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INTRODUCTION Hydrocephalus persists in 10-40% of children with posterior fossa tumours (PFT). A delay in commencement of adjuvant therapy (AT) can negatively influence survival. The objective of this study was to determine whether postoperative cerebrospinal fluid (CSF) diversion procedures caused potentially preventable delays in AT. METHODS A retrospective study of children diagnosed with PFT requiring AT from 2004 to 2018 from two large centres was conducted. Data on histology, timing of ventriculo-peritoneal shunt (VPS) insertion, and AT was collected. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) score was calculated. The primary outcome was delay in AT beyond 40 days post-resection. Progression-free and overall survival were assessed. RESULTS Out of 196 primary PFT resections, 144 fitted the inclusion criteria. Mean age was 6.57 ± 4.62. Histology was medulloblastoma (104), ependymoma (27), and others (13). Forty patients had a VPS inserted; 17 of these experienced a delay in AT. A total of 104 patients were not shunted; 15 of these had delayed AT (p = 0.0007). Patients who had a VPS insertion had longer intervals from surgery to commencement of AT (34.5 vs 30.8, p = 0.05). There was no significant difference in mCPPRH score between those who had a VPS (4.03) and those who did not (3.61; p = 0.252). Multivariable linear regression modelling did not show a significant effect of VPS or mCPPRH on progression-free survival or OS. CONCLUSION CSF diversion procedures may cause a preventable delay in the initiation of adjuvant therapy. Early post-operative VP shunt insertion, rather than a 'wait and see policy' should be considered in order to reduce this delay.

Background/aim Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. Patients and methods We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. Results Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). Conclusion Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

As treatment protocols for medulloblastoma (MB) are becoming subgroup-specific, means for reliably distinguishing between its subgroups are a timely need. Currently available methods include immunohistochemical stains, which are subjective and often inconclusive, and molecular techniques—e.g., NanoString, microarrays, or DNA methylation assays—which are time-consuming, expensive and not widely available. Quantitative PCR (qPCR) provides a good alternative for these methods, but the current NanoString panel which includes 22 genes is impractical for qPCR. Here, we applied machine-learning–based classifiers to extract reliable, concise gene sets for distinguishing between the four MB subgroups, and we compared the accuracy of these gene sets to that of the known NanoString 22-gene set. We validated our results using an independent microarray-based dataset of 92 samples of all four subgroups. In addition, we performed a qPCR validation on a cohort of 18 patients diagnosed with SHH, Group 3 and Group 4 MB. We found that the 22-gene set can be reduced to only six genes (IMPG2, NPR3, KHDRBS2, RBM24, WIF1, and EMX2) without compromising accuracy. The identified gene set is sufficiently small to make a qPCR-based MB subgroup classification easily accessible to clinicians, even in developing, poorly equipped countries.

To report the 10-year experience of two tertiary medical centers with children presenting with proptosis due to an intraorbital space-occupying lesion. Patients were identified by file review. Data were collected on demographics, findings on ophthalmologic and imaging evaluations, etiology, treatment, and outcome. Nineteen children (7 male) were included. Eleven patients had optic nerve glioma, including 9 with substantially decreased visual acuity. Treatment consisted of chemotherapy alone or with radiation, resection or anti-VEGF agents, MEK inhibitor, or observation only (n = 1). Visual and cosmetic outcomes were poor in all cases. Outcome for arteriovenous malformations was good following corticosteroid treatment (n = 1), but catheterization led to persistent proptosis and fluctuating visual acuity (n = 1). Compound capillary hemangioma (n = 1) was treated with laser and systemic beta blockers with satisfactory results. Rhabdomyosarcoma had a good prognosis in one patient treated with resection and radiation but was fatal in another even after chemotherapy. Juvenile xanthogranuloma, frontal bone osteoma, and localized hypertrophic neuropathy of the supraorbital nerve (n = 1 each) were treated by resection with good visual and cosmetic outcomes. Proptosis accompanied by visual loss is an uncommon presentation in children and suggests an orbital tumor. We found that visual outcome was better when the nerve was not involved by tumor. Optic nerve glioma was the most common cause and failed to respond to various treatments. Catheterization for arteriovenous malformation did not prevent proptosis, and final visual acuity fluctuated. Surgery for rhabdomyosarcoma and xanthogranuloma led to remission with preservation of vision in 2 of 3 cases.

