Progression in pediatric brain tumor growth is thought to be the net result of signaling through various protein kinasemediated networks driving cell proliferation. Defining new targets for treatment of human malignancies, without a priori knowledge on aberrant cell signaling activity, remains exceedingly complicated. Here, we introduce kinome profiling using flow-through peptide microarrays as a new concept for target discovery. Comprehensive tyrosine kinase activity profiles were identified in 29 pediatric brain tumors using the PamChip kinome profiling system. Previously reported activity of epidermal growth factor receptor, c-Met, and vascular endothelial growth factor receptor in pediatric brain tumors could be appreciated in our array results. Peptides corresponding with phosphorylation consensus sequences for Src family kinases showed remarkably high levels of phosphorylation compared with normal tissue types. Src activity was confirmed applying Phos-Tag SDS-PAGE. Furthermore, the Src family kinase inhibitors PP1 and dasatinib induced substantial tumor cell death in nine pediatric brain tumor cell lines but not in control cell lines. Thus, this study describes a new high-throughput technique to generate clinically relevant tyrosine kinase activity profiles as has been shown here for pediatric brain tumors. In the era of a rapidly increasing number of small-molecule inhibitors, this approach will enable us to rapidly identify new potential targets in a broad range of human malignancies. [Cancer Res 2009;69(14):5987-95]

Bonn, Germany) performed 19 fetal endoscopic procedures. Three procedures resulted in fetal death, three procedures were interrupted by iatrogenic hemorrhages and 13 procedures were successful. We matched each successfully treated fSBA infant with another nSBA infant of the same age and level of lesion, resulting in 13 matched pairs (mean age 14mo; SD 16mo; f ⁄ m=1.6; female-16, male-10). Matched fSBA and nSBA pairs were compared in terms of segmental neurological function and leg muscle ultrasound density (MUD). We also determined intraindividual difference in MUD (dMUD) between myotomes caudal and cranial to the myelomeningocele (reflecting neuromuscular damage by the myelomeningocele) and compared dMUD between fSBA and nSBA infants. Finally, we correlated dMUD with segmental neurological function. RESULTSWe found that, on average, the fSBA group were born at a lower gestational age than the nSBA group (median 32wks [range 25-34wks] vs 39wks [34-41wks]; p=0.001) and experienced more complications (chorioamnionitis, premature rupture of the amniotic membranes, oligohydramnios, and infant respiratory distress syndrome necessitating intermittent positive-pressure ventilation). Neurological function was better preserved after fSBA than after nSBA (median motor and sensory gain of two segments; better preserved knee-jerk [p=0.006] and anal [p=0.032] reflexes). The dMUD was smaller in fSBA than in nSBA infants (mean difference 24, 95% confidence interval [CI] 15-33; p<0.05), which was associated with better preserved segmental muscle function.INTERPRETATION Fetal endoscopic surgery is associated with spinal segmental neuroprotection, but it results in more complications. Before considering clinical implementation of fetal endoscopic myelomeningocele closure as standard care, the frequency of complications should be appropriately reduced and results assessed in larger groups over a longer period of time.

Nasal encephaloceles can be divided into frontoethmoidal and basal encephaloceles. Both conditions are very rare, but frontoethmoidal encephaloceles show a relatively high incidence (1:5,000) in Southeast Asia. The pathogenesis of encephaloceles may be explained by a disturbance in separation of surface ectoderm (epithelial layer) and neurectoderm (nervous tissue) in the midline just after closure of the neural folds. It should be regarded as a 'late' neurulation defect taking place during the 4th gestational week. Apoptosis appears to be related to this separation process. Frontoethmoidal encephaloceles can be recognized as a facial mass covered with normal skin, while basal encephaloceles may cause nasal obstruction or symptoms related to herniation of basal structures. Diagnostic CT or MR imaging delineates the anatomy of the herniated mass. Therapy for frontoethmoidal encephaloceles consists in excision of the cele, watertight closure of the dural defect and reconstruction of the skull defect. Basal encephaloceles may harbour vital herniated structures which should be saved. Hydrocephalus should be dealt with first, followed by elective single-stage reconstructive surgery. The prognosis appears to be better for patients with frontoethmoidal encephaloceles than for patients with occipital or parietal encephaloceles, and it depends largely on the presence of additional congenital anomalies of the brain. The differential diagnosis of a nasal mass must include nasal glioma, dermoid cyst, and nasal polyp.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.