bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDCT-04. ETMR ONE: AN INTERNATIONAL REGISTRY AND RESEARCH PLATFORM FOR CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYER ROSETTES
Authors: Hanson Derek 
Published: November 2019

Abstract
Embryonal tumor with multilayer rosettes (ETMR) is a rare and highly-aggressive CNS neoplasm which occurs almost exclusively in young children and is associated with an extremely poor prognosis. Due to the rare nature of ETMR and its recent classification, no large clinical investigations have been conducted to determine the optimal therapy for these tumors. Historical data suggests that extensive surgical resection, radiotherapy, and high-dose chemotherapy are not sufficient treatment in the vast majority of cases with a reported 1-year EFS of 36% and 1-year OS of 45% using these approaches. New treatment regimens incorporating the known biology of ETMR must be investigated. Pre-clinical drug screens using the ETMR BT183 cell line and its xenograft have demonstrated responses to the chemotherapy agents topotecan, doxorubicin, and actinomycin D. Based on this data, a modified IRS-III chemotherapy regimen incorporating these active agents was developed and a small cohort of four children with ETMR were then treated. Three patients completed therapy without subsequent relapse and have EFS of >30 months. The ETMR One international registry and its associated consensus treatment protocol represent the first prospective evaluation of treatment outcomes for children with ETMR. The consensus regimen involves maximal feasible surgical resection, modified IRS-III chemotherapy, high-dose chemotherapy with autologous stem cell rescue, and radiotherapy (as indicated). Patients enrolled on the registry will have their cases periodically reviewed by a medical advisory board that will offer management recommendations, particularly regarding the use of radiotherapy or the need for additional surgical interventions. Through the procurement of patient tumor samples and development of additional cell lines and xenografts, the registry aims to serve as a platform for translational research. Pre-clinical findings will be used to modify the consensus protocol therapy as indicated or to generate additional biology-based phase I/II trials for ETMR.
PDCT-15. EFFICACY AND SAFETY OF BEVACIZUMAB IN TREATING RECURRENT PEDIATRIC LOW-GRADE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PATIENT OUTCOMES
Authors: Lu Victor , Welby John , Daniels David 
Published: November 2019

Abstract

BACKGROUND
Although rare, the propensity for pediatric low-grade glioma (pLGG) to recur despite upfront intervention presents a management conundrum for clinicians. One novel salvage option is anti-angiogenic bevacizumab, however, its safety and efficacy in this specific demographic is poorly defined. Correspondingly, our aim was to pool systematically-identified metadata in the literature to substantiate the clinical relevance of bevacizumab in treating recurrent pLGG.

METHODS
Searches of 7 electronic databases from inception to June 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of loss was then pooled by random-effects meta-analysis of proportions.

RESULTS
Six pertinent studies described the outcomes of 110 recurrent pLGG patients managed with bevacizumab. While on-treatment, the rate of clinical response was 58% (95% CI, 43–72%), and the rate of radiographic response was 80% (95% CI, 58–96%). Additionally, the rate of serious adverse events (Grade 3 and above) was 11% (95% CI, 5–18%), with proteinuria the most common of those events. By the time patients were off-treatment, the rate of progression was estimated to be 51% (95% CI, 28–74%). Certainty of these results ranged from very low to low.

CONCLUSIONS
The use of bevacizumab as therapy for recurrent pLGG appears to confer appreciable clinical and radiographic response with relatively low serious adverse events risk while on-treatment. However, the long-term off-treatment benefits of this therapy have yet to be consolidated. Traditional clinical heterogeneity concerns preclude the formalization of any recommendations until larger, more standardized investigations can be performed.
PDTM-07. DEFINING THE MECHANISMS UNDERLYING NF1 OPTIC GLIOMA PENETRANCE
Authors: Brossier Nicole , Cobb Olivia , Gutmann David 
Published: November 2019