OBJECTIVEHemorrhage (also known as apoplexy) in optic pathway gliomas (OPGs) is rare. Because of the variable presentations and low incidence of OPG hemorrhages, little is known about their clinical course and the best treatment options. The aim of this work was to review risk factors, clinical course, and treatment strategies of optic glioma hemorrhages in the largest possible number of cases.METHODSA total of 34 patients were analyzed. Nine new cases were collected, and 25 were identified in the literature. Data regarding demographics, radiological and histological features, treatment, and outcome were retrospectively reviewed.RESULTSThe majority of patients were younger than 20 years. Only 3 patients were known to have neurofibromatosis. The histopathological diagnosis was pilocytic astrocytoma in the majority of cases. Five patients had intraorbital hemorrhages, whereas 29 patients had intracranial hemorrhage; the majority of intracranial bleeds were treated surgically. Six patients, all with intracranial hemorrhage, died due to recurrent bleeding, hydrocephalus, or surgical complications. No clear risk factors could be identified.CONCLUSIONSIntracerebral OPG hemorrhages have a fatal outcome in 20% of cases. Age, hormonal status, neurofibromatosis involvement, and histopathological diagnosis have been suggested as risk factors for hemorrhage, but this cannot be reliably established from the present series. The goals of surgery should be patient survival and prevention of further neurological and ophthalmological deterioration.

Sivan Gershanov,1 Helen Toledano,2,3 Shalom Michowiz,3,4 Orit Barinfeld,3,5 Albert Pinhasov,1 Nitza Goldenberg-Cohen,5–7 Mali Salmon-Divon1 1Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel; 2Department of Pediatric Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Department of Pediatric Neurosurgery, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; 5The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Beilinson Hospital, Petah Tikva, Tel Aviv, Israel; 6Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel; 7The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa,Israel Purpose: Medulloblastoma (MB), the most common malignant brain tumor in children, is divided into four tumor subgroups: wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. ­Ideally, clinical practice and treatment design should be subgroup specific. While WNT and SHH subgroups have well-defined biomarkers, distinguishing Group 3 from Group 4 is not straightforward. MicroRNAs (miRNAs), which regulate posttranscriptional gene expression, are involved in MB tumorigenesis. However, the miRNA–messenger RNA (mRNA) regulatory network in MB is far from being fully understood. Our aims were to investigate miRNA expression regulation in MB subgroups, to assess miRNA target relationships, and to identify miRNAs that can distinguish Group 3 from Group 4. Patients and methods: With these aims, integrated transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 18 children with MB, using miRNA sequencing (miRNA-seq), RNA sequencing (RNA-seq), and quantitative PCR. Results: Of all the expressed miRNAs, 19 appeared to be significantly differentially expressed (DE) between Group 4 and non-Group 4 subgroups (false discovery rate [FDR]

Background/AimsBenign positional vertical opsoclonus in infants, also described as paroxysmal tonic downgaze, is an unsettling phenomenon that leads to extensive work-up, although benign course has been reported in sporadic cases. We describe long-term follow-up of a series of infants with the phenomenon.MethodsThis retrospective cohort included all infants diagnosed with rapid downgaze eye movement in 2012–2015 and followed until 2016. The databases of two medical centres were retrospectively reviewed. Benign positional vertical opsoclonus was diagnosed based on clinical findings of experienced neuro-ophthalmologists. Data were collected on demographics, symptoms and signs, neuro-ophthalmological and neurological evaluations, and outcome. Imaging studies were reviewed. Main outcome measures were long-term outcome and findings of the thorough investigation.ResultsThe cohort included six infants. All infants were born at term. Age at presentation was several days to 12 weeks. Episodes lasted a few seconds and varied in frequency from ConclusionsOur identification of six patients in only 3 years suggests benign positional vertical opsoclonus may be more prevalent than previously described. In our experience, it affects otherwise healthy infants and resolves spontaneously. In view of the good long-term outcome, a comprehensive clinical investigation may not be necessary.

