bluuebunny/crossref_metadata_2025 huggingface dataset:
EPCO-24. COMPUTATIONAL APPROACH TO IDENTIFYING NEUROINFLAMMATION IN GLIOBLASTOMA MULTIFORME (GBM)
Authors: Sherman Wendy , Martin Katie , Rossell Larissa , Nguyen Kelly , Grady Pamela , Zimmermann Cynthia , Chesla David , Mackeigan Jeffrey
Published: December 2020

INTRODUCTION

Glioblastoma multiforme (GBM) is an aggressive brain cancer with dismal prognosis, despite aggressive surgery, radiation and chemotherapy. Therapies directed to the immune system are an exciting prospect in oncology and require an understanding of the interaction between tumors and immune cells. Our objective was to use computational tools to estimate immune infiltration in GBM and determine whether specific immune cell types are associated with clinical outcomes.

METHODS

RNA sequencing and targeted DNA sequencing (to 981 oncology genes) was performed from 37 surgically-resected GBM tumors. Tumor mutations were identified, and gene-level transcript counts were used to estimate tumor-associated cell types using bioinformatics tools. Clinical variables, including survival from surgery and diagnosis, were collected and tested for associations with molecular data.

RESULTS

We detected leukocyte fractions (i.e., immune infiltration) ranging from 2% to 50% in GBMs, with an average of 10.2%. Specifically, we found a statistically significant association between high Th2 cell estimates and reduced overall survival (from both surgery and diagnosis). Nine patients with high Th2 tumors had a median OS from surgery of 187 days, compared with a median of 454 days for 28 patients with low Th2 tumors (log-rank Matel-Cox test; p = 0.0023, HR = 3.1). We also found an association between NF1 mutant tumors, which were enriched for a KRAS signaling signature, and high immune infiltration (p < 0.05).

CONCLUSION

Our computationally-driven approach predicted significant immune infiltration in GBM and a potential association between poor prognosis and Th2 cells. The specific class of CD4+ helper T-cells is generally associated with poor anti-tumor immunity and a Th2-bias has been reported in gliomas. Our data adds to the collective understanding of the molecular landscape of GBM, as well as the complex immune environment, which will have important implications in tumor treatment and prognosis.
EPCO-27. GLIOMA SINGLE CELL MULTI-OMIC ANALYSES REVEALS REGULATORS OF PLASTICITY AND ADAPTIVE STRESS RESPONSE
Authors: Johnson Kevin , Anderson Kevin , Courtois Elise , Barthel Floris , Varn Frederick , Luo Diane , Yi Eunhee , Kim Hoon , Estecio Marcos , Tang Ming , Navin Nicholas , Maurya Rahul , Ngan Chewyee , Bulsara Ketan , Samuels Michael , Das Sunit , Robson Paul , Verhaak Roel
Published: December 2020

Extensive intra- and intertumoral heterogeneity in glioma contributes to therapeutic resistance and poor patient outcomes. Alterations to DNA methylation (DNAme) modulate epigenetic homeostasis, allowing tumor cells to sample alternative cell states to promote tumorigenesis. However, the epigenetic mechanisms that promote cellular plasticity and regulate cell states are still poorly understood. To characterize the epigenetic mechanisms underlying glioma heterogeneity we profiled 914 single-cell methylomes, 55,284 single-cell transcriptomes, and bulk whole genomes across 11 patient samples spanning initial and recurrent time points and 3 molecular subtypes delineated by IDH mutation status. Local DNAme disorder, defined as epimutation burden, was increased in tumor cells relative to nontumor cells, higher in IDH wild-type than in IDH mutant glioma and was positively associated with copy number alteration (CNA). Epimutation was positively associated with transcriptional variability and enriched at genes involved in cellular differentiation. Epimutation was also increased in the binding sites of transcription factors (TFs) associated with response to extracellular stimuli, suggesting that stochastic DNAme alterations enable cellular plasticity and diverse responses to microenvironmental stressors. Integrative clustering of DNAme and scRNAseq profiles defined stem-like and differentiated-like cell states which exhibited differences in TF activity. Stem-like cells were enriched for differentially methylated binding sites of TFs associated with hypoxia response. scDNAme and scRNAseq-derived copy number profiles were compared with bulk copy number profiles and inferred tumor phylogenies to assess how the timing of CNAs impact epigenetic instability, with results suggesting that early CNA events propagate both genetic and epigenetic heterogeneity. Bulk longitudinal data was used to validate the relationship of epigenetic instability with CNA burden as well as differentially methylated binding sites of cell stress response TFs. Our work suggests that local DNAme disorder promotes cellular plasticity and enables adaptive response to cellular stress such as hypoxia.
EPID-02. STEREOTACTIC RADIOSURGERY AND CHEMOTHERAPY TREATMENT PATTERNS IN BREAST CANCER BRAIN METASTASES
Authors: Wang Jacqueline , Ascha Mustafa , Kruchko Carol , Iorgulescu Bryan , Barnholtz-Sloan Jill S
Published: December 2020

Brain metastases (BM) are typically treated with systemic chemotherapy and stereotactic radiosurgery (SRS). Population-level studies exploring SRS use in different patient populations and its impact on chemotherapy treatment patterns are needed. This study examines data from Surveillance, Epidemiology, and End-Results (SEER) from 2010–2012 and Medicare claims from 2008–2014 to identify the utility of SRS and associated chemotherapy treatment patterns in the breast cancer BM patient population. 25,954 breast cancer patients were identified, of which 6,657 (26%) received SRS. Chi-square and Fisher’s exact tests were used for initial univariate analyses. Univariable logistic regression models were fit for each predictor and multivariable models were selected using LASSO. Compared to patients without SRS, patients who received SRS were older, diagnosed at later disease stages, and less likely to have the Her2-/HR+ subtype. Patients with SRS most commonly received aromatase inhibitors (53.5%), followed by selective estrogen receptor modulators (SERM; 31.7%), taxanes (27.2%), alkylating agents (21.2%), monoclonal antibodies (22.2%), antimetabolite drugs (18.3%), anthracyclines (11.4%), and platinating agents (6.8%). Increased odds of SRS were associated with drug classes including taxanes (aOR: 1.29), monoclonal antibodies (aOR: 1.67), antimetabolites (aOR: 1.77), anthracyclines (aOR: 1.32), and topoisomerase-II inhibitors (aOR: 3.16). Aromatase inhibitors were associated with decreased odds of SRS use (aOR: 0.84). Alkylating agents, platinating agents, and SERM had no such associations. Our findings suggest that use of many chemotherapeutic agents increases with SRS regardless of ability to penetrate the blood-brain-barrier and parallels standard systemic breast cancer treatments. Because large-scale studies on the impact of SRS on breast cancer BM patients are lacking, it is important to identify differences in treatment usage and patterns. Important clinical implications regarding drug usage frequency, adherence to treatment guidelines, and use of different agents across SRS patients may arise by analyzing differences amongst and between populations of patients with and without SRS.
EPID-10. MITOCHONDRIAL DNA SEQUENCE VARIATION AND RISK OF GLIOMA
Authors: Samanic Claudine , Teer Jamie , Thompson Zachary , Creed Jordan , Nabors Louis , Williams Sion , Egan Kathleen
Published: December 2020

Malignant gliomas are the most common primary adult brain tumors, with poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, but research on glioma is lacking. We examined the association of germline mtDNA variants and haplogroups with glioma risk in 1,654 glioma cases and 1,065 controls from a US case-control study, and 427 glioma cases and 1,541 controls from the UK Biobank, all genotyped using the UKBiobank array with 276 tiled mtDNA variants. The analysis was restricted to participants of European ancestry, and risk of glioblastoma (GBM) and lower grade glioma (LGG) was examined separately. Distribution of mitochondrial haplogroups (H/HV,I,J,K,R,T,U,V,W,X) were similar in both study populations, with 46.4% and 48.1% of controls in the US and UK studies respectively, identified as H/HV, the most common haplogroup. In the US study there was an inverse association between haplogroup W and glioma (OR=0.43, 95%CI: 0.23–0.79) when compared with the H/HV haplogroup, which was not seen in the UK study (OR=1.10, 95%CI: 0.49–2.49). In the US study, a significant inverse association was observed with the previously reported mtDNA variant m.14798T > C (PMID: 31323957), resulting in the amino acid substitution F18L, for LGG (OR=0.73; 95%CI: 0.53–0.99) though not for GBM (OR=0.86; 95%CI: 0.66–1.11). In the UK study, the F18L substitution was associated with an increased risk of GBM (OR=1.48; 95%CI: 1.07–2.04), and no association was observed for LGG (OR=0.95; 95%CI: 0.53–1.68). Among cases in the US study with isocitrate dehydrogenase 1 (IDH1) status available (747 gliomas), a nonsignificant inverse association of the F18L substitution was observed in glioma cases with wild type (OR=0.72; 95%CI: 0.52–1.01) but not mutant (OR=1.08; 95%CI: 0.70–1.69) IDH1. No other common mtDNA variant (minor allele > 5%) was associated with glioma risk in either study. These associations merit further study.
EPID-12. TREATMENT OUTCOMES OF MIDLINE GLIOMAS WITH H3K27 M: OUR BARROW NEUROLOGICAL INSTITUTE EXPERIENCE
Authors: Azadi Amir , Fonkem Ekokobe , Ranade Tejas
Published: December 2020

BACKGROUND

H3 K27M glioblastoma is an aggressive grade IV tumor located in midline structures, added in 2016 by the WHO. Current outcomes are poor. The rarity of these tumors presents a challenge for definitive research on developing optimal treatments.

METHODS

We conducted a case series of 12 patients at the Barrow Neurological Institute who were diagnosed with biopsy-proven H3 K27M glioblastoma. The clinical status of these patients was followed from dates of first and last contact. Factors included first line treatment, best response to first line treatment, recurrences, second line treatments, response assessment criteria for all treatment rounds, any discovered metastases, and vital status by date of last contact.

RESULTS

Of the initial 12 patients, 5 were lost to follow-up before meaningful clinical outcomes could be recorded. Of the remaining 7, all underwent temozolomide and radiation as components of first-line treatment. After first-line treatment, 1/7 (14.2%) had partial response, 3/7 (42.8%) had stable disease, and 3/7 (42.8%) had progressive disease. 4 patients elected to undergo second line treatment: 2 underwent bevacizumab with lomustine, 1 underwent bevacizumab and irinotecan, and 1 underwent surgery with carmustine. Of the 2 who underwent bevacizumab and lomustine, 1 (50%) improved from progressive to stable disease and 1 (50%) stayed at stable disease. Of the 1 patient who underwent bevacizumab and lomustine, outcome worsened from stable to progressive disease. Of the 1 patient who underwent surgery and carmustine, outcome improved from progressive to stable disease.

CONCLUSIONS

H3 K27M is a highly aggressive tumor with poor outcomes. This case series demonstrates that multiple treatment rounds with chemotherapy and radiation therapy may benefit patients, with bevacizumab/lomustine and surgery/carmustine appearing to lead to promising outcomes. Further research is needed to establish evidence-based protocols so quality of life and survival time in these patients may improve.
EPID-13. A RETROSPECTIVE ANALYSIS TO STUDY THE SURVIVAL CHARACTERISTICS OF PATIENTS WITH FIRST PROGRESSION OF GLIOBLASTOMA AT THE CLEVELAND CLINIC
Authors: Rauf Yasmeen , Yao Jimmy , Barnett Addison , Chen Yanwen , Hobbs Brian , Stevens Glen , Peereboom David , Ahluwalia Manmeet
Published: December 2020

BACKGROUND

Glioblastoma (GBM) is the most aggressive primary central nervous system malignancy. The median overall survival is 15 to 18 months with treatment and decreases to nine months after first progression.

METHODS

This is a retrospective study. Data was collected from all patients with first progression of GBM treated at CCF between Jan 2012 to Jan 2020. Eight cohorts of patients were evaluated: Group 1 received cytotoxic chemotherapy, Group 2 received bevacizumab alone, Group 3 received surgical or reirradiation alone, Group 4 were enrolled in clinical trials. Each group was divided into methylated and unmethylated cohorts.

RESULTS

Median overall survival was 12.4 months for patients with first progression of GBM (n= 248). Among the methlylated patients, the median overall survival was 16.5 months for group 1, 13.4 for group 2, 23.7 for group 3, and 17.3 for group 4. Among the unmethylated patients, the Median overall survival was 8.6 months for group 1, 7.7 months for group 2, 11.7 months for group 3 and 10.7 months for group 4. (p= 0.00016). Progression free survival (PFS) was 4.3 months for all patients with first progression of GBM. Among the unmethlylated patients, the PFS was 3.6 months for group 1, 15.3 months for group 2, 4.8 months for group 3, and 6.1 months for group 4. Among the unmethylated patients, the PFS was 2.3 months for group 1, 3.9 months for group 2, 3.8 months for group 3, and 4.4 months for group 4. (p < 0.0001).

CONCLUSION

Patients with first progression of GBM had the best overall survival in the cohort that underwent a surgical or reirradiation. The best progression free survival was for patients who were treated with Bevacizumab if they were methylated and those enrolled in clinical trials if they were unmethylated. The study was statistically significant.
EPID-18. GLIOBLASTOMA CHARACTERIZATION IN FEMALES WITHIN RURAL PENNSYLVANIA: A SINGLE INSTITUTIONAL RETROSPECTIVE REVIEW
Authors: Giombetti Maia , Jakubek Emilia , Gatson Na Tosha , Bross Shane
Published: December 2020

BACKGROUND

Glioblastoma (GBM) is the most common malignant brain tumor in adults with a slightly higher incidence and shortened survival in males as compared to females in the United States. Recently, there has been a focus on specific health disparities between rural versus urban populations. There is growing interest in these disparities as it pertains to CNS tumors. Here, we characterize a rural population of females diagnosed with GBM as part of an ongoing investigation to drive research and further discussion around this important topic.

METHODS

We performed a single institutional retrospective review of patients with GBM in rural Pennsylvania between 2006 and 2019. We collected clinical, demographic, and tumor specific data including chronic comorbid disease, marital status, age at diagnosis, obstetric history, BMI, and tumor location.

RESULTS

Of the 611 patients diagnosed with GBM from 2006–2019, 41% (n= 249) were female with a median overall survival of 9.5 months compared to 10.7 months in males. At diagnoses, 69% (n=173) of females had chronic comorbid allergy/immunology disorders, 41% (n=101) had endocrine disorders, 53% (n=132) had hypertension, and 43% (n=106) had mood disorders. Tumor laterality was predominantly right-sided (58%, n=145) and frequently involved the frontal lobe (38%, n=94). The temporal lobe was the second most commonly involved (32%, n=80). The median age at diagnosis was 65-years-old [range, 21–92]. Fifty-six percent (n=140) of women were married with an average of 2.27 childbirths. The median body mass index (BMI) was 27.5 [range, 16.3–64.9] with 66% of females classified as overweight/obese at diagnosis. Greater than 95% of females were insured.

CONCLUSION

There is a high incidence of chronic comorbid disease and obesity amongst females in this rural population, and females demonstrated a poorer overall survival as compared to males. Further comparisons are needed to characterize rural female GBM populations versus those in urban areas.
EPID-19. RACIAL/ETHNIC DISPARITIES IN TREATMENT PATTERN AND TIME TO TREATMENT FOR ADULTS WITH GLIOBLASTOMA IN THE US
Authors: Ostrom Quinn , Patil Nirav , Cioffi Gino , Barnholtz-Sloan Jill S
Published: December 2020

BACKGROUND

Race/ethnicity have been previously shown to significantly affect survival after diagnosis with glioblastoma, but the cause of this survival difference is not known. The aim of this study was to examine variation in treatment pattern and time to treatment by race/ethnicity, and the extent to which this affects survival.

METHODS

Data were obtained from the National Cancer Database (NCDB) for adults >= 40 with glioblastoma (histologic codes 9440–9442 and topographical codes C71.0–C71.9) from 2004–2016 (N=117,710). Treatment patterns and time to treatment by race/ethnicity were compared using univariable and multivariable logistic and linear regression models, respectively. Models were adjusted for age, sex, insurance status, pre-existing comorbidities, type of treating institution, and distance to institution.

RESULTS

Black non-Hispanics (BNH) were 17% less likely to receive radiation (p=1.47x10-8) and 32% less likely to receive chemotherapy (p=1.10x10-31) than White non-Hispanics (WNH). Among those that did receive treatment, it took 3.3 additional days on average for BNH to receive radiation (p=2.12x10-11) and 4.6 additional days to receive chemotherapy in comparison to WNH (p=4.14x10-10). Hispanics were 21% less likely to receive radiation (p=4.79x10-12), and 23% less likely to receive chemotherapy (p=7.51x10-14) than WNH. Among those that did receive treatment, it took 3.3 additional days on average for Hispanics to receive radiation (p=4.07x10-9) and 4 additional days to receive chemotherapy in comparison to WNH (p=1.51x10-6). There were no significant differences in time to surgery, or in to treatment for Asian Pacific Islanders or American Indian/Alaska Natives.

CONCLUSIONS

Both likelihood of receiving treatment and time to radiation and chemotherapy vary significant between BNH and Hispanics as compared to WNH, and this difference is not fully explained by comorbidities or access to health care.
EPID-22. CHARACTERIZATION OF RADIATION-INDUCED MENINGIOMAS IN A BRAIN TUMOR DATABASE
Authors: Vaghjiani Nilan , Schwieder Andrew , Uppalapati Sravya , Kons Zachary , Kazarian Elizabeth , Sattiraju Srikar , Opalak Charles , Harris Timothy , Broaddus William
Published: December 2020

PURPOSE

Radiation-induced meningiomas (RIMs) are associated with previous exposure to therapeutic irradiation. RIMs are rare and have not been well characterized relative to spontaneous meningiomas (SMs).

METHODS

1003 patients with proven or presumed meningiomas were identified from the VCU brain tumor database. Chart review classified RIM patients and their characteristics.

RESULTS

Of the 1003 total patients, 76.47% were female with a mean ± SD age of 67.55 ± 15.50 years. 15 RIM patients were identified (66.67% female), with a mean ± SD age of 52.67 ± 15.46 years, 5 were African American and 10 were Caucasian. The incidence of RIMs was 1.49% in our data set. The mean age at diagnosis was 43.27 ± 15.06 years. The mean latency was 356.27 ± 116.96 months. The mean initiating dose was 44.28 ± 14.68 Gy. There was a significant difference between mean latency period and ethnicity, 258.3 months for African American population, and 405.2 months for Caucasian population (p = 0.003). There was a significant difference between the mean number of lesions in females (2.8) versus males (1.2; p = 0.046). Of the RIMs with characterized histology, 6 (55%) were WHO grade II and 5 (45%) were WHO grade I, demonstrating a prevalence of grade II tumors approximately double that found with SMs. RIMs were treated with combinations of observation, surgery, radiation, and medical therapy. Of the 8 patients treated with radiation, 4 demonstrated response. 8 of the 15 patients (53%) demonstrated recurrence/progression despite treatment.

CONCLUSION

RIMs are important because of the associated higher grade histology, gender, and ethnic incidences, and increased recurrence/progression compared to SMs. Despite the presumed contributory role of prior radiation, RIMs demonstrate a significant rate of responsiveness to radiation treatment.
EPID-25. SKULL BASE MENINGIOMAS ARE ASSOCIATED WITH OBESITY IN MALES
Authors: Shahin Maryam , Stedelin Brittany , Ramos Christian Lopez , Rae Ali , Edwards Jared , Bagley Jacob , Bowden Stephen , Bullis Carli , Wood Matthew , Cetas Justin , Han Seunggu
Published: December 2020

BACKGROUND

The female predominance of meningiomas may reflect hormonal influences on meningioma development, with known presence of estrogen and progesterone receptors. Progestin-associated meningiomas demonstrate a shift in the mutational landscape and are more frequently located at the skull base. Obesity and increased adipocytes increase aromatase and affect male hormone synthesis, thus increases circulating estrogen.

OBJECTIVE

Report prevalence of obesity in a consecutive series of male patients presenting with meningioma and the interaction with obesity.

METHODS

A retrospective review (20012019) was performed of male patients diagnosed with meningioma. Body mass index (BMI) >30 kg/m2 was considered obese. Obese male meningioma patients were characterized and compared to nonobese male meningioma patients.

RESULTS

Of 239 male patients with meningioma, 97 (40.6%) were obese at the time of surgery with overall mean BMI (30.0 kg/m2). This is above the age-adjusted baseline prevalence of obesity for males in Oregon, which was 34.8% between 2015–2016. Mean age at diagnosis for obese males was 55.3 years and 57.0 years for nonobese males. Within the obese group, most lesions were located on the skull base (48.5% n=47) compared to 34.0% convexity (n=33), 15.4% falx (n=16) and 1.0% multiple (n=1). Tumors were WHO grade I (73.6%), grade II (25.6%) or grade III (1.2%). Of the men in our series, patients with skull base meningiomas were more likely to be obese (OR: 1.7, 95% CI: 1.01–2.9, p=0.0309).

CONCLUSIONS

There is likely a hormonal influence on the pathogenesis of meningioma, and many men diagnosed with this disease are obese. Of 239 male patients with meningioma in our series, 97 (40.6%) were obese which exceeds the 34% age-adjusted baseline prevalence of obesity for males in Oregon. Patients with skull base meningiomas were more likely to be obese, consistent with prior series and suggestive of a hormone-driven association with skull base meningioma.
EPID-28. THE IMPACT OF RITUXIMAB COMBINATION CHEMOTHERAPY ON THE CLINICAL OUTCOMES OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL): AN UPDATED META-ANALYSIS
Authors: Haddad Philip , Hammoud Dalia , Gallagher Kevin
Published: December 2020

BACKGROUND

PCNSL is a rare diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system accounting for approximately 2–5% of all primary brain tumors. Although there is no standard combination of chemotherapy, high-dose methotrexate is considered the backbone of all PCNSL chemotherapy regimens. Rituximab, an anti-CD20 antibody, has been a standard component of DLBCL combinations since it improves progression-free (PFS) and overall survival (OS). However, the role of Rituximab in the treatment of PCNSL has been controversial with contradictory RESULTS: A small meta-analysis conducted in 2019 found no associated survival advantage for Rituximab when added to chemotherapy. However, this meta-analysis was small and included only 2 studies. The purpose of this updated meta-analysis is to evaluate in a more comprehensive way the impact of Rituximab combination chemotherapy on the clinical outcomes of patients with PCNSL incorporating all available comparative studies.

METHODS

A review of the medical literature was conducted using online databases. Inclusion criteria consisted of PCNSL diagnosis, English language, and studies reporting OS and PFS with hazard ratios (HR) or Kaplan-Meier curves that compared similar regimens with and without Rituximab. A meta-analysis using an inverse variance method with a random-effects model was conducted.

RESULTS

Four comparative studies with a total of 467 patients were included in this meta-analysis. Two of these studies were retrospective comparative studies and two were randomized phase II trials. When added to chemotherapy, Rituximab was found to significantly improve the OS and PFS (HROS 0.75, 95%CI: 0.59–0.96, p=0.02; HRPFS 0.67, 95%CI: 0.53–0.85, p=0.001) with a heterogeneity estimate, I2=0%.

CONCLUSIONS

This is the first meta-analysis to show that adding Rituximab to chemotherapy is associated with OS and PFS in patients with PCNSL. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the routine use of Rituximab combinations in PCNSL.
EPID-29. CAUSES OF DEATH FOR PRIMARY BRAIN AND CNS TUMOR PATIENTS IN THE UNITED STATES (2001 – 2016): A POPULATION BASED STUDY
Authors: Penuela Maria , Patil Nirav , Cioffi Gino , Kruchko Carol , Barnholtz-Sloan Jill S
Published: December 2020

BACKGROUND

Population-based data on the various causes of death among Primary Brain and CNS tumor patients are lacking. We evaluated the causes of death for all eligible patients using the National Program of Cancer Registries (NPCR) data.

METHODS

The population-based cancer survival data collected by the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) were used to analyze the causes of death for patients of all ages with primary brain and CNS tumors diagnosed between 2001 and 2016. Patients for whom the cause of death was not listed on the death certificate or whose state death certificate was not available were excluded. Additional analyses to identify factors associated with brain tumor-specific mortality for the most common malignant (Glioblastoma) and non-malignant (Meningioma) were performed using univariable and multivariable logistic regression analysis.

RESULTS

Major cause of death for patients with malignant tumors was death due to brain and other CNS tumors (49.29%), and for non-malignant tumors were other benign and malignant tumors (31.5%) and heart disease (17.9%). Overall mortality was 36.4% (n=331,953) in patients with Primary Brain and CNS Tumors during the study period. Specifically, 163,621 (49.29%) patients died due to brain and other CNS tumors. A significant proportion of patients with malignant tumors had brain tumor-specific mortality compared to non-malignant tumors (75.4% in malignant vs 4.2% in non-malignant). The factors associated with brain specific mortality in Glioblastoma patients were Age (p< 0.001), Race (p< 0.001) and Primary Site (p< 0.001). Further, the factors associated with brain specific mortality in Non-malignant Meningioma patients were Age (p< 0.001), Sex (p< 0.001), Race (p< 0.001) and Primary Site (P< 0.001).

CONCLUSION

Cause of death attributed to the brain tumor was significantly higher in malignant brain tumors compared to non-malignant brain tumors.
EXTH-02. TUMOR-HOMING INDUCED NEURAL STEM CELL THERAPY INHIBITS THE PROGRESSION OF BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL CARCINOMATOSIS
Authors: Jiang Wulin , Valdivia Alain , Mercer-Smith Alison , Anders Carey , Hingtgen Shawn
Published: December 2020

INTRODUCTION

Breast cancer brain metastasis, including leptomeningeal carcinomatosis (LC), remains one of the most lethal CNS diseases. New therapies are urgently needed to treat this highly aggressive disease. Here we used models of both breast cancer brain parenchymal metastasis and leptomeningeal metastasis to investigate the efficacy of engineered tumor-homing neural stem cells (NSCs) therapy.

METHODS

Personalized NSCs were created using Sox2 overexpression to transdifferentiate human fibroblasts into induced NSCs (iNSCs), followed by genetic engineering to enable iNSCs to secrete cytotoxic TRAIL (iNSC-TRAIL). For the parenchymal metastasis study, iNSC-TRAIL therapy was infused intracerebroventricularly (ICV) into Nude mice bearing established intracranial MDA-MB-231-Br human breast cancer cells expressing fluorescent and bioluminescent reporters. For LC studies, we established the disease model by inoculating Nude mice with MDA-MB-231-Br tumor cells via intracisternal infusion. iNSC-TRAIL therapy was evaluated by infusing therapy ICV either 1 week prior to or 3 days after tumor inoculation to mirror prophylactic or established tumor treatment, respectively. Tumor progression in the brain and spine was monitored by serial bioluminescence imaging (BLI), and survival was analyzed.

RESULTS

Serial BLI showed ICV-infused iNSC-TRAIL reduced parenchymal tumor volumes by 72% 3 weeks post-ICV infusion, and extended median survival from 37 to 52 days. Testing iNSC-TRAIL therapy against established LC tumors, serial BLI showed ICV iNSC-TRAIL therapy reduced established tumors 196-fold in the brain and 500-fold in the spine within 2 weeks post-infusion, while extending median survival from 25 to 47 days. In the prophylactic LC model, iNSC-TRAIL therapy markedly delayed tumor development with tumors in the brain remaining > 1000-fold smaller than control, and tumors in the spine below the limit of detection through 1 month post-treatment. The therapy also eliminated mortality through 50 days post-therapy.

CONCLUSION

These data suggest iNSC therapy could be a promising treatment option for breast cancer brain metastasis patients.
EXTH-03. IODINE NANOPARTICLE RADIOTHERAPY OF HUMAN BREAST CANCER GROWING IN THE BRAINS OF ATHYMIC MICE
Authors: Hainfeld James , Ridwan Sharif M , Stanishevsky Yaroslav , Smilowitz Henry
Published: December 2020

About 30% of breast cancers metastasize to brain; those widely disseminated are fatal typically in 3–4 months, even with the best available surgery, drugs, and radiotherapy. To address this dire situation, we have developed iodine nanoparticles (INPs) that target brain tumors after intravenous (IV) injection. The iodine then absorbs X-rays during radiotherapy (RT), creating free radicals and local tumor damage, effectively boosting the local RT dose at the tumor. Efficacy was tested using the very aggressive human triple negative breast cancer (TNBC, MDA-MB-231 cells) growing in the brains of athymic nude mice. With a well-tolerated non-toxic IV dose of the INPs (7 g iodine/kg body weight), tumors showed a heavily iodinated rim surrounding the tumor having an average uptake of 2.9% iodine by weight (peaks at 4.5%), calculated to provide dose enhancement factors of ~5.5 (peaks at 8.0) -- the highest ever reported for any radio-sensitizing agents. With 15 Gy, single dose RT, all animals died by 72 days; INP pretreatment resulted in longer-term remissions with 40% of mice surviving 150 days and 30% surviving > 280 days. Fluorescence confocal microscopy revealed most INP staining co-localized with CD31in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+blood-vessels. The significant radiation dose enhancement to the prolific INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new NP, particularly INP, tumor-homing target.
EXTH-06. INTEGRATED MOLECULAR PROFILING REVEALS TARGETABLE MOLECULAR ABNORMALITIES SHARED ACROSS MULTIPLE HISTOLOGIES OF BRAIN METASTASIS
Authors: Fukumura Kazutaka , Malgulwar Prit Benny , Fischer Grant , Hu Xiao Ding , Debeb Bisrat Godefay , Yu Dihua , Davies Michael , Huse Jason
Published: December 2020

Brain metastases (BMs) occur in approximately 20–40% of patients with advanced cancer, and the estimated prevalence of new BMs in United States is between 200,000–300,000 per year. While the incidence of BM has increased over the past decades due to improvements in brain tumor detection technology, the prognosis is still very poor with the median overall survival times from weeks to few months. Therefore, identification of the precise molecular landscape and therapeutic targets for BMs is absolutely essential in tangible improvement of patient management. Here, we performed integrated genomic, transcriptional, and proteomic profiling in a cohort of lung, breast, and renal cell carcinomas consisting of both BMs and patient-matched primary or extracranial metastatic tissues to identify shared cellular and molecular factors driving BMs across distinct primary tumor histologies. Although the comprehensive analysis identified the unique genomic, transcriptional and proteomic landscapes according to the different histopathologies, elevated PI3K/AKT and RAS/MAPK signaling was observed as a generalizable feature across the entire specimen cohort, along with relative immunosuppression and metabolic upregulation of the electron transport chain (ETC). Interestingly, immunosuppression via T cell depletion was significantly associated with unfavorable prognosis of patients with BMs, and ETC inhibition as the prospective therapeutic target for BM patients was demonstrated using in vitro and in vivo disease models. Taken together, our findings suggest that abnormalities involving oncogenic signaling, metabolism, and the immune microenvironment are shared across multiple histologies of BMs, and may be amenable to therapeutic targeting.
EXTH-08. MINIPIG MODELS OF NEUROFIBROMATOSIS TYPE 1 FOR THERAPEUTIC DEVELOPMENT
Authors: Watson Adrienne , Osum Sara , Taisto Mandy , Tschida Barbara , Duerre Dylan , Moertel Christopher , Kirstein Mark , Largaespada David , Oribamise Eunice
Published: December 2020

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. Using gene-editing technology, we have developed a minipig model of NF1 that exhibits clinical hallmarks of the disease, including café au lait macules, neurofibromas, and optic pathway glioma. We have conducted pharmacological studies in our NF1 minipigs to assess the pharmacokinetic and pharmacodynamic properties of MEK inhibitors for NF1. We have demonstrated that oral administration of several MEK inhibitors results in clinically relevant plasma concentrations and consequent inhibition of Ras signaling in immune cells, and certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. Because over 20% of NF1 patients harbor NF1 nonsense mutations, we are assessing safety and efficacy of nonsense mutation suppressors that may be effective in treating NF1. We evaluated six drugs known to induce nonsense mutation suppression in several primary cell types isolated from NF1 minipigs and show that several of these drugs have the propensity to induce the production of full length neurofibromin protein, leading to a subsequent reduction in MAPK signaling. Information acquired from this NF1 minipig preclinical model will be leveraged towards initiating a clinical trial in NF1 patients. The NF1 minipig provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1 therapies.
EXTH-09. NEO-ADJUVANT TEMOZOLOMIDE INCREASES THE EFFICACY OF SUBSEQUENT CONCURRENT CHEMORADIATION IN A TRANSGLUTAMINASE-2 DEPENDENT MANNER
Authors: Daniel Paul , Meehan Brian , Sