Society For Neuro-Oncology Research Articles

The Korean Society for Neuro-Oncology (KSNO) Guideline for WHO Grade III Cerebral Gliomas in Adults: Version 2019.01.

BackgroundThere was no practical guideline for the management of patients with central nervous system tumor in Korea in the past. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, developed the guideline for glioblastoma successfully and published it in Brain Tumor Research and Treatment, the official journal of KSNO, in April 2019. Recently, the KSNO guideline for World Health Organization (WHO) grade III cerebral glioma in adults has been established.MethodsThe Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searches in PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords. Scope of the disease was confined to cerebral anaplastic astrocytoma and oligodendroglioma in adults.ResultsWhenever radiological feature suggests high grade glioma, maximal safe resection if feasible is globally recommended. After molecular and histological examinations, patients with anaplastic astrocytoma, isocitrate dehydrogenase (IDH)-mutant should be primary treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy whereas those with anaplastic astrocytoma, NOS, and anaplastic astrocytoma, IDH-wildtype should be treated following the protocol for glioblastomas. In terms of anaplastic oligodendroglioma, IDH-mutant and 1p19q-codeletion, and anaplastic oligodendroglioma, NOS should be primary treated by standard brain radiotherapy and neoadjuvant or adjuvant PCV (procarbazine, lomustine, and vincristine) combination chemotherapy.ConclusionThe KSNO's guideline recommends that WHO grade III cerebral glioma of adults should be treated by maximal safe resection if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors.

ISNO consensus guidelines for practical adaptation of the WHO 2016 classification of adult diffuse gliomas

Recent advances in the molecular biology of adult diffuse gliomas have brought about a paradigm shift in their diagnostic criteria, as witnessed in the World Health Organization (WHO) 2016 guidelines for central nervous system tumors. It is now mandatory to perform several molecular tests to reach a definitive integrated diagnosis in most of the cases. This comes with additional cost and higher turnaround time, which is not always affordable in developing countries like India. In addition, the non-uniform distribution of advanced research and diagnostic testing centers adds to the difficulty. The Indian Society of Neuro-oncology (ISNO) multidisciplinary expert panel consisting of neuropathologists, neurosurgeons, and radiation/medical oncologists convened to prepare the national consensus guidelines for approach to diagnosis of adult diffuse gliomas. Algorithms for arriving at an integrated diagnosis of adult diffuse gliomas predominantly using immunohistochemistry and with minimum possible additional molecular testing were agreed upon, thus addressing the problems of cost, accessibility, and turnaround time. Mandatory and optional tests were proposed for each case scenario. This document represents the consensus of the various neuro-oncology disciplines involved in diagnosis and management of patients with adult diffuse gliomas. The article reflects a practical adaptation of the WHO recommendations to suit a resource constrained setup.

The Korean Society for Neuro-Oncology (KSNO) Guideline for WHO Grade II Cerebral Gliomas in Adults: Version 2019.01.

BackgroundThere was no practical guideline for the management of patients with central nervous system tumor in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has developed the guideline for glioblastoma. Subsequently, the KSNO guideline for World Health Organization (WHO) grade II cerebral glioma in adults is established.MethodsThe Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searching PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords regarding diffuse astrocytoma and oligodendroglioma of brain in adults.ResultsWhenever radiological feature suggests lower grade glioma, the maximal safe resection if feasible is recommended globally. After molecular and histological examinations, patients with diffuse astrocytoma, isocitrate dehydrogenase (IDH)-wildtype without molecular feature of glioblastoma should be primarily treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy (Level III) while those with molecular feature of glioblastoma should be treated following the protocol for glioblastomas. In terms of patients with diffuse astrocytoma, IDH-mutant and oligodendroglioma (IDH-mutant and 1p19q codeletion), standard brain radiotherapy and adjuvant PCV (procarbazine+lomustine+vincristine) combination chemotherapy should be considered primarily for the high-risk group while observation with regular follow up should be considered for the low-risk group.ConclusionThe KSNO's guideline recommends that WHO grade II gliomas should be treated by maximal safe resection, if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors and clinical characteristics of patients.

Editorial introductions

Editorial introductions

Neuro-oncologists have spoken - the role of bevacizumab in the inpatient setting. A clinical and economic conundrum.

