Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration, and recurrence, and are thereby considered important therapeutic targets. Recent clinical studies have suggested that the choice of general anesthetic (GA), particularly propofol, during tumor resection, affects subsequent tumor response to treatments and patient prognosis. In this study, we investigated the molecular mechanisms underlying propofol's anti-tumor effects on GSCs and their interaction with microglia cells. Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers, and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations, propofol induced a large degree of cell death, as demonstrated using microfluid chip technology. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM, and silencing of this lncRNA partially abrogated propofol's effects. Propofol also inhibited the pro-tumorigenic GSC-microglia crosstalk via extracellular vesicles (EVs) and delivery of BDNF-AS. In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized these cells to radiation and TMZ, and inhibited their pro-tumorigenic interactions with microglia via transfer of BDNF-AS by EVs.

Supplementary Figure S1; Supplementary Methods; Supplementary Table S1.

The use of the anti-GD2 antibody naxitamab (Danyelza) is associated with significant adverse effects (AEs) requiring complex supportive care. Israel was the first country outside the USA in which Naxitamab use was approved; however, experience with Naxitamab related toxicity is limited. We report on the safety and feasibility of a simplified administration protocol for naxitamab that will facilitate its use in institutions with no prior participation in a naxitamab clinical study. Methods: Between November 2021 and July 2023, 102 Naxitamab infusions were administered to 9 patients at the Shaare Zedek Medical Center in Jerusalem. Treatment was given as part of a compassionate use protocol or following approval of the Israeli Ministry of Health (February 2022). Patients received standard premedication, including paracetamol, dipyrone, promethazine, saline bolus, and low-dose opiate. IV naxitamab was given over 30 minutes. Ketamine was used as the only analgesic drug used concurrently with the infusion of naxitamab . Results: Pain was controlled in all cases and other AEs were reported in only 20/95 infusions (21%). Grade 3-4 AEs, including hypotension/ hypertension or desaturation, occurred in 10/102 infusions (10%). All AEs were transient, occurring in the first two treatment cycles, and no patient stopped naxitamab therapy due to infusion-related AEs. Two additional pediatric oncology centers in Israel have adopted a modified version of this protocol. Conclusion: Single agent ketamine is a safe and effective treatment for naxitamab-infusion-related pain. Its use is feasible in multiple clinical settings. Significant infusion-related AEs after completion of the 3 treatment cycle are rare.

The use of the anti-GD2 antibody naxitamab (Danyelza) is associated with significant adverse effects (AEs) requiring complex supportive care. Israel was the first country outside the USA in which Naxitamab use was approved; however, experience with Naxitamab related toxicity is limited. We report on the safety and feasibility of a simplified administration protocol for naxitamab that will facilitate its use in institutions with no prior participation in a naxitamab clinical study. Methods: Between November 2021 and July 2023, 102 Naxitamab infusions were administered to 9 patients at the Shaare Zedek Medical Center in Jerusalem. Treatment was given as part of a compassionate use protocol or following approval of the Israeli Ministry of Health (February 2022). Patients received standard premedication, including paracetamol, dipyrone, promethazine, saline bolus, and low-dose opiate. IV naxitamab was given over 30 minutes. Ketamine was used as the only analgesic drug used concurrently with the infusion of naxitamab . Results: Pain was controlled in all cases and other AEs were reported in only 20/95 infusions (21%). Grade 3-4 AEs, including hypotension/ hypertension or desaturation, occurred in 10/102 infusions (10%). All AEs were transient, occurring in the first two treatment cycles, and no patient stopped naxitamab therapy due to infusion-related AEs. Two additional pediatric oncology centers in Israel have adopted a modified version of this protocol. Conclusion: Single agent ketamine is a safe and effective treatment for naxitamab-infusion-related pain. Its use is feasible in multiple clinical settings. Significant infusion-related AEs after completion of the 3 treatment cycle are rare.

Supplementary Table S2 from BRAF-KIAA1549 Fusion Predicts Better Clinical Outcome in Pediatric Low-Grade Astrocytoma

