bluuebunny/crossref_metadata_2025 huggingface dataset:
MEDB-58. Risk factors and risk prediction models for medulloblastoma recurrence
Authors: Li Juan , Lai Mingyao , Cai Linbo
Published: June 2022

BACKGROUND: There is a clear need for systematic appraisal of models/factors predicting medulloblastoma recurrence because clinical decisions about adjuvant treatment are taken on the basis of such variables. METHODS： A total of 273 patients diagnosed with medulloblastoma were retrospectively analyzed. The pre-rediotherapy neutrophile-lymphocyte ratio (NLR) was calculated, and other clinical characteristics were collected such as genetic type , whether with dissemination, degree with excision. The Kaplan-Meier method was used for survival analysis. Cox regression models was used to identify independent prognostic factors. R software was used to develop a nomogram with all the independent prognostic factors included. The prognostic predictive ability of the nomogram was evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. RESULTS: The median median progression-free survival time was 63.8 months in overall cohort. Univariate and multivariate cox hazards regression analysis identified independent prognostic factors associated with the PFS of patients with medulloblastoma to include age, residual tumor volume ＞1.5cm3 after excision, NLR ＞4.5, whether with dissemination before RT, and whether the genetic type is group 3,which were integrated to establish a nomogram. The C-indexes of nomogram were 0.696 and 0.676 in the training and validation cohort, respectively. The AUC of predicting 3-years PFS showed satisfactory accuracy as well (Training cohort: AUC=0.696; Validation cohort: AUC=0.676). The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the PFS showed significant differences between nomogram predictive low-, and high groups (P < 0.001). CONCLUSIONS: We found that pre-treatment NLR was an independent prognostic factor for recurrence or metastasis of medulloblastoma after treatment. In combination with NRL and clinical factors, nomogram has a good prediction of PFS in patients with medulloblastoma after radiotherapy. It has the potential to facilitate more precise risk stratification to guide personalized treatment of medulloblastoma.
MEDB-62. Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation
Authors: Chen Zhuoyao , Ioris Rafael , Richardson Stacey , Van Ess Ava , Vendrell Iolanda , Kessler Benedikt , Buffa Francesca , Busino Luca , Clifford Steven , Bullock Alex , D'Angiolella Vincenzo
Published: June 2022

Genomic studies in medulloblastoma have identified distinct disease subgroups: wnt/wingless (WNT), sonic hedgehog (SHH), and non-WNT/non-SHH, comprising group 3 and group 4. Alterations in WNT and SHH signalling form the pathogenetic basis for their subgroups, whereas those for non-WNT/non-SHH tumours remain largely elusive. Recent analyses have revealed recurrent in-frame insertions in the E3 ubiquitin ligase adaptor Kelch Repeat and BTB Domain Containing 4 (KBTBD4) in cases of group 3 and group 4 medulloblastoma. Critically, group 3 and 4 tumours with KBTBD4 mutations typically lack other gene-specific alterations, such as MYC amplification, indicating KBTBD4 insertion mutations as the primary genetic driver of these malignancies. Delineating the role of KBTBD4 mutations in medulloblastoma thus offers significant opportunities to understand its pathogenesis and exploit underpinning mechanisms therapeutically, however their function is currently unknown. Here, we show a novel mechanism in cancer pathogenesis whereby indel mutations in KBTBD4 drive its recognition of neo-substrates for degradation. We observe that KBTBD4 mutants promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. The degradation of CoREST promoted by KBTBD4 mutations diverts epigenetic programmes inducing significant alterations in transcription to promote increased stemness of cancer cells. Transcriptional analysis of >200 human group 3 and 4 medulloblastomas by RNA-seq, highlights the presence of CoREST and stem-like signatures in tumours with KBTBD4 mutations, which extend to a further sub-set of non-mutant tumours, suggesting CoREST alterations as a novel pathogenetic mechanism of wide relevance in group 3 and 4. Our findings uncover KBTBD4 mutation as a novel driver of epigenetic reprogramming in non-WNT/non-SHH medulloblastoma, establishes a novel mode of tumorigenesis through gain-of-function mutations in ubiquitin ligases (neo-substrate recruitment) and identifies both mutant KBTBD4 and CoREST complexes as new druggable targets for improved tumour-specific therapies.
MEDB-78. Unified rhombic lip origins of Group 3 and Group 4 medulloblastoma
Authors: Smith Kyle , Bihannic Laure , Gudenas Brian , Gao Qingsong , Haldipur Parthiv , Tao Ran , Iskusnykh Igor , Chizhikov Viktor , Scoggins Matthew , Zhang Silu , Edwards Angela , Deng Mei , Glass Ian , Overman Lynne , Millman Jake , Sjoboen Alexandria , Hadley Jennifer , Mankad Kshitij , Onar-Thomas Arzu , Gajjar Amar , Robinson Giles , Aldinger Kimberly , Hovestadt Volker , Tillman Heather , Orr Brent , Patay Zoltán , Millen Kathleen , Northcott Paul
Published: June 2022