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF), a key player in tumor angiogenesis. The drug can halt tumor progression, treat radiation necrosis, and reduce peritumoral edema. Although it does not increase overall survival, bevacizumab can improve progression-free survival and quality of life. In many countries, bevacizumab use in the inpatient setting is restricted due to its significant cost. Here, we explore attitudes towards the use of bevacizumab amidst practitioners treating brain tumors and assess ease of accessing the drug in the inpatient setting. A 10-question survey querying practitioners' opinions of inpatient bevacizumab utility and its availability was distributed to the membership of the Society of Neuro-Oncology in July 2016. Eighty-seven percent felt that there was a role for bevacizumab in the inpatient setting, and 69% reported favorable experiences with bevacizumab use. However, 40% encountered difficulty in obtaining approval for inpatient use. We present two contrasting clinical cases that highlight favorable and unfavorable outcomes when bevacizumab use was and was not permitted, respectively. In this sample of neuro-oncology practitioners, there is general consensus that bevacizumab plays an important role in the inpatient treatment of brain tumors. In light of ongoing barriers to inpatient bevacizumab use due to cost concerns, these data motivate the creation of standardized policies for inpatient bevacizumab use that balances its important role in improving quality of life with financial considerations.

Meeting Update-Society for Neuro-Oncology 2017 Annual Meeting.

Meeting Update-Society for Neuro-Oncology 2017 Annual Meeting.

Procarbazine, lomustine and vincristine for recurrent high-grade glioma.

Recurrent high-grade glioma (HGG) carries an extremely poor prognosis. There is no current standard of care or guideline-based recommendations. Nitrosourea-based multidrug chemotherapy or PCV - procarbazine, lomustine (CCNU) and vincristine - is one of the treatment options at recurrence. There has been no meta-analysis which looks at the benefits and harms of PCV chemotherapy in adults with recurrent HGG. To assess the effectiveness and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy with other interventions in adults with recurrent high-grade glioma. To investigate whether predefined subgroups of people benefit more or less from chemotherapy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4, 2017), MEDLINE (1946 to 22 May 2017), and Embase (1980 to 22 May 2017). We searched trial registries including the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch) and the National Institutes of Health (NIH; ClinicalTrials.gov). We searched the reference lists of all identified studies; the electronic table of contents of the Journal of Neuro-Oncology (1983 to 2016) and Neuro-Oncology (1999 to 2016); and conference abstracts from the Society for Neuro-Oncology (SNO) and the American Society of Clinical Oncology (ASCO 2004 to 2016). We also searched unpublished grey literature and other regional databases. There were no language restrictions. Randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) where PCV was used to treat adults with recurrent HGG. Comparison arm included no chemotherapy, other second line chemotherapy or best supportive care. Two review authors extracted the data and undertook a 'Risk of bias' assessment and critical appraisal of the studies. We identified two RCTs meeting our inclusion criteria. The two trials tested different comparisons.One RCT included 35 participants and compared PCV with 'eight drugs in one day' multidrug chemotherapy, which is a combination of drugs with different mechanisms of action. Median survival was 6 months for the PCV group and 6.5 months for the 'eight drugs in one day' group. Adverse event outcomes were not graded or quantified. Progression-free survival (PFS) and quality of life (QoL) were not described in the methods and were not an outcome of interest. The sample size in this study was small, which lead to insufficient statistical power to detect clinical differences. According to the GRADE approach we judged the quality of evidence to be low for survival outcome and very low for chemotherapy toxicityThe second multi-institutional RCT included 447 participants and compared PCV with Temozolomide (TMZ). Participants were randomised into three arms to receive PCV, and two different regimens of TMZ in a 2:1:1 ratio at first recurrence. The trial reported a median overall survival of 6.7 months and 7.2 months for the PCV and TMZ group respectively. It reported a PFS of 3.6 months for the PCV group and 4.7 months for the TMZ group. There was no observed difference of effect on overall survival (hazard ratio (HR) 0.91, 95% CI 0.74 to 1.11; P = 0.35) or PFS (HR 0.89, 95% CI 0.73 to 1.08; P = 0.23) in participants receiving PCV or TMZ chemotherapy. The proportion of people with at least one grade 3 or 4 adverse event was not clinically important at 9.2% versus 12.2% in PCV and TMZ arms respectively. Mean QoL scores calculated at baseline, 12 weeks and 24 weeks was 51.9 versus 59.8 favouring TMZ (P = 0.04) which is statistically but not clinically significant and was less than the pre-defined 10 point change for moderate improvement. We judged the GRADE quality of evidence to be moderate for overall survival, PFS, and chemotherapy toxicity and low for QoL. Evidence is based on a single large trial analysis as the other trial was small, with inadequate power to detect survival difference. Chemotherapy-naive patients with HGG at first recurrence when treated with PCV or TMZ have similar survival and time-to-progression outcomes. Adverse events are similar and QoL scores are statistically but not clinically significant between TMZ and PCV. Further RCTs should be conducted with adequate power following CONSORT guidelines with emphasis on QoL outcomes.

