bluuebunny/crossref_metadata_2025 huggingface dataset:
MEDB-70. Metabolism mediated radiation resistance in MYC-driven Medulloblastoma
Authors: Veo Bethany , Goodspeed Andrew , Prince Eric , Venkataraman Sujatha , Vibhakar Rajeev
Published: June 2022

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children and demonstrates a high level of heterogeneity. Treatment for MB includes chemotherapy and radiation often resulting in long-term morbidity. MYC-driven MB, are high-risk tumors with poor long-term survival and increased susceptibility to develop recurrent tumors. Recurrent MB is far more aggressive with limited treatment options leading to a 5-year survival rate of 12%. To understand what drives MYC-amplified MB relapse we performed single-cell RNA sequencing of irradiated MB xenograft tumors. We identified an overall enhancement of metabolic activity in radiation-resistant cells. We further observe enhanced wild-type IDH1 and IDH2 expression in two clusters, which coincide with hypoxia and Nestin expression, marking a stem-cell like niche. Stem-like cancer cells are notoriously resilient against radiation therapy. Furthermore, wtIDH1 and IDH2 represent a unique target in radiation-resistant MB which has not previously been identified. Wild type IDH1/IDH2 are more recently shown to promote tumor proliferation and mediate metabolic reprogramming through the production of oncometabolites and substrates that functionally alter chromatin structure and gene transcription. We hypothesized that MYC modulation of wtIDH1/IDH2 facilitates metabolic reprogramming and promotes radiation-resistant cell populations. We show the change in the structural integrity of chromatin altered in radiation-resistant MB by metabolic adaptation and the effect of disrupting IDH1/IDH2 activity. We further compare these results to the chromatin profile of patient primary and matched relapsed MB samples at the single-cell level. We demonstrate that targeting IDH1/2 with chemical inhibitors suppresses MB cell growth. Our results disclose insights into the development of radiation resistance and provide a potential therapeutic target for the treatment of relapsed MYC-MB.
MEDB-84. The French experience of ELP1-related medulloblastomas
Authors: Tauziède-Espariat Arnault , Guerrini-Rousseau Léa , Perrier Alexandre , Torrejon Jacob , Bernardi Flavia , Filser Mathilde , Varlet Pascale , De Carli Emilie , Pagnier Anne , Leblond Pierre , Faure-Conter Cécile , Doz Francois , Bertozzi Anne-Isabelle , Mansuy Ludovic , Willems Marjolaine , Palenzuela Gilles , Entz-Werle Natacha , Bourneix Christine , Hasty Lauren , Delattre Olivier , Blauwblomme Thomas , Beccaria Kevin , Metais Alice , Ayrault Olivier , Chrétien Fabrice , Bourdeaut Franck , Dufour Christelle , Masliah-Planchon Julien
Published: June 2022

Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.
MEDB-86. A re-induction regimen for children with recurrent medulloblastoma
Authors: O'Halloran Katrina , Phadnis Sheetal , Metrock Laura , Friedman Gregory , Davidson Tom , Robison Nathan , Dhall Girish , Margol Ashley
Published: June 2022

Medulloblastoma is the most common malignant brain tumor of childhood. Despite multi-modal therapies, ~30% of patients experience disease recurrence, which portends a poor prognosis. At initial recurrence, intensive chemotherapy may be effective prior to various consolidation therapies including high dose chemotherapy with autologous stem cell rescue or irradiation. We report outcomes for nine children treated at two institutions with the following regimen: cyclophosphamide 1500mg/m2/dose days 1,2; irinotecan 125mg/m2/dose days 1,8; temozolomide 150mg/m2/dose days 1-5, and oral etoposide 50mg/m2/dose days 1-7. Patients received 2-4 cycles based upon disease response and physician preference. The mean time from initial diagnosis to first recurrence was 19 months. After receiving two cycles of therapy, two patients had complete response (CR) and proceeded to consolidation. Of the remaining seven patients, five had partial response (PR) and two had stable disease (SD). Overall response rate was 78% after 2 cycles. Two patients with PR proceeded directly to consolidation with irradiation. Five patients (3 PR, 2 SD) received 2 additional cycles. After four cycles there was one CR, two with minimal residual disease, one SD and one progressive disease (PD). Four patients (44%) are alive with no evidence of disease (NED). One patient died of consolidation-related toxicity but had NED at time of death 28 months from initial recurrence. Five patients developed PD. Two patients died of disease, two are alive with disease, and one is alive with NED after PD and additional therapy. There were no treatment-related deaths. Infection was the most common complication. Five patients had febrile neutropenia and two developed sepsis. One patient required dose reduction for prolonged thrombocytopenia. Peripheral blood stem cell collection was achieved in all patients for whom it was attempted. This re-induction regimen is generally well-tolerated and effective in inducing responses for children with recurrent medulloblastoma.
NFB-09. Treatment of cardiac fibroma in aPTCH1-mutated Gorlin syndrome with medulloblastoma
Authors: Piccolo Gianluca , Verrico Antonio , Trocchio Gianluca , Derchi Maria , Siboldi Alessandra , Stagnaro Nicola , Crocco Marco , Giannatale Angela Di , Ghiorzo Paola , Milanaccio Claudia , Garrè Maria Luisa
Published: June 2022

