Search

Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.

BACKGROUND Paediatric brain tumour survivors may have treatment toxicity associated with signal change on follow-up MRI. Quantitative MRI texture features can potentially be used as surrogates of the underlying tissue changes following radiation therapy. MATERIAL AND METHODS Longitudinal retrospective study in 51 paediatric primary brain tumours treated with photon (N=30) and proton (N=21) radiotherapy (RT). T2 MRI scans at baseline and multiple time point from the date of surgery to 2 years following radiotherapy were selected for the textural analysis. Scans were bias corrected, registered with the CT dose maps and with baseline scan for each patient using 3Dslicer. Regions of interest (ROI) of fixed diameter were drawn in 11 predetermined non-tumoral regions of brain including in peri-tumoural region (PTV). ROIs were placed in homogenous white/grey matter. Radiation dose was calculated in each of these 11 ROIs and texture features were extracted using pyradiomics. Data were analysed using machine learning and statistical analysis. General linear multivariate model was used to corelate primary texture features over period of 24 months and radiation dose, time, effect of dose*time together at each ROI separately. RESULTS There were Brainstem 4, Cerebellar19, Hemispheric cerebral 7 and Supratentorial midline 10 tumours. Median age at diagnosis was 8.26 years (range: 0–20). Median RT treatment dose was 28.52Gy (0-60Gy). Multivariate analysis shows significant corelation (p < 0.001) between radiation dose and longitudinal primary texture features in all 11ROIs. Time showed corelation with feature values only in 3 ROIs and dose* time showed corelation in 5ROIs. Primary (statistical) feature values showing consistent correlation with dose in all 11 ROIs over 24 months are total energy, 10%, 90%, energy, entropy, mean, median, and minimum. CONCLUSION Radiomic texture analysis is a promising modality to understand dose related textural changes in the normal part of brain in paediatric brain tumour patients treated with radiation therapy. Radiomic changes need to be related to neurological outcomes in future research.

Introduction Brain tumours are a common cause of death in the paediatric population. We have previously shown that MR imaging and spectroscopy can be used to non-invasively differentiate between tumour types. Here, we demonstrate that functional imaging can be highly predictive of survival and grade in a paediatric cohort. Methods Perfusion (PWI) and diffusion weighted imaging (DWI) were performed in a multi-site (Birmingham Children’s Hospital, Royal Victoria Infirmary, Alder Hey, Nottingham) cohort ([grade, 5-year survival alive:dead number] = [I,15:1],[II, 5:1],[III,2:3],[IV,8:11]). ROIs were drawn on T2 imaging and functional imaging features (mean, standard deviation, skewness, and kurtosis) were derived. Supervised machine learning was used to predict 5-year survival and tumour grade from features. ANOVA and post-hoc tests were used to assess differences in features between grade and 5-year survival status. Results 5-year survival was predicted with 89%, 85%, and 87% accuracy with all imaging, perfusion, or diffusion features, respectively. A significant difference in perfusion was found between surviving and diseased participants (1.71 ± 0.82 vs 2.62 ± 1 mL/100g/min, respectively, p < 0.05). A significant difference in ADC (mm2 s-1) between tumour grades was found (1 vs 4 (1533 ± 458 vs 857 ± 239), 4 vs 3 (857 ± 239 vs 1197 ± 137), 4 vs 2 (857 ± 239 vs 1440 ± 557), corrected p < 0.05). Conclusion We have shown that perfusion and diffusion imaging features can be used to non-invasively assess tumour grade and estimate 5-year survival status in a cohort of paediatric brain tumours.

Disease relapse occurs in ~30% of children with medulloblastoma, and is fatal in the majority. We sought to establish whether clinico-molecular characteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinical management. We surveyed the clinical features of medulloblastoma relapse (time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in 247 centrally-reviewed patients who relapsed following standard-upfront-therapies. We related these to clinico-molecular features at diagnosis, prognostic factors, and first-line/relapse treatment. Patients who received upfront craniospinal irradiation (CSI-treated) displayed prolonged time-to-relapse compared to CSI naïve patients (p