Practice-Changing Abstracts From the 2016 Society for Neuro-Oncology Annual Scientific Meeting.

The most relevant practice-changing presentations at the 2016 Society for Neuro-Oncology (SNO) Annual Scientific Meeting revolved around the topic of the new 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The most notable change in this new classification is the introduction of molecular markers into the morphologic classification of diffuse gliomas (isocitrate dehydrogenase [IDH] mutation, 1p19q codeletion, and H3K27M mutation), ependymomas (RELA fusion), medulloblastomas (WNT- and sonic hedgehog-activated), and other embryonal tumors (C19MC amplification), thus allowing for more precise diagnosis of these entities compared with the use of morphologic features alone. Among the clinical trials presented, only one phase III trial evaluating a device therapy for treatment of newly diagnosed glioblastoma (EF14; tumor-treating fields) met prespecified statistical criteria for success, showing a modest benefit in progression-free survival and overall survival in patients without progression after radiation and concurrent temozolomide. Other topics of interest included the spatial and temporal heterogeneity of primary brain tumors and the prevalence of burnout among neuro-oncologists.

The role of tumor board conferences in neuro-oncology: a nationwide provider survey.

The tumor board or multidisciplinary cancer meeting (MCM) is the foundation of high value multidisciplinary oncology care, coordinating teams of specialists. Little is known on how these meetings are implemented in Neuro-oncology. Benefits of MCMs include coordination, direction for complicated cases, education, and a forum for communication, emerging technology, and clinical trials. This study identifies participation and utilization of neuro-oncology MCMs. A cross-sectional descriptive survey was dispersed through an internet questionnaire. The Society of Neuro-Oncology and the American Brain Tumor Association provided a list of dedicated neuro-oncology centers. All National Cancer Institute designated centers, and participants in the Adult Brain Tumor Consortium or the Brain Tumor Trials Collaborative were included, identifying 85 centers. Discussion included primary brain tumors (100%), challenging cases (98%), recurrent disease (96%), neoplastic spine disease (93%), metastatic brain lesions (89%), pre-surgical cases (82%), pathology (76%), and paraneoplastic disease (40%). MCMs were composed of neuro-oncologists, neurosurgeons, and radiation oncologists (100%), radiologists (98%), pathologists (96%), and clinical trial participants (64%). Individual preparation ranged from 15 to 300min. MCMs were valued for clinical decision making (94%), education (89%), and access to clinical trials (69%). 13% documented MCMs in the medical record. 38% of centers used a molecular tumor board; however, many commented with uncertainty as to how this is defined. Neuro-oncology MCMs at leading U.S. institutions demonstrate congruity of core disciplines, cases discussed, and perceived value. We identified variability in preparation time and implementation of MCM recommendations. There is high uncertainty as to the definition and application of a molecular tumor board.

Meeting update-Society for Neuro-Oncology 2016 annual meeting.

Meeting update-Society for Neuro-Oncology 2016 annual meeting.

Practice-Changing Abstracts From the 2016 Society for Neuro-Oncology Annual Scientific Meeting

The most relevant practice-changing presentations at the 2016 Society for Neuro-Oncology (SNO) Annual Scientific Meeting revolved around the topic of the new 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The most notable change in this new classification is the introduction of molecular markers into the morphologic classification of diffuse gliomas (isocitrate dehydrogenase [IDH] mutation, 1p19q codeletion, and H3K27M mutation), ependymomas (RELA fusion), medulloblastomas (WNT- and sonic hedgehog-activated), and other embryonal tumors (C19MC amplification), thus allowing for more precise diagnosis of these entities compared with the use of morphologic features alone. Among the clinical trials presented, only one phase III trial evaluating a device therapy for treatment of newly diagnosed glioblastoma (EF14; tumor-treating fields) met prespecified statistical criteria for success, showing a modest benefit in progression-free survival and overall survival in patients without progression after radiation and concurrent temozolomide. Other topics of interest included the spatial and temporal heterogeneity of primary brain tumors and the prevalence of burnout among neuro-oncologists.