Identification and characterization of lineage-specific beginnings of distinct medulloblastoma (MB) subgroups is a fundamental challenge in the field. Genetically engineered mouse models and cross-species transcriptomics have provided mounting evidence of discrete, subgroup-specific developmental origins. Likewise, murine single-cell transcriptional atlases of cerebellar development have recently provided further clues into MB subgroup origins, particularly for poorly defined Group 3 and Group 4-MB. However, initial studies were underpowered to characterize rare populations and lacked robust validation, resulting in incomplete findings. Herein, we leveraged a large harmonized murine cerebellar atlas, targeted lineage enrichment, and integrative multi-omic strategies to deeply dissect MB origins. Isolation of spatially and temporally discrete developmental trajectories of key glutamatergic lineages born out of the murine upper rhombic lip provided an enhanced reference for mapping MB subgroup origins, especially for Group 3 and Group 4-MB. However, human-specific anatomic and cellular complexity, particularly within the rhombic lip germinal zone complicated murine-derived inferences. Further tumor-normal integrations using a novel single-cell atlas of the human fetal cerebellum, companioned with laser-capture micro-dissected transcriptional and epigenetic datasets, reinforced developmental insights extracted from candidate murine cerebellar lineages. Characterization of compartment-specific transcriptional signatures identified in the human upper rhombic lip implicated convergent cellular correlates of Group 3 and Group 4-MB, suggestive of a common developmental trajectory underlying their ancestry. Systematic imaging review and 3D summarization of a large clinical trial series of patient tumors, coupled with our advanced insights into developmental signatures, substantiated subgroup-specific tumor location patterns observed at diagnosis. Together, our results strongly implicate a common lineage trajectory of the upper rhombic lip as the probable origin of Group 3 and Group 4-MB. These important findings provide unprecedented opportunities to explore context-dependent mechanisms of MB pathogenesis and will foster generation of improved preclinical models that more faithfully recapitulate tumor biology.
QOL-06. What impact does a posterior fossa tumor in childhood have on motor procedural learning? Group performance depending on radiotherapy status and individual differences on a perceptivo-motor sequence learning task and a motor adaptative task (IMPALA prospective study)
Authors: Baudou Eloïse , Pollidoro Lisa , Tallet Jessica , Danna Jérémy , Pariente Jérémie , Chaix Yves , Laprie Anne
Published: June 2022

INTRODUCTION: Procedural memory (PM) is a skill learning system that allows, through training, the automatization of procedures and progressive improvement of performances. The aim of this work was to explore the impact of a posterior fossa tumor (PFT) on PM. We hypothesized that motor adaptation, depending on cortico-cerebellar system, was impaired in PFT survivors treated with and without radiotherapy, and motor sequence learning, depending on cortico-striatal system, was only impaired in PFT treated with radiotherapy. METHODS: We investigated PM in 60 participants from the IMPALA study (NCT04324450) divided into three groups: 39 cured from a PFT in childhood (22 irradiated (PFT+RT group) and 17 non-irradiated (PFT group)) and 21 healthy volunteers (Control group) matched on age, sex and handedness with the PFT+RT group. We used a visuo-motor learning test, the Serial Reaction Time task (SRTT) and a motor adaptation task (MAT) of backwards handwriting. ANOVA and mixed models were used for statistical analysis. RESULTS: SRTT performance analysis showed an effect of Block in specific sequence learning (F(1)48.70,p<0.001) with a preserved specific learning in the three groups. However individual differences were observed with 7/22 patients in PFT+RT group and 4/17 in PFT group who did not have specific learning. MAT performance analysis showed an effect of interaction between Orientation (forward or backward) and Group for speed (F(2)15.58,p<0.001), linearity (F(2)8.39,p<0.001) and amplitude standard deviation (F(2)15.70,p<0.001) traducing an impairment both in PFT+RT and PFT groups, more marked in the PFT+RT group. CONCLUSION: We showed impairment, predominantly on motor adaptation but also, at individual level, in motor sequence learning whose origin requires additional work. This study brings new insights on the long-term impact of a PFT in childhood on a rarely investigated part of memory that is PM.
SURG-07. The impact of early targeted therapy on the neurosurgical approach to pediatric low-grade glioma
Authors: Piatelli Gianluca , Pavanello Marco , Piccolo Gianluca , Rossi Andrea , Garrè Maria Luisa , De Marco Patrizia , Iurilli Valentina , Antonelli Manila , Gaggero Gabriele , Caruggi Samuele , Verrico Antonio , Crocco Marco , Milanaccio Claudia
Published: June 2022

We report two cases of pediatric low-grade glioma (pLGG) treated with vemurafenib, an oral BRAF-inhibitor: a 12-year-old girl with involvement of basal ganglia, hypothalamus, and diencephalic junction; a 3-year-old boy, with an optic pathway/hypothalamic glioma extending along the left optic tract and basal ganglia. Both received a biopsy and molecular analysis was performed in the girl’s tumor, showing BRAF V600E mutation. Therefore, instead of surgical removal planned by neurosurgeons, first-line treatment with vemurafenib was started: after one month 45% reduction of the mass according to RANO criteria was found, as well as better balance control and strong reduction of the right arm paresis; five months later, a 70% shrinkage was detected, stabilized to 76% after a year. The young boy first started chemotherapy with vincristine and carboplatin, but at the end of the induction phase the tumor had increased and ascites, hydrocephalus, and visual impairment occurred. Molecular testing showing BRAF V600E mutation on the initial tumor biopsy was obtained; therefore, the surgical option was postponed and therapy with vemurafenib started. After only three days, visual acuity and muscle tone improved; brain MRI showed a 34% reduction of the mass after one week, increased up to 65% after six months. Therefore, no ulterior surgery was necessary. In pLGG, the neurosurgical biopsy is essential to let an early and rapid molecular diagnosis of BRAF mutations and guide subsequent targeted therapies. Our cases demonstrate how a prompt radiological response to vemurafenib and the related clinical improvement can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae. To our knowledge, this is the first report assessing such a quick shrinkage in pLGG treated with vemurafenib, highlighting the importance of an early investigation of BRAF status in all cases of LGG in children.
OTHR-08. Pediatric Neurologic Assessment in Neuro-oncology (pNANO) Scale: A tool to assess neurologic function for Response Assessment in Neuro-oncology (RAPNO)
Authors: Malbari Fatema , Erker Craig , Driever Pablo Hernáiz , Pillay-Smiley Natasha , Avery Robert A , Castellino Robert Craig , Schouten-van Meeteren Antoinette A Y N , Lenzen Alicia C , Brandsma Rick , Kramer Kim , Baxter Patricia A , Dhall Girish , Goldman Stewart , Wen Patrick Y , Prados Michael , Packer Roger J , Warren Katherine E , Nayak Lakshmi
Published: June 2022