BACKGROUND Brain tumours are clinically and biologically highly diverse and account for 25% of paediatric neoplasms. They carry the highest mortality and morbidity of tumour groups. Their management presents significant challenges with performing modern diagnostic assessments, applying multimodal treatment and establishing interdisciplinary cooperation. Outcomes across Europe differ significantly with varying 5year survival reports of 42–79%. This SIOP-Europe PaedCan survey assessed the structures and facilities for individual states and highlight areas for cooperation and support. DESIGN: An online questionnaire was sent to SIOP-Europe Brain Tumour Group members. This had 55 questions assessing pathology, staging, surgery, radiotherapy and paediatric oncology infrastructure. For analysis of the data we divided countries into lower and higher economic status according to GDP (World Bank 2019) with a cut off of $30,100. RESULTS There were 388 respondents from 44 countries in 181 different institutions. In the lower GDP group we noted decreased access to biological characterisation of tumours and interdisciplinary tumour boards. In this group of nations, patients were less likely to have treatment by a paediatric specialist neurosurgeon, paediatric neuro-oncologist, neuroradiologist, and paediatric radiation oncologist. There was also less availability to perform early MRI (ventilated) and less access to proton beam therapy. This study supports the aim of the ERN to produce a roadmap document with specific standards and publish guidelines for all relevant diagnostic and therapeutic components of care. The ERN also aims to identify a network of institutions to provide patient advice and training to equalise treatment and outcomes for all children across Europe.

INTRODUCTION The COVID-19 pandemic has led to widespread change in the delivery of rehabilitation. The Teenage Cancer Trust reported that 69% of young people with cancer saw their physiotherapist less than usual during the pandemic raising concerns about physiotherapy input. METHODS Retrospective analysis of all children’s therapy input managed under the Neuro Oncology Rehabilitation Team (NORT) between 1st April and 30th July 2020. Descriptive analysis of change to physiotherapy provision during this time period by Tertiary and local community services. RESULTS 49 children were managed under the NORT Therapy Team during this timeframe. 9 children were newly diagnosed with CNS tumours. There was no impact on inpatient therapy provision, 3 had delayed local therapy provision on discharge requiring increased virtual input by the Tertiary centre. 40 children were outpatients managed under the NORT therapy team. 16 children were also receiving regular local physiotherapy input prior to the COVID-19 pandemic. 13 of these children subsequently had their local physiotherapy input suspended during this time period, 8 children were offered virtual input as an alternative by the Tertiary centre, 2 children received increased face to face appointments at the Tertiary centre. 14 of the 24 children managed solely under the Tertiary NORT Therapy Team changed to virtual therapy reviews. DISCUSSION There is a clear change in therapy provision as a result of the COVID-19 pandemic. Future research should consider the effectiveness of neurorehabilitation conducted virtually and the impact on physical function of reduced local therapy provision in children with CNS tumours.

INTRODUCTION A multi-disciplinary Neuro-Oncology Rehabilitation Team (NORT) was established at our institution in 2014. We reviewed NORT inputs, processes and outputs in 2018 to 2019 compared to our previously presented data from 2015, soon after service inception. METHODS Retrospective analysis of patients who received NORT input June 2018 - May 2019 compared to 2015 data. Descriptive analysis of changes to NORT operational processes and structure. Complexity of rehabilitation needs was measured using the Rehabilitation Complexity Scale-Extended V13 (RCS). RESULTS 54 children received NORT input in 2018–2019 (10 children in 2015) with total of 129 outputs. NORT input was highest in children with high grade glioma (median reviews: 3; median RCS: 5) and ependymoma (median reviews: 3; median RCS: 5). Pilocytic astrocytoma formed the largest tumour group (n = 11; median reviews: 2; median RCS: 7). 11% patients were referred to neurologist (9% already known); 17% referred to community services (44% already known); 31% referred to neuropsychology. In 2015, outputs were predominantly referral to occupational therapy and physiotherapy. 6 patients (11% of 54) were discharged in 2018–2019 (40% of 10 patients in 2015). 4 patients died. Between 2015 and 2019, developments included: clarifying referral and discharge pathways, use of screening measures, neuropsychology integration, therapy-led drop-in clinics, use of RCS-E. DISCUSSION: There has been a clear increase in utilisation and scope of work of NORT over last 4 years. The strength of this team is multidisciplinary working and expertise. Further developments planned: multidisciplinary rehabilitation interventions and NORT outcome tools.