Purpose To determine whether Toll-like receptor 4 knockout protects mice from corneal neovascularization following chemical injury compared to wild-type (WT) mice. Methods A chemical burn (75% silver nitrate, 25% potassium nitrate) was created under anesthesia in the central right cornea of 32 WT and 31 Toll-like receptor 4 knockout mice. Corneal neovascularization was evaluated at 3, 4, 6, 8, 10, and 35 days after injury using digital photography, fluorescein angiography, gelatin perfusion with fluorescence vascular imaging, immunofluorescence staining, and molecular analysis. Results There was no significant between-group difference in relative corneal burn area at 10 days after injury (39.0 ± 2.4% vs. 38.8 ± 9.8%, respectively). Neovascularization was detected in all corneas in vivo and perfusion was detected by fluorescence vascular imaging, reaching maximum area on day 10. The relative area of neovascularization was significantly smaller in the knockout than the WT mice on days 6 (33.3 ± 4.2% vs. 46.8 ± 7.4%, respectively, p = 0.005) and 8 (36.6 ± 1.1% vs. 52.2 ± 6.4%, respectively, p = 0.027), although neovascularization was intensive in both groups. In line with the immunostaining findings of angiogenesis and inflammatory infiltration of damaged corneas, molecular analysis (performed on day 3) revealed elevated expression levels of angiogenesis-related genes (vascular endothelial growth factor, VEGFR2, VEGFR1) and inflammation-related genes (CD45 and TGFβ1) in the WT mice. The knockout mice had higher TNF-α expression than the WT mice. Conclusion In a mouse corneal chemical burn model, lack of Toll-like receptor 4 expression did not completely inhibit angiogenesis, but did have a relative effect to reduce neovascularization as compared to the WT.

To evaluate the effect of bevacizumab and sildenafil on stroke parameters in a mouse model, middle cerebral artery occlusion was induced in male C57Bl/6 mice using an intra-arterial filament method. The filament was removed after 60 minutes, and the mice were immediately given a single intraperitoneal injection of saline, bevacizumab, or sildenafil. An additional group of mice (n=7) received bevacizumab 6 h after MCAO induction. The mice were euthanized 24 hours later and evaluated for infarct area and brain edema using triphenyltetrazolium chloride staining and ImageJ. In the saline-treated mice (n=16), total stroke volume was19.20±6.38 mm3, mean penumbra area was4.5±2.03 mm3, and hemispheric asymmetry was 106.5%. Corresponding values in the bevacizumab group (n=19) were17.79±5.80 mm3,7.3±3.5 mm3, and 108.6%; in the delayed (6 h) bevacizumab injected mice (n=7) they were9.80±8.00 mm3,2.4±2.0 mm3, and 98.2%; and in the sildenafil group (n=16) they were18.42±5.41 mm3,5.7±2.02 mm3, and 109.9%. The bevacizumab group had a significantly larger mean penumbra area when given immediately and smaller total stroke area in both groups than the saline- (p=0.03) and sildenafil-treated (p=0.003) groups. Only delayed bevacizumab group had reduced edema. Bevacizumab, injected immediately or delayed after injury, exerts a neuroprotective/salvage effect, whereas immediate treatment with sildenafil does not. Inflammation may play a role in the neuroprotective effect.

In this paper, we describe the rare phenomena of descending transtentorial herniation and paradoxical ventriculomegaly due to low pressure hydrocephalus. This resulted as a complication of treatment in a 14year old male patient, who had undergone multiple ventriculo-peritoneal shunt placements for hydrocephalus after resection of pilocytic astrocytoma. We discuss the etiology of this rare complication and our strategy for treatment. We emphasize the need for strategic placement of programmable shunts to avoid over shunting and associated complications such as tentorial herniation.

Aim This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic–ischemic insult (HII), and acute toxic leukoencephalopathy (ATL). Methods The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014. Results All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved. Conclusions Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted.

Falls from heights are the most common traumatic event associated with emergency department visits in children. This study investigated the incidence and clinical course of cranial neuropathies caused by falls from heights in children. The computerized records of a tertiary pediatric medical center were searched for all patients admitted to the emergency department in 2004–2014 with a head injury caused by falling from a height. Those with cranial neuropathies involving optic and eye-motility disturbances were identified, and their clinical, imaging, and outcome data were evaluated. Of the estimated 61,968 patients who presented to the emergency department during the study period because of a fall, 18,758 (30.3 %) had head trauma. Only 12 (seven boys, five girls, average age 6.7 years) had a visual disturbance. Eight were diagnosed with traumatic optic neuropathy, one after a 6-month delay, including two with accompanying cranial nerve (CN) III injuries. Five patients had anisocoria or an abnormal pupillary response to light at presentation, one patient had CN VI paralysis and temporary vision loss, and one patient had an isolated CN III injury diagnosed on follow-up. Visual improvement varied among the patients. Cranial neuropathies due to falls from heights are rare in children and are associated with high visual morbidity. Vision or ocular motility impairment, especially monocular vision loss, may be missed during acute intake to the emergency department, and a high index of suspicion is needed. Assessment of the pupillary response to light is essential.