PP21. AWAKE CRANIOTOMY FOR RESECTION OF BRAIN TUMOURS: SURVEY OF THE UNITED KINGDOM PRACTICE IN 2015

ABSTRACT: Awake craniotomy (AC) is a useful surgical technique to help identify and preserve eloquent areas during cortical and subcortical tumour resections. Here the UK practice of AC in 2015 is reviewed. MATERIAL AND METHODS: An online survey (SurveyMonkey LTD) supported by the British Neuro-Oncology Society (BNOS) regarding AC practice was sent to a neurosurgical consultant with a specialist interest in oncology at all thirty neurosurgical centres in the UK. RESULTS: 100% of units responded to the survey. 27/30 UK neurosurgical units performed AC in 2015. 575 AC were performed by 60 neurosurgical consultants (range 1–4, median 2 per unit). 87 anaesthetic consultants routinely covered AC lists (range 1–6, median 3 per unit). A general anaesthetic/ awake/ general anaesthetic or awake technique was performed in 18 units, while conscious sedation/awake /conscious sedation was performed in 14 units. Dexmedetomidine and Remifentanil were the favoured agents used in 6 units with the rest using Propofol and Remifentanil. Depending on patient factors AC was performed purely under local anaesthetic in 10 units. All neurosurgical units would consider AC for resection of low grade glioma (LGG), 20 units for high grade glioma (HGG), 10 units for metastases, 8 units for epilepsy and 3 units for some vascular indications. Less than half of units use DTI for tractography or fMRI for language localisation. Bipolar stimulation for direct cortical and subcortical mapping was used in 26 units; monopolar stimulation alone was used in 1 unit and both modalities of stimulation were used in 7 units. A third of units routinely measured motor evoked potentials and somatosensory evoked potentials during AC and a quarter routinely measured after discharges. Intra-operative neuropsychological paradigms were tested by either a speech and language specialist (16 units) or neuropsychologist (12 units) and in 4 units, paradigms were routinely tested by the anaesthetic team or nursing staff. Paradigm testing was performed in conjunction with direct cortical or subcortical stimulation and during resective surgery. A post operative MRI head within 48 hours was routinely performed at 22 units, and day case AC was offered at 3 units. DISCUSSION: This is a unique snapshot of how AC was performed predominantly for tumour resection in eloquent cortex in 2015 in the UK. Since 2008 there has been an increase in the number of UK units from 19 to 27 offering AC, and the number of consultant anaesthestists being involved with cases has almost doubled (1). AC is predominantly used and reported for resection of LGG (2). However in our study, 75% of units would consider AC for HGG. With the increasing use of AC by dedicated teams using different techniques, this offers a valuable opportunity to compare results, optimise safety, improve techniques and potentially provide a more unified approach allowing national collaboration.

EPID-04. TUMOR BOARD CONFERENCES IN NEURO-ONCOLOGY: A NATIONWIDE PROVIDER SURVEY

Tumor board or multidisciplinary cancer meetings (MCM) are the centerpiece of coordinated specialized neuro-oncology care. Little is known on how these meetings are implemented. Benefits of MCM include coordination, direction for complicated cases, education, and a forum for communication, emerging technology, and clinical trials. This study identifies participation and utilization of neuro-oncology MCM with the goal of improving practice patterns and establishing models for high value care. A cross-sectional descriptive internet survey was used. 85 neuro-oncology centers were identified by the Society for Neuro-Oncology and the American Brain Tumor Association. In addition, NCI designated cancer centers, participants in the Adult Brain Tumor Consortium, or the Brain Tumor Trials Collaborative were asked to participate. 46 centers completed the survey. All centers reviewed primary brain tumors, 93% discussed neoplastic spine disease, 89% metastatic brain lesions, 40% paraneoplastic disease. 98% discuss “challenging cases”, 96% recurrent disease, 82% undiagnosed or pre-surgical cases, 89% utilize radiology review. 100% of MCM included Neuro-Oncologists, Neurosurgery, and Radiation Oncology; Radiologist 98%, Pathologist 96%, and clinical trials 64%. Geneticist, Behavioral Health, and Social Work less than 15%. 76% reviewed Pathology. 80% meet weekly, and 36% include satellite centers. Individual preparation time varied 15-300 minutes. 94% value MCM for clinical decision-making, access to clinical trials 69%, and education 89%. Only 13% document MCM in the medical record. 38% of centers use a molecular tumor board, however many commented with uncertainty as to how this is defined. Neuro-oncology MCMs at leading U.S. institutions show high congruity of core disciplines, cases discussed, and perceived value. There is strong agreement on the role of clinical decision making and education, but the implementation of recommendations varies widely. We identified marked variability in preparation time, documentation, and high uncertainty as to the definition and application of a molecular tumor board.