INTRODUCTION Magnetic Resonance Imaging (MRI) is routinely used in the assessment of children’s brain tumours. Reduced diffusion and increased perfusion on MRI are commonly associated with higher grade but there is a lack of quantitative data linking these parameters to survival. Machine learning is increasingly being used to develop diagnostic tools but its use in survival analysis is rare. In this study we combine quantitative parameters from diffusion and perfusion MRI with machine learning to develop a model of survival for paediatric brain tumours. METHOD: 69 children from 4 centres (Birmingham, Liverpool, Nottingham, Newcastle) underwent MRI with diffusion and perfusion (dynamic susceptibility contrast) at diagnosis. Images were processed to form ADC, cerebral blood volume (CBV) and vessel leakage correction (K2) parameter maps. Parameter mean, standard deviation and heterogeneity measures (skewness and kurtosis) were calculated from tumour and whole brain and used in iterative Bayesian survival analysis. The features selected were used for k-means clustering and differences in survival between clusters assessed by Kaplan-Meier and Cox-regression. RESULTS Bayesian analysis revealed the 5 top features determining survival to be tumour volume, ADC kurtosis, CBV mean, K2 mean and whole brain CBV mean. K-means clustering using these features showed two distinct clusters (high- and low-risk) which bore significantly different survival characteristics (Hazard Ratio = 5.6). DISCUSSION AND CONCLUSION Diffusion and perfusion MRI can be used to aid the prediction of survival in children’s brain tumours. Tumour perfusion played a particularly important role in predicting survival despite being less routinely measured than diffusion.

BACKGROUND: Postoperative paediatric cerebellar mutism syndrome (POPCMS) is a complication affecting 8%-31% of children undergoing posterior fossa tumour resection. Injury to the proximal efferent cerebellar pathway during surgery is increasingly implicated in its causation but the exact pathogenesis remains unclear. Identifying MRI changes in the brain stem and cerebellum of these children can further the understanding of the pathogenesis and anatomical substrates involved. METHODS: Longitudinal analysis of follow -up MRI in 40 children with and without POPCMS following posterior fossa tumour resection was performed using a fully automated quantitative analysis of the brainstem and cerebellum in 3D space using the following steps: segmentation, registration, longitudinal interpolation of the MR images and machine learning techniques for feature selection and data classification. RESULTS: Longitudinal analysis and machine learning of the first 7 month MRI data following surgery identified six features at specific locations in Crus I, VI, VIIb, VIIb & IX of the anatomical right cerebellar hemisphere following surgery that are potential biomarkers of POPCMS. Three of these are identified at 1 month, two at 2 months and one at 5 months following surgery. CONCLUSION: This novel fully automated quantitative analysis of MRI in children following posterior fossa tumours resection reveals biomarkers that help to further the understanding the pathogenesis of POPCMS. This is one of the few studies that support the involvement of the right cerebellar hemisphere in the development of POPCMS. These biomarkers could also serve as imaging surrogates to the severity of the injury and prognosis.

CNS-PNET is no longer regarded a single disease but encompassed many distinct molecular entities. After removal of the term from the 2016 WHO classification of CNS tumours, diagnostic and therapeutic uncertainty remains. Through a world-wide collaboration, tumour samples from patients with the “historic” diagnosis of CNS-PNET were re-evaluated by DNA methylation profiling (n=405) and blinded neuropathological panel review (n=256). Clinical data on treatment and outcome were pooled with data on previously published patients. The given numbers represent preliminary data of the ongoing project. The re-evaluation by DNA methylation identified many distinct entities as expected, including high grade glioma (HGG, n=70), embryonal tumors with multilayered rosettes (ETMR, n=57) and CNS-neuroblastoma with FOXR2 alteration (CNS-NB-FOXR2, n=42) as the most frequent molecular diagnostic categories. Poor clinical outcome was confirmed for patients with HGG (5y-PFS 12%/5y-OS 12%, n=24), and ETMR (5y-PFS 12%/5y-OS 18%, n=62), while most patients with CNS-NB-FOXR2 survived (5y-PFS 52%/5y-OS 96%, n=31). Seven of 12 relapses/progressions of CNS-NB-FOXR2 occurred in radiotherapy-naïve patients. Classification into other newly described and less common entities included HGNET-MN1 (n=19), HGNET-BCOR (n=11), and EFT-CIC (n=13). Independent neuropathological review demonstrated that samples of these entities presented as non-embryonal tumours. Furthermore, marked clinical differences exist (HGNET-MN1: 5y-PFS 25%/5y-OS 95%, n=22; HGNET-BCOR: 5y-PFS 0%/5y-OS 44%, n=16; CNS-EFT-CIC: 5y-PFS 40%/5y-OS 60%, n=10). Our results show that implementation of DNA methylation profiling together with histopathological analysis will improve prospective diagnostic accuracy and facilitates the retrospective outcome analysis of treatment protocols used for this variety of biologically distinct entities.