Mycotic intracranial aneurysms are rare entities that can be rapidly fatal. The pathology of these lesions are usually due to bacterial infections however in exceptional cases such as immunocompromise, fungal agents are also found to be the cause. In this study, we present the case of a 43-year old, immunocompromised, male patient who suffered from a ruptured mycotic aneurysm after undergoing surgical evacuation of a basal ganglia brain abscess. Pathological analysis of the lesion showed that Aspergillus fumigatis was the causative agent. Since these types of lesions are rare, there are few clinical guidelines for treatment. We emphasize that in an immunocompromised patient with sudden neurological deterioration, mycotic intracranial aneurysm should be in the differential diagnosis.

Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Complete resection is impossible. Overexpression of epidermal growth factor receptor (EGFR) by the tumor has been associated with the level of malignancy and possibly with prognosis. Monoclonal antibodies may be used to identify tumor borders. The aim of the present study was to investigate the value of immunostaining with anti-EGFR antibodies conjugated to gold nanoparticles (GNPs) for detecting tumor infiltration into adjacent tissue. Methods: Fresh GBM samples were collected intraoperatively from 14 patients treated at a tertiary medical center in 2014-2015, in accordance with the guidelines of the local and national ethic committees. Demographic, clinical, and outcome data of the patients were recorded. Analysis for EGFR overexpression by polysomy or amplification was determined by calculating the ratio of expression between pairs of the following genes: EGFR, GPER, and RNaseP. Tumor sample with known overexpression of EGFR underwent immunostaining with GNPconjugated anti-EGFR antibodies followed by light-scattering spectroscopy and electron microscopy. The findings were compared with routine hematoxylin and eosin staining. Results: On molecular analysis, EFGR overexpression was identified in 10/14 GBM samples (71%). Amplification was detected in 50% and polysomy in 27%, and one sample showed both. Patients whose samples were characterized by an overexpression of EGFR died within 3-10 months, whereas 2 of the patients with normal EGFR expression were still alive 9 and

Post traumatic dural sinus vein stenosis has been rarely described in pediatric population. We present a case of a 9-year-old child that had sustained a head injury after a fall from height causing an acute epidural hematoma compressing the dominant sigmoid sinus. The patient had developed sub acutely signs and symptoms of increased intracranial pressure. Prophylactic treatment with anticoagulants was initiated despite the presence of an intracranial bleeding. Clinical and radiological improvements were achieved. We had also reviewed the literature regarding this uncommon entity and discussed other existing diagnostic and therapeutic alternatives. Further gathering of information is essential in order to form a therapeutic protocol.

Objective To investigate the use of peripapillary optical coherence tomography for monitoring optic neuropathy in pediatric craniopharyngioma. Design Retrospective, consecutive-cohort, single-centre chart analysis. Participants Twenty children with craniopharyngioma treated at a pediatric medical centre from 1999 to 2011. Methods The medical files were reviewed for demographics and optic nerve function. Findings for visual acuity and visual fields were analyzed against repeated optical coherence tomography (OCT) measurements of peripapillary nerve fibre layer thickness (using either time-domain Stratus OCT or spectral-domain Cirrus OCT). Results Average age at diagnosis was 6.5 ± 3.88 years. The most common presenting symptom was headache; only 1 child complained of visual loss. Mean best corrected visual acuity (logMAR) was 0.036 ± 0.06 in the 17 healthy eyes and 1.05 ± 1.45 in the 23 eyes with optic neuropathy. Positive signs included relative afferent pupillary defect (8/20), visual acuity loss (7/20), temporal visual field loss (bilateral 4/15, unilateral 4/15), papilledema (3/20), and unilateral/bilateral optic disc pallor (14/20). RNFL thickness was significantly lower in eyes with optic neuropathy than in healthy eyes (65 ± 22 µm vs 86.2 ± 29 µm; p = 0.000) and correlated with visual acuity (r = –0.43 to –0.17, p = 0.0001) and presence or absence of a visual field defect (mean difference, 26.1 ± 5.8 µm, p = 0.003). Ten children showed no change in RNFL thickness over time (mean 18 ± 14.2 months). Conclusions A thinner RNFL on ocular coherence tomography is correlated with poorer visual acuity and visual field loss. Ocular coherence tomography may serve as an objective method to quantify axonal loss caused by craniopharyngioma. Further investigation is needed to determine its use for evaluating progressive axonal loss over time.