Abstract
While most children develop cancer without a clear etiology, some pediatric cancers arise in the context of tumor predisposition syndromes, typically caused by germline mutations in genes that regulate cell growth. The most common of these syndromes, Neurofibromatosis type 1 (NF1), affects ~1:3,000 individuals worldwide, 15% of whom will develop low-grade tumors of the optic pathway (optic pathway gliomas; OPGs). However, it is currently unclear which children with NF1 will develop an OPG, making risk assessment for each individual child difficult. Recent evidence suggests that the specific NF1 germline mutation that each child is born with may be one factor that modulates tumor penetrance. To address the hypothesis that specific germline NF1 gene mutations differentially increase the risk of optic glioma formation through cell-intrinsic effects on the tumor cell of origin, we designed a series of studies to examine the impact of different NF1 germline gene mutations on neuroglial progenitor cell populations in the developing brain. We first defined the putative cells of origin – neuroglial progenitor cells within the third ventricular zone (TVZ) – over normal mouse brain development using Nestin-CFPnuc reporter mice. Three cell populations were identified, and these populations display distinct spatial localizations and are dynamic over the course of late embryonic and early postnatal development. Functional differences were identified between these populations in vitro (e.g., differential clonogenic incidence and proliferation), and additional differences were identified by RNA sequencing. After characterizing these populations, we evaluated their spatiotemporal dynamics in mice genetically engineered to harbor different NF1 patient-derived germline Nf1 gene mutations. Interestingly, some, but not all, Nf1 gene mutations resulted in increased GFAP+ progenitor content and progenitor proliferation. Taken together, these findings provide early experimental evidence for mutational specificity in specific putative brain tumor cells of origin relevant to glioma penetrance.
PDTM-11. GAINING INSIGHTS INTO THE INFLAMMATORY MICROENVIRONMENT OF PEDIATRIC HIGH-GRADE GLIOMAS USING GEMMs AND PATIENT SAMPLES
Authors: Ross James , Chen Zhihong , Herting Cameron , Szulzewsky Frank , Becher Oren , MacDonald Tobey , Schniederjan Matthew , Hambardzumyan Dolores 
Published: November 2019

Abstract
Pediatric high-grade gliomas (pHGG) account for the most cancer-related deaths in children, as there are no effective therapies available. It is known tumor associated macrophages (TAM) can make up 30–40% of the total tumor cell mass in adult high-grade gliomas, promoting tumor growth and immune evasion. This raises the question of whether pHGGs possess a distinct constituency of TAMs due to their unique genetic and epigenetic landscapes. To uncover the composition and behavior of TAMs in pHGG we utilize RCAS/tva, a somatic cell-type specific gene transfer system which allows us to recapitulate all major subtypes of pHGG in newborn immunocompetent mice, including histone wild-type and histone-mutant tumors. We combine RCAS-H3.3K27M, RCAS-H3.3G34R/V, or RCAS-H3.3WT along with their driver mutations such as RCAS-shp53 and RCAS-PDGFA or RCAS-PDGFB. These tumors are induced in Nestin-positive cells, each in their respective locations found in the human population. Tumors driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumors and have increased infiltration of lymphocytes and TAMs, specifically inflammatory monocytes. In vitro bone marrow derived monocyte and microglial cultures demonstrate the BMDM population is most responsible for the production of inflammatory chemokines and angiogenic factors in the tumor microenvironment. We performed histological analyses on over 40 human patient samples to determine the role of the stromal population in TAM infiltration. Matched human samples were also utilized for pan-cancer immune profiling with NanoString to further characterize the innate and adaptive immune microenvironments. These analyses indicate DIPG/K27M tumors have a higher immune cell infiltrate compared to G34R/V and histone wildtype tumors. Further, we observe higher infiltration of T-cell populations in pHGGs compared to adult HGGs, suggesting these tumors may be amenable to immunotherapy despite being considered “immune cold.” These studies provide the critical foundation needed for the development of novel therapeutics targeting these tumors.
PDTM-26. NOVEL SHARED AND DISTINCT EPIGENOMIC MECHANISMS OF G34R AND K27M MUTATIONS IN CHILDHOOD GLIOMA
Authors: Chen Michael , Bush Kelly , Lewis Nichole , Cervantes Vanessa , Knoepfler Paul 
Published: November 2019