A 2,5-year-old girl presented vomiting episodes associated with severe motor delay, macrocephaly, and distal hypotonia. Brain MRI showed hydrocephalus and a non-metastatic lesion in the posterior fossa. A pre-operative ECG showed isodifasic T waves in leads V4R and V1, follow-up was recommended. Histology after gross total resection was consistent with Desmoplastic/Nodular Medulloblastoma. At chest X-rays a bifid rib was noted, leading to the diagnosis of Gorlin syndrome (GS; c.3306 + 1G>T in PTCH1). During chemotherapy, ventricular tachycardia (VT) occurred, requiring synchronized electrical cardioversion. An echocardiogram revealed an echogenic mass of the left ventricle free wall, but normal coronaries and ventricular function. Cardiac MRI (CMR) confirmed a 21x40x38mm mass, with eccentric development and intense homogeneous enhancement, indicative of cardiac fibroma (CF). A computed tomography excluded local calcifications. Therapy with amiodarone and beta-blocker was initiated. TREATMENT STRATEGY: priority to chemotherapy vs cardiac surgery; full-dose chemotherapy, preferring drugs with minor cardiotoxicity; administration in ICU under continuous vital parameters and ECG-monitoring. Other three VTs occurred during treatment or anesthesia, resolved after electrical cardioversion (unsuccessful attempts with i.v. adenosine and amiodarone). Lacking specific guidelines concerning CF in GS, a wait-and-see approach was preferred with close tumor follow-up and regular cardiological assessment (ECG, stress-test, Holter monitoring, CMR). No further arrhythmias were recorded in a 10-year-long follow-up and CMR confirmed CF stability. Medulloblastoma has never recurred. PTCH1 variants are rarely associated with medulloblastoma (<2%). Only 3–5% of GS present CF, responsible for arrhythmias in 32%. Being non-regressing, total surgical resection is usually performed (without recurrence), with a 27-year-long median survival. When surgery risk/benefit ratio is not favorable or the patient is paucisymptomatic, the treatment plan remains unclear; probably, a conservative approach under a strict cardiological follow-up can be reasonable. In young children with syndromic medulloblastoma, a routine echocardiogram should be performed to rule out CF.
NFB-13. Rhabdoid Tumor Predisposition Syndrome (RTPS) – Finding Evidence by systematic Analyses
Authors: Nemes Karolina , Bens Susanne , Johann Pascal D , Steinbügl Mona , Gruhle Miriam , Kachanov Denis , Teleshova Margarita , Hauser Peter , Simon Thorsten , Tippelt Stephan , Eberl Wolfgang , Woessmann Wilhelm , Kratz Christian , Abbink Floor , Hernáiz-Driever Pablo , Eyrich Matthias , Sumerauer David , Milde Till , Reinhard Harald , Leipold Alfred , de Wetering Marianne v , Gil-da-Costa Maria João , Ebetsberger-Dachs Georg , Marques Carmen Hernandez , Bauer Nina , Biassoni Veronica , Meneses Clarice Franco , Knirsch Stephanie , Lauten Melchior , Gerber Nicolas U , Chada Martin , Kerl Kornelius , Lemmer Andreas , Heidrun Boztug , Kuhlen Michaela , Furtwängler Rhoikos , Kordes Uwe , Schneppenheim Reiner , Vokuhl Christian , Hasselblatt Martin , Kröncke Thomas , Bison Brigitte , Melchior Patrick , Timmermann Beate , Gerss Joachim , Siebert Reiner , Frühwald Michael C
Published: June 2022