In pediatric brain tumours, dissemination of malignant cells within the central nervous system confers poor prognosis and determines treatment intensity, but is often undetectable by imaging or cytology. This study describes the use of fluorescence lifetime (FLT) imaging microscopy (FLIM), a novel diagnostic tool, for detection of metastatic spread. The study group included 15 children with medulloblastoma and 2 with atypical teratoid/rhabdoid tumour. Cells extracted from the tumour and the cerebrospinal fluid (CSF) 2 weeks postoperatively and repeatedly during chemo/radiotherapy were subjected to nuclear staining followed by FLT measurement and cytological study. Control CSF samples were collected from patients with infectious/inflammatory disease attending the same hospital. Median FLT was prolonged in tumour cells (4.27 ± 0.28 ns; P −16) and CSF metastatic cells obtained before chemo/radiotherapy (6.28 ± 0.22 ns; P −16); normal in inflammatory control cells (2.6 ± 0.04 ns) and cells from children without metastasis before chemo/radiotherapy (2.62 ± 0.23 ns; P = 0.858) and following treatment (2.62 ± 0.21 ns; P = 0.053); and short in CSF metastatic cells obtained after chemo/radiotherapy (2.40 ± 0.2 ns; P −16). FLIM is a simple test that can potentially identify CSF spread of brain tumours. FLT changes in accordance with treatment, with significant prolonged median values in tumours and metastases. More accurate detection of metastatic cells may guide personalised treatment and improve the therapeutic outcome.

MB-28. MicroRNA EXPRESSION IS HIGHLY SUBGROUP SPECIFIC IN MEDULLOBLASTOMA Sivan Gershanov1,2, Shalom Michowiz3,4, Orit Barinfeld2,3, Mali Salmon-Divon1, Nitza Goldenberg-Cohen3,4, and Helen Toledano3,4; Ariel University, Ariel, Israel; Felsenstein Medical Research Center, Petah-Tiqwa, Israel; Tel-Aviv University, Tel-Aviv, Israel; Schneider Children’s Medical Center of Israel, Petah-Tiqwa, Israel Medulloblastoma (MB), the commonest malignant brain tumor of childhood, is divided into four tumor subgroups representing distinct clinical and molecular entities. MicroRNAs (miRNAs) are involved in carcinogenesis and tumor progression by regulating post-transcriptional gene expression. However, our understanding of the miRNA-mRNA regulatory network is incomplete. The aim of the study is to identify novel miRNA subgroup biomarkers and their target mRNAs for rapid and specific diagnosis and future targeted therapy. With this aim, integrated whole transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 10 MB patients. 867 mature miRNAs were identified in at least a single MB sample, of them 462 were common to all 4 subgroups. 25 (2.5%) of all expressed miRNAs appeared to be significantly differentially expressed between the MB subtypes (FDR , 0.1). Namely, upregulation of hsa-miR-224-5p and hsa-miR-449c-5p was found exclusively among WNT, while downregulation of hsa-miR-135b-5p characterized SHH. Among groups 3 and 4, hsa-miR-20a-5p was upregulated or downregulated, respectively. RNA-seq from the same tumor samples identified 500 genes that vary between subtypes (q value ,0.05), among which 69 (13.8%) have anticorrelated miRNA-mRNA interactions with the 25 detected miRNA biomarkers. The predicted mRNAs targets of these miRNAs are associated with different signaling pathways, known to have a role in MB biology. Our study demonstrates that miRNAs are readily detectible and are highly specific to distinct MB subgroups. Understanding the involvement of miRNAs and their targets in MB related signaling pathways may improve diagnosis and advance the development of targeted treatment for MB. Neuro-Oncology 18:iii97–iii122, 2016. doi:10.1093/neuonc/now076.26 #The Author(s) 2016. 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.

