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Purpose: The aim of this study was to investigate MRI-derived diffusion weighted imaging (DWI) and arterial spin labeling (ASL) perfusion imaging in comparison with 18 F-dihydroxyphenylalanine (DOPA) PET with respect to diagnostic performance in tumor grading and outcome prediction in pediatric patients with diffuse astrocytic tumors (DAT)., Methods: We retrospectively analyzed 26 children with histologically proven treatment naïve low and high grade DAT who underwent ASL and DWI performed within 2 weeks of 18 F-DOPA PET. Relative ASL-derived cerebral blood flow max (rCBF max) and DWI-derived minimum apparent diffusion coefficient (rADC min) were compared with 18 F-DOPA uptake tumor/normal tissue (T/N) and tumor/striatum (T/S) ratios, and correlated with World Health Organization (WHO) tumor grade and progression-free survival (PFS). Statistics included Pearson's chi-square and Mann-Whitney U tests, Spearman's rank correlation, receiver operating characteristic (ROC) analysis, discriminant function analysis (DFA), Kaplan-Meier survival curve, and Cox analysis., Results: A significant correlation was demonstrated between rCBF max, rADC min, and 18 F-DOPA PET data (p < 0.001). Significant differences in terms of rCBF max, rADC min, and 18 F-DOPA uptake were found between low- and high-grade DAT (p ≤ 0.001). ROC analysis and DFA demonstrated that T/S and T/N values were the best parameters for predicting tumor progression (AUC 0.93, p < 0.001). On univariate analysis, all diagnostic tools correlated with PFS (p ≤ 0.001); however, on multivariate analysis, only 18 F-DOPA uptake remained significantly associated with outcome (p ≤ 0.03), while a trend emerged for rCBF max (p = 0.09) and rADC min (p = 0.08). The combination of MRI and PET data increased the predictive power for prognosticating tumor progression (AUC 0.97, p < 0.001)., Conclusions: DWI, ASL and 18 F-DOPA PET provide useful complementary information for pediatric DAT grading. 18 F-DOPA uptake better correlates with PFS prediction. Combining MRI and PET data provides the highest predictive power for prognosticating tumor progression suggesting a synergistic role of these diagnostic tools.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

Background: (1)H-MR spectroscopy (MRS) and (18)F-dihydroxyphenylalanine (DOPA) PET are noninvasive imaging techniques able to assess metabolic features of brain tumors. The aim of this study was to compare diagnostic and prognostic information gathered by (18)F-DOPA PET and (1)H-MRS in children with supratentorial infiltrative gliomas or nonneoplastic brain lesions suspected to be gliomas., Methods: We retrospectively analyzed 27 pediatric patients with supratentorial infiltrative brain lesions on conventional MRI (21 gliomas and 6 nonneoplastic lesions) who underwent (18)F-DOPA PET and (1)H-MRS within 2 weeks of each other. (1)H-MRS data (choline/N-acetylaspartate, choline-to-creatine ratios, and presence of lactate) and (18)F-DOPA uptake parameters (lesion-to-normal tissue and lesion-to-striatum ratios) were compared and correlated with histology, WHO tumor grade, and patient outcome., Results: (1)H-MRS and (18)F-DOPA PET data were positively correlated. Sensitivity, specificity, and accuracy in distinguishing gliomas from nonneoplastic lesions were 95%, 83%, and 93% for (1)H-MRS and 76%, 83%, and 78% for (18)F-DOPA PET, respectively. No statistically significant differences were found between the 2 techniques (P > .05). Significant differences regarding (18)F-DOPA uptake and (1)H-MRS ratios were found between low-grade and high-grade gliomas (P≤.001 and P≤.04, respectively). On multivariate analysis, (18)F-DOPA uptake independently correlated with progression-free survival (P≤.05) and overall survival (P = .04), whereas (1)H-MRS did not show significant association with outcome., Conclusions: (1)H-MRS and (18)F-DOPA PET provide useful complementary information for evaluating the metabolism of pediatric brain lesions. (1)H-MRS represents the method of first choice for differentiating brain gliomas from nonneoplastic lesions.(18)F-DOPA uptake better discriminates low-grade from high-grade gliomas and is an independent predictor of outcome., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K ("responder" genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the "responder" profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas., (© 2014 UICC.)