BACKGROUND: Individuals with rhabdoid tumor predisposition syndrome (RTPS1 – SMARCB1, RTPS2 – SMARCA4) have a propensity to develop malignant rhabdoid tumors (MRT). Affected patients typically present < age 12 months with synchronous tumors (SYN) exhibiting an unusually aggressive clinical behavior. Due to the rarity of RTPS, standards for management are evolving. METHODS: Clinical, genetic, and treatment data of 90 patients with RTPS from 16 countries were analyzed (2004 – 2020). Therapy followed the EU-RHAB recommendations. Tumors and matching blood samples were investigated for SMARCB1 and/or SMARCA4 mutations using FISH, MLPA and sequencing. DNA-methylation subgroups were determined using DNA methylation arrays. RESULTS: The median age at diagnosis of 52 girls and 38 boys was 5.5 months (0 – 203). 55.5% (50/90) of patients presented with an atypical teratoid/rhabdoid tumor (ATRT), 23.5% (21/90) demonstrated SYN, and 21% (19/90) extracranial MRT. RTPS1 was present in 84-, RTPS2 in six patients. In 77% (65/84) complete data on SMARCB1 mutational status were generated. Methylation subgroup status was available in 59% (40/68) of ATRT or SYN. The 5-year overall- (OS) and event free survival rates of patients with RTPS1 were 19.8 ± 4.8% and 15 ± 4.2%, respectively. Age < 1 year at diagnosis (10.1±4.3% vs. 46.7±11.1%), presence of SYN (5.3±5.1% vs. 24.8±6%), histological diagnosis (ATRT vs. eMRT/RTK/SYN) (26.8±7.1% vs. 11.9±5.6%), localized disease (34.5±8 vs. 8.3±4.6%), and presence of PGV at C-terminal (33±8.6% vs. 9.4±5.3%) were significant prognostic factors for 5-year OS in univariate analysis. INTERPRETATION: In the largest cohort of patients with RTPS, predictors significant for positive outcome could be detected: age > 1 year, absence of SYN, histological diagnosis ATRT, localized disease and PGV located at C-terminal. In our research project, we aim to characterize the complete pheno- and genotype of patients with RTPS to develop a risk score including surveillance recommendation.
QOL-01. Inflammatory biomarkers and psychological sequela in pediatric brain tumor survivors
Authors: Turner Emily , Johal Sonal , Marshall Gailen , Herrington Betty , Criddle Jannie , Reddy Alyssa , Sukumaran Anju , Hmada Youssef Al , Shiflett James M , Karlson Cynthia
Published: June 2022

BACKGROUND AND AIMS: Pediatric brain tumors are the second most common type of pediatric cancer, and these patients face the worst health related quality of life (HRQOL) outcomes. Adult studies show increased inflammation association with lower HRQOL in adult brain tumor survivors. This relationship has not been explored in pediatric brain tumor survivors (PBTS). We conducted a case-control study to explore the relationship between inflammatory biomarkers and psychological sequela (i.e., sleep disturbance, fatigue, pain, negative affect) in PBTS. METHODS: Survivors aged 7-14 years with a primary brain tumor diagnosis were recruited from UMMC (N=29) and UAB (N=4) between 2016-2019. A control group (N=12) was recruited from UMMC well-child appointments. Parents and children completed self-reported surveys of pain, sleep, fatigue, and mood. The primary aims were to: (1) examine levels of C-reactive protein (CRP) inflammation in PBTS compared to controls (2) examine if higher CRP and SOX2 (from tumor tissue) were associated with psychological sequela. Independent samples T-Tests and spearman correlations evaluated aims. RESULTS: The final sample included 33 PBTS: median age=12.42 years; sex=51.5% female; race=63.6% Caucasian, 33.3% African American; pathologic diagnoses=67% astrocytoma/glioma, 11% medulloblastoma, 6% ependymoma, 12% other. Twelve controls had a median age=11.98 years; sex=41.7% female; race=16.7% Caucasian, 83.8% African American. There were marginal elevations in CRP for PBTS (44%, n=13) compared to controls (13%, n=1) (p=0.06). In PBTS, higher CRP levels were associated with greater parent-reported fatigue (p=0.035), sleep-wake disorders (p=0.017), excessive somnolence (p=0.042) and longer pain duration (p=0.037). From 13 tumor samples, positive SOX2 (69% of samples) was associated with increased parent-reported sleep-wake disorders (p=0.016), excessive somnolence (p=0.036), and both child and parent-reported sleep disturbance (child: p=0.014; parent: p=0.034). CONCLUSIONS: Elevated inflammation in PBTS, up to 9 years post-treatment, is consistently associated with increased sleep disturbance and fatigue. These relationships warrant further investigation in PBTS.
OTHR-03. Oxaliplatin as a hearing-sparing alternative to carboplatin in tandem autologous stem cell transplants in pediatric CNS malignancy
Authors: Cho Soohee , Miller Kristen , Rowley Jacqueline , Sabus Ashley , Winzent-Oonk Shelby , Bray Stacy , Koo Jane , Levy Jean Mulcahy
Published: June 2022