Background: The Neurologic Assessment in Neuro-Oncology (NANO) scale, a standardized metric to objectively measure neurologic function in adult brain tumor patients, complements radiographic assessment in evaluating outcomes of neuro-oncology patients in clinical trials and clinical practice. Currently, there is no standardized measure for neurologic function in pediatric neuro-oncology patients despite their distinct clinical presentations and tumor locations. Therefore, we developed a dedicated pediatric NANO (pNANO) scale. Methods: An international group of pediatric neurologists and adult and pediatric neuro-oncologists convened bi-weekly over 5 months to draft the pNANO scale as an objective and quantifiable measure of neurologic function in children that can be administered during routine examination by pediatric-trained providers of any sub-specialty and be utilized together with other indicators to assess response in clinical trials. Results: Ten relevant domains of neurologic function were identified based on common pediatric brain tumor locations: gait, strength, cerebellar function, visual fields, visual acuity, facial strength, level of consciousness, extraocular movements, dysarthria and dysphagia. For each domain, developmental age appropriate levels of function were defined and categorized. Each domain, based on direct observation and testing during any routine neurological exam, can be used for longitudinal monitoring. Conclusions: The pNANO scale has been developed and aims to provide an objective metric of neurologic function for pediatric brain tumor patients. This scale will be tested for reliability, feasibility and inter-observer variability. Consistent evaluation of neurologic function using pNANO along with radiographic assessment will enable more comprehensive and standardized response assessment in pediatric neuro-oncology patients enrolled in clinical trials.
OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
Authors: Keck Michaela-Kristina , Sill Martin , Wittmann Andrea , Kumar Piyush Joshi , Stichel Damian , Sievers Philipp , Wefers Annika K , Roncaroli Federico , Hayden James , McCabe Martin G , Kranendonk Mariëtte E G , Zapotocky Michal , Vasiljevic Alexandre , Schüller Ulrich , Sturm Dominik , Blattner-Johnson Mirjam , von Deimling Andreas , Korshunov Andrey , Sahm Felix , Perry Arie , Solomon David , Pfister Stefan , Jones David T W
Published: June 2022

Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with copy number and RNAseq analysis, we identify a rare, novel pediatric CNS tumor type (n=32) which is characterized by focal high-level amplification and consecutive overexpression of one of the PLAG family genes – PLAGL1 or PLAGL2. It is epigenetically divergent from other known tumor types such as high-grade gliomas, medulloblastomas, embryonal tumors, or CNS sarcomas. The wide range of original histopathologic diagnosis rendered attests to their polyphenotypic nature in terms of morphology. We suggest that these tumors may arise from early to intermediate neural progenitor cells with some neuronal commitment. Using ChIPseq data, we show that both PLAGL1 and PLAGL2 act as transcription factors for: i) the oncogenic kinase RET, a potential drug target, that was overexpressed in our cohort; ii) components of the Wnt/β-Catenin pathway; iii) a set of imprinted genes, reported to regulate the imprinted gene network in mouse models, that was deregulated in the PLAGL-amplified tumors. Consequently, a 250-gene expression PLAGL-signature indicated dysregulation of imprinting control and differentiation/development as a prominent feature. We report differences regarding age and sex distribution between PLAGL1- and PLAGL2-amplified tumors and shed light on differences in clinical behavior and outcomes between these subtypes in male and female patients. PLAGL1-amplified tumors were more prevalent in school-age children and teenagers, while PLAGL2-amplified cases occurred in very young patients. Kaplan-Meier analysis showed a trend towards a more favorable outcome in patients with PLAGL1-amplified tumors and in female patients. Survival rates remained constant after 5 years with a five-/ten-year overall survival of 75% for PLAGL1, 24% for PLAGL2, 18% for male patients, and 88% for female patients.
LINC-21. PROGNOSTIC FACTORS AND SURVIVAL OF LOW-GRADE GLIOMAS IN CHILDREN AND ADOLESCENTS – A MULTICENTER STUDY IN PERU
Authors: Diaz-Coronado Rosdali , Hernández-Broncano Eddy , Casavilca-Zambrano Sandro , Campos-Sanchez Danny , Maza Ivan , Tello Mariela , Leon Esmeralda , Cañari Hernan , Custodio Javier , Ojeda-Medina Luis , Negreiros Tatiana , Cordova Olga , Mora-Alferez Pamela , Garcia-Leon Juan , Vasquez Liliana , Moreira Daniel , Qaddoumi Ibrahim
Published: June 2022

