bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-58. SEX DIFFERENCES IN CONTRAST-ENHANCING GLIOMAS AT PRESENTATION
Authors: Johnston Sandra , Khurana Aditya , Whitmire Paula , Sharma Akanksha , Hawkins-Daarud Andrea , Ranjbar Sara , Hu Leland , Rubin Joshua , Egan Kathleen , Canoll Peter D , Porter Alyx , Mrugala Maciej , Kumthekar Priya , Swanson Kristin
Published: November 2019

Sex differences in brain tumor related epilepsy (BTE) as an initial symptom of glioma are rarely investigated. Sex differences are being explored with increased interest more recently. Epidemiological studies have generally indicated overall incidence of epilepsy to be slightly higher in males than females, but a higher incidence of idiopathic generalized epilepsy has been seen in females in some studies. Clinicians regularly face the challenge of anti-epileptic drug prescription determination in patients with newly identified brain mass and would greatly benefit from knowing clinical characteristics in BTE. We analyzed clinical characteristics in patients with pathologically-determined glioma with known seizure status at clinical presentation using non-parametric and Fisher’s Exact tests with the entire cohort and male and female separately. From our clinical data repository, we identified 223 patients (females, n=86 (39%); males, n=137 (61%)) divided by those that presented with seizure (SP, n=96, 43%; F, n= 28; M, n= 68) and those that presented without seizure (nSP, n=127, 57%, F n=58, M n=69). In sex-specific analysis males had a significantly (x2=6.28, p=0.01) higher proportion of SP (49.6%) than females (32.6%). There was a dependence between seizure presentation status and tumor grade in males (x2=5.94, p=0.015). Tumor kinetics in the female cohort showed significantly (p< 0.0001) more diffuse tumors in SP compared to nSP. Right-sided tumors were predominantly nSP, while left-sided tumors were split more evenly between SP and nSP. The predominance of nSP among right-sided tumors seems to be driven by females (74%), male right-sided tumors were split more evenly between SP and nSP. Seizure status is dependent on tumor location for the combined cohort, however not for males (x2=5.23, p=0.16) or females (x2=4.34, p=0.23). Clearly there are sex differences and similarities in clinical characteristics at glioma presentation. Further characterization could lead to improved adherence of national standards for AED prescription.
NIMG-65. PREDICTING PROGNOSIS AND CANCER HOTSPOT MUTATIONS USING QUALITATIVE MR IMAGING ANALYSIS IN GLIOBLASTOMA
Authors: Verduin Maikel , Compter Inge , Primakov Sergey , van Kuijk Sander , te Dorsthorst Maarten , Revenich Elles , ter Laan Mark , Pegge Sjoert , Meijer Anton , Beckervordersandforth Jan , Jan Speel Ernst , Jochems Arthur , de Leng Wendy , Anten Monique , Broen Martijn , Ackermans Linda , Schijns Olaf , Vooijs Marc , Tjan-Heijnen Vivianne , Lambin Philippe , Eekers Danielle , Jacobi-Postma Linda , Hoeben Ann
Published: November 2019

INTRODUCTION

Tumor heterogeneity poses one of the major limitations in improving the treatment for glioblastoma (GBM), which calls for new clinically relevant predictive models. This study aims to investigate non-invasive diagnostic methods, including patient characteristics and qualitative imaging analysis as a prognostic classifier and predictor for druggable oncogenes.

METHODS

We performed a retrospective analysis on 143 GBM patients (discovery cohort). Diagnostic MRIs were re-analyzed for qualitative imaging features (VASARI features). DNA was extracted from formalin-fixed, paraffin-embedded GBM tissue of the discovery cohort for next-generation sequencing (Ion Torrent Cancer Hotspot panel v2Plus), TERT-promoter mutation and MGMT-methylation analysis. Multivariable regression analysis was used to determine the prognostic and predictive value of VASARI features.

RESULTS

Of the 143 patients, median age was 61.4 years (range 15.5–84.6) with a median overall survival of 12 months (range 0–142). We observed IDH1 R132H mutation in 8.5%, MGMT-promotor methylation in 26.1%, TERT-promotor mutation (C250T;C228T) in 69.5%, EGFR mutation in 20.3% and EGFR amplification in 37.5% of all patients. A set of eight VASARI features was identified to be associated with overall survival (p< 0.001), which is currently being validated in an external dataset (n= 184). Interestingly, VASARI features appeared to be associated with IDH1-mutation (four features, p=0.004), TERT-promotor mutation (five features, p-value < 0.001), EGFR mutation (five features, p-value < 0.001) and EGFR amplification (seven features, p-value < 0.001) but not with MGMT-methylation (two features, p-value=0.054). Additional cancer hotspots are currently being analyzed and internal validation is ongoing.