Highlights ► We investigated the occurrence of BRAF, GNAQ, and GNA11 mutations in pediatric low-grade glioma. ► We found an increase in the copy number of BRAF. ► BRAF and GNAQ mutations are mutually exclusive. ► Understanding the molecular basis of low-grade glioma may increase treatment options., Fifty-two samples of pediatric low-grade glioma (48 primary, 4 recurrent) were analyzed for BRAF copy number variation (digital PCR analysis, CopyCaller) and point mutations of BRAF V600E, and exon 5 Q209 in GNAQ, and GNA11, using the MALDI-TOF mass spectrometer with validation by direct sequencing. An increased BRAF copy number was found in 18/47 primary samples tested; 15 of them (83.3%) were pilocytic astrocytomas. A BRAF mutation was found in 3/48 primary tumors, all with a normal BRAF copy number and no GNAQ mutation. One sample had a GNAQ209 mutation (Q209P626) with a normal BRAF gene; none of the tumors had a GNA11Q209 mutation. Recurrent or progressive tumors, analyzed in four patients, had the same molecular genotype as their primary. Increased BRAF copy number and activating BRAF mutations may be involved in the development of low-grade glioma via overactivation of the Ras/Raf pathway. This is the first report of a mutation in GNAQ209 in pediatric low-grade glioma. Understanding the molecular mechanisms underlying glioma initiation and growth may assist in the development of targeted therapies.

Hydrocephalus is usually treated by placement of a ventriculo-peritoneal (VP) shunt. Distal VP shunt failure is a common complication of this procedure, especially in the paediatric population. Distal shunt revisions are often made more technically difficult by challenging abdominal anatomy. In this technical note, we describe a simple technique utilizing tenting sutures and the previous shunt tract for placement of the distal abdominal catheter accurately into the peritoneal space during distal shunt revision.

Metastatic disease at presentation of medulloblastoma is present in approximately 30% and confers a poor prognosis. Metastases are usually spinal and occult intracranial metastases maybe overlooked. The infundibular recess of the third ventricle is a known site of metastases in various tumors particularly at relapse. The diagnostic brain and spinal imaging of all our medulloblastoma patients from 1/2007 to 12/2017 were assessed by 2 radiologists blinded to patient outcome. We collected clinical data retrospectively from the charts. RESULTS: Of 69 children with medulloblastoma over 11 years, 6 (8.7%) were found to have metastases in this location at presentation (male:female 1:1, mean age 8). In 1 patient the metastasis was biopsied and showed pathology identical to the primary tumor. In 1 patient the metastasis was missed at diagnosis. He was treated on an average risk protocol and subsequently relapsed in the third ventricle. In 2 patients this was a solitary area of metastasis whereas in 4 there was additional extensive spinal disease. In one patient the suprasellar metastasis was symptomatic causing the appearance of the menstrual period at age 8 leading to the diagnostic imaging. None of the others had symptoms referable to their suprasellar metastasis. One patient died due to postoperative complications and 2 died of progressive disease. 3 are still alive (range 9 months - 8 years since diagnosis) including the one who relapsed. CONCLUSION: The infundibular recess of the third ventricle is a not uncommon site of metastatsis at diagnosis of medulloblastoma and should be actively assessed.

Ependymoma is a malignant pediatric brain tumor, often incurable with current treatment regimens. We aimed to identify new genes involved in pediatric ependymoma using copy number SNP array analysis. We analyzed 34 primary tumors, in 10 cases we analyzed the paired diagnosis-relapse samples and in 5 of them we also analyzed the corresponding peripheral blood (PB) sample. The most prevalent alterations identified were gain of 8q (18%), deletion of 10q (18%), gain of 11q (12%) and gain of 17q (53%). The locus of the 17q21.31 gain contains only one gene - KANSL1 (KAT8 regulatory NSL complex subunit 1) gene. The gain affected exons 1–4 of the gene. This gain was identified in 9 out of the 10 (90%) relapse samples and in all of the PB samples. The gain was validated at the RNA level and a significant overexpression of KANSL1 mRNA was detected in the samples exhibiting gain versus the samples with normal copy number (p=0.04). KANSL1 is part of the NSL complex which functions as a histone acetyltransferase. The 17q21.31 locus contains a common inversion duplication polymorphism enriched in European populations. Recently, a new fusion was discovered in high frequencies in adult malignancies between KANSL1 and ARL17, termed KANSARL, both located on 17q21.31. KANSARL fusion was detected in 71% of our samples. All the samples that exhibited gain of KANSL1 were positive for the KANSARL fusion. Our results suggest that the gain precedes the formation of the fusion which may be a predisposing event in ependymoma.