BACKGROUND: Low-grade gliomas (LGG) are the most common central nervous system (CNS) tumors in children. Peru is an index country for the Global Initiative for Childhood Cancer (GICC). As part of the Initiative, a multidisciplinary brain tumor team was formed in 2020 that includes five national reference centers: National Institute of Neoplastic Diseases, National Children’s Health Institute-San Borja, National Children’s Health Institute-Breña, Edgardo Rebagliati Martins National Hospital and Guillermo Almenara Irigoyen National Hospital. This multicenter study sought to evaluate the survival and prognostic factors of patients younger than 18 years diagnosed with LGG, an index cancer for the GICC. METHODS: A retrospective study included all patients diagnosed with LGG in the five centers between 2014 and 2018. We analyzed clinical characteristics, histology, and treatment modalities. We used the Kaplan-Meier method for survival. RESULTS: 194 patients were registered; 136 patients were included. M/F ratio was 1.2, mean age 7 years old. The most frequent location was infratentorial (42.2%), supratentorial (34.9%), optic/chiasm/sellar (11%) and brainstem (11.9%). The most frequent histological types were pilocytic astrocytoma (61%), diffuse astrocytoma (10.3%), oligodendroglioma (5.2%), and other low-grade neoplasms (23.5%). Surgery was performed in 109 patients (83.2%). Chemotherapy alone was used in 17 (12.5%), while radiotherapy in 20 (14.7%). Overall survival at 5 years was 82.9% (95% CI 73.3 - 89.4). Age younger than 3 years (p=0.002), diffuse histological type (p=0.04), and location in the brainstem (p=0.001) were factors associated with a worse prognosis. CONCLUSIONS: Within the framework of the GICC, this work is one of the first steps to understand the current context of pediatric CNS tumor care in Peru. Although the reported survival rate is about the GICC goal of 60%, further improvements in care are needed to increase survival to level closer to high-resource setting and decrease long term morbidity.
MODL-15. High-throughput combination drug screening identifies synergism between retinoic acid treatment and BCL-XL-inhibition in MYC(N)-driven medulloblastoma and neuroblastoma models
Authors: Seiboldt Till , Zeiser Constantia , Salem-Altintas Rabia , Nguyen Duy , Holland-Letz Tim , Peterziel Heike , Witt Olaf , Oehme Ina
Published: June 2022

PURPOSE: Despite remarkable improvements in childhood cancer survival, certain high-risk entities including malignancies of the nervous system still carry dismal prognoses. Retinoic acid (RA) treatment has long been administered in high-risk neuroblastoma patients and preclinical data suggest a benefit in applying retinoids in selected brain tumor entities. However, limited single-agent efficacy and developing treatment resistance provide a rationale for investigating improved combination treatments. METHODS: We assessed the RA sensitivity of 16 cell lines and patient-derived cultures of pediatric nervous system tumors from the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) registry. Bulk RNA sequencing was performed for five sensitive models undergoing RA treatment. All models were screened for drug sensitivity to 76 clinically relevant drugs alone and combined with RA. Beneficial hit combinations were further investigated for synergy, as well as their effect on differentiation and apoptosis by high-content fluorescence microscopy and caspase activity assay. Results from in vivo experiments are pending. RESULTS: Group 3 medulloblastoma and high-risk neuroblastoma models were most sensitive to RA treatment leading to significant changes in gene expression of apoptotic regulation. Drug sensitivity screening revealed similar patterns of response to combination treatments in MYC-driven Group 3 medulloblastomas and MYCN-amplified neuroblastomas. Apoptosis regulating BCL-XL-inhibitors (A-1155463, navitoclax) were identified as top hits across RA sensitive models, whereas epigenetic BET family inhibitor I-BET151 and histone deacetylase inhibitor entinostat suggested entity-specific combination benefits in neuroblastoma and medulloblastoma models, respectively. In both entities, combining RA with navitoclax was synergistic and significantly increased caspase-3 activity. The combination led to a morphological shift from differentiation under RA treatment to cell death. CONCLUSION: Exploring combinations for RA treatment in pediatric nervous system tumors, we found that MYC(N)-driven medulloblastoma and neuroblastoma not only share responsiveness to RA treatment, but also demonstrate enhanced vulnerability in combination with BCL-XL-inhibition resulting in increased apoptosis.
MODL-20. Metabolic rewiring support the onset of chemotherapy resistance in medulloblastoma
Authors: Bortolozzi Roberta , Mariotto Elena , Rampazzo Elena , Manfreda Lorenzo , Marchioro Chiara , Rruga Fatlum , Persano Luca , Viola Giampietro
Published: June 2022

Medulloblastoma (MB) is the deadliest brain tumor of childhood, intrinsically characterized by fast growth, high invasiveness, and resistance to treatments. With the aim to deepen the molecular basis of MB aggressiveness and recurrence, we established an in vitro model of MB resistance to chemotherapy, in which, a weekly exposure to a cocktail of chemotherapeutics commonly used in MB treatment (Vincristine, Etoposide, Cisplatin, Cyclophosphamide – VECC) induces the selection of cells that progressively acquire resistance to subsequent VECC treatments. Preliminary data on our model of MB resistance show that resistant cells induce the activation of the two main regulator of pentose phosphate pathway TKT and G6PD via the activation of Nrf2 transcriptional activity. Moreover, resistant cells show an increase in hypoxia inducible factor-1α (HIF-1α) together with an augmented expression of glycolytic enzymes HK1, PFKB-3, PDK1 and LDHA and increased glycolytic capacity. Interestingly, enrichment analysis on label free mass spectrometry data reveal that the most significant terms deriving from the upregulated proteins, that characterized resistant cells, were related to metabolic processes such as “carbon metabolism”, “fatty acid beta oxidation”, “tricarboxylic acid cycle” and “carboxylic acid catabolic processes”.Consistently with recent studies that highlight the relevance of metabolic plasticity of cancer cells in chemotherapy adaptation, our data suggest a metabolic uncoupling in which MB resistant cells, through the alteration of peculiar metabolic processes, may satisfy their altered energetic demands through alternative metabolic pathways. In this way, the generation of a new balance of intracellular metabolites finally provide increased resistance to external insults (i.e., chemotherapeutics) and a greater ability of detoxifying the intracellular compartments.
MODL-31. Novel in vivo models of post-radiation recurrent pediatric high-grade glioma show increased susceptibility to MAPK inhibition
Authors: Knox Aaron , DeSisto John , Nelson-Taylor Sarah , Coleman Philip , Van Court Benjamin , Donson Andrew , Karam Sana , Green Adam
Published: June 2022

BACKGROUND: Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer mortality, with median survival of less than one year. The standard of care for pHGG includes radiation therapy (RT), but almost all patients who respond initially relapse with aggressive, radiation-resistant disease. Matched primary/recurrent models and effective therapies for recurrent pHGG have not been adequately developed. METHODS: Orthotopic patient derived xenograft (PDX) models of radiation-resistant pHGG were developed by implanting BT245 (H3K27M) and HSJD-GBM-001 (GBM1, H3-wt) cells into mice. Resultant tumors were irradiated at 8Gy (4Gy x 2d) and allowed to regrow. Recurrent, radiation-resistant tumors (BT245MR and GBM1MR) and initial tumors (BT245M and GBM1M) were collected for bulk RNA-Seq analysis and ex vivo cell culture. Dose-response experiments were conducted in explant cells to identify drugs with increased effectiveness against recurrent (MR) cell lines versus wild-type cell lines. RESULTS: In both BT245 and GBM1 explant cells, geneset enrichment analysis (GSEA) showed upregulated mesenchymal (BT245MR: NES=3.4, FDR=0; GBM1MR: NES=2.4, FDR<0.002) and hypoxia-related (BT245MR: NES=3.6, FDR=0; GBM1MR: NES=3.4, FDR=0) pathways. GBM1MR tumors also showed enrichment in MAPK signaling (NES=4.7, FDR=0). RNA processing (NES=-6.5, FDR=0) and translation (NES=-5.8, FDR=0) pathways were depleted in BT245MR cells, and DNA repair pathways (NES=-5.8, FDR=0) were depleted in GBM1MR cells. The MAPK inhibitor trametinib demonstrated increased effectiveness in BT245MR and GBM1MR cell lines versus wild-type controls (BT245 IC50 158.7nM (wt) vs. 56.0 (MR), p<0.05; GBM1 IC50 150.7 (wt) vs. 53.4 (MR), p<0.05). BT245MR and GBM1MR cells reliably form PDX tumors after injection into mice. CONCLUSION: BT245MR and GBM1MR represent novel in vivo models of radiation-resistant pHGG, with gene expression alterations consistent with an irradiated phenotype. GSEA and in vitro dose-response data suggest MAPK inhibition may be effective in radiation-resistant pHGG. We are currently conducting in vivo experiments to validate increased trametinib sensitivity in these models.
RONC-03. Secondary Neoplasms in Children with Central Nervous System (CNS) Tumors Following Radiotherapy in the Modern Era
Authors: Indelicato Daniel , Tringale Kathryn , Bradley Julie , Vega Raymond Mailhot , Morris Christopher , Casey Dana , Wolden Suzanne
Published: June 2022

PURPOSE: To assess reduction of secondary radiation-induced neoplasms over the past two decades, focusing on children with CNS tumors who received intensity modulated radiotherapy (IMRT) or proton therapy (PT). METHODS: A total of 1044 children received radiotherapy for a primary CNS tumor at 2 institutions between 1999 and 2020, including 99 treated with IMRT and 945 treated with PT. Median age was 8.7 years old. Median follow-up was 6.0 years and included 83 and 510 patients with >5 years follow-up in the IMRT and proton cohorts, respectively. Cumulative incidence method provided estimates of secondary neoplasms encompassing benign and malignant solid tumors as well as leukemia. Multiple variables were assessed using proportional hazard regression for competing risks. RESULTS: Ten-year overall survival was 87.4%. Patients treated with IMRT were significantly older, with a median age of 10.4 vs 8.4 years old (p <0.001), but were more likely to receive craniospinal irradiation (31.3% vs 14.2%, p <0.001) or alkylating chemotherapy (50.5% vs 29.7%, p <0.001). The 5- and 10-year cumulative incidence of second neoplasm was 0.7% and 2.3%, respectively. On multivariate analysis, age <5 (4.9% vs 0.7% at 10 years) and tumor predisposition syndrome (34.3% vs 1.5% at 10 years) were significantly associated with a second neoplasm (p < 0.01 for each). On both univariate and multivariate analyses, PT was not associated with a lower incidence of second neoplasm. Following IMRT, 1/2 second solid tumors occurred outside the target volume, compared to 2/11 after PT. CONCLUSION: Following modern radiotherapy, approximately 2% of children with a CNS tumor will develop a second neoplasm within 10 years of treatment. Compared to IMRT, PT was not associated with an overall reduction in second neoplasms. More events and follow-up beyond 10 years are needed to determine if proton therapy reduces the incidence of second solid tumors occurring specifically in the low dose region.
RONC-12. Evaluation of brain network segregation using resting state functional MRI in pediatric brain tumor patients treated with proton beam therapy
Authors: Dowling Anna , Seitzman Benjamin , Mitchell Timothy , Olufawo Michael , Agamah Miriam , Butler Rachel , McMichael Alana , Dierker Donna , Anandarajah Hari , Dworetsky Ally , Coalson Rebecca , Jiang Catherine , Gu Hongjie , Barbour Dennis , Schlaggar Bradley , Limbrick David , Strahle Jennifer , Rubin Joshua , Shimony Joshua , Perkins Stephanie
Published: June 2022

INTRODUCTION: Mechanisms of cognitive injury in pediatric brain tumor (BT) patients are poorly understood and biomarkers predicting cognitive deficits are lacking. Resting state functional MRI (rsfMRI) can evaluate large-scale brain networks to provide insight into neural changes that follow diagnosis and treatment. This project evaluated functional brain network segregation in pediatric BT patients treated with proton beam radiation therapy (PBRT). METHODS: rsfMRI scans were acquired from 21 pediatric patients (5 female, 16 male) with any brain tumor diagnosis treated with PBRT. Data were processed to reduce contamination, and correlation matrices were generated using all gray matter voxels. Brain network segregation (BNS) was measured and compared to 139 age-matched controls. Analysis included comparison of BNS in association systems (comprised of default mode, frontoparietal, dorsal attention, language, salience, and cingulo-opercular networks) and somatosensory systems (including auditory, visual, and somatomotor networks). Patient and clinical factors were evaluated for relationships with BNS. Patients underwent cognitive testing utilizing the NIH Toolbox Cognitive Domain (NIH-TCD). RESULTS: Median age at PBRT was 10 years (range 2.2-17.9). PBRT volume was whole brain in 10 and conformal in 11. rsfMRI occurred at a median of 2.9 years (range 1.0-5.6) after PBRT. Average BNS of association systems was significantly lower in patients than in controls (t= -8.1, p<10-10), but there was no significant difference in BNS of somatosensory systems (p=0.4). There was a trend towards worse BNS in association systems in patients <10 years old at PBRT (p=0.07). Patients demonstrated deficits in cognitive testing as assessed by the NIH-TCD; however, there were no significant relationships between score and network segregation. CONCLUSION: Pediatric BT patients treated with PBRT demonstrated normal BNS in somatosensory systems. However, BNS of association systems, which control high-level cognitive functions including social cognition, attention, and memory formation, was significantly decreased in BT patients treated with PBRT.
RONC-13. Change in hippocampus volume as a function of radiation dose: Results from a prospective trial with standardized imaging and morphometric evaluation
Authors: Hall Matthew , Odia Yazmin , Von Werne Katherine , Niazi Toba , Maher Ossama , Khatib Ziad , Mohler Alexander , Kotecha Rupesh , Kalman Noah , Tom Martin , Abrams Kevin , Naidoo Reshma , Chuong Michael , Wroe Andrew , Gutierrez Alonso , Mehta Minesh
Published: June 2022

PURPOSE/OBJECTIVES: MRIs were prospectively collected at baseline and during follow-up in pediatric and young adult brain tumor patients (Age<35) to measure volumetric changes in multiple brain substructures with neurocognitive, laboratory, and quality-of-life assessments. In this planned interim analysis, we model early outcomes for change in hippocampal volume at 6 and 12 months following radiotherapy. MATERIALS/METHODS: As of 2/6/2021, 60 patients enrolled on this prospective study and 41 completed 6 and 12-month post-treatment assessments after fractionated intensity-modulated proton therapy. Left and right hippocampus volumes were independently measured on T1 sagittal precontrast MRI at baseline, 6-months, and 12-months after radiotherapy using automated software and physician-delineated contours. The relationship between mean hippocampus dose and change in volume was assessed by Pearson’s correlation coefficient. A linear mixed-effects model was applied to evaluate other predictors associated with change in hippocampal volume, assuming random effects of subjects. RESULTS: Mean hippocampus dose was strongly correlated with change in hippocampal volume at 12 months following radiotherapy (r=−0.707, 95% CI [-0.805,-0.572], p<0.001). Changes in hippocampal volumes over time were similar between software and physician contours. In the mixed-effects model, only mean hippocampus dose was significantly associated with hippocampal volume change (p<0.001) at both 6 and 12 months. The final model predicted changes in hippocampal volume of -3.6% and -10.1% for every 10 Gy increase in mean dose at 6 and 12 months, respectively. Hippocampal volume was significantly reduced for mean doses >5 Gy (meanΔ -38.1%±20.3%, p<0.001), while no significant volume change was observed with mean doses ≤5 Gy (meanΔ -1.7%±5.0%). CONCLUSIONS: Change in hippocampal volume was correlated with hippocampus mean dose at 6 and 12 months following radiotherapy. Future analyses will assess volumetric changes in additional brain substructures as a function of radiation dose and correlate with measured neurocognitive and quality-of-life effects.
SWK-08. Implementing awareness practice in Neuro-Oncology
Authors: DeRosa Veronica
Published: June 2022

Awareness practices are mind-body medicine techniques that help quiet the chatter of worry, fear, or the "to-do list" in the mind and allows the individual to experience calm and focus. Neuro-Oncology families undergo a variety of stressors that increase the "mind chatter" once their child is diagnosed with a brain tumor. These families not only have to manage the day-to-day tasks of family life, but they are thrust into a world of uncertainty which often can breed anxiety. To help mitigate the stress and anxiety that Neuro-Oncology families undergo, sessions focusing on awareness practices were offered to parent caregivers once a week for 15-20 minutes via the Zoom platform. The goal of these sessions was to offer respite from mental and emotional challenges brought on by the cancer diagnosis and the COVID 19 pandemic. Separate sessions were also offered to Oncology nurse case managers to help decrease compassion fatigue as these nurses also walk alongside oncology families through the cancer journey providing advocacy and patient/family support. Breath awareness, imagery, and meditation practices were used during the sessions to activate the body's relaxation response to allow for rest and restoration.
SWK-10. Survivorship: Education, Clinical Guidelines, and Transition to Adult Care
Authors: Hemenway Molly , Dorris Kathleen , Foreman Nicholas , Winzent Shelby , Kissell Erin , Kasson Julie
Published: June 2022

As the cure rates of patients with pediatric brain tumors increases, the long term care needs of the survivors increase as well. Survivorship includes several facets of multidisciplinary care including education, clinical care guidelines, and transition to adult medical care. The neuro-oncology program at a large tertiary care hospital has developed a team to address survivorship needs. The Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers was utilized as a backbone that was then customized for neuro-oncology patient education including disease type and treatment. The education was compiled into patient handouts as well as electronic medical record (EMR) statements that can easily be added to a clinic note or letter to referring providers. In addition, a diagnosis and treatment summary was placed both in the EMR as well as given to patients at various time points to ensure long term knowledge. Next, follow-up guidelines and roadmaps were developed and customized to tumor type and treatment received (surgery, radiation, chemotherapy). The roadmaps ensure patients are receiving high-quality comprehensive follow-up and screening from a large multidisciplinary team. Finally, patients will transition to adult care. With a large seven state catchment area, the adult care providers vary on local provider availability, knowledge, and medical complexity of the survivor. Each patient is evaluated based on their needs, availability of care locally, and ability to travel. The team developed relationships with the clinical team at the academic center adjacent to the pediatric hospital to support a smooth transition to adult care. The adult neuro-oncology care team can also serve as a consulting service for local adult providers. The survivorship team will continue to address the complex needs of brain tumor survivors and provide education for a smooth transition to adult care.
TBIO-02. Mapping the origins of pediatric brain tumors to cell type lineages in the developing cerebellum.
Authors: Okonechnikov Konstantin , Joshi Piyush , Sepp Mari , Leiss Kevin , Sarropoulos Ioannis , Jones David T W , Kool Marcel , Jäger Natalie , Kutscher Lena M , Kaessmann Henrik , Pfister Stefan M
Published: June 2022

Understanding the cellular origins of cerebellar tumors at single cell resolution may help identify novel therapeutic vulnerabilities to overcome current impediments in pediatric neuro-oncology. One approach to answer this important question involves the mapping of tumor profiles onto normal embryonal central nervous system development. Previous attempts in this regard focused on integrating human tumor data with developing mouse cerebellum atlases, however, these approaches were inherently limited due to species-specific differences. In order to address this critical issue, we use a high resolution developing human cerebellum single cell atlas in order to compare to extended bulk and single cell transcriptomes profiles from pediatric solid tumors. In result, we provide novel and confirmatory findings for the cellular association of medulloblastoma SHH, Group3 and Group4 as well as pilocytic astrocytoma, using comprehensive approaches to decipher the cellular composition and map the origins of childhood brain tumors. We also shed light on the cellular origins of posterior fossa ependymoma and radiation-induced glioma (secondary tumor, occurring after medulloblastoma). As a common feature among the tumor similarity to normal cell types, we identify gradients of differentiation, starting from early progenitor cells to more differentiated cell states, observed in all cerebellar tumor entities investigated at single cell level; thus reflecting possible lineages of origin. Pertaining to clinical application, we identified specific developmental genes shared between cerebellar lineages and associated tumors, and tumor-specific genes absent in all cerebellar lineages. These two categories of genes comprise candidate lineage markers for faithful modeling and, if absent from other organ systems after birth, could become an important source of potential therapeutic targets. Importantly, all analysis results are publicly available via an interactive online user interface (brain-match.org) that serves as an open valuable resource for the scientific community.
INSP-04. Confirmatory adaptive designs for survival trials with several time-to-event endpoints
Authors: Schmidt Rene
Published: June 2022

Confirmatory adaptive designs comprise a range of statistical methods that allow to modify the sample size of an ongoing trial in a data-dependent way without compromising control of the type I error rate. For short-term endpoints (e.g., 3-month response rate), comprehensive methodology of adaptive designs exists. However, clinical trials in oncology often have a special focus on long-term outcome and therefore often choose a time-to-event endpoint as the primary endpoint. Typical examples are progression-free survival (PFS) or overall survival (OS). But subtle statistical problems arise when adaptively analysing survival trials. Classical designs for survival trials are therefore commonly limited to a single primary endpoint, which combines the occurrence of progression, toxicities, deaths, and other events of potential interest into a single statistical measure (composite endpoint). However, the complexity of oncological diseases can be mapped more accurately using multi-stage models, where the occurrence of progressions, toxicities and deaths is modelled jointly instead of combining them into a single composite endpoint. We present and discuss adaptive design methodology for single-arm phase II survival trials for testing hypotheses on the joint distribution of several time-to-event endpoints in the context of multi-state models. We illustrate the methodology using the example of adaptive hypothesis tests for the joint distribution of progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model. The methodology is motivated from application in pediatric oncology.
INSP-07. Improving cognitive outcomes for children treated for cancer: moving beyond the cure
Authors: Conklin Heather
Published: June 2022

With improved survival rates, increasing numbers of childhood cancer survivors are living with long-term cognitive deficits that negatively impact their ability to attain important life milestones. Our collaborative research program has focused on characterizing cognitive outcomes associated with specific treatment modalities to inform modifications in front-line therapy. This line of investigation has demonstrated the negative cognitive impact of high radiation dose/large treatment volume, posterior fossa syndrome, treatment-related ototoxicity, and lower socioeconomic status (SES). Research-informed, treatment approaches under investigation include proton radiotherapy and hippocampal sparing irradiation, molecularly based risk-adapted therapy, surgical approaches with reduced risk of injury, and on-therapy otoprotectants, as well as identification of modifiable factors that are driving the protective effects of higher SES. Our research also strives to improve specification of cognitive deficits following treatment, at the behavioral and neural systems level, to identify targets for intervention. Study findings have revealed disease- and treatment- related alterations in neural systems supporting attention, working memory, and executive functions, as well as genetic factors that increase risk for cognitive late effects. We are now using sophisticated connectivity brain mapping with enhanced sensitivity to behaviorally-relevant changes in brain organization and sensitivity to intervention-based neuroplasticity to guide cognitive intervention development. A primary research focus moving forward is development of empirically validated interventions that prevent or mitigate cognitive late effects among childhood cancer survivors. Our studies have demonstrated the efficacy of stimulant medications, computerized cognitive training, and aerobic exercise for children treated for cancer, as well as the limitations to these approaches. Current investigations include use of neuroprotectant agents during radiotherapy, combining multiple interventions, interventions tailored to children undergoing treatment in infancy, and the use of virtual reality to increase intervention engagement. Our ultimate benchmark of success is ensuring children are not only cured of cancer but also experience a high quality of life.
INSP-10. Minimal residual disease monitoring for pediatric brain tumors using ctDNA whole genome sequencing: opportunities and challenges
Authors: Snuderl Matija
Published: June 2022

Liquid biopsy offers a noninvasive approach to monitor cancer burden during therapy and surveillance. However, in pediatric brain cancers, liquid biopsy methods from the blood have been unsuccessful due to a low tumor burden and low number of mutations in coding regions. In contrast with targeted panels, whole genome sequencing (WGS)-derived patient specific mutational signature from a matched tumor-normal WGS can provide a personalized, highly specific approach to detect mutations in circulating cell free tumor DNA (ctDNA) and provide blood-based monitoring in pediatric patients with high sensitivity. Furthermore, it can be performed on lower amount of peripheral blood since WGS requires less depth compared to targeted ctDNA panels. We have profiled a diverse cohort of brain tumors including medulloblastomas, ependymomas, low- and high-grade gliomas. Using WGS of matched tumor-normal and plasma samples, we could derive a personalized mutational pattern and used an AI-based error suppression model for quantification and ultra-sensitive detection of ctDNA in plasma samples. A patient-specific personalized genome-wide compendium of somatic mutations could be established across all tumor types and ctDNA tested at the time of diagnosis, during the therapy or surveillance period. An AI-based error suppression model is implemented to filter out the noise in the cell free DNA (cfDNA) while the personalized mutational signature was used to detect the ctDNA in the cfDNA and to amplify the somatic signal contained in it. The ctDNA Tumor Fraction (TF) is compared to the clinical status and MR-based imaging. All subtypes of pediatric brain tumors contain sufficient number of mutations to derive personalized signatures and corelate with the clinical status. Patient-specific WGS tumor signature in ctDNA from blood can be used for sensitive monitoring of children with brain tumors. However, correlation between ctDNA levels and therapeutic response need to be established for various subtypes of brain tumors.
INSP-14. Novel approaches to molecular diagnostics
Authors: Sahm Felix
Published: June 2022

The 2021 WHO classification of brain tumors introduces a variety of novel tumor types and subtypes, especially in pediatric neuro-oncology. Most of these tumor types are characterized by specific molecular profiles and alterations. In turn, diagnostic molecular evaluation of brain tumor specimen becomes substantially more complex. The talk will review the basic concepts of the new WHO classification and present novel methodology developments with the respective implications in diagnostic routine. This covers, first, RNA sequencing for fusion detection and expression profiling, highlighting examples of novel tumor types identified by pathognomonic rearrangements. Second, long-read sequencing approaches selecting DNA fragments of interest during sequencing will be discussed. Third, an outlook on the use of artificial intelligence to classify and detect molecular alterations based on H&E staning alone will be provided.