BACKGROUND: Intensive chemotherapy with tandem autologous stem cell transplants (autoSCT) is shown to improve survival for children with CNS malignancy. Platinum-based chemotherapeutic agents in these regimens, mainly cisplatin and carboplatin, have resulted in significant sensorineural hearing loss. Oxaliplatin, a newer platinum-based agent, is considered less ototoxic. Empiric substitution of oxaliplatin for carboplatin in preparative regimens for autoSCT have been tried. However, the survival and ototoxicity outcomes have not been studied. OBJECTIVE: To compare the overall survival and ototoxicity of oxaliplatin versus carboplatin preparatory chemotherapy regimens in children who received tandem autoSCT for treatment of CNS malignancy. METHODS: We performed a retrospective chart review of all pediatric patients with primary CNS tumors who received tandem autoSCT from 2011 to 2018 at Children’s Hospital Colorado. Demographics, clinical outcomes, and medication administration records were extracted from electronic medical records. Hearing evaluations, performed at pre-transplant, after each transplant episode, and at follow-up visits, were reviewed and graded by an audiologist. Comparisons were performed using Fisher’s exact tests and log rank test statistics. RESULTS: 32 pediatric patients with CNS tumors met inclusion criteria. Seven patients received oxaliplatin in place of carboplatin in one or more preparatory regimens. There was no statistically significant difference in overall survival between the two groups (p=0.99). A total of 85 follow-up audiograms were available for assessment, including long-term follow up. Of the 13 audiograms that showed hearing loss, one (8%) had prior oxaliplatin exposure, compared to 18/72 (25%) audiograms without hearing loss had prior oxaliplatin exposure (p=0.28). CONCLUSIONS: Oxaliplatin is effective and well-tolerated when used in lieu of carboplatin in preparatory regimen for autoSCT for pediatric CNS malignancy. This study is limited by its small size. A larger, multi-center study is warranted to confirm oxaliplatin’s safety and effect on survival and ototoxicity in pediatric autoHSCT.
MODL-17. The Childhood Brain Cancer Cell Line Atlas: A Resource for Biomarker Identification and Therapeutic Development
Authors: Daniel Paul , Sun Claire , Koptyra Mateusz , Drinkwater Caroline , Chew Nicole , Bradshaw Gabrielle , Loi Melissa , Shi Claire , Tourchi Motahhareh , Parackal Sarah , Chong Wai Chin , Fernando Dasun , Adjumain Shazia , Nguyen Hoang , Habarakada Dilru , Sooraj Dhanya , Crombie Duncan , Zhukova Nataliya , Jones Chris , Rubens Jeffrey , Raabe Eric , Vinci Maria , Dun Matt , Ludlow Louise , Nazarian Javad , Fletcher Jamie , Ekert Paul , Ziegler David , Loh Amos Hong Pheng , Low Sharon Yin Yee , Monje Michelle , Neeman Naama , Williams Bryan , Resnick Adam , Gough Daniel , Cain Jason , Firestein Ron
Published: June 2022

Cell lines represent the most versatile and widely used models of cancer and, as such, are critical for identifying and advancing new therapies. Strikingly, there is a significant gap in both the number of childhood brain cancer cell lines and their characterisation compared to their adult counterparts. To address this inequity, we established a childhood brain cancer cell line atlas (publicly available at vicpcc.org.au/dashboard) encompassing over 180 childhood CNS-derived cell lines, representing 20 tumour types and 11 molecular subtypes. Cell lines are characterized by whole genome, RNA-sequencing, phospho- and total proteomics, DNA methylation and ATAC-seq analyses. Multi-omic factor analysis revealed distinct lineage-specified classification of our cell line cohort. In parallel, high throughput drug and CRISPR/Cas9 screens were conducted to map the functional dependencies in over 70 childhood CNS cell lines, including 47 paediatric high grade glioma models. These screens identified both lineage and molecular-subtype specific genetic and drug dependencies, underscoring the utility of this wide-scale approach. Machine based learning approaches to predict genotype-phenotype correlations uncovered distinct paediatric-specific biomarkers of growth dependency, highlighting the unique genetic wiring underlying paediatric CNS tumours. Finally, by integrating functional, molecular and drug profiles of paediatric CNS cell lines, we construct a system to prioritize investigation of novel therapeutic target-biomarkers pairs in specific CNS tumour types.
RONC-05. Peri-transplant Radiation Therapy for Young Children Treated with High-Dose Chemotherapy for Primary Brain Tumors
Authors: Milgrom Sarah , Koo Jane , Foreman Nicholas , Liu Arthur , Campbell Kristen , Dorris Kathleen , Green Adam , Dahl Nathan , Donson Andrew , Vibhakar Rajeev , Mulcahy-Levy Jean
Published: June 2022