Mibefradil Dihydrochloride With Hypofractionated Radiation for Recurrent Glioblastoma: Preliminary Results of a Phase 1 Dose Expansion Trial

ATNT-15. MIBEFRADIL DIHYDROCHORIDE WITH HYPOFRACTIONATED RADIATION FOR RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS OF A PHASE I DOSE EXPANSION TRIAL Nataniel H. Lester-Coll1, Jeannie Kluytenaar1, Kira F. Pavlik2, James B. Yu1, Joseph N. Contessa1, Jennifer Moliterno3, Joseph M. Piepmeier3, Kevin P. Becker4, Joachim M. Baehring4, Anita J. Huttner5, Alexander O. Vortmeyer5, Ramachandran Ramani6, Rachel J. Lampert7, Xiaopan Yao8, and Ranjit S. Bindra1; Departmentof TherapeuticRadiology, YaleUniversity School of Medicine, New Haven, CT, USA; Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA; Department of Cardiology, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA BACKGROUND: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput drug screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. Follow-up studies by our group and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and hypofractionated radiation (RT), in a Phase I study of patients with recurrent GBM. A subset of patients are enrolled on a molecular biomarker sub-study, in which the drug is administered prior to surgical re-resection, and the tissue is analyzed for tumor penetration and in situ activity. METHODS: The inclusion criteria are histologically proven GBM progressive or recurrent following RT and temozolomide treatment. Patients receive mibefradil, in escalating dose from 150mg/day until the maximum tolerated dose (MTD) or a dose of 350 mg/day is reached using a standard 3 + 3 design. RT consists of 5 fractions of 600 cGy each, delivered over 2 weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. RESULTS: To date, eight patients have been enrolled including two patients on the molecular biomarker sub-study, and seven have been successfully treated. The first dose level cohort has completed accrual. Median progression-free survival was 2.5 months. One patient experienced a complete radiographic response on MRI and one had grade 3 or higher drug-related toxicity. CONCLUSIONS: This Phase I dose-escalation study assesses the safety and determines the MTD of mibefradildihydrochlorideas anovel radiosensitizer inpatientswith recurrent GBM. Our preliminary data suggest that mibefradil and RT can be safely co-administered with the potential to improve disease response as a novel radiosensitizer. Neuro-Oncology 17:v10–v17, 2015. doi:10.1093/neuonc/nov205.15 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Radiotherapy for diffuse brainstem glioma in children and young adults.

