bluuebunny/crossref_metadata_2025 huggingface dataset:
EPCO-30. A RADIOMICS BASED REGRESSION MODEL TO PREDICT GLIOBLASTOMA CELL MOTILITY
Authors: Mulford Kellen , McMahon Mariah , Odde David , Wilke Christopher
Published: December 2020

PURPOSE

Radiomics has shown considerable success as a diagnostic tool in the classification of tumor grade, stage, and prognosis. The purpose of this work is to examine the potential for radiomics techniques to accurately predict the motility properties of glioblastoma cells.

METHODS

Tissues specimens were obtained from a total of 31 patients undergoing surgical resection of glioblastoma. Mean tumor cell motility was calculated from time-lapse videos using previously described methods (Bangasser et al. Nat Comm 2017). Preoperative, post-contrast T1-weighted MR images with 1 mm voxels were obtained from the medical records for each patient. Manual segmentation was used to define the border of the enhancing tumor and 108 radiomics features were extracted from the normalized image volumes using the PyRadiomics software package. Imaging features that correlated strongly with cellular motility were selected in a stepwise manner by p-value. The four features most strongly correlated with cellular motility were included in a regression model using the adaptive lasso technique with leave-one-out cross validation (LOOCV).

RESULTS

Two first order and two gray-level run length matrix features were selected for the model. The R-squared value for the predictive model was 0.60 with p-values for each individual parameter estimate less than 0.0001. An analysis of the residual values of the predicted model did not show any evidence of bias in the estimate. The average root mean squared error between the predicted and actual motility from the LOOCV for the model was 0.75.

CONCLUSION

The results of this work suggest that it is possible for a quantitative image feature-based model to predict the cellular motility of glioblastomas. Further work will prospectively test the model and explore the role of cellular motility in clinical outcomes such as time to recurrence and patterns of failure.
EPCO-34. CLINICAL AND GENETIC EVOLUTION OF EPENDYMOMA
Authors: Chen Zhong-ping , Wang Jing , Yang Qun-ying , Zeng Jing
Published: December 2020

Ependymomas are glial brain tumors accounting for approximately 2~3% of all primary tumors in central nervous system (CNS), and 12% of all pediatric intracranial tumors. To better understand the evolution process of ependymomas, we studied the clinical, pathological and genetic development of a rare girl case with repeatedly recurrent ependymoma. This girl was diagnosed as anaplastic ependymoma at age of 9 years old, and experienced 7 times tumor relapse and received 9 times surgeries but finally ceased at19 years old with multiregional recurrences. The pathological characteristics, radiographic images and therapeutic strategies of the patient were all retrieved. Molecular markers confirmed the diagnosis based on the updated WHO guideline for CNS tumors. Whole-genome sequencing (WGS) was performed to elucidate the landscape of mutation signatures and to identify potential driver mutations along the tumor progression. The seven tumor specimens showed a highly branched evolutionary pattern. There were six gene mutations found in 5 of the 7 specimens (PCDHA4, PCDHA8, SEC14L6, SETD2, RIOK2, and SLCO2A1) and three in 6 of 7 the samples (RYR1, SNX25, DSC2). Strikingly, there was one gene, ADGRL3, which was found to be consistently mutated in the entire disease progression process. Our findings therefore suggest that ADGRL3 might play roles in the disease progression of ependymoma patient.
EPCO-35. SINGLE-CELL RNA-SEQ OF PEDIATRIC EPENDYMOMA REVEALS PROGNOSTIC IMPACT OF IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION
Authors: Englinger Bernhard , Gojo Johannes , Jiang Li , Hübner Jens M , Shaw McKenzie , Hack Olivia , Liu Ilon , Madlener Sibylle , Kirchhofer Dominik , Pyrdol Jason , Hovestadt Volker , Mazzola Emanuele , Mathewson Nathan , Trissal Maria , Lötsch Daniela , Dorfer Christian , Haberler Christine , Halfmann Angela , Mayr Lisa , Peyrl Andreas , Geyeregger Rene , Schwalm Benjamin , Mauermann Monica , Pajtler Kristian , Milde Till , Shore Marni , Geduldig Jack , Pelton Kristine , Czech Thomas , Ashenberg Orr , Wucherpfennig Kai , Rozenblatt-Rosen Orit , Alexandrescu Sanda , Ligon Keith , Pfister Stefan , Regev Aviv , Slavc Irene , Berger Walter , Suva Mario , Kool Marcel , Filbin Mariella
Published: December 2020

Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, the intratumoral heterogeneity and developmental origins of these groups are only partially understood, and effective treatments are still lacking for about 50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/single nucleus RNA-sequencing to analyze 24 tumor specimens across major molecular subgroups and anatomic locations. We additionally analyzed ten patient-derived ependymoma cell models and two patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating from undifferentiated neural stem cell-like populations towards different degrees of impaired differentiation states comprising neuronal precursor-like, astro-glial-like, and ependymal-like tumor cells. While prognostically favorable ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations. Projection of transcriptomic signatures onto an independent bulk RNA-seq cohort stratified patient survival even within known molecular groups, thus refining the prognostic power of DNA methylation-based profiling. Furthermore, we identified novel potentially druggable targets such as IGF- and FGF-signaling within poorly prognostic transcriptional programs. Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate identified target genes in functional follow-up analyses. Taken together, our analyses reveal a developmental hierarchy and transcriptomic context underlying the biologically and clinically distinct behavior of ependymoma groups. The newly characterized cellular states and underlying regulatory networks could serve as basis for future therapeutic target identification and reveal biomarkers for clinical trials.
EPID-01. METASTATIC BRAIN TUMORS IN THE CENTRAL TEXAS MILITARY AND VETERAN POPULATION
Authors: Murillo Jennifer , Benge Jared , Levacic Danijela , Anyanda Elizabeth
Published: December 2020

There are relatively few studies on brain metastases in the military population, despite increased risk factors for the development of some cancers. This data was compared to the results from previously published epidemiological data Surveillance, Epidemiology, and End Results (SEER; Cagney et al, 2017) from the general population. PURPOSE: The purpose of our research was to compare the frequency and etiology of metastatic brain cancer in the military and veteran population in our database relative to the general population. METHODS: Retrospective chart review of diagnoses retrieved from the Electronic Medical Record dated January 1, 2016 to July 1, 2019 capturing visits to the Baylor Scott & White Medical Center with specific ICD 10 brain cancer codes for nonhematologic malignancies originating outside of the CNS. RESULTS: Data from 63 individuals that met criteria for the study was analyzed. The military group was predominantly male (92.1%), white (66.7%) and non-Hispanic (90.5%). In our current sample (N=63) 74.6% had metastatic lung cancer with a histology subset of 24.5% having adenocarcinoma. Compared to the SEER general population our sample was more likely to have metastatic lung cancer with a similar frequency in the histologic subset adenocarcinoma. CONCLUSION: In this exploratory study using retrospective data, trends were found for lung cancer diagnosis with brain metastatic disease, appearing more common in the military sample from a single-center relative to previously published estimates in the general population. Rates were similar for adenocarcinoma. More research into the higher frequency of lung cancer in the military population compared to the general population should be further explored.
EPID-08. PRE-SURGERY IMMUNE PROFILES OF ADULT GLIOMA PATIENTS
Authors: Bracci Paige , Rice Terri , Hansen Helen , Francis Stephen , Lee Sean , McCoy Lucie , Shrestha Pavan , Warrier Gayathri , Clarke Jennifer , Molinaro Annette , Taylor Jennie , Wiencke John , Wrensch Margaret
Published: December 2020

Changes in glioma patients’ immune profiles over the course of disease may predict outcomes. DNA based immunomethylomics quantifies blood immune cells based on cell specific DNA methylation signatures. To assess changes in immune profiles, we are longitudinally collecting blood samples from glioma patients pre-surgery and at other clinically relevant time points. Here we report patients’ pre-surgery immune profiles. All patients underwent biopsy or resection of a presumed new glioma or recurrent lower grade glioma. Blood DNA methylation was assessed with Illumina EPIC methylation arrays. Relative cell fractions of CD4, CD8, B-cells, natural killer cells, monocytes, and neutrophils, were estimated via our validated deconvolution algorithm. Total nucleated cell counts from Nexcelom cytometry were used to compute absolute cell counts. Other measures include total lymphocytes, CD4/CD8 ratio, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio (LMR)). The first 125 participants includes 56 newly diagnosed glioblastomas (GBM), 28 newly diagnosed grade II-III gliomas, and 41 recurrent grade II-III gliomas. Median patient age is 49 years. 53 (43%) had recent dexamethasone exposure. In overall non-parametric analyses, most cell subsets, especially CD4, differed across grade, diagnosis group, WHO classification and dexamethasone exposure. In post-hoc pairwise analyses, immune profiles of IDH wildtype GBM patients who had taken dexamethasone differed from patients with GBM or grade II-III glioma who had not taken dexamethasone; they had clinically relevant and statistically significantly lower absolute CD4 counts, total white cell counts, and percent of total lymphocytes, and higher absolute neutrophil counts, NLR and LMR. However, some dexamethasone naïve GBM patients also had altered immune profiles. Comparisons of relative immune cell fractions with those from 454 non-glioma controls from the UCSF Adult Glioma Study showed that across grade and WHO classification, for the most part, immune profiles of glioma patients not exposed to dexamethasone did not differ from controls.
EPID-11. A MULTI-INSTITUTIONAL COMPARATIVE ANALYSIS OF THE CLINICAL, GENOMIC, AND SURVIVAL CHARACTERISTICS OF PEDIATRIC, YOUNG ADULT AND OLDER ADULT PATIENTS WITH IDH-MUTANT GLIOMA
Authors: Jane Lim-Fat Mary , Vogelzang Jayne , Woodward Eleanor , McGovern Alana , Ma Clement , Al-sayegh Hasan , Alexandrescu Sanda , Margol Ashley , Cotter Jennifer , Cole Kristina , Li Marilyn , Owens Emily , Smith Amy , Goldman Stewart , Kaneva Kristiyana , Burton Emily , Nazemi Kellie , Wright Karen , Wen Patrick , Warren Katherine , Touat Mehdi , Reardon David , Bi Wenya Linda , Ligon Keith , Yeo Kee Kiat
Published: December 2020

BACKGROUND

Prognostic significance of IDH-mutation in glioma is incompletely understood in children and adolescents/young adults (YAs). We compared the clinico-genomic features, outcomes and prognostic factors observed in IDH-mutant gliomas across age groups.

METHODS

Clinical, histologic and molecular data of patients with IDH-mutant gliomas from 8 pediatric institutions (spanning twenty years) and adult patients from two institutions (from 2013–2019) were identified. Patients were grouped as pediatric (< 19y), YA (19y to < 40y) or older adult (≥ 40y). Genomic alterations, including somatic mutations and copy number variants, were captured with institutional next generation sequencing. Factors were compared across age categories using Fisher’s exact test or analysis-of-variance. Cox proportional-hazards regression tested factors for association with overall (OS) and progression-free survival (PFS).

RESULTS

Of 379 patients, 48(13%) were pediatric, 204(54%) YA and 127(33%) older adult. Histological subtype differed significantly by age group (p< 0.0001). YAs had higher rates of malignant transformation (p=0.01) and shorter time-from-diagnosis-to-malignant transformation (p=0.01) compared to other age groups. Analysis of genomic alterations revealed an age-related difference in distribution in ATRX mutations only (p=0.0018). Median PFS and OS for the entire cohort were 4.62 and 17.19 years. In univariate models, PFS differed by age group (p=0.0012), with YAs having the worst outcomes. Lack of MGMT methylation (p=0.024) predicted poorer OS. Upfront observant management was predictive of poorer PFS. Gene mutations were not associated with PFS. In multi-variable models, YAs had shorter PFS compared to pediatric (hazard ratio [HR]=2.03, p=0.01) and older adults (HR=1.59, p=0.003) after adjusting for histology, extent of resection, and initial therapy. Age at diagnosis was not associated with OS in multi-variable analysis.

CONCLUSIONS

Within our cohort, YA with IDH-mutant tumors progressed more quickly compared to their pediatric counterparts. Further study of YA patients with IDH-mutant glioma is critical to better define best practices for this group.
EPID-14. RACIAL DIFFERENCES AND DISPARITIES IN PATIENTS WITH GLIOMAS: A SINGLE COMPREHENSIVE CANCER CENTER EXPERIENCE FROM 2008–2020
Authors: Coffee Elizabeth , Tucker Zachary , Lobbous Mina , Baskin Monica , Markert James , Fiveash John , Miller C Ryan , Nabors Louis
Published: December 2020

BACKGROUND

Disparities in healthcare delivery in the United States based on race and socioeconomic status are well-documented. Our study examined these disparities along with demographic differences in patients with gliomas.

METHODS

Data was collected retrospectively from an NCI Comprehensive Cancer Center between 2008–2020; 163 African-American patients and 1207 non-Hispanic white patients were included. Demographic variables were entered as predictors of tumor grade and type in an ANOVA model and multinomial logistic regression, respectively. A MANOVA model was used to assess differences in treatments received. Predictors of outcome were determined using cox regression.

RESULTS

Significant differences (p< 0.05) were found between African-American and non-Hispanic white patient groups in; age at diagnosis (48.68 vs 56.12 years, respectively), male/female gender ratio (0.75 vs 1.22), annual household income ($29,442 vs $40,028), insurance type (53.1% private and 42% public vs 63.4% private and 33.6% public) and marital status (43% married vs 74.1%). When controlling for these, there were no significant differences in tumor grade, type, MGMT methylation or IDH1 alteration statuses. Race alone did not predict treatment received, however, two-way interactions between race and other variables did. While gender differences in resection were small for non-Hispanic white controls, resection took place more often in African-American females than males (F = 4.779, p = 0.029). The deleterious effect of increased age on overall survival was diminished in African-Americans (B = -0.033, p < 0.001), while the effect of tumor grade was more pronounced (B = 0.595, p < 0.001).

DISCUSSION

This study suggests that disparities in outcomes are identified when race is considered within the context of other demographic, socioeconomic, and clinical factors. Moreover, these observations demonstrate the need for further studies into intersectional effects on treatment access and clinical outcomes, along with aggressive countermeasures to ensure equity of care.
EPID-15. RACIAL AND SOCIOECONOMIC DISPARITIES DIFFERENTIALLY AFFECT OVERALL AND CAUSE-SPECIFIC SURVIVAL IN GLIOBLASTOMA
Authors: Liu Elisa , Yu Sharon , Sulman Erik , Kurz Sylvia
Published: December 2020

BACKGROUND

The prognostic role of racial and socioeconomic factors in patients with glioblastoma is controversially debated. We aimed to evaluate how these factors may affect survival outcomes in an overall and cause-specific manner using large, national cancer registry cohort data in the temozolomide chemoradiation era.

METHODS

The National Cancer Institute’s Surveillance, Epidemiology, and End Results database was queried for patients diagnosed with glioblastoma between 2005 and 2016. Overall survival was assessed using Cox proportional hazard models using disease intrinsic and extrinsic factors. Cause-specific mortality was assessed using cumulative incidence curves and modeled using multivariate cumulative risk regression.

RESULTS

A total of 28,954 patients met the prespecified inclusion criteria and were included in this analysis. The following factors were associated with all-cause mortality: age, calendar year of diagnosis, sex, treatment receipt, tumor size, tumor location, extent of resection, median household income, and race. Asian/Pacific Islanders and Hispanic Whites had lower mortality compared to Non-Hispanic Whites. Cause-specific mortality was associated with both racial and socioeconomic groups. After adjusting for treatment and tumor-related factors, Asian/Pacific and black patients had lower glioblastoma-specific mortality. However, lower median household income and black race were associated with significantly higher non-glioblastoma mortality.

CONCLUSION

Despite the aggressive nature of glioblastoma, racial and socioeconomic factors influence glioblastoma-specific and non-glioblastoma associated mortality. Our study shows that patient race has an impact on glioblastoma-associated mortality independently of tumor and treatment related factors. Importantly, socioeconomic and racial differences largely contribute to non-glioblastoma mortality, including death from other cancers, cardio- and cerebrovascular events.
EPID-16. EPIDEMIOLOGICAL TRENDS FOR LONGER TERM GBM SURVIVORS POST STUPP
Authors: Forner Samantha , Al-Salihi Omar , Brazil Lucy , Swampillai Angela
Published: December 2020

Patients with Glioblastoma Multiforme (GBM) have a poor prognosis with few long-term survivors (>2 years from diagnosis). This review analyses key characteristics of this cohort. METHODS: Retrospective single-centre review of GBM patients treated with the STUPP protocol at a Regional Neuro-oncology centre, Nov-09–Sept-19. Demographics, histology and treatment details were reviewed, with progression (PFS) and overall survival (OS) analysed. RESULTS: In 282 patients (mean age 55 years;M:F ratio 2:1), 77% of patients underwent de-bulking surgery and 35% were MGMT-methylated. Median OS was 72.1 weeks with a statistically significant survival benefit in patients who underwent debulking surgery (p=0.0001), were methylated for MGMT (P=0.0026) or those less than 50yrs (p=< 0.0001). 14% patients were treated within clinical trials. 66 patients (23%) were alive at 24 months. Baseline characteristics - mean age 52yrs; 53% MGMT-methylated; 88% debulking surgery; 16 (24%) patients with histological low grade components and 1 (1%) was of small cell. 55 (83%) relapsed of which (19) 35% received 2 lines of further treatment,14 (25%) had re do surgery, 32 (80%) received CCNU/PCV with or without surgery (24% vs 56%), 7 (13%) received TMZ-alone and 3 (5%) were not suitable for treatment. 8 (3%) were alive at 5 years. Baseline characteristics - mean age 46 years; MGMT (4 methylated, 2 unmethylated, 2 unknown); 3 (38%) had lower-grade histological components. 6 (75%) relapsed - 1 patient received TMZ (within a clinical trial) and 5 PCV/CCNU (2 within a clinical trial). 3 patients had further progression of which 2 received a further 1 line of treatment and 1 a further 3 lines. 6 (75%) remain alive, 2 (33%) in remission following STUPP. CONCLUSIONS: This real world data demonstrates that despite poor prognosis, features including methylation, younger age and surgical resection assist to predict long-term survivors. This highlights the importance of clinical trials.
EPID-30. PREDICTORS ASSOCIATED WITH LONG-TERM SURVIVORSHIP FOR PATIENTS WITH GLIOBLASTOMA USING THE NATIONAL CANCER DATABASE (NCDB)
Authors: Zhu Ping , Du Xianglin , Esquenazi Yoshua , Zhu Jay-Jiguang
Published: December 2020

OBJECTIVES

To investigate the long-term survival rates and the related predictors in patients with glioblastoma (GBM) using NCDB.

METHODS

A total of 51570 GBM patients were derived from the NCDB from 2004 to 2011. Three long-term survival measures were defined as patients who lived for at least 3-year, 5-year, or 10-year after diagnosis, respectively. Multivariable binary logistic regressions were performed to identify predictors in relation to 3-year, 5-year, and 10-year survival rates. The relative importance of each survival predictors was calculated, and random forest method was performed to validate the variable importance and decision tree as well.

RESULTS

A total of 4782 (9.3%), 1481 (3.9%), and 51 (0.9%) GBM patients survived at least 3-year, 5-year, and 10-years, respectively. Significant predictors related to both 3-year and 5-year survival rates from multivariable logistic regression included tumor resection, recent year of diagnosis, age < 65 years, private insurance, adjuvant therapy, non-whites, female, treatment at facility located in South regions or academic facilities, higher income, and non-comorbidity. Moreover, patients who traveled >50 miles for treatment and received care transition were significantly more likely to survival at least 3 years. However, only five predictors were associated with 10-year survivorship: residence-hospital distance >20 miles, non-whites, age < 65 years, resection, and higher income. Based on the calculations of relative importance and random forest method, the most important five factors to predict long-term survival were age, tumor resection, year of diagnosis, comorbidity, and adjuvant therapy (3-year survival); age, tumor resection, comorbidity, gender, and insurance (5-year survival); and age, race, residence-hospital distance, income, and comorbidity (10-year survival), respectively.

CONCLUSIONS

This study identifies non-molecular factors predicting long-term survivorship among GBM patients using NCDB dataset. Our findings suggested that 3-year and 5-year survivors share similar determinants, while 10-year survivors could be more different in socio-demographics and clinical features.
EPID-34. THE DETRIMENTAL EFFECT OF BIOPSY PRECEDING RESECTION IN SURGICALLY ACCESSIBLE GLIOBLASTOMAS: RESULTS FROM THE NATIONAL CANCER DATABASE
Authors: Zhu Ping , Du Xianglin , Blanco Angel , Ballester Leomar Y , Tandon Nitin , Zhu Jay-Jiguang , Hadjipanayis Constantinos , Berger Mitchel , Esquenazi Yoshua
Published: December 2020

OBJECTIVES

To investigate the impact of biopsy preceding resection compared to upfront resection in glioblastoma overall survival (OS) and post-operative outcomes using the National Cancer Database (NCDB).

METHODS

A total of 17,334 GBM patients diagnosed between 2010 and 2014 were derived from the NCDB. Patients were categorized into two groups: “upfront resection” versus “biopsy followed by resection”. Primary outcome was OS. Post-operative outcomes including 30-day readmission/mortality, 90-day mortality, and prolonged length of inpatient hospital stay (LOS) were secondary endpoints. Kaplan-Meier methods and accelerated failure time (AFT) models with gamma distribution were applied for survival analysis. Multivariable binary logistic regression models were performed to compare differences in the post-operative outcomes between these groups.

RESULTS

Patients undergoing “upfront resection” experienced superior survival compared to those undergoing “biopsy followed by resection” (median OS: 12.4 versus 11.1 months, log-rank test: P=0.001). In multivariable AFT models, significant survival benefits were observed among patients undergoing “upfront resection” (time ratio [TR]: 0.83, 95% CI: 0.75–0.93, P=0.001). Patients undergoing upfront GTR had the longest survival compared to upfront STR, GTR following STR, or GTR and STR following an initial biopsy (14.4 vs. 10.3, 13.5, 13.3, and 9.1, months), respectively (TR: 1.00 [Ref.], 0.75, 0.82, 0.88, and 0.67). Recent years of diagnosis, higher income and treatment at academic facilities were significantly associated with the likelihood of undergoing upfront resection after adjusting the covariates. Multivariable logistic regression revealed that 30-day mortality and 90-day mortality were decreased by 73% and 44% for patients undergoing “upfront resection” over “biopsy followed by resection”, respectively (both p < 0.001).

CONCLUSIONS

Pre-operative biopsies for surgically accessible tumors with characteristic imaging features of Glioblastoma lead to worse survival despite subsequent resection compared to patients undergoing upfront resection.
EPID-36. ANTIDEPRESSANT DRUG USE IN GLIOBLASTOMA PATIENTS: AN EPIDEMIOLOGICAL VIEW
Authors: Gramatzki Dorothee , Rogers James , Neidert Marian , Hertler Caroline , Rhun Emilie Le , Roth Patrick , Weller Michael
Published: December 2020

PURPOSE

Antidepressant drugs have shown anti-tumor activity in preclinical glioblastoma studies. Antidepressant drug use, as well as its association with survival, in glioblastoma patients has not been well characterized on a population level.

METHODS

Patient characteristics, including the frequency of antidepressant drug use, were assessed in a glioblastoma cohort diagnosed in a 10-year time-frame between 2005 and 2014 in the Canton of Zurich, Switzerland. Cox proportional hazards regression models were applied for multivariate analysis. Kaplan-Meier survival curves were used to estimate overall survival data and the log-rank test was performed for comparisons.

RESULTS

Four hundred four patients with isocitrate dehydrogenase (IDH) wildtype glioblastoma were included in this study. Sixty-five patients (16.1%) took antidepressant drugs at some point during the disease course. Patients were most commonly prescribed selective serotonin reuptake inhibitors at any time (N=46, 70.8%). Nineteen patients (29.2%) were on antidepressant drugs at the time of their tumor diagnosis. No differences were observed in overall survival between those patients who had taken antidepressants at some point in their disease course and those who had not (p=0.356). These data were confirmed in a multivariate analysis including age, Karnofsky performance status, gender, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and first-line treatment as cofounders (p=0.315). Also, there was no association of use of drugs modulating voltage-dependent potassium channels (citalopram; escitalopram) with survival (p=0.639).

CONCLUSIONS

This signal-seeking study does not support the hypothesis that antidepressants have antitumor efficacy in glioblastoma on a population level.
EXTH-07. TUMOR-HOMING INDUCED NEURAL STEM CELLS SECRETING A CYTOTOXIC PAYLOAD AS AN ADJUVANT TREATMENT FOR NON-SMALL CELL LUNG CANCER BRAIN METASTASES
Authors: Mercer-Smith Alison , Jiang Wulin , Valdivia Alain , Bago Juli , Floyd Scott , Khagi Simon , Hingtgen Shawn
Published: December 2020

INTRODUCTION

Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases.

METHODS

To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation.

RESULTS/CONCLUSION

Following ICV infusion, hiNSCs persisted in the brain for > 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes > 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.
EXTH-11. PATIENT DERIVED INDUCED NEURAL STEM CELLS FOR TREATMENT OF GLIOBLASTOMA
Authors: Buckley Andrew , Hagler Shaye , Lettry Vivien , Bago Juli , Maingi Spencer , Khagi Simon , Ewend Matthew , Miller C Ryan , Hingtgen Shawn
Published: December 2020

Induced neural stem-cells (iNSCs) represent a new opportunity in the emerging field of cellular immunotherapy. Patient-derived iNSCs modified to produce anti-tumoral compounds could lead to less rejection and safer outcomes than an off-the-shelf therapy. In this study, we established fibroblast lines (PFs) from skin-biopsies of patients being treated for glioblastoma (GBM) and transdifferentiated those fibroblasts into iNSC lines that produce anti-tumor compounds. We designed a combination of genomic and functional testing to assess iNSC line efficacy. Functional testing revealed differences in rate of transdifferentiation, therapeutic agent production, and tumor-homing amongst cell lines all of which varied among patients. RNAseq profiles of individual cells lines revealed biomarker signatures that differed in tumor-homing-pathways. There was no observed neuronal differentiation in the iNSCs from the transcriptomic profiles, indicating stability after transdifferentiation amongst PFs. Anti-tumor activity of patient-derived iNSCs was measured in vivo by surgical-resection mouse models with invasive CD133+ GBM cells. Patient-derived iNSCs showed variable tumoricidal effectiveness; more highly effective iNSC cells lines reduced tumor burden and increased survival post-resection from 28 to 45 days, whereas less effective cells lines could increase post-resection survival with increased iNSC dosage. PF origination and transcriptomic profile accounted for the differences amongst the iNSC lines. Identification of differentially expressed genes could indicate the cellular pathways that are most important for guaranteeing high, anti-tumoral activity. Further, the cellular profile of the patient-derived fibroblast influences the resulting cellular profile of the iNSC; potentially, correlation of fibroblast gene expression profile could predict tumoricidal efficacy of derived iNSCs.
EXTH-15. INHIBITION OF 2-HG LEADS TO UPREGULATION OF A PRO-INFLAMMATORY GENE SIGNATURE IN A NOVEL HLA-A2/HLA-DR1 TRANSGENIC MOUSE MODEL OF IDH1R132H-EXPRESSING GLIOMA
Authors: Chuntova Polly , Nicolay Brandon , Hudson Christine , Narayanaswamy Rohini , Ronseaux Sebastien , Montoya Megan , Downey Kira , Okada Hideho
Published: December 2020

Recent studies have demonstrated the impacts of 2-HG on the anti-tumor immune response in isocitrate dehydrogenase (IDH)-mutant gliomas. Our laboratory has reported that mutant IDH1 (IDH1R132H) suppresses STAT1, the master regulator of IFN-responses and IFN-inducible chemokines, thereby contributing to the “cold” tumor environment. Our data also indicated that inhibition of 2-HG production, through the use of a small molecular inhibitor of mutant IDH, can restore anti-tumor immunity. As the IDH1R132H mutation has been shown to elicit a CD4+ T-cell response in human leukocyte antigen (HLA)-DR1 hosts, to establish a clinically relevant mouse model of IDH1R132H glioma, we generated a novel IDH1R132H glioma cell line syngeneic to the HLA-A2/HLA-DR1-transgenic mice. The cell line expresses the IDH1R132H protein, produces ~65 µg/ml 2-HG in vitro, and forms 2-HG producing orthotopic glioma in vivo. Furthermore, ex vivo sorted tumor-associated myeloid cells (TAMCs) demonstrate high levels of intracellular 2-HG (60–80ng/1M cells), suggesting 2-HG may be taken up by these TAMCs in vivo. Treatment of tumor-bearing mice with vorasidenib, a pan-mutant IDH inhibitor, resulted in a 10-fold reduction of 2-HG levels in the tumor cells, correlate reduction in intracellular 2-HG levels in TAMCs, and 2-fold smaller tumors at time of sacrifice. Analysis of tumor tissues using the NanoString platform revealed enhanced pro-inflammatory IFN-related responses as a result of IDH1R132H inhibition with vorasidenib. Furthermore, vorasidenib treatment increased CD4+ tumor-infiltrating T-cells coupled with upregulation of HLA-DR on tumor-infiltrating myeloid cells, suggesting the opportunity for enhanced antigen presentation. Currently ongoing studies are evaluating the benefit of combining this enhanced immune response with additional immunomodulatory treatments, such as vaccine therapy and immune checkpoint inhibition. These data represent highly translational findings as our major histocompatibility complex (MHC)-humanized model addresses current challenges in the study of IDH1R132H-specific immunity and utilizes a clinically relevant inhibitor in phase 3 clinical development.
EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES
Authors: Dhir Nikita , Chandrahas Sheila , O’Suoji Chibuzo , Al-Rahawan Mohamad
Published: December 2020

BACKGROUND

The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation.

OBJECTIVE

Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors.

METHODS

We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy.

DISCUSSION

Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors.

CONCLUSION

The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.
EXTH-22. THE CNS PENETRATING TAXANE TPI 287 AND THE AURKA INHIBITOR ALISERTIB IMPROVE SURVIVAL IN VIVO
Authors: Williams Brian , Zumbar Cory , Sak Muge , Lehman Norman
Published: December 2020

Glioblastoma is the most common primary malignant brain tumor in adults and has a poor prognosis with current standard of care. The AURKA inhibitor alisertib exhibits antiproliferative activity against glioblastoma in vitro including our previous work. Unlike current clinically used taxane drugs, the novel taxane TPI 287 penetrates the CNS. In this study we stereotactically implanted human GB9 xenografts into nude mice brains and tested the activity of alisertib alone, TPI 287 alone and both together compared to control. Five days after implantation treatment was started using twice daily 20 mg/kg alisertib orally administered 5 days per week and/or 18 mg/kg TPI-287 administered intravenously every 4 days for a total of 3 treatments. Survival was assessed as well tumor volume using MR imaging at 2 weeks and 4 weeks after tumor implantation. Monotherapy with alisertib improved survival, which was further improved with the addition of TPI 287 (p=0.0058). TPI 287 alone did not significantly improve survival. Tumor volume was significantly decreased in all treatment groups at 2 weeks compared with control. At 4 weeks the alisertib and TPI 287 groups showed a trend toward decreased tumor volume with a significant decrease in the combination therapy group. This data supports the potential use of this combination therapy in human trials.
EXTH-27. YAP/TAZ TRANSCRIPTIONAL CO-ACTIVATORS CREATE THERAPEUTIC VULNERABILITY TO VERTEPORFIN IN EGFR MUTANT GLIOBLASTOMA
Authors: Read Renee , Vigneswaran Krishanthan , Boyd Nathaniel , Oh Se-Yeong , Lallani Shoeb , Boucher Andrew , Neill Stewart , Olson Jeffrey
Published: December 2020

Glioblastoma (GBM), neoplasms derived from glia and neuro-glial stem/progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months with current treatments. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Using a Drosophila glioma model and human patient-derived GBM cells, we identified the YAP and TAZ transcription co-activators, effectors of the Hippo pathway that promote gene expression via TEAD co-factors, as key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling. YAP and TAZ are highly expressed in EGFR mutant human GBMs, and their knockdown in EGFR mutant GBM cells inhibits proliferation, blocks neuro-glial stem/progenitor cell fate, and elicits apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulate transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation as well as stem/progenitor cell fate in human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD mediated transcription, specifically induced apoptosis of cultured patient-derived GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe and verify verteporfin uptake into tumor cells in GBM tumors in human patients. Together, our data indicate that verteporfin is a promising therapeutic agent for EGFR amplified and mutant GBM. On the basis of these results, we have initiated as phase 1/2 clinical trial of Visudyne in patients with recurrent GBM characterized by EGFR amplification and/or mutation.
EXTH-29. INHIBITION OF LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A (KDM1A/LSD1) SENSITIZES GLIOBLASTOMA CELLS TO CHEMO AND RADIATION THERAPY
Authors: Alejo Salvador , Palacios Bridgitte , Venkata Prabhakar Pitta , Chen Yihong , He Yi , Viswanadhapalli Suryavathi , Pratap Uday , Zheng Siyuan , Brenner Andrew , Vadlamudi Ratna , Sareddy Gangadhara
Published: December 2020

BACKGROUND

Despite treatment advances, glioblastoma (GBM) is the deadliest tumor of the central nervous system. Patients face a dismal 15-month median survival and average 5-year survival rate of 13%. Current standard of care includes surgical resection, external beam radiation therapy, and adjuvant chemotherapy with temozolomide (TMZ). Unfortunately, GBM patients often relapse and succumb to their disease. Recently, we have shown that lysine-specific histone demethylase 1A (KDM1A/LSD1) is overexpressed in GBM. In this study, we tested the hypothesis that KDM1A is essential for DNA damage response (DDR), inhibiting KDM1A thereby sensitizes GBM to either TMZ or radiation therapy.

METHODS

KDM1A knockout (KDM1A-KO) and knockdown (KDM1A-KD) cells were generated using CRISPR/Cas9 and KDM1A specific shRNA, respectively. Cell viability, clonogenic survival, and apoptotic assays were used to study the effect of KDM1A-KO, -KD, or pharmacological KDM1A inhibitors (NCD-38 and NCL-1) on radiation and TMZ sensitization. Mechanistic studies were conducted using RNA-seq, RT-qPCR, and western blot analysis. Furthermore, in vivo efficacy of KDM1A inhibitor and TMZ was established using orthotopic models of GBM.

RESULTS

Cell viability, survival, and apoptotic assays demonstrated that knockout/knockdown or inhibition of KDM1A sensitized GBM cells to both TMZ or radiation therapy. KDM1A inhibitors used in combination with radiation or TMZ significantly increased apoptosis in GBM cells. RNA-seq analysis and signaling studies showed attenuation of DDR pathways in KDM1A-KD cells. Radiation or TMZ treatment enhanced DNA damage in KDM1A-KD cells compared to controls. Importantly, combination of KDM1A inhibitor and TMZ significantly reduced in vivo tumor progression and improved overall survival in orthotopic GBM murine models.

CONCLUSIONS

Our results provide strong evidence that KDM1A inhibition sensitizes GBM to TMZ or radiation therapy via modulation of DDR. This suggests combination of KDM1A inhibitors with TMZ or radiation therapy could serve as a novel treatment for GBM patients.
EXTH-31. INCREASING TUMOR TREATING FIELDS (TTFIELDS) EFFICACY BY TARGETING THE G2 CELL CYCLE CHECKPOINT WITH WEE1 OR CHK1 INHIBITORS IN GLIOBLASTOMA CELL LINES
Authors: Slangen Paul L G , de Gooijer Mark C , van Geldorp Mariska , van Tellingen Olaf , Borst Gerben R
Published: December 2020

Tumor Treating Fields (TTFields) are a novel, noninvasive FDA-approved treatment modality for glioblastoma (GBM) that utilizes alternating electric fields. While the mechanism of action was at first exclusively attributed to the effects of TTFields on cells during mitosis, additional effects during interphase have recently come to light. The aim of our research is to elucidate the effect of TTFields on the cell cycle to advance the understanding of TTFields and to find novel targets for increasing its efficacy. We studied the effect of TTFields on cell cycle distribution by (propidium iodide and phospho-Histone H3 labeling) flow cytometry using double-thymidine block (DTB) synchronized cell populations. Following the release of the DTB, TTFields treatment caused GBM cells to accumulate in G2, which was prevented by concomitant exposure to a Wee1 inhibitor. Next, we compared the efficacy of TTFields with or without Wee1 or Chk1 inhibitors in multiple GBM cell lines (A172, SNB-19, and U251) by colony formation assays and observed a strong and synergistic decrease in colony formation potential in all cell lines. To investigate the underlying mechanism of G2 arrest, we quantified the amount of DNA damage, but found no difference in either γH2AX foci or comet tail moments between control and TTFields treated cells. To follow up on this surprising observation, we are using live cell imaging (inovitro Live™) of PIP-FUCCI-transduced cells. This tool will allow us to track individual cells, to evaluate the time spent in each phase of the cell cycle and to determine the ultimate cell fate in control and treatment conditions. Our finding that Wee1 or Chk1 inhibition dramatically boosts the efficacy of TTFields may have great implications for treatment of patients with TTFields. The in vivo validation of our in vitro findings will be performed in tumor-bearing mice by using the inovivo™ system.
EXTH-34. PHASE I TRIAL OF CONVECTION-ENHANCED DELIVERY OF IL13RA2 AND EPHA2 RECEPTOR TARGETED CYTOTOXINS IN DOGS WITH SPONTANEOUS INTRACRANIAL GLIOMAS
Authors: Rossmeisl John , Herpai Denise , D’Agostino Ralph , Rossmeisl John , Tatter Stephen , Dickinson Peter , Debinski Waldemar
Published: December 2020

The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection enhanced delivery (CED) method. In this study, IL-13 mutant and Ephrin-A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy. In this Phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI-monitoring. The primary end point was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas. Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40–94%). Cytotoxins were well tolerated over a dose range of 0.012–1.278 mg/mL delivered to the target volume (median, 0.099 mg/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 mg/mL. This study provides pre-clinical data fundamental to the translation of this multi-receptor targeted therapeutic approach to the human clinic.