PURPOSE: The role of peri-transplant radiation therapy (RT) in young children with primary brain tumors is unclear. We characterized our institutional practice patterns and patient outcomes. MATERIALS AND METHODS: The cohort included all patients treated with high-dose chemotherapy for primary brain tumors at our institution from 2011-2017. Rates of local control (LC), progression-free survival (PFS), overall survival (OS), and radiation-associated injury were assessed. RESULTS: Of 37 eligible patients, 29 (78%) received peri-transplant RT at a median age of 4 years. Patients treated with RT were more likely to have metastatic (p=0.0121) and incompletely resected (p=0.056) disease, and to have high-risk histologies including atypical teratoid rhabdoid tumor, nongerminomatous germ cell tumor, pineoblastoma, primitive neuro-ectodermal tumor, glioneuronal tumor and group 3 medulloblastoma. Of those treated with RT, 13 (45%) received craniospinal irradiation (CSI) and 16 (55%) received focal RT. The median CSI dose was 23.4 Gy (IQR: 18-36; boost median 54 Gy [IQR: 53.7-55.8]) and focal RT dose was 50.4 Gy (IQR: 50.4-54.5). Compared to the focal RT group, patients treated with CSI were older (p=0.0499) and more likely to have metastatic disease (p=0.0004). For the complete cohort, at a median follow-up of 3.8 years, the 2-year rate of LC was 82% (95% CI: 70-96%), PFS was 63% (95% CI: 49-81%), and OS was 65% (95% CI: 51-82%). These rates did not differ significantly between patients treated with and without peri-transplant RT. Two cases of fatal myelopathy were observed after spinal cord doses within the highest tertile (41.4 CGE and 36 Gy); both cases occurred in patients who received RT before high-dose chemotherapy. CONCLUSION: Peri-transplant RT was used for high-risk disease. Oncologic outcomes after RT were encouraging. However, 2 cases of grade 5 myelopathy were observed. If used cautiously, RT may contribute to durable remission in patients at high risk of relapse.
RONC-11. Permanent alopecia in pediatric patients with medulloblastoma treated by craniospinal irradiation: looking for a threshold dose
Authors: Satragno Camilla , Verrico Antonio , Giannelli Flavio , Ferrero Alfonso , Cavagnetto Francesca , Schiavetti Irene , Garrè Maria Luisa , Garibotto Federica , Milanaccio Claudia , Ramaglia Antonia , Profio Sonia Di , Belgioia Liliana , Barra Salvina
Published: June 2022

BACKGROUND: Permanent alopecia in adult survivors of childhood cancer is a late effect that has a negative impact on vitality and social function, and it is not clear if it is only associated with radiotherapy or also with high-dose chemotherapy. In this study, we analysed a cohort of medulloblastoma survivors treated with craniospinal irradiation (CSI) with long follow-up looking for radiotherapy parameters associated with permanent hair loss. METHODS: We retrospectively analysed 42 patients with medulloblastoma with median follow up of 10 years. In 27 pts, Eclipse subgroup, the scalp was accurately re-contoured and were estimated specifics dosimetric parameters. Any relationship between presence of alopecia and other characteristics was investigated by univariate and multivariate analysis, in both groups. For each significant predictor variable, a Receiver Operating Characteristic curve was drawn for calculating the Area Under the Curve and identifying the optimal dose discriminatory cut-off value for prediction of alopecia. RESULTS: The best predictor for the occurrence of permanent alopecia was the dose of CSI (OR: 1.002; 95%CI: 1.001-1.003; p=0.003), with a cut-off value of 30.9 Gy. In Eclipse subgroup median Dose hair skin was statistically significant, (OR: 1.216; 95%CI: 1.030-1.435; p=0.021), with a cut-off value of 28.7 Gy. If the median dose of each Gy unit of D median is exceeded, the probability of alopecia increases by 21.6% (3.0% - 43.5%), with a specificity of 90.9%. None of the other variables was statistically significant. CONCLUSIONS: Pediatric Medulloblastoma survivors have a high risk of developing permanent alopecia.Our study supports the finding that permanent hair loss is dose-dependent and identified a threshold dose, the median dose of 28.7 Gy, to prevent the occurrence of permanent alopecia in paediatric patients undergoing radiotherapy. Therefore, we suggest that this dosimetric parameter should be evaluated when planning radiation treatment, especially when planning CSI in low- and standard-risk medulloblastoma.
SWK-03. Neuroimaging in CNS tumours: To GA , or not to GA, that is the question.
Authors: Ryles Jade , Ternent Lisa , Halliday Gail , Hill Rebecca M , Bailey Simon
Published: June 2022

Children with a Central Nervous System (CNS) tumour have frequent magnetic resonance imaging (MRI) scans during their disease trajectory. Younger children routinely have these performed under general anaesthetic (GA) with an associated risk and inconvenience. Our project over a two-year period was to introduce a structured programme to any child over the age of five years old to achieve an MRI scan without the need for a GA. Thirty-six patients took part. The motivation behind this project was to enhance the hospital experience for patients and their families, lessen time spent in hospital and minimise risk. In addition, there was an added incentive of cost saving and increased availability of GA scans for other specialities within the hospital setting. During the COVID pandemic, it has also resulted in a reduction of our patients requiring COVID swabs, and isolation and in turn a reduction in aerosol generating procedures. As part of the structured programme, each child had an initial assessment with the nurse specialist followed by a minimum of one play preparation session with the play specialist. Children were required to demonstrate they could follow simple instructions, engage in social stories and role-play with hospital equipment and specialised resources. During these sessions, the children visited the MRI department where they practiced lying flat on the MRI bed as it moved into the scanner. Over the two-year period, of the total number of MRI scans performed, the amount of MRI scans requiring a GA reduced from 41% to 31%. The quality of the MRI scans was scrutinised and shown not to be significantly affected. In summary, by introducing a structured programme, it is possible to significantly reduce the need for GA in children requiring CNS imaging as part of their tumour journey.
SWK-06. Structured transition from pediatric neuro-oncology to adult survivorship follow-up care - Can we close the gap?
Authors: Krottendorfer Kerstin , Baumgartner Alicia-Christina , Boehm Alexandra , Ziomek Sabina , Peyrl Andreas , Gsell Hannah , Schneider Carina , Rosenmayr Verena , Gojo Johannes Salomon , Azizi Amedeo , Rinner Sarah , Burger Sabine , Huemer Marlene , Pucher Anna , Leiss Ulrike
Published: June 2022