The aim of the study was to investigate the incidence of nystagmus at diagnosis in children with optic pathway glioma involving the chiasm and hypothalamus.Twenty-two patients with a measurable optic pathway/hypothalamic glioma (without neurofibromatosis-1) were followed in our center from 2001 to 2013. The medical files were retrospectively reviewed for demographic and clinical findings, and the imaging scans, for tumor characteristics.There were 9 boys and 13 girls of mean age 3.5 ± 4.4 years at diagnosis; 15 were aged2 years. Tumor size ranged from 10 × 6 mm to 62 × 29 mm. Mean duration of follow-up was 8.3 ± 5.4 years. Nystagmus was detected at diagnosis in 10 children (45%), all2 years old (66.6% of the younger group); no child older than 2 years presented with nystagmus. Nystagmus, once present, did not resolve and continued throughout follow-up. There were no cases of new onset of nystagmus during follow-up in the children in whom it was not detected at diagnosis. Treatment consisted of partial resection/biopsy with/without shunting (n = 13) and chemotherapy (n = 19) with (n = 2) or without adjuvant radiation. Of the 22 children, 6 had a radiographic response to treatment, 8 remained stable, and 8 (all of whom received chemotherapy) showed disease progression despite treatment.In conclusion, monocular nystagmus is a more common presenting sign of optic pathway/hypothalamic glioma in children2 years old than previously estimated. Although subtle, nystagmus has a very narrow differential diagnosis, and its presence should raise suspicions of a chiasmal tumor with prompt referral for imaging. The visual prognosis is moderate to poor.

To examine the effects of hyperbaric oxygen (HBO) therapy and knockout of toll-like receptor 4 (TLR4) on the outcome of temporary middle cerebral artery occlusion (MCAO) in a mouse model.MCAO was induced in anesthetized male C57Bl/6 mice (WT) and TLR4 knockout mice (TLR4(-/-)) using an intra-arterial filament method. After 30 or 90 min, the filament was removed, and the mice were given either no treatment (WT and TLR4(-/-) groups) or HBO (WT only). Mice were euthanized 24 h after MCAO, and the brain infarct area was examined using 2,3,5-triphenyltetrazolium chloride (TTC) staining.In the WT group, without treatment, lesion volume was 120 ± 13 mm(3) in the mice subjected to 30 min' MCAO and 173 ± 23 mm(3) in the mice subjected to 90 min' MCAO. Respective values with HBO treatment were 66.5 ± 36.7 mm(3) and 53.2 ± 17.2 mm(3). The difference was significant only for 90-minute MCAO (p0.01, nonparametric test). In the TLR4(-/-) group (all untreated), lesion volume was 95.9 ± 17.9 after 90 min of MCAO, which was significantly lower than in the untreated WT animals (p0.05, nonparametric test).A single treatment of HBO immediately after MCAO followed by 24 h' reperfusion significantly reduces edema and may improve perfusion. TLR4 knockout protects mice from MCAO damage, but to a lesser extent than HBO treatment.

We describe five cases of children with ventriculoperitoneal shunt who underwent abdominal and perineal procedures under spinal anesthesia. Four of them had been born prematurely, and all had suffered from severe neonatal complications. All of our patients suffered from severe respiratory impairment, that had required mechanical ventilation, and three of them suffered additionally from apnea of prematurity. Four patients had ventriculoperitoneal shunt inserted because of obstructive hydrocephalus and one because of congenital central nervous system anomalies. Two underwent subsequently shunt revision. The benefits of spinal anesthesia in this high-risk population are described. The risks of spinal anesthesia in the presence of a ventricular shunt device, especially infection and dural leakage, are discussed, and the literature about this topic briefly reviewed.

Cerebellar involvement in motor and non-motor sequence learning was examined with serial reaction time tasks (SRT). Our sample consisted of 8 children and adolescents who had undergone surgical removal of a benign posterior fossa tumor (PFT) during childhood. None of them had undergone chemotherapy or cranial radiation therapy (CRT). Ages ranged from 1–11 years at surgery and 9–17 years at testing. The children were tested not earlier than 2.5 years after surgery (M= 5.9 years), enabling brain plasticity and recovery of functions. Their performance was compared with a matched control sample. The PFT group was not impaired in the implicit learning of sequences, as reflected in their performance in blocks with a repeated sequence, both before and after a random block. However, in the perceptual task, their performance deteriorated more than that of the control group when a random block was introduced, suggesting that it was more difficult for the patients to respond flexibly or change their response set when encountering changing task demands. These results are in line with another study by our group on task switching with the same patients. (JINS, 2005,11, 482–487.)

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o′)tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.

Primary malignant melanoma of the leptomeninges of the central nervous system is a rare and aggressive tumor in children. We report our experience from 1964 to 1990 with this tumor in eight children. The mean age at diagnosis was 4.9 years (range, 1.3 to 13 yr). Five children presented with signs and symptoms of raised intracranial pressure from hydrocephalus secondary to tumoral obliteration of the basal cisterns, but the time from the initial symptomatology to diagnosis was frequently delayed. Three patients in this series had hairy nevi in association with their leptomeningeal melanoma. Cerebrospinal fluid (CSF) analysis typically showed raised opening pressures, decreased glucose, and increased protein concentrations. Malignant melanoma cells were found in the CSF in three patients. Confirmatory radiographic examinations included air encephalography, myelography, and computed tomographic and magnetic resonance scanning. Four patients were treated with lumboperitoneal shunts, and one patient was treated with a ventriculoperitoneal shunt for hydrocephalus. Two patients underwent craniotomies and subtotal excisions of their tumors. In seven patients, a definitive diagnosis of leptomeningeal melanoma was made by pathological examination of tissues sent at surgery or at post mortem. In one case, the diagnosis was established by a detailed cytological analysis of the CSF. Four children died of fulminant disease and tumor spread before treatment could be instituted. The four children who received treatment had a combination of radiation therapy and chemotherapy. One child received intrathecal methotrexate. The two children with the longest survivals (2 and 3 yr, respectively) received cisplatinum and dimethyltriazenoimidazole carboxamide in addition to craniospinal irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Most survivors of childhood acute lymphoblastic leukemia (ALL) and T-cell lymphoma (T-NHL) treated before 1990 received cranial radiation. This study assessed the occurrence of second tumors in irradiated and non-irradiated survivors. Methods Two hundred and ten survivors of ALL and T-NHL were treated between 1974 and 1997 by several protocols. Imaging (MRI, CT) was performed every 3–6 years in 76/88 irradiated and 74/122 non-irradiated patients for the last 20 years. Results From January 1998 through 2004, meningiomas were detected in 16 survivors (8 female, 8 male) at age 20–39 years (median 28.7); 15 were asymptomatic. Cranial imaging done 2–8 years previously in 11 revealed no abnormalities. Fifteen had been diagnosed with ALL or T-NHL 10–29 years earlier (median 21) and received cranial irradiation (24 Gy in 14) at age 2–14 years (median 7.6). Fifteen tumors arose in the convexity. Three patients had multiple lesions. Complete resection was performed in 12 patients, with one complication. One patient had a recurrence, and four with small tumors are under surveillance. Only one low-grade glioma and two basal-cell carcinomas were found. Only one of the 74 non-irradiated patients (median follow-up 14 years) developed meningioma. The Kaplan-Meier estimate of incidence of meningioma was 14.8 ± 7.6 at 20 years. Conclusions Survivors of childhood ALL treated with cranial radiation require prolonged surveillance because of a high incidence of late meningiomas. Early detection, when the tumor is still small, facilitates resection and may reduce complications. Pediatr Blood Cancer 2007;49:294–297. © 2007 Wiley-Liss, Inc.

The authors of this study investigated task switching following cerebellar damage. The study group consisted of 7 children and adolescents (M age=13.8 years) who underwent surgical removal of a benign posterior fossa tumor. They were tested at a sufficient interval after surgery (M lag=6.13 years) for restoration of normal cognitive skills and intelligence. Although all showed normal learning of the task compared with control participants, when rapid behavioral changes were required (short preparation time), they exhibited behavioral rigidity manifested by enhanced switching cost. These results are in line with another study on serial reaction time with the same patients (A. Berger et al., in press). They have important implications for our understanding of the cognitive sequelae of early cerebellar damage as well as the involvement of the cerebellum in task switching.

✓ The occurrence of papilledema in a patient with progressive spastic paraparesis due to herniation of the T11–12 intervertebral disc is reported. The papilledema resolved following discectomy. The association and possible pathogenetic mechanisms between spinal cord lesions and signs of raised intracranial pressure are reviewed.