR from genomic DNA of paraffin-embedded tumors. c-myc gene amplification was present in 5 of 62 cases (8.3%), Therefore, c-myc amplification was obviously not the cause of c-myc mRNA expression in most samples, Kaplan-Meier estimation revealed a significant correlation between c-myc mRNA expression and survival (total mean follow-up 4.6 +/- 3.6 years, log-rank p = 0.02), Multivariate logistic regression analysis including sex, age, histological type, degree of surgical resection and expression of synaptophysin, GFAP and c-myc, was carried out on 54 patients who received both radiotherapy and chemotherapy. The analysis identified expression of c-myc as an independent predictive factor of death from disease. (C) 2000 Wiley-Liss, Inc

Spontaneous modifications of contrast enhancement in childhood non-cerebellar pilocytic astrocytomas

INTRODUCTION: Pilocytic astrocytoma (PA) is classified by the World Health Organization as a grade I tumor. Magnetic resonance imaging (MRI) is the gold standard in the diagnosis and follow-up of this neoplasm, and assessment of contrast enhancement (CE) pattern is essential. The purpose of this study was to investigate CE changes of non-cerebellar PA (n-C PA) stable in size with serial MRI. METHODS: Nine hundred and twelve MRI exams of 140 children with histologically proven PA were retrospectively reviewed. Patients were chosen for study inclusion if they were off therapy, without neurofibromatosis type 1, and without dimensional changes of tumor/residual tumor. In patients with CE changes, tumor size and CE size were calculated with a cross product. Descriptive statistics were calculated for continuous variables; effects of possible factors influencing changes of contrast-enhanced areas were tested. RESULTS: Of 39 n-C PA satisfying the inclusion criteria, 12 showed CE changes in terms of appearance/increase or disappearance/decrease of CE areas. Three of these 12 PA were infratentorial and nine supratentorial. There were no significant correlations between age, gender, tumor localization, tumor size, and modification of CE areas. CONCLUSION: In our experience, n-C PA may show variable CE over time in the absence of tumor/residual tumor dimension change. We recommend that CE fluctuations alone cannot be considered an indicator of tumor progression/regression