Diffuse brainstem glioma is a devastating disease with very poor prognosis. The most commonly used radiological treatment is conventional fractionated radiation. So far, there is no meta-analysis or systematic review available that assesses the benefits or harms of radiation in people with diffuse brainstem glioma. To assess the effects of conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem gliomas in children and young adults aged 0 to 21 years. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, and EMBASE to 19 August 2015. We scanned conference proceedings from the International Society for Paediatric Oncology (SIOP), International Symposium on Paediatric Neuro-Oncology (ISPNO), Society of Neuro-Oncology (SNO), and European Association of Neuro-Oncology (EANO) from 1 January 2010 to 19 August 2015. We searched trial registers including the International Standard Randomised Controlled Trial Number (ISRCTN) Register, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the register of the National Institutes of Health to 19 August 2015. We imposed no language restrictions. All randomised controlled trials (RCTs), quasi-randomised trials (QRCTs), or controlled clinical trials (CCTs) that compared conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem glioma in children and young adults aged 0 to 21 years. Two review authors independently screened studies for inclusion, extracted data, assessed the risk of bias in each eligible trial, and conducted GRADE assessment of included studies. We resolved disagreements through discussion. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified two RCTs that fulfilled our inclusion criteria. The two trials tested different comparisons.One multi-institutional RCT included 130 participants and compared hyperfractionated radiotherapy (six-week course with twice a day treatment of 117 cGy per fraction to a total dose of 7020 cGy) with conventional radiotherapy (six-week course with once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy). The median time overall survival (OS) was 8.5 months in the conventional group and 8.0 months in the hyperfractionated group. We detected no clear evidence of effect on OS or event-free survival (EFS) in participants receiving hyperfractionated radiotherapy compared with conventional radiotherapy (OS: hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.75 to 1.53; EFS: HR 1.26, 95% CI 0.83 to 1.90). Radiological response (risk ratio (RR) 0.94, 95% CI 0.54 to 1.63) and various types of toxicities were similar in the two groups. There was no information on other outcomes. According to the GRADE approach, we judged the quality of evidence to be low (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate) for OS and EFS, and very low (i.e. we are very uncertain about the estimate) for radiological response and toxicities.The second RCT included 71 participants and compared hypofractionated radiotherapy (39 Gy in 13 fractions over 2.6 weeks, 3 Gy per fraction) with conventional radiotherapy (54 Gy in 30 fractions over six weeks, 1.8 Gy per fraction). This trial reported a median OS of 7.8 months for the hypofractionated group and 9.5 months for the conventional group. It reported a progression-free survival (PFS) of 6.3 months for the hypofractionated group and 7.3 months for the conventional group. We found no clear evidence of effect on OS (HR 1.03, 95% CI 0.53 to 2.01) or PFS (HR 1.19, 95% CI 0.63 to 2.22) in participants receiving hypofractionated radiotherapy when compared with participants receiving conventional radiotherapy. The mainly observed adverse effect was local erythema and dry desquamation especially behind the auricles. There were some other toxicities, but there was no statistically significant difference between treatment groups. There was no information on other outcomes. We judged the quality of evidence to be moderate (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) for OS, and low for PFS and toxicities. It should be mentioned that the sample size in this RCT was small, which could lead to insufficient statistical power for a clinically relevant outcome. We could make no definitive conclusions from this review based on the currently available evidence. Further research is needed to establish the role of radiotherapy in the management of newly diagnosed diffuse brainstem glioma in children and young adults. Future RCTs should be conducted with adequate power and all relevant outcomes should be taken into consideration. Moreover, international multicentre collaboration is encouraged. Considering the potential advantage of hypofractionated radiotherapy to decrease the treatment burden and increase the quality of remaining life, we suggest that more attention should be paid to hypofractionated radiotherapy.

PCM-21EXPRESSION OF IMMUNE CHECKPOINT PROTEINS IN PATIENT-DERIVED PEDIATRIC BRAIN TUMOR XENOGRAFTS

PCM-21. EXPRESSION OF IMMUNE CHECKPOINT PROTEINS IN PATIENT-DERIVED PEDIATRIC BRAIN TUMOR XENOGRAFTS Eric Ring, Blake Moore, Li Nan, Tina Etminan, James Markert, G. Yancey Gillespie, and Gregory Friedman; University of Alabama at Birmingham, Birmingham, AL, USA Pediatric brain tumors represent the most common solid tumor in children and the leading cause of cancer morbidity and mortality. Standard of care includes surgery, chemotherapy and radiation, which are all very damaging to a developing child. While these therapies have improved survival rates, outcomes remain extremely poor for patients with refractory disease. To improve outcomes and lessen toxicities, novel, directed therapies are needed. Recently, immunosuppressive checkpoint molecules that negatively regulate immune cell function and enable local tumor escape, such as PD-L1, CTLA-4, CD200andIndolamine2,3-dioxygenase (IDO),havebeendescribed inadultbrain tumors.Agentsdesigned to inhibit theseproteinshave shownsignificant efficacy in human adult solid tumor studies. Little is known about expression of these checkpoint molecules in pediatric brain tumors. After disaggregation of six patient derived xenografts (2 glioblastoma (GBM), 2 medulloblastoma (MB), and 2 supratentorial primitive neuroendocrine tumors (SPNETs)) harvested from athymic nude mice, we performed flow cytometry to quantify expression of CTLA-4, PD-L1, CD200, and IDO. All three tumor types had high expression levels of IDO (range 60.3-98.7%) and low expression of CD200 (0.5-14.4%). MB and SPNETs expressed low levels of CTLA-4 (2.2-7.5% and 4.2-11.6%, respectively) while GBM showed variable expression (20.5-38.3%). PD-L1 was highly expressed in MB (90.2-91.9%) and variably expressed in SPNETs and GBM (13.2-63.8% and 13.2-87.8%, respectively). Our results suggest that pediatric brain tumors express targetable immune checkpoint molecules, with expression of IDO consistently high, PD-L1 variable, and CD200 and CTLA-4 low. Neuro-Oncology 18:iii139–iii144, 2016. doi:10.1093/neuonc/now080.21 #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.

QOS-42QUALITY OF SURVIVAL AFTER BRAIN TUMOUR IN CHILDHOOD. DATA FROM A PSYCHOSOCIAL AND NEUROPSYCHOLOGICAL FOLLOW UP PROGRAM

QOS-42. QUALITY OF SURVIVAL AFTER BRAIN TUMOUR IN CHILDHOOD. DATA FROM A PSYCHOSOCIAL AND NEUROPSYCHOLOGICAL FOLLOW UP PROGRAM Torhild Berntsen1, Anne-Britt Skarbo1, Antia Puhr1, Kristine Stadskleiv1, and Stein Andersson2; Oslo University Hospital, Oslo, Norway; University of Oslo, Oslo, Norway AIM: To investigate the impact on quality of life (QoL) of medical complications, adjuvant treatment, cognitive function, gender and age at diagnosis 5 or more years after the initial treatment for brain tumour in childhood. MATERIALS AND METHODS: 66 children were included, 41 girls and 25 boys, 43 with benign and 23 with malignant tumours. All have completed a comprehensive neuropsychological and psychosocial evaluation 5 years after end of treatment, included answering the questionnaire Pediatric Quality of Life Inventory (PedsQL), both children and parents. RESULTS: Children who had benign tumours, but who had medical complications after the initial operation (SC), reported significantly (p , 0.05) more problemscompared to thosewhohadanoperationonly (SO), onall PedsQLdimensions. Children who had adjuvant treatment (SA) reported significantly (p , 0.05) more problems compared to children who had surgery only on the physical, social, and school dimensions, but not on the emotional dimension on PedsQL. No significant differences were found between the groups with medical complications and adjuvant treatment. The parents’ ratings on PedsQL did not differ significantly from the children’s. There were no significant differences between the three groups with regards to IQ, age at diagnosis and gender. CONCLUSION: Having a childhood benign tumour that needs medical treatment after the operation, has a significant impact on quality of life, long after treatment is completed, equal to having a malignant tumour needing adjuvant treatment. Factors as IQ, gender and age at diagnosis are less influential. Neuro-Oncology 18:iii145–iii158, 2016. doi:10.1093/neuonc/now081.42 #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.

PCM-16MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS

PCM-16. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS Sebastian Brabetz1, Susanne N. Groebner1, Huriye Seker-Cin1, Norman L. Mack1, Volker Hovestadt1, David T. W. Jones1, Florian Selt1,2, Till Milde1,2, Madison T. Wise3, Jessica M.Rusert4, Kyle Pedro3, Karina Bloom3, Olaf Witt1,2, Sarah E. Leary3, Xiao-Nan Li5, Robert J. Wechsler-Reya4, James M. Olson3, Stefan M. Pfister1,2, and Marcel Kool1; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Center for Individualized Pediatric Oncology (ZIPO) and Pediatric Brain Tumors, Department of Pediatric Oncology, University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany; Fred Hutchinson Cancer Research Center and Seattle Children’s Hospital, Seattle, WA, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Baylor College of Medicine, Houston, TX, USA Orthotopic patient-derived xenograft (PDX) models are an excellent platform for biomarker and preclinical drug development. Prior to drug selection and testing, extensive molecular characterization is needed to precisely determine the distinct molecular subgroup and constellation of genetic alterations for each PDX model, and thus identify its targetable oncogenic drivers. In an international effort we have characterized a large repertoire of PDX models reflecting many different molecular subtypes of pediatric brain tumors and assessed inter-tumoral heterogeneity within these subtypes. Thus far, we have collected and characterized 70 established PDX models from 6 ATRTs, 8 ependymomas, 16 high-grade gliomas, 38 medulloblastomas, and 2 CNS-PNETs. All PDX models and matching primary tumors (if available) have been analyzed by whole-exome and low-coverage wholegenome sequencing, as well as DNA methylation and gene expression profiling.PDXmodels always retain theirmolecular subtypeand in thevastmajority of cases also the mutations and copy number alterations when compared to their primary tumors. Only in rare cases do we observe additional aberrations, which most likely represent outgrowths of subclones from the primary tumor. Analysis of our entire cohort identified an overrepresentation of the most aggressive tumor subtypes, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma. Our molecular characterization of PDX models will provide an unprecedented resource to study tumorbiologyandpave theway for improving treatment strategies forchildren with malignant brain tumors. Neuro-Oncology 18:iii139–iii144, 2016. doi:10.1093/neuonc/now080.16 #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.