Abstract
Alterations in histone H3.3 are common driver mutations in high-grade pediatric gliomas, but the central oncogenic mechanisms remain an open question. To identify important mutant H3.3 effectors, we used CRISPR-Cas9 to precisely introduce H3.3 K27M and G34R mutations into previously H3.3-wildtype human astrocyte and glioma cells, while in parallel reverting mutations in glioma cells back to wildtype. K27M and G34R mutations invoked some strikingly similar epigenomic effects supporting a new model in which some major aspects of their oncogenic functions are shared. For instance, both K27M and G34R induced changes at many of the same genomic loci in specific histone marks, with the largest changes in H3K27me3 including in particular within super-enhancers, which also exhibited perturbed transcriptional function. K27M and G34R mutations induced some gene expression changes that were unique to each mutation, but both mutations changed similar functional ontological clusters and ASCL1 is a shared key putative effector. H3.3 mutant glioma cells are sensitive to ASCL1 knockdown or overexpression, resulting in cell viability that is reduced or increased, respectively. Comparison of our panel of glioma cells gene-edited with precise point mutations to edited glioma cells in other studies that performed gene knockout or overexpression reveals striking differences in the resulting phenotypes. We also determined that certain drugs exhibited specificity to H3.3 mutation-bearing cells including DAPT, JQ1, and ONC201. In vivo, we found that reversion of K27M to WT in glioma cells significantly reduced tumorigenicity in mouse xenograft assays and introduction of G34R mutations in previously WT glioma cells increased tumor growth. Overall, gene editing of gliomas and comparison of otherwise isogenic sets of cells defines both distinct and shared gliomagenesis mechanisms that can be targeted for development of oncohistone-based therapeutics.
PDTM-43. THERAPEUTIC TARGETS FROM BIG DATA: INTEGRATIVE DISCOVERY OF TREATMENTS FOR HIGH-RISK NEUROBLASTOMA
Authors: Almstedt Elin , Wärn Caroline , Elgendy Ramy , Hekmati Neda , Rosén Emil , Larsson Ida , Påhlman Sven , Bexell Daniel , Vanlandewijck Michael , Jörnsten Rebecka , Krona Cecilia , Nelander Sven 
Published: November 2019

Abstract
Despite major advances in the molecular exploration of pediatric cancers, approximately 50 % of children with high-risk neuroblastoma lack effective treatment. To identify new therapeutic options for this group of high-risk patients, we have combined integrative data analysis with experimental evaluation in patient-derived xenograft cells. We propose a new algorithm, TargetTranslator, which combines data from tumor biobanks, pharmacological databases, and cellular networks, to predict how particular targeted interventions will affect mRNA signatures associated with high patient risk. We find more than 80 known and novel targets to be associated with neuroblastoma risk and differentiation signatures. To evaluate these predictions, we performed RNA sequencing of drug-treated cell lines derived from high-risk patients and show that predicted compounds suppress risk signatures and malignant phenotypes. Using a xenograft model, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method (made available as a public tool, targettranslator.org) will enhance and expedite the discovery of risk-associated targets for pediatric and adult cancers.
QOLP-11. PSYCHOSOCIAL IMPAIRMENT IN PEDIATRIC NEURO-ONCOLOGY PATIENTS AND THEIR CAREGIVERS
Authors: Kissoon Trisha , Fisher Jennifer , Gururangan Sridharan 
Published: November 2019

Abstract

BACKGROUND
Complex multi-modality treatment for children with brain tumors can cause major distress for patients and caregivers. Active coordination of medical and psychosocial services can improve QoL for affected patients and their caregivers. Few studies have evaluated manifestations of psychosocial distress in pediatric neuro-oncology patients and their caregivers.

OBJECTIVE
We aim to describe symptoms of psychosocial impairment in children with brain tumors and their caregivers in order to identify possible actionable determinants of psychological wellness.

METHODS
Children older than 3 years of age diagnosed with a malignant brain tumor receiving care at a large tertiary center and their caregivers underwent psychosocial assessment using the Kessler-10 and the Pediatric Symptoms Checklist. Questionnaires were voluntarily completed at routine visits. Rates of primary outcomes, patient and caregiver distress as defined by the respective scoring scales, were calculated for both groups. Correlation between patient and caregiver distress was evaluated with a Spearman’s Rho calculation.