Background: High-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs., Methods: We explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line., Results: Comparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG., Conclusions: Our results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG.

Background: Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency., Methods: Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l₁l₂ that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR., Results: We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase (MAPK) pathway in LGGs, but still point to an active involvement of TGF-beta signaling pathway in the PA development and pick out some hitherto unreported genes worthy of further investigation for the mixed glial-neuronal tumours., Conclusions: The identification of a brain region-specific gene signature suggests that LGGs, with similar pathological features but located at different sites, may be distinguishable on the basis of cancer genetics. Molecular fingerprinting seems to be able to better sub-classify such morphologically heterogeneous tumours and it is remarkable that mixed glial-neuronal tumours are strikingly separated from PAs.

Introduction: In this study, we investigated the prognostic and predictive value of MGMT promoter methylation and protein expression in 30 pediatric high grade gliomas (pHGG)., Methods: MGMT promoter methylation was assayed by methylation-specific polymerase chain reaction (MSP), whereas MGMT protein expression was evaluated by immunohistochemistry (IHC)., Results: MGMT promoter methylation was observed in 7/24 (30%) cases, whereas MGMT protein overexpression was found in 19/28 (68%) cases with similar distribution in grade III and grade IV gliomas. Median survival of methylated and unmethylated patients was 16 and 8 months, respectively. Moreover, overall survival and progression-free survival showed a trend toward reduction in patients with unmethylation (p = 0.9 and p = 0.7, respectively). For MGMT protein expression, the median survival was 8.5 and 17 months for patients with MGMT overexpression or low expression, respectively. Although these two groups did not show statistically significant differences in terms of overall survival or progression-free survival (p = 0.8 and p = 0.7, respectively), there was a significant correlation between MGMT protein expression and MGMT promoter methylation status (p = 0.01)., Conclusions: Our findings indicate that, in pHGG, (a) MGMT promoter methylation is less frequent than in adult malignant gliomas, (b) there is a high correlation between MGMT MSP and MGMT IHC, and (c) as in adults, MGMT status is associated with prognosis, although this observation has to be statistically validated on larger series of patients.

Objective: To investigate the clinical features and outcome of epilepsy in children under 3 years of age with supratentorial brain tumors., Methods: Patients under 3 years with primary supratentorial hemispheric brain tumors were collected during a 10-year period through a database including demographic and clinical features, neuroimaging, tumor location, developmental outcome, pharmacological and surgical treatment, and tumor histology. Postoperative outcome was assessed according to Engel classification., Results: Among 28 children evaluated, twenty (71.4%) suffered from epilepsy. Mean age at seizure onset was 18.7 months (range: 1-60). In fifteen (75%) children, epilepsy was an early manifestation or the presenting symptom of the tumor; seizures were focal in 8 (53.3%) and generalized in 7 (46.7%) individuals. Three (15%) children presented with an epileptic encephalopathy and continuous spike-waves during sleep. Of the five children with epilepsy onset after surgery, four had focal seizures. Post-surgical follow-up ranged from 4 to 10 years (mean: 7.6+/-3.74). The outcome of epilepsy was generally good, with most children (76.4%) being seizure free (Engel I) or showing >90% improvement in seizure frequency (Engel II) after surgery. However, in about 20% of the cases, epilepsy persisted despite surgery and different AEDs regimen. Best epilepsy outcome was observed in patients with low-grade tumors (p<0.01) and without neurological deficits after surgery (p<0.001)., Conclusions: Epilepsy is a common and early symptom in infants with brain tumors. Its outcome is negatively influenced by high tumor malignancy and by the persistence of neurological deficits after surgery. Treatment of these patients needs a multidisciplinary approach.