CONCLUSION AND FUTURE PERSPECTIVES

We propose an integrated prognostic classifier comprising MRI features, also associated with GBM-specific molecular alterations. Additionally, quantitative MRI radiomics features are being extracted from the discovery and validation set and incorporated in the prognostic classifier. Subsequently, radiomics and VASARI features will be correlated to intratumoral heterogeneity, assessed by tissue micro-array analysis of the discovery cohort.
NIMG-73. NEUROLOGICAL ASSESSMENT IN NEURO-ONCOLOGY (NANO) CORRELATES WITH INTEGRATED PREDICTIVE RADIOGRAPHIC BIOMARKERS OF PROGRESSED HIGH GRADE ASTROCYTIC TUMORS (IPROMPT): A PROPOSED SUPPLEMENT TO RANO
Authors: Tosha Gatson Na , Bross Shane , Lockard Laura , Leese Erika , Manikowski Jesse , Mahadevan Anand , Conger , Andrew , Mongelluzzo Gino
Published: November 2019

This year nearly 86,000 persons in the US will be diagnosed with a primary brain tumor. Glioblastoma (GBM) is the deadliest and most common of these tumors in adults with overall survival around 15mos. Disease progression is inevitable, and effective second-line therapies are few. Delays in identifying progressed GBM risks neurologic decline, continuation of ineffective therapies, and increased tumor-mutational-burden, potentially rendering treatment less-effective. Brain tumor imaging can be ambiguous and is an active topic in neuro-oncology as there are currently no validated approaches to assessment of tumor treatment response. We present a single institution database including 622 gross-totally-resected GBMs (2006–2018) to evaluate changes in T2/FLAIR signal intensity (T2FSI), diffusion restriction, and contrast enhancement both in and around the resection cavity (RC) to determine earliest indicators of tumor progression. Analysis of NANO score was completed to correlate with predicted tumor progression. This is an early data release of an ongoing two-phased retrospective/prospective study with findings that support a novel integration of radiographic sequences and NANO to supplement established RANO criteria in earlier detection of GBM progression. Of 622 confirmed GBMs, 158 fit the rigorous criteria – included here are 58 cases. We report 70% (n=41) of patients show RC T2FSI correlating with restricted diffusion and increasing NANO score (0.5–1.4) as early as 3.8mos prior to and at time of radiographic progression, respectively. Previous studies have reported similar T2FSI but without associated NANO, less rigid inclusion criteria, and limited MRI sequences. We also report imaging phenomena, not previously described, such as FLAIR migration and FLAIR coring timed closely with progression. The proposed technique uses routine MRI, therefore readily standardized in clinical practice. With further validation, this novel integration of imaging and neurologic assessment might serve to supplement existing response criteria in GBM and improve clinician confidence in earlier detection of progression.
NCMP-01. RISK FACTORS ASSOCIATED WITH LATE HYPERGLYCEMIA IN BRAIN TUMOR PATIENTS WITH POSTOPERATIVE ADMINISTRATION OF DEXAMETHASONE
Authors: Ho Yang Seung
Published: November 2019

Dexamethasone is the corticosteroid most commonly used for the management of vasogenic edema in patients with brain tumors. The occurrence of hyperglycemia following corticosteroid administration is well known to physicians and health care givers. The purpose of the study is to investigate late onset of hyperglycemia and associated factors in patients with brain tumors. The inclusion criteria are as follows; 1) brain tumor patients underwent craniotomy; 2) steroid administered for at least 3 days longer perioperatively or postoperatively; 3) serum glucose levels examined for at least 3 months postoperatively The exclusion criteria are as follows; 1) steroid administered for less than 3 days; 2) patients diagnosed with type 1 diabetes, renal failure, hepatic failure or autoimmune diseases; 3) other medical illness treated with corticosteroid. A total of 101 patients were enrolled for the analysis. Fasting blood glucose of diabetes patients and non-diabetes patients was 160±93 mg/dl and 114±43 mg/dl, respectively. There was no difference of type of brain tumors, body mass index, hypertension, smoking history, hyperlipidemia, GOT, GPT, ESR, CRP, and Cr between diabetes patients and non-diabetes patients. The peak of Fasting blood glucose was noted on day 1 postoperatively in non-diabetes patients. Two peak of Fasting glucose levels were found on day 1 and 6 postoperatively in diabetes patients. Late hyperglycemia was determined as in patients with fasting blood glucose of >125 mg/dl during 3~6 months postoperatively. Fifteen patients out of 86 non-diabetes patients developed late hyperglycemia. There were significant differences of duration and total dose of dexamethasone administration between late hyperglycemia patients and non-late hyperglycemia patients. Steroid-induced hyperglycemia can develop late postoperatively even in non-diabetic patients with brain tumor treated with dexamethasone. Fasting blood glucose during the first week postoperatively can predict late hyperglycemia. Duration and total dosage of dexamethasone administered are associated with late hyperglycemia.
NCMP-07. SECONDARY ADRENAL INSUFFICIENCY IN ADULT PATIENTS WITH GLIOMA: A CASE SERIES
Authors: Mantilla Emmanuel , Abramowitz Jessica , Dan Tu , Pan Edward
Published: November 2019

Glucocorticoids (GC) are a mainstay in the treatment of gliomas to reduce cerebral edema and improving symptoms related to swelling. Prolonged GC use can lead to adrenal insufficiency (AI) due to the suppression of the hypothalamic-pituitary-adrenal axis. AI is challenging to diagnose as the tumor itself or the chemotherapy are blamed for the symptoms. This study aims to evaluate the risk factors predisposing patients with gliomas to develop AI during their treatment course.

METHODS

This is a retrospective case review. Charts in the neuro-oncology clinic from July 2018 to March 2018 were reviewed. Inclusion criteria include > 18 y/o, diagnosis of glioma WHO Grade II to IV, and diagnosis of secondary AI. Demographic profile, tumor characteristics, radiation dose, exposure or proximity to HPA, current treatment, and dexamethasone dose and duration of treatment were tabulated and compared.

RESULTS

Nine of ten patients were started on high dose of dexamethasone (> 8mg daily), and only one was started on a lower dose (< 4mg daily). Majority of the patients (50%) were on dexamethasone for less than a year (4–8 months), and a significant portion (40%) of the patients remained on dexamethasone for > 2 years, with one patient on steroids for 64 months. The minimum dose of dexamethasone needed to prevent symptoms ranged from 0.5mg to 2mg daily. Most received 60Gy of radiation, two received 59.4 Gy, and one received 54 Gy. Six patients had radiation exposure to the HP axis, while four didn’t.

CONCLUSION

Secondary adrenal insufficiency results from prolonged glucocorticoid use in patients with glioma. Dose and duration of GC are risk factors to its development. Radiation to the HPA axis may be a contributing factor to the development of AI in patients with glioma, although it can also be seen in patients with radiation distant from the HPA.
NCMP-19. STROKE IN CANCER PATIENTS
Authors: Ching Marilou , Komlodi-Pasztor Edina
Published: November 2019

Patients with malignancy have an increased tendency for venous and arterial embolism, and for increased risk for bleeding. Clinical decisions regarding anticoagulation in this population has been challenging and complicated by the availability of various anticoagulants. Currently, there is no evidence-based guideline available for the prevention of arterial embolism and thrombosis, such as stroke, in cancer patients. The aim of the study is to assess the use of anticoagulant medications in cancer patients who suffer a stroke. ICD-9/-10 codes were used to identify patients with cancer who were admitted between September 1, 2017 and November 30, 2017 to the Buffalo General Hospital with the diagnosis of stroke. Chart review was used to verify the history of cancer and stroke and to collect additional information. The diagnosis of acute stroke and cancer were verified in 87 patients. Among them, 31 patients had active malignancy. Of the 31 patients, 9 were diagnosed with intracranial hemorrhage and 22 with ischemic strokes. Of the 9 patients with intracranial hemorrhage,3 were anticoagulated and 1 patient was off anticoagulation. Of the 22 patients with ischemic stroke, 4 patients were anticoagulated, although 1 patient was underdosed based on INR. Seven of the 22 patients were taken off of anticoagulation; 3 had side effects and 4 were awaiting a surgical procedure. Five of the 9 patients with intracranial hemorrhage and 10 of the 22 patients with ischemic stroke were made comfort care and passed away shortly after the diagnosis of stroke.
PDCT-02. UNIQUE CONCURRENT ASSOCIATION OF SOMATIC AND GERMLINE NF1 MUTATIONS WITH GERMLINE MISMATCH REPAIR MUTATIONS IN PEDIATRIC GLIOBLASTOMA MULTIFORME
Authors: Baig Muhammed , Fuller Greg , Gupta Sumit , Tran Grace , Mork Maureen , Slopis John , Kamiya Carlos , Khatua Soumen , Zaky Wafik , Sadighi Zsila
Published: November 2019

INTRODUCTION

We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD). Pediatric GBMs in NF1 are rare but increase with age. LS and CMMRD differ by inheritance: autosomal dominant with heterozygous germline mutation (LS), or biallelic mutation (CMMRD) of one of the 4 (possibly 5) MMRD genes (MLH1, MSH2, MSH6, PMS2, or MSH3) - both can develop GBM.

METHODS

Two pediatric GBM cases with prior NF1 clinical diagnoses (neurocutaneous stigmata) were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively.

RESULTS

Sixteen-year-old male with prior NF1 clinical diagnosis had headaches for one year preceding diagnosis and resection of right frontal GBM with somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed pathogenic MSH2 and NF1 mutations, confirming LS and NF1. Current treatment is chemoradiation. Nineteen-year-old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain diagnosed and biopsied (after 3 months of right hemiparesis) with somatic PMS2 and NF1 mutations, and a second left frontal lobe tumor diagnosed and resected 11 months later, with 2 pathogenic germline mutations of PMS2, inherited one from each parent, confirming CMMRD without NF1. Treatment was focal radiation administered to both sites followed by adjuvant chemotherapy.

CONCLUSION

Children with NF1 stigmata and GBM may have either concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Confirmatory germline and somatic MMR gene and NF1 mutation testing in children with GBM and NF1 stigmata should be considered as the specific diagnosis affects management.
PDCT-04. ETMR ONE: AN INTERNATIONAL REGISTRY AND RESEARCH PLATFORM FOR CHILDREN WITH EMBRYONAL TUMOR WITH MULTILAYER ROSETTES
Authors: Hanson Derek
Published: November 2019

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

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

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

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

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

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

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

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

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

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

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.
RTHP-04. PEDIATRIC STEREOTACTIC RADIOSURGERY FOR BENIGN NEUROLOGIC DISEASE: A 25-YEAR INSTITUTIONAL EXPERIENCE
Authors: Sherry Alexander , Bingham Brian , Kim Ellen , Facer Benjin , Chukwuma Valentine , Luo Guozhen , Attia Albert , Vogel Jennifer , Cmelak Anthony
Published: November 2019

Long-term outcomes and sequalae of pediatric stereotactic radiosurgery (SRS) for benign neurologic disease are poorly understood. We sought to explore the efficacy and late effects of SRS in pediatric patients treated our institution. After institutional review board approval, we performed a retrospective analysis of patients age 21 or younger treated between 1990 and 2016. Covariates were summarized with descriptive statistics. 56 consecutive patients were enrolled. Patients were primarily Caucasian (n=51, 93%) males (n=30, 54%). Diagnoses included arterio-venous malformation (n=41, 73%) and functional pituitary adenoma (n=9, 16%) as well as vestibular schwannoma, craniopharyngioma, meningioma, papilloma, and ganglioglioma. Average age was 14 years (95% CI 13–16 years). SRS was often the first intervention (n=22, 44%); treatments prior to SRS included embolization (n=18, 36%) and surgery (n=10, 20%). SRS was typically single fraction (n=45, 94%) with a median total dose of 16 Gy (IQR 15–18 Gy). Most patients had no acute side effects of SRS (n=40, 87%). Median follow-up time after SRS was 12 years (IQR 6–18 years, max 26 years). 91% of patients had no late sequelae of SRS. One patient was diagnosed with radionecrosis one year after repeat SRS for residual malformation. Two patients had malformation hemorrhage. One patient with brainstem malformation developed focal weakness after ischemia from treatment effect; another patient with malformation developed seizures related to SRS edema. Over 673 patient-years following SRS, no patient developed radiation-induced malignancy or malignant transformation. Median disease-free survival after SRS was 6 years (IQR 3–13) with 66% overall local control; 84% of local failures occurred within 5 years of SRS. At last follow-up, 95% of patients remained without evidence of disease with 100% overall survival. These data support the long-term safety and efficacy of pediatric SRS.
RTHP-11. THE EFFECT OF PRESCRIPTION ISODOSE LINE ON LOCAL CONTROL AND RADIOGRAPHIC RESPONSE IN GAMMA KNIFE RADIOSURGERY OF VESTIBULAR SCHWANNOMA
Authors: Teyateeti Achiraya , Graffeo Christopher , Perry Avital , Brown Paul , Pollock Bruce , Michael Link
Published: November 2019

Traditionally, the 50% isodose line (IDL) is used for prescription dose when vestibular schwannomas (VS) are treated with Gamma Knife radiosurgery (GKRS). To compare the effect of IDL on treatment outcomes, propensity score-matched analysis according to age at time of GKRS and tumor volume (TV) between cohorts treated at 40%IDL and 50%IDL was performed. Patients with no history of neurofibromatosis, GKRS prescribed marginal dose of 12–14 Gy and TV ≤ 10 cc were identified. Patients were excluded if follow-up time was < 2 years. Eventually, 30 and 28 patients were included in 40%IDL and 50%IDL cohorts, respectively. Mean age and TV were not significantly different between 40%IDL and 50%IDL groups; 54.5 versus 54.0 years (p=0.891) and 2148.61 versus 2031.10 mm3 (p=0.844), respectively. Median prescription dose was 12 Gy in both groups. At median follow-up times of 111 and 72 months, the 2, 5 and 10-year local control were 100%, 96.4% and 96.4% for 40%IDL and 96.4%, 86.7%, and 86.7% for 50%IDL (p=0.243), respectively. Among 40 patients with accessible follow-up MRIs (40%IDL-n=19, 50%IDL-n=21), volume reduction at last follow-up MRIs and rate of reduction per year for 40%IDL and 50%IDL were 48.1% versus 38.3% (p=0.05) and 5.5% versus 6% (p=0.749), respectively. Of 21 patients with serviceable hearing prior to GKRS and available audiograms after GKRS (40%IDL-n=8, 50%IDL-n=13), the 2, 5 and 10-year hearing preservation rate were 100%, 83.3% and 62.5% for 40%IDL versus 76.2%, 57.1% and 11.4% for 50%IDL (p=0.017). Facial paresthesia, facial palsy and ataxia/gait disturbance requiring steroid and/or shunt were lower in 40%IDL compared to the 50%IDL; 6.7% versus 17.9% (p=0.208) and 3.3% versus 7.1% (p=0.532). To summarize, VS treated at 40%IDL have slightly better local control, although not statistically significant, compared to tumors treated at 50%IDL. However, hearing preservation and safety seem to be more favorable toward 40%IDL group.
RTHP-19. ANESTHETIC INDICATIONS, TECHNIQUES AND COMPLICATIONS FOR GAMMA KNIFE RADIOSURGERY
Authors: Dang Anh , Vachhani Shital , Briere Tina , Prabhu Sujit , McGovern Susan
Published: November 2019

PURPOSE

We sought to describe our experience regarding anesthetic indications, techniques and complications with Gamma Knife radiosurgery (GKRS).

METHODS

We retrospectively evaluated the use of anesthesia for both adult and pediatric patients at a high-volume center.

RESULTS

Twenty-two adult cases and 10 pediatric cases were identified. For adult patients, the median age was 55.5 years. Pediatric patient ages ranged from 3 to 16 years. For adult patients, indications for sedation were claustrophobia (n=16), anxiety (n=4), chronic pain (n=1), and severe comorbidity (n=1). Twenty-five patients received general anesthesia with a secure airway (GA). Seven patients received total intravenous anesthesia with spontaneous ventilation (TIVA). One of these patients required placement of an airway after initial TIVA. The median sedation to treatment ratios for pediatric patients (3.76) and adult patients (4.06) did not significantly differ (P=0.49). However, the median sedation to treatment ratios for patients who received GA (4.08) was significantly higher than patients who received TIVA (1.88, P=0.0005). Anesthetic complications included cutaneous flushing, excessive secretions and airway obstruction that required unplanned placement of an airway, wheezing attributed to propofol sedation, and unspecified anesthetic issues that resulted in a MRI scan with a suboptimal time interval. All complications occurred in adult patients.

CONCLUSIONS

Gamma Knife radiosurgery with GA was associated with a longer sedation to treatment ratio compared to TIVA. However, despite the prolonged sedation time, use of GA was associated with few complications, none of which were severe and observed only in adult patients. Practitioners should consider the need for anesthesia in adult and pediatric patients who are intolerant to GKRS due to severe claustrophobia, anxiety, or pain when evaluating patients prior to GKRS. Due to the increased risk of respiratory complications in these patients, we recommend the use of general anesthesia with a secure airway despite the prolonged sedation time.