RESULTS
A total of 30 patient-caregiver dyads consented to participation and 60 total questionnaires were analyzed. Median patient age was 10 years. 80% of caregivers (N= 24/30) scored high for symptoms of psychological illness on Kessler-10 assessments. Patients exhibited substantial psychosocial impairment in physical (N= 22/30), emotional (N= 18/30), cognitive (N= 12/30), and social (N= 26/30) subdomains of the PSC. There was a significant correlation between clinical manifestations of patient and caregiver psychosocial distress, specifically with regards to symptoms of anxiety (p < 0.05) and depression (p < 0.05).

CONCLUSIONS
Pediatric neuro-oncology patients and caregivers report considerable levels of psychosocial impairment, particularly in physical, cognitive, emotional, and social function, as well as fatigue and insomnia. The majority of patients and caregivers exhibited coinciding symptoms, suggesting that family-based intervention may improve psychosocial stressors. This hypothesis requires future study to determine optimal timing and methods for intervention.
QOLP-34. DOSE FREQUENCY MODIFICATION OF TRAMETINIB TO MITIGATE SEVERE RASH AND IMPROVE QUALITY OF LIFE IN PEDIATRIC LOW-GRADE GLIOMA PATIENTS
Authors: Archambault Bridget , Landi Daniel , Schroeder Kristin 
Published: November 2019

Abstract
Circumscribed low-grade glioma is generally driven by MAP kinase pathway activation, and this discovery motivates use of the non-competitive MEK 1/2 inhibitor trametinib for children and adults with progressive disease. However, rash is a common dose-limiting toxicity with trametinib. Accordingly, we evaluated intermittent, 3-days-on, 1-day-off dosing in an effort to reduce the incidence and severity of rash. Seven patients with MAP-kinase activated low grade glioma were treated with trametinib (6 pilocytic astrocytoma (PA), one desmoplastic infantile ganglioglioma with V600E). Patients initiated treatment at 0.025mg/kg/day up to the maximum adult dosing of 2mg. Three teenage patients with PA were treated with the maximum daily adult dose of 2mg. All three developed a painful, grade 3 acneiform rash within 3 weeks, requiring trametinib hold and treated with topical cleansers and oral antibiotics. One patient discontinued treatment, and two restarted trametinib at a reduced dose (1.5mg) administered 3-days-on and 1-day-off. With this modified dosing, patients experienced no more than grade 1 rash. Two younger patients initiated trametinib with daily dosing, and both developed grade 1 eczematous rash within 3 weeks, progressing to grade 2 in one patient. The rash resolved without recurrence after dose frequency modification to 3-days-on, 1-day-off at the same overall dose. Two younger patients initiated trametinib with 3-days-on, 1-day-off dosing and have not developed a rash. All of the younger patients are currently continuing on therapy with no progression to date. However, both teenage patients developed progressive disease by 11 months into therapy. In conclusion, acneiform rash appears to preferentially impact teenage or young adult patients but can be mitigated with modified dose frequency 3 days on, 1 day off. However, continued assessment is needed to evaluate the effect of dosing frequency modification on treatment response.
QOLP-36. THE IMPORTANCE OF SLEEP DISTURBANCE IN PRIMARY BRAIN TUMOR (PBT) PATIENTS: CLINICAL CHARACTERISTICS & CO-OCCURRENCE WITH TUMOR-RELATED & PSYCHOLOGICAL SYMPTOMS
Authors: King Amanda , Shuboni-Mulligan Dorela , Vera Elizabeth , Crandon Sonja , Aboud Orwa , Antony Ramya , Boris Lisa , Bryla Christine , Burton Eric , Cordova Christine , Gartland Carrie , Grajkowska Ewa , Penas-Prado Marta , Reyes Jennifer , Leggiero Nicole , Siegel Christine , Theeler Brett , Wall Kathleen , Wu Jing , Gilbert Mark , Armstrong Terri 
Published: November 2019

Abstract
Sleep disturbance (SD) is a common symptom reported by PBT patients and research has demonstrated a link between sleep and stress circadian pathways. SD can impact perceived severity of other symptoms and development of psychopathology. This study explored the prevalence of moderate-severe SD in PBT patients, identifying associated clinical characteristics and co-occurrence with other tumor-related and psychological symptoms. Demographic, clinical characteristics, MDASI-Brain Tumor, and PROMIS Depression and Anxiety Short-Forms were collected at study entry. Descriptive statistics, Chi-square tests, and independent t-tests were used to report results. The sample included 424 patients (58% male, 81% Caucasian) with a median age of 49 years (range 18–81) and 58% with high-grade gliomas. Most had received treatment with surgery, radiation or chemotherapy prior to study entry, with 44% reporting a past recurrence. Moderate-severe SD (³ 5 on a 0–10 scale) was reported in 19% of patients and was associated with younger age (mean difference = 5 years), poor KPS (OR 2.2), current steroid use (OR 2.4), and tumor progression on MRI (OR 2). Those with moderate-severe SD had a higher overall symptom burden (mean difference = 2.3) and reported more moderate-severe symptoms (8 vs. 2). Patients reporting moderate-severe SD also reported higher severity in affective and cognitive symptom domains and mood-interference, with fatigue (72%), drowsiness (59%), and distress (56%) the most frequently co-occurring symptoms. Patients with moderate-severe SD also had increased prevalence of moderate-severe anxiety (32%) and depression (23%), compared to 10% in those without SD. PBT patients with moderate-severe SD are more symptomatic and have higher incidence of mood disturbance, suggesting a key role for sleep in the development of tumor-related and psychological symptoms. Future work delineating specific pathways involving sleep disturbance and co-occurring symptoms will be foundational for designing targeted sleep interventions to improve symptom burden and quality of life.
RDNA-03. AUTOPHAGY AS A NOVEL THERAPEUTIC TARGET IN MUTANT IDH1 GLIOMAS
Authors: Nunez Felipe , Garcia-Fabiani Maria , Kadiyala Padma , Hong Hanna , Comba Andrea , Lyssiotis Costas , Cheng Shi-Yuan , Lowenstein Pedro , Castro Maria 
Published: November 2019

Abstract
Mutated Isocitrate dehydrogenase 1 (IDH1R132H; mIDH1) is found in 50% of all adult gliomas and in 80% of lower-grade gliomas. IDH1R132H promotes 2-hydroxyglutarate production which inhibits histone and DNA demethylases, inducing epigenetic reprogramming of the tumor transcriptome. We recently demonstrated that epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 glioma, harboring p53 and ATRX loss. Furthermore, several studies indicate that IDH1R132H triggers cellular metabolism reprogramming. In this study, RNA-seq data revealed that mIDH1 glioma neurospheres (mIDH1-NS) have downregulated gene ontologies related to mitochondrial metabolism. Analysis of mitochondrial and glycolytic activity, using a Seahorse Analyzer, showed that mIDH1-NS have decreased levels of oxygen consumption and extracellular acidification rates, characteristic of quiescent state. Nevertheless, mIDH1 glioma cells can grow and generate tumors, suggesting that they might maintain self-renewal via autophagy. To investigate this hypothesis, we studied autophagy in wild-type and mIDH1 glioma cells analyzing LC3 conversion, p62 expression, and ULK1 protein phosphorylation. Mouse and human mIDH1 glioma cells exhibited increased expression of pULK1-S555, enhanced conversion of LC3I to LC3II, and decreased expression of p62, indicating that mIDH1 cells have an augmented autophagy. Also, key proteins involved in autophagy, including MST4 and UVRAG, are upregulated in mIDH1-NS. We also studied autophagy flux using LC3-mCherry-GFP reporter to identify LC3 recruitment at the autophagosome membranes and the autolysosome activity. Our results showed that mIDH1 cells have increased LC3 recruitment and enhanced autolysosome activity. Interestingly, autophagy has been related with glioma radioresistance. In our study, mouse and human mIDH1 glioma cells are sensitive to autophagy inhibition. In addition, autophagy inhibition restored radiosensitivity in mouse and human mIDH1 glioma cells, and in our mIDH1 glioma model, enhancing median survival compared with radiation alone. In conclusion, our results indicate that mIDH1 glioma cells maintain self-renewal via activation of autophagy, which represents a novel therapeutic target.
RDNA-06. TARGETING IDH1/2-MUTANT GLIOMAS WITH UNIQUE COMBINATIONS OF DNA REPAIR INHIBITORS
Authors: Sule Amrita , Bindra Ranjit 
Published: November 2019

Abstract
Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of glioblastoma.