PURPOSE: Advances in treatment have increased survival rates and quality of life of pediatric CNS tumor patients leading to a growing number of long-term survivors. However, there is sufficient clinical and scientific evidence for the need of a highly specialized lifelong follow-up care due to multidimensional late effects. Furthermore, adolescence and young adulthood are challenging age periods when patients frequently get lost to follow-up potentially having severe impact on health and well-being. Since 2020, we have established a structured transfer of long-term survivors older than 18 years to a newly founded highly specialized adult care follow-up setting for childhood cancer survivors (IONA). The aim of this study was to evaluate the current transition process. RESEARCH DESIGN: The standard of care transition process at the neuro-oncology unit of the MUV includes a joint appointment with the patient, a pediatric neuro-oncologist, psychologist and/or social worker and the team of the adult care facility (physician, psychologist). Different elements are used to end care safely in the pediatric structure and building trust in the upcoming out-patient-department at the same time. The transition process was evaluated statistically and analyzed qualitatively with regard to the factors that define a safe transition. RESULTS: After two years (01/2020-12/2021) 114 patients had a joint transition appointment, two patients contacted IONA directly. Shortly after the joint appointment all patients had a scheduled follow-up meeting at IONA. 102 patients (87.9%) showed up, seven patients (6%) already had a planned appointment, two patients (1.7%) were in contact with IONA but had no possibility to show up in person. Only five patients (4.3%) did not attend the appointment and were lost to follow-up. CONCLUSION: A structured interdisciplinary transition concept is a successful option to establish controlled and patient-safe transition from pediatric to adult care setting.
TBIO-01. Mutation Profiling of Paediatric Solid Tumours in a Cohort of South African Patients
Authors: Lamola Lindiwe , Manolas Erin , Krause Amanda
Published: June 2022

BACKGROUND: The incidence of childhood cancer incidence is increasing gradually in low-middle income countries, such as South Africa. Globally, there is an extensive range of familial- and hereditary-cancer syndromes, where underlying germline variants increase the likelihood of developing cancer in childhood. Next-Generation Sequencing (NGS) technologies have been key in determining the occurrence and genetic contribution of germline variants to paediatric cancer development. We aimed to design and evaluate a candidate gene panel, specific to inherited cancer-predisposing genes to provide a comprehensive insight into the contribution of germline variants to childhood cancer. METHODS: 32 paediatric patients (aged 0-18 years) diagnosed with a malignant tumour were recruited and biological samples were obtained. After quality control, DNA was sequenced using an ion Ampliseq 50 candidate gene panel design and Ion Torrent S5 technologies. Sequencing variants were called using Ion Torrent Suite software and were subsequently annotated using Ion Reporter and Ensembl's VEP. High priority variants were manually analysed using tools such as MutationTaster, SIFT-INDEL and VarSome. Putative identified candidates were validated via Sanger Sequencing. RESULTS: The patients studied had a variety of cancers, the most common being nephroblastoma (13), followed by osteosarcoma (4) and astrocytoma (3). We identified 10 pathogenic / likely pathogenic variants in 10 patients, most of which were novel. CONCLUSIONS: According to literature, we expected ~10% of our patient population to harbour pathogenic or likely pathogenic germline variants, however we reported about 3 times (~30%) more than we expected. Majority of the identified variants are novel; this may be because this is the first study of its kind in an understudied South African population
TBIO-12. Screening for Cancer Predisposition Syndromes in Pediatric Neuro-Oncology Patients: a Single Institution Experience
Authors: Johns Claire , Kline Cassie , Solomon David , Mueller Sabine , Banerjee Anu , Gupta Nalin , Reddy Alyssa
Published: June 2022