BACKGROUND:Paediatric onset IBD [PIBD] is characterised by a more extensive phenotype than adult-onset IBD and a higher utilisation of immunosuppressive medications; both may be associated with malignancy. We aimed to assess the risk of cancer in a nationwide cohort of PIBD and to explore the risks associated with medical treatments. METHODS:PIBD patients [<18 years old] were included from the epi-IIRN cohort, covering 98% of the Israeli population from 2005, linked to the national cancer registry. We matched PIBD children to non-IBD children for calculating the cumulative incidence of cancer. RESULTS:In all, 3944 PIBD cases were included (2642 [67%] Crohn's disease, 1302 [33%] ulcerative colitis) translating into 23 635 person-years of follow-up, individually matched to 13 005 non-IBD children. By 30 years of age, 14 IBD patients [0.35%, 5.9/10 000 patient-years] were diagnosed with cancer and one [0.03%] with haemophagocytic-lymphohistiocytosis [HLH], compared with 14 [0.11%, 1.9/10 000 patient-years] cases of cancer {relative risk (RR) 2.5 (95% confidence interval [CI] 1.05-6.2); p = 0.04} and no HLH in the comparison-group. There were no cases of hepatosplenic T cell lymphoma, adenocarcinoma, or cholangiocarcinoma. Cancer risk was 15.6 cases/10 000 person-years in those treated with thiopurines alone (RR compared with IBD patients never exposed to either thiopurines or anti-tumuor necrosis factor [TNF] 1.8 [95% CI 0.6-6.1]; p = 0.2), 11.1/10 000 in those treated with anti-TNF alone (RR 1.3 [95% CI 0.3-6.6]; p = 0.5), and 23.1/10 000 treated with combination therapy of anti-TNF and thiopurines (RR 2.8 [95% CI 0.6-13.8]; p = 0.2). CONCLUSIONS:PIBD confers an increased risk for malignancy compared with non-IBD in children. However, the absolute risk is very low and no differences in risk with specific therapies were apparent in our data.

Abstract BACKGROUND: DICER mutation is a known tumor driver involved in pleuropulmonary blastoma ,renal tumors, masses in the thyroid and ovary and multiple other manifestations. Brain tumors are considered to be a rare manifestation of germline DICER mutation. Currently, brain imaging is not included in the standard follow up of patients with DICER germline mutation, and data re the prevalence of somatic DICER mutations in brain tumors is limited. AIMs: evaluation of prevalence of DICER mutations in a large cohort of rare/relapsed brain tumors. METHODS: over the last year all patients with tumors lacking curative standard therapy in Israel were sent for next generation sequencing,. Molecular evaluation was done using either panel based evaluation (ONCOMINE/Foundation) or whole exome and whole transcriptome (INFORM consortium). Epidemiological data as well as clinical outcome were provided by the treating physician. RESULTS: Between April 2021 and January 2022 one hundred twenty nine samples were sent for molecular analysis, 58 of them were brain tumors. Six patients had DICER associated malignant tumors , 33% of them were brain tumors . One patient with pinealoblastoma was diagnosed with a highly metastatic disease associated with a very grave prognosis. CONCLUSION: brain tumors are an important group among malignant DICER associated tumors. Surveillance may lead to early detection which may be associated with a better outcome.

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

LG-52. THEOPHYLLINE IN VISION IMPAIRED CHILDREN WITH OPTIC PATHWAY GLIOMA Gail Halliday, Peter Ling, Michal Zapotocky, Arun Reginald, Uri Tabori, Iris Fried, Eric Bouffet, Lee Dupuis, and Ute Bartels; The Hospital for Sick Children, Toronto, ON, Canada PURPOSE: Preclinical models suggest that phosphodiesterase inhibitors may slow or prevent axonal damage to the optic nerve in mice with visual pathway glioma likely through elevation of cAMP. A feasibility study was performed to evaluate the safety and efficacy of theophylline in vision impaired children with optic pathway glioma (OPG) at risk of visual loss. METHODS: Patients were treated with theophylline for a planned duration of 12 months. Eight of the eleven patients received concurrent standard OPG chemotherapies. The initial theophylline dose was calculated based on ideal body mass and subsequently adjusted according to trough serum levels. The primary end point was safety, defined by grade 3-4 toxicity using the National Cancer Institute Common Toxicity Criteria version 4.0. Secondary end points included visual acuity response rate. RESULTS: Preliminary data analysis of eleven patients, with a median age of 9.2 years, treated with theophylline at the Hospital for Sick Children, Toronto between 2009 and 2015 is detailed here. After a mean duration of 10.5 months no grade 3-4 treatment related toxicities were identified. Of the three patients who discontinued therapy prematurely two experienced grade 1 toxicities. Three of eleven patients studied showed improvements in binocular vision whilst on theophylline therapy with a further three patients showing stabilization of vision. CONCLUSIONS: Combining theophylline with standard chemotherapies for OPG in children is safe and feasible. In a proportion of patients with progressive visual decline despite prior chemotherapy theophylline enabled stabilization or improvement in visual acuity. Phase III proof of efficacy trials are warranted. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.52 #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.

Molecular portraits of numerous tumors have flooded oncologists with vast amounts of data. In parallel, effective inhibitors of central pathways have shown great clinical benefit. Together, this promises potential clinical benefits to otherwise end-stage cancer patients. Here, we report a clinical service offering mutation detection of archived samples using the ion Ampliseq cancer panel coupled with clinical consultation. A multidisciplinary think tank consisting of oncologists, molecular-biologists, genetic counselors, and pathologists discussed 67 heavily pretreated, advanced cancer patient cases, taking into account mutations identified using ion Ampliseq cancer panel, medical history, and relevant literature. The team generated a treatment plan, targeting specific mutations, for 41 out of 64 cases. Three patients died before results were available. For 32 patients, the treating oncologists chose not to include the panel recommendation in the treatment plan for various reasons. Nine patients were treated as recommended by the panel, 5 with clinical benefit, and 4 with disease progression. This study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team-based decision making. Administration of personalized based therapies at an earlier stage of disease, expansion of genetic alterations examined, and increased availability of targeted therapies may lead to further improvement in the clinical outcome of metastatic cancer patients.