ATRTs have low mutation rates and few classically-actionable variants to direct molecularly targeted therapies; loss of SMARCB1 is the sole recurrent mutational event in >90% of ATRTs. We have designed and implemented a genome-scale strategy for target identification and prioritization in tumors devoid of significant actionable mutations. Re-expression of SMARCB1 causes ATRT cells to cease proliferation and differentiate; we therefore hypothesized that identifying and counteracting critical downstream SMARCB1-dependent events represents a primary route to therapeutic intervention. We identify such events using an integrated genome-wide approach encompassing genome-scale CRISPR/Cas9 functional screens (GeCKO screening; 122,411 sgRNAs) alongside expression/DNA methylation profiling of primary ATRTs and ATRT cells following SMARCB1 re-expression and/or treatment with demethylating agents. Cross-referencing these analyses, we use a rational selection algorithm, to identify critical tumorigenic genes/pathways and proceed to validate their ability to be targeted as therapeutic targets. Our strategy identifies, ranks and prioritizes multiple SMARCB1-dependent pathways/genes functionally essential to ATRT, and characteristic of the primary tumour; including those previously described (Rb/CDK4/6, SHH, MYC), those less well evidenced (mTOR, TGF-β, HGF, Stat3/Jak) and novel SMARCB1-dependent synthetic lethalities (NuA4 complex, PIM1). We also describe the repressive genome-wide effect of SMARCB1 mutation on the transcriptome, through altered SWI/SNF binding, associated histone marks and localized hypermethylation and the therapeutic possibilities implied therein. Data and web-based interactive analysis and visualization tools will be made publically available to help guide and benchmark future pre-clinical testing in ATRT. This study pinpoints SMARCB1-dependent therapeutic susceptibilities in MRTs with the capacity to inform future treatment strategies.

BACKGROUND: International consensus recognises four medulloblastoma molecular subgroups - WNT (MBWNT), SHH (MBSHH), Group 3 (MBGrp3) and Group 4 (MBGrp4) - each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. Subgroups harbor distinct clinico-pathological and molecular features, underpin current disease sub-classification and initial subgroup-directed therapies are underway in clinical trials (i.e. reduced risk-adapted treatments for favorable-risk MBWNT patients; SMO inhibitors for MBSHH patients). However, significant biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. METHODS: We undertook comprehensive molecular profiling and unsupervised class discovery (non-negative matrix factorization, t-SNE) of test and validation cohorts (n=704 in total), to identify consensus primary molecular subgroups within childhood medulloblastoma (3.0 years). FINDINGS: Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified, characterized by distinct biological/clinical features. For instance, MBSHH comprised two age-dependent subgroups, while MBGrp3 and MBGrp4 each split into two subgroups with significantly different survival rates. Survival analysis identified secondary features predictive of outcome. Cross-validated subgroup-dependent models incorporating these novel subgroups along with secondary features and established disease risk-factors, outperformed current disease risk-stratification schemes. These schema stratified patients into four clinical risk-groups - favorable-risk (91% 5-year survival, 25% of patients), standard-risk (81%, 23%), high-risk (42%, 38%) and very high-risk (28%, 13%) - to be considered for treatment reduction, intensification or novel therapies respectively. INTERPRETATION: The discovery of seven novel, clinically-significant, subgroups significantly improves disease risk-stratification and provides a new foundation for future research and clinical investigations.

Item does not contain fulltext Background.: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods.: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results.: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age >/=4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients /=4 years, PFS/OS were 72 +/- 7%/73 +/- 7% for patients without metastases, and 50 +/- 10%/55 +/- 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion.: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