PNR-20PRIMARY METASTATIC LEIOMYOSARCOMA OF THE SKULL

PNR-20. PRIMARY METASTATIC LEIOMYOSARCOMA OF THE SKULL Alexandra Paul1, Olinda Rebelo2, and Alice Carvalho1; Pediatric Oncology Department, Centro Hospitalar e Universitario de Coimbra-EPE, Coimbra, Portugal; Neuropathology Department, CentroHospitalar e Universitario de Coimbra-EPE, Coimbra, Portugal We report the case of a previous healthy 11 yearold-boy, with a one month history of worsening headache which appeared apparently in the context of trauma. He had an x-ray of the skull that showed a right fronto-parietal lytic lesion with 10 cm in size and with ill-defined borders. CT scan and MRI of the skull revealed a soft tissue mass invading the cranial cavity just beyond the lytic lesion, compressing the brain parenchyma, the upper sagittal sinus and the right ventricle. Skeletal scintigraphy with technetium 99m showed a positive uptake of the proximal left femur and the distal right femur. Chest CT scan detected multiple bilateral lesions of the lung. Blood tests were normal, HIV 1 and 2 were negative. Histopathological results of the soft tissue biopsy were compatible with an unspecified high-grade sarcoma and a second opinion was requested to Prof. Christopher Fletcher Harvard Medical School, USA. His examination was compatible with a high-grade spindle cell malignant neoplasm with extensive necrosis. Immunohistochemistry showed multifocal positivity for smoth muscle actin, numerous scattered cells were positive fordesmin andalsowith quiteextensivekeratinpositivity,while caldesmon, CD34 and epithelial membrane antigen were negative, suggesting a high grade leiomyosarcoma. A high complex karyotype was detected by genetic analysis. Despite chemotherapy and radiotherapy, the disease progressed and he died five months after the diagnosis. Neuro-Oncology 18:iii7–iii15, 2016. doi:10.1093/neuonc/now067.17 #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.

PNR-02DESMOPLASTIC NON-INFANTILE GANGLIOGLIOMA: A RARE CASE OF MALIGNANT TRANSFORMATION

PNR-02. DESMOPLASTIC NON-INFANTILE GANGLIOGLIOMA: A RARE CASE OF MALIGNANT TRANSFORMATION Natalie Smith, Bhaskar Thakur, Miren Aizpurua, Angela Calado Bravo, Safa Al-Sarraj, Sanjeev Bassi, Chris Chandler, and Bassel Zebian; King’s College Hospital, London, UK INTRODUCTION: Desmoplastic infantile gangliogliomas (DIG) are rare, supratentorial glioneuronal tumours of infants. They are histologically benign and consideredasWHO grade I tumours.When presenting in childrenover the age of 1, they are termed desmoplastic non-infantile ganglioglioma (DNIG). They are not usually associated with malignant behaviour. We present a rare case of recurrent DNIG with malignant transformation. CASE REPORT: A four year-old girl presented with a four-month history of worsening headaches, aggressive behaviour and left facial droop. MRI revealed a large right parieto-occipital lesion with mass effect. The lesion was subtotally resected. Histology was consistent with desmoplastic infantile ganglioglioma, WHO Grade I. Follow up MRIs demonstrated aggressive growth requiring further debulking in 7 months and 10 months. The subsequent biopsies showed similar features; however increasing mitotic activity in the predominant desmin positive astrocytic cells. The proliferation index (Ki67) was focally up to 4% in the first biopsy; increasing to 8% and 12% in the subsequent biopsies. Histology from the third resection was consistent with anaplastic ganglioglioma, WHO Grade III. CONCLUSION: This case of DNIG demonstrated aggressive growth despite multiple operative interventions, and histology strongly suggesting malignant transformation. Histology has shown malignant transformation, which has only been reported in a handful of cases in the literature. This has important implication for the follow up and management of these lesions. Neuro-Oncology 18:iii7–iii15, 2016. doi:10.1093/neuonc/now067.2 #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.