BACKGROUND: Traditional screening for cancer predisposition syndromes centers on family history, phenotypic features, and tumor histology. With expanded accessibility of next generation sequencing, identification of de novo germline mutations is increasing and the predictive value of family history has become less clear. While identification of germline mutations often affects care of pediatric neuro-oncology patients, germline sequencing is not currently standard of care. We hypothesize that routine screening for germline mutations in pediatric neuro-oncology patients reveals unsuspected cancer predisposition syndromes and impacts care. METHODS: A retrospective analysis was performed on pediatric neuro-oncology patients at a single institution who had targeted next generation sequencing of approximately 500-cancer associated genes (UCSF500) on tumor and paired germline DNA. We determined the proportion of patients with germline mutations and assessed impact on future screening and current tumor treatment. We interrogated clinical notes, family history, and interviewed treating physicians to determine if predispositions were previously suspected. RESULTS: Between June 2015-December 2019, 187 patients had paired testing; of these 29 (16%) harbored germlines mutations that were pathogenic or likely pathogenic. Germline mutations were found in patients with high-grade glioma (n=12), low-grade glioma (n=7), medulloblastoma (n=4), ATRT (n=2), and choroid plexus papilloma (n=1). Known cancer predisposition syndromes were identified or confirmed in 18 patients. Of these, the most common alterations were in TP53 (n=6), CHEK2 (2), NF1 (n=2), SMARCB1 (n=2), and PTEN (n=2). Patients were referred to genetic counseling in 26 cases and malignancy screenings were implemented in 25 cases. Germline findings affected malignancy treatment in 10 cases, most often through use of targeted therapeutics or avoidance of radiation. CONCLUSIONS: In our series, we found that 16% of pediatric neuro-oncology patients harbored germline mutations, the majority of which were associated with cancer predisposition syndromes. These results support standardizing screening for pathogenic germline mutations in pediatric neuro-oncology patients.
INSP-01. What to do when you cannot randomize? Leveraging Historical Data in Efficient Study Designs for Pediatric Neuro-Oncology.
Authors: Onar-Thomas Arzu
Published: June 2022

BACKGROUND: Randomized phase III studies represent the gold standard in clinical trial design for many good reasons. They control bias and the effects of known and unknown covariates on outcomes of interest. Recent examples from Children’s Oncology Group Medulloblastoma studies have demonstrated their utility in providing insights that likely would not have been possible otherwise. However, experience with these trials also reaffirmed that large, randomized studies often take too long to keep up with the ever-changing landscape in pediatric Neuro-Oncology, and the rarity of these tumors is a significant barrier in utilizing such designs effectively. METHODS: Recent global efforts in pediatric Neuro-Oncology have led to rich, well annotated repositories that contain patient-level data. While these data suffer from the well-known limitations when used as sole comparison cohorts for ongoing studies, they also offer an opportunity to design more efficient studies in ultra-rare patient populations that trialists in pediatric neuro-oncology often face. Therefore, there is renewed effort in the statistical community in devising methodologies that can effectively utilize external data in the design of prospective studies. These approaches include incorporating external data as a supplement to a small fraction of patients randomized to standard of care arms and prospectively assessing similarity with an intent to minimize overall sample size. Others focus on patient selection methodologies from external controls with an intent to optimize matching between the retrospective and prospective cohorts to control for known covariates. Additional considerations include incorporating arms into the study that retain standard of care treatments to capture the magnitude of drift in outcome over time due to improved supportive care.

CONCLUSIONS: While there are important limitations to designs based on external controls, judicious choice of design parameters and careful selection of controls could provide a viable alternative when rarity of patient populations make randomized designs infeasible.
INSP-02. WHO 2021 classification of CNS tumors
Authors: Wesseling Pieter
Published: June 2022

In line with recommendations of the cIMPACT-NOW consortium, the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5 classification) is substantially different from the previous (revised 4th) edition. Salient changes include the separation of pediatric-type low- and high-grade diffuse gliomas from adult-type diffuse gliomas, refinement of the classification of ependymal tumors, and the addition of a newly recognized embryonal CNS tumors. Furthermore, for some tumors the name was changed. For example, diffuse midline glioma (DMG), H3K27M-mutant is now DMG, H3K27-altered (because there are H3-wildtype DMGs that do show loss of nuclear H3K27me3 staining and with a similar prognosis as DMGs, H3K27M-mutant), and supratentorial ependymoma, RELA fusion-positive was changed into ZFTA fusion-positive (as ZFTA (‘zinc finger translocation associated’, the new name for c11orf95) is the more frequent fusion partner in these tumors). The WHO CNS5 tumor classification certainly is an improvement, but it brings several (new) challenges as well. For example, for more CNS tumors it is now impossible to reach a state-of-the-art ‘histomolecular’ diagnosis in case molecular tools for assessment of essential diagnostic characteristics are not available. In those situations, adding NOS (not otherwise specified) to the histology-based diagnosis is the way to go. Furthermore, designing the optimal therapeutic management for newly defined tumor types is challenging. And while a more precise classification facilitates enrollment of more homogeneous populations of patients in clinical studies, the higher granularity of CNS tumor taxonomy makes it more difficult to perform studies on a large number of patients for particular tumor types. Still, one would like to think that patients suffering from a CNS tumor are better served by a more precise diagnosis because this allows for a better estimation of prognosis and, hopefully sooner than later, for a more tailored and effective therapeutic approach.
INSP-03. Neuronal regulation of glioma progression
Authors: Monje Michelle
Published: June 2022