NS-18. ROLE OF METFORMIN IN THE TREATMENT OF HYPOTHALAMIC OBESITY SYNDROME (HOS) Arundoss Gangadharan1, Aliki Bogiatzopoulou1, Joanne Blair1, Barry Pizer2, Lisa Howell2, James Hayden2, Conor Mallucci3, Benedetta Pettorini3, and Mohammed Didi1; Department of Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK; Department of Oncology, Alder Hey Children’s Hospital,Liverpool, UK; Department of Neurosurgery,Alder HeyChildren’s Hospital, Liverpool, UK BACKGROUND: HOS in children with structural hypothalamic lesions is characterised by weight gain refractory to standard lifestyle interventions. Disruption of hypothalamic function results in hyperphagia, hyperinsulinemia and possible reduction of energy expenditure. Metformin induces anorectic effects, but its role in these patients has not been studied. OBJECTIVE: To compare BMI of patients with HOS before and after treatment with Metformin. METHOD: BMI of 6 children with HOS unresponsive to demonstrable change in lifestyle measures was compared before and after treatment with metformin by converting BMI to BMI standard deviation scores (SDS). Tolerance to metformin was assessed. RESULTS: There were 6 females. [Hypothalamic hamartoma (N 1⁄4 2), craniopharyngioma (N 1⁄4 2), hypothalamic astrocytoma (N 1⁄4 2)]. Treatment included surgery (N 1⁄4 5), primary fractionated radiotherapy (N 1⁄4 1), additional proton beam radiotherapy (N 1⁄4 1) and chemotherapy (N 1⁄4 1). Results are given as median (range). Age at diagnosis was 10.1years (1.3-13.8). Metformin was introduced at 12.5years of age (4.5-18.1). The change in BMI SDS was +0.42/year (+0.06 to +3.6) after 4.3 years (0.2 to 7.1). The change in BMI SDS between commencement of metformin and the final assessment was +0.15/ year (-0.31 to +0.22) after follow up of 1.9 years (1.3-5.4). The rate of change in BMI SDS before and after introduction of metformin is statistically significant (p1⁄4 0.043). CONCLUSION: Use of metformin in addition to lifestyle change is associated with control of obesity in patients with HOS and structural disease where lifestyle change alone was not successful. A prospective study is warranted to rigorously examine its role in this difficult group of patients. Neuro-Oncology 18:iii127–iii134, 2016. doi:10.1093/neuonc/now078.18 #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.

HG-54. THE ROLE OF HIGH-DOSE MYELOABLATIVE CHEMOTHERAPY (HDCT) WITH HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN CHILDREN WITH HIGH GRADE GLIOMAS (HGG) OR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): RESULTS OF A SYSTEMATIC REVIEW Caroline Main1, Madeline Adams2, Katherine Cooper3, Sophie Wilne4, Bob Phillips5, Martin English6, Pamela R. Kearns1,6, Barry Pizer3, Simon P. Stevens1, Keith Wheatley1, and Jayne S. Wilson1; Cancer Research UK Clinical Trials Unit; University of Birmingham, Birmingham, UK; Bristol Children’s Hospital, Bristol, UK; Alder Hey Children’s NHS Foundation Trust, Liverpool, UK; Nottingham University Hospitals’ NHS Trust, Nottingham, UK; UK Centre for Reviews and Dissemination, University of York, UK; Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK OBJECTIVES: To assess the impact of HDCT/HSCT in children with HGG or DIPG. METHODS: Ten electronic databases were searched from 1985 to Oct 2015 for studies assessing HDCT/HSCT in HGG and DIPG. Outcomes included overall survival (OS), response rates (RR), adverse events and treatment related mortality (TRM). Standard systematic review methods were used to minimise bias. RESULTS: For HGG, 167 patients were included, 56% newly diagnosed and 44% relapsed. Mean age was 8.7 years. Mean follow-up was 2.8-years (range: 0.2-5.4). HDCT mainly consisted of one cycle, with preor post radiotherapy (RT) used in 59% of patients. Median OS for newly diagnosed HGG was between 9-14 months (range: 1-65) (n 1⁄4 27), with one and four year OS 73%+13% (n 1⁄4 11) and 43% (n 1⁄4 21) respectively. Overall RR was 30% (n 1⁄4 26). For relapsed HGG median OS was 12.7months (n 1⁄4 18). Across the studies nine TRM occurred. Sixty-two patients with DIPG were included, 68% newly diagnosed and 32% relapsed. Mean age was 6.8-years. Median follow-up was 1.5 years (range: 0.1-7). HDCT consisted of one cycle, with 77% patients receiving prior RT. For newly diagnosed patients with DIPG, median OS was 10-11.4 months (range: 6.4-17.1) (n 1⁄4 42), and for relapsed patients 4.8 months (0.1-18.7) (n 1⁄4 16). Across the studies five toxicity related deaths occurred (8%). CONCLUSIONS: The limited evidence on HDCT/HSCT in children with HGG or DIPG does not allow reliable conclusions to be drawn. However, use of HDCT/HSCT in these patient groups is associated with a significant toxicity profile and TRM. Neuro-Oncology 18:iii48–iii77, 2016. doi:10.1093/neuonc/now073.50 #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.

BACKGROUND: Despite identification of numerous pre-operative cerebellar mutism syndrome (CMS) clinical and radiological predictors, a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. We have previously assembled a cohort of posterior fossa tumour patients and developed a pre-operative risk stratification model using classification algorithms. Our aim is to further develop a preliminary risk-scoring scheme to flag patients at higher risk of post-operative CMS. METHODS: The combined cohort consists of 89 patients from two major treatment centres (age: 2-23yrs, gender 28M,61F, MRI pathology estimate 36 medulloblastoma, 40 pilocytic astrocytoma, 12 ependymoma, 1 non-committal). Post-operative CMS status was ascertained from clinical notes and pre-operative MRI scans, blinded to CMS status, underwent structured evaluation. Multiple logistic regression coefficients for the six predictors selected by decision tree (cerebellar hemisphere invasion, bilateral invasion at middle cerebellar peduncle, dentate nucleus invasion, pathology estimate ependymoma, middle cerebellar peduncle compression and age > 12.4 years) were converted into risk scores. Predicted CMS probability, diagnostic and predictive values were calculated to explore the potential cut-off points. RESULTS: Of the 89 patients, 26 (29%) developed post-operative CMS. Patient's total risk score ranged from -57 to 263, with a greater number being associated with increased risk of CMS. The cut-off with the highest sum of sensitivity and specificity was total score ≥1, with sensitivity 92%, specificity 86%, positive predictive value 73% and negative predictive value 96%. Using cut-off of 0 and 15 allowed separation of the cohort into low (46/89, predicted probability 50%). CONCLUSIONS: A risk stratification model for post-operative CMS could flag patients at increased risk pre-operatively and may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme may be utilised during the surgical consenting process.

Posterior fossa syndrome (PFS), also referred to as cerebellar mutism syndrome (CSM), is a well-recognized complication in children following posterior fossa tumor surgery and was first described by Rekate et al in 1985.1 It is characterized by neurological problems including diminished speech, ataxia, hypotonia, cranial nerve palsies, and emotional lability.2 The incidence of PFS after posterior fossa surgery varies between 11% and 29%.3 Although the symptoms improve with time, many children can exhibit long-term neurological sequelae that impact on the patient, the carer, and the health care provider.4,5 Although surgery is the primary predisposing event, the exact pathophysiology of PFS is not fully understood. Various hypotheses have been proposed, with varying levels of evidence.3 Among various factors that have been implicated in its etiology, interruption of the dento-thalamo-cortical (DTC) pathway and in particular, damage to structures of the proximal efferent cerebellar pathway (pECP) namely the dentate nucleus (DN) the superior cerebellar peduncle (SCP) and the mesencephalic tegmentum (MT) have been well documented in literature.6–10 Surgical damage to the cerebellar vermis has also been implicated in the etiology of PFS.11,12 These abnormalities can be detected on the immediate postoperative MRI, which is usually performed 24–48 hours following surgery. Assessment of postsurgical damage can be challenging on the conventional MRI sequences, namely the T1-weighted, T2-weighted, and the fluid-attenuated inversion recovery (FLAIR) sequence due to multiple factors including mass effect of the tumor on adjacent structures and preexisting peritumoral edema. Diffusion-weighted imaging is sensitive in identifying acute postsurgical changes, but the appearances can vary depending on the timing of the scan and postoperative factors such as hemorrhage and artifacts related to intracranial air. Since October 2009, surgical resection of intracranial tumors has been guided by intraoperative MRI (ioMRI) at our tertiary level pediatric neurosurgical center. During these procedures, the final (preclosure) ioMRI has served as the immediate postoperative MR scan if no further resection had been performed following the scan. Our postoperative MRI protocol includes diffusion-weighted imaging (DWI) or diffusion tensor imaging (DTI) depending on the needs of the patient. In our initial experience with the use of ioMRI, the DWI and DTI data have been useful for identifying surgically induced parenchymal abnormalities that include edema (cytotoxic/vasogenic) and hemorrhage.13,14 The availability of these postoperative scans performed at a uniform time period (immediately following surgery) provides an opportunity to study the association between diffusion abnormalities in children undergoing posterior fossa tumor surgery and the occurrence of PFS. In particular, these scans offer an opportunity for potentially predicting postoperative neurological deficits at the earliest possible time point and prior to any other potentially confounding postoperative events. The aim of this study was to evaluate if diffusion abnormalities on the final ioMRI could predict the development of PFS following posterior fossa tumor resections.

INTRODUCTION: Intra-operative MRI (ioMRI) is increasingly being used by some neurosurgical units to ensure maximal tumour resection and therefore improved outcome. Its use has also extended to other non-oncological neurosurgical procedures. METHOD: We report our ioMRI experience in Alder Hey over a period of 53 months and compare the results with a historical cohort prior to the introduction of ioMRI specifically looking at the group of patients where complete surgical tumour resection was the desired outcome. RESULTS: ioMRI was used in 183 cases since its introduction at Alder Hey. Of these, 143 were debulkings / resections of tumours, 6 biopsies, 1 cyst drainage, 25 epilepsy cases, 7 craniofacial and 1 abscess drainage. Approximately 30% of patients underwent second-look surgery following ioMRI. None have required return to theatre for resection of residual disease. This compares to 14% in the historical cohort prior to availability of ioMRI. There was no increase in morbidity - infection or otherwise - directly attributable to ioMRI. CONCLUSION: The use of ioMRI has proven to be safe and effective at ensuring that the goals of surgery are met and has allowed for an improved service by reducing return to theatre rates.

INTRODUCTION: Arterial spin labeling (ASL) is a MR technique that allows for noninvasive quantification of cerebral blood flow (CBF). This technique, predominately used in research, has seen significant technical developments in the last few years that have led to more clinical applications. Currently, the main MR method used to provide perfusion measures in brain tumours is dynamic susceptibility contrast (DSC). DSC traces the signal changes caused by the transit of a bolus of gadolinium contrast agent. ASL has the advantage of not requiring bolus injection of contrast. We have performed a comparative study of DSC and multi-timepoint ASL in paediatric brain tumours (PBT). METHOD: Data from a total of 19 PBT patients (mean age: 9 ± 5 years; 10 females, 9 males) were included in the analyses for this study. Data used were from first presentation scans performed before any surgical intervention. Comparisons of the quantitative measures of CBF and blood arrival time between the two techniques were carried out to test the feasibility of ASL to provide useful quantification measures of CBF in PBT. RESULTS: DSC measurements of tumour blood flow showed a significant decrease in flow in comparison with normal brain, but this is not seen with ASL. There was a strong correlation between ASL and DSC measures of blood flow in normal brain (r = 0.65, p = 0.009), but not in tumour blood flow (r = 0.33, p = 0.2). CONCLUSION: This study demonstrates the feasibility and potential utility of ASL as a non-invasive technique for measuring blood flow in PBT. However, there is a discrepancy between ASL and DSC measures, that may be due to leakage of gadolinium contrast, reflecting the abnormal characteristics of tumour blood vessels in PBT.

INTRODUCTION: Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) is less than 40%. The Milan Strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed myeloablative high dose chemotherapy (HDC) or maintenance chemotherapy was reported in a study of 33 patients with MMB to improve 3-year OS to 77% (95% CI 61, 93) and 5-year OS to 73% (59, 87). We report the outcomes of patients treated using this strategy in UK centres. METHOD: Questionnaires were sent to all 20 UK paediatric oncology centres to collect retrospective data on treatment delivered, toxicity and survival with the Milan strategy. RESULTS: Between February 2009 and October 2011, 34 patients with MMB in 14 centres fulfilled the entry criteria of the original study. The median age at presentation was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the Milan series. The incidence of grade 3 haematological toxicities with IC and HDC was 83-100%. 16/16 patients who achieved CR by the end of therapy remain alive and in remission but only 3/18 with lesser responses are still alive (p < 0.0001). With follow up of 30-60 months, we estimate 3-year OS of 55% (95% Cl 38, 71). This result is outside the 95% CI of the Milan results and encompasses the historical result of 40%. We did not observe major late neurotoxicity. CONCLUSION: We did not replicate the improved results reported by the Milan group. The reasons could include differences in patient sub-groups and protocol compliance.