OBJECTIVE:We investigated the prevalence, onset, characteristics, and long-term course of epilepsy disease in children who underwent surgical intervention for diagnosed brain tumors. METHODS:We reviewed the medical records of children with diagnosed brain tumors who underwent surgery during 2004-2014 at the Hadassah Medical Center. All patients with epilepsy were invited to a clinical visit that included a neurologic examination. The primary outcome measures were neurologic status according to the Glasgow outcome score (GOS) and postoperative seizure outcome according to the Engel system. We compared clinical characteristics according to the timing of epilepsy onset. RESULTS:The mean follow-up was 49 months. Of 128 patients included in the study, 44 (34%) had seizures; 23 (18%) developed epilepsy after surgery. Of the 30 patients with epilepsy who survived, 21 (70%) are in Engel class I and 13% Engel are in class II. Forty-five percent of the children are classified as GOS 5. Children who developed epilepsy after surgery were more likely to be in GOS 1-2 than were those who had seizures before surgery (P = 0.0173). Children with seizures were more likely to have cortical tumors and less likely to have tumors of the posterior fossa (P < 0.001). Children who underwent gross total resection were less likely to have epilepsy (P < 0.001). CONCLUSIONS:We show a high incidence of epilepsy in the late course of pediatric brain tumor disease. In the long term, seizure outcome was excellent. However, postsurgical onset of epilepsy was associated with a less favorable neurologic outcome.

Objective: Relapse of ependymoma in childhood portends a grave prognosis. While the detection of local recurrence is usually simple, spotting leptomeningeal metastasis might be challenging. We aimed to evaluate possible "hotspots" where metastasis tend to appear.Materials and methods: Medical records and Magnetic Resonance (MR) studies of all patients diagnosed with brain ependymomas between the years 2000-2015 were reviewed.Results: Leptomeningeal spread was detected among 42% of relapsed patients. The most common sites were spine and hypothalamic area (26% each).Conclusion: A meticulous assessment of the brain and spine including a thorough evaluation of the hypothalamic area is recommended. (C) 2017 Elsevier Inc. All rights reserved.

Diffuse intrinsic pontine glioma (DIPG) is an incurable disease with a median overall survival of 10 months. Immune modulating antibodies have recently emerged as a highly promising treatment modality in multiple cancer types. We present results from the first study to evaluate the immune modulating antibody MDV9300 (pidilizumab) in pediatric patients with DIPG. All patients aged 3 years and older, diagnosed with DIPG between February 2014 and June 2015 in Israel, were offered to participate in the study. Enrolled patients were started on biweekly 6 mg/kg MDV9300 after radiation completion. Treatment was continued until disease progression on imaging. Patients were followed biweekly for the occurrence of neurological deficit toxicities and side effects. Secondary endpoints were event free survival and overall survival. Of 13 children diagnosed with DIPG during the study period, nine were enrolled in the study. The patients underwent radiotherapy and none had chemotherapy. A total of 83 cycles of MDV9300 (range 2–16) were applied. The main side effects were neutropenia (CTCAE grade 1–3), mild to moderate fatigue, and acute elevation of blood pressure. Four patients died within 1 year of the diagnosis, another three died within 2 years and two children are still alive nearly 30 months from diagnosis, with stable disease. The median event free survival is 9.3 months (range 6.8–24) and the median overall survival is 15.6 months (range 6.9–28). Preliminary results demonstrate that MDV9300 treatment is safe and may be effective in the treatment of children with DIPG.

BACKGROUNDThe determinants of outcomes for adult survivors of pediatric low‐grade glioma (PLGG) are largely unknown.METHODSThis study collected population‐based follow‐up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.RESULTSAt a median follow‐up of 12.73 years (range, 0.02‐33 years), only 93 deaths (7.7%) were recorded, and the 20‐year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor‐related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3‐fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6‐6.6; P = .001) and an approximately 4‐fold increased risk of tumor‐related deaths (HR, 4.4; 95% CI, 1.3‐14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all‐cause deaths (HR, 3.0; 95% CI, 1.3‐7.0; P = .012) and tumor‐related deaths (HR, 4.4; 95% CI, 1.3‐14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non‐oncological causes.CONCLUSIONSThe course of PLGG is associated with excellent long‐term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. Cancer 2016;122:1261–9. © 2016 American Cancer Society.

BACKGROUND:Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS:We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS:Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION:An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING:C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.