The nervous system regulates stem and precursor cell behavior across a range of tissues. In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity regulates initiation and promotes progression of gliomas in preclinical models. Crucial mechanisms mediating activity-regulated glioma progression include secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. NLGN3 is necessary for the growth of gliomas in a range of preclinical models, and therapeutic targeting of NLGN3 is presently under clinical investigation. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.
INSP-06. Recent advances in improving neuropsychological outcomes for paediatric brain tumour patients - Are we entering a new era?
Authors: Mabbott Donald
Published: June 2022

Children and youth treated for brain tumours can sustain a brain injury as a consequence of the tumour and curative therapy leaving them with significant cognitive challenges. Advances in treatment for paediatric brain tumours – particularly the delivery of radiotherapy – have been associated with improved neuropsychological outcome in survivors, however. This presentation will first focus on work documenting the impact of changes in cranial radiotherapy delivery and modality on neuropsychological late effects in children treated for medulloblastoma. Outcomes in patients treated on modern protocols are substantially improved relative to prior therapy, however challenges remain. Second, novel approaches for cognitive recovery and brain repair in survivors of paediatric brain tumours will be discussed, with a focus on novel approaches for fostering endogenous neuroplasticity for cognitive recovery and brain repair in children and youth treated for paediatric brain tumours.
INSP-11. Patient-centered monitoring and care of cognitive late effects in pediatric brain tumor survivors with and without Cerebellar Mutism Syndrome (CMS).
Authors: Walsh Karin , Sady Maegan , Tiplady Kaitlyn , van Scoyoc Shawna , Weisman Hannah , Hardy Kristina
Published: June 2022

Risks of cognitive late effects in children with brain tumors is well-established. However, group heterogeneity may limit generalizability and result in inadequate neurocognitive monitoring and care. Children with CMS have unique long-term cognitive risks and current knowledge may not adequately describe their experience or needs. The establishment and implementation of patient-centered, empirically-derived assessment of cognitive change following tumor diagnosis and treatment is a novel, precision-based approach to patient care. METHODS: 30 patients diagnosed with posterior fossa tumor who had at least 2 neuropsychological evaluations were included. Primary outcomes were processing speed (Wechsler PSI) and working memory (WMI). Secondary outcomes were verbal and nonverbal intellect. Reliable change indices (RCIs) were computed (Chelune et al., 1993). Using an 80% CI, 10% would be expected to decline, while 90% would stay stable or improve. RESULTS: Mean age in the full sample was 9.2 (3.32) years at T1 and 13.0 (4.11) years at T2, with an average of 2.7 (2.58) years between assessments. Males made up 56.7% of the sample. Five of the 30 (17%) were CMS+. The CMS+ patients were similar in age to CMS- patients, were predominantly male (80%), and mostly received photon radiation (60%). The full sample showed greater prevalence of declining verbal (21%), spatial (58%) and working memory (29%) functions than the expected (10%). The CMS+ group had higher rates of processing speed (50% v. 7%) and working memory (50% v. 27%) declines than the CMS- group. In contrast, the CMS- group appeared to show more prevalent declines in spatial reasoning than the CMS+ group (67% v. 33%). CONCLUSIONS: There appear to be unique domains impacted in the CMS+ group, which can convey specific long-term outcomes specific to this subgroup of patients. These results highlight the utility of individualized, empirically-driven analysis of change in cognitive functioning in this patient population.
INSP-12. Molecular architecture of the human brain and brain cancer
Authors: Linnarsson Sten
Published: June 2022

Single-cell gene expression analysis has revolutionized biomedical research, leading to comprehensive atlases of human tissues, insights into development and homeostasis and allowed highly multiplexed perturbations with cell type specificity. Here, I present our comprehensive single-cell atlas of the human nervous system, both in development and in the adult. We describe unexpected regional diversity among human glial cell types, with implications for regions-specific glial brain disease. However, in single-cell analysis, spatial context is lost, complicating the analysis of cell-cell interactions, spatial gradients and patterns of cell distribution. Spatial methods of gene expression analysis have therefore increased in importance, and are currently a very active are of research and development. We have developed a scalable and highly multiplexed method of spatial gene expression analysis based on electrophoretic capture of mRNA. I showcase its throughput and robustness by presenting complete spatial atlases of the adult mouse brain, as well as the whole developing human head at 7 weeks post-conception. Furthermore, I will discuss our ongoing work to apply these methods to human glioblastoma in order to reveal the spatial architecture of this devastating tumor.
INSP-13. Malignant networks in brain tumors: from basic discoveries to clinical implications
Authors: Winkler Frank
Published: June 2022

Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for early brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma progression (Venkataramani et al., Nature 2019). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed.