bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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&lt;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&lt;0.05; GBM1 IC50 150.7 (wt) vs. 53.4 (MR), p&lt;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

Abstract
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 &gt;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 &lt;0.001), but were more likely to receive craniospinal irradiation (31.3% vs 14.2%, p &lt;0.001) or alkylating chemotherapy (50.5% vs 29.7%, p &lt;0.001). The 5- and 10-year cumulative incidence of second neoplasm was 0.7% and 2.3%, respectively. On multivariate analysis, age &lt;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 &lt; 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

Abstract
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&lt;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 &lt;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

Abstract
PURPOSE/OBJECTIVES: MRIs were prospectively collected at baseline and during follow-up in pediatric and young adult brain tumor patients (Age&lt;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&lt;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&lt;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 &gt;5 Gy (meanΔ -38.1%±20.3%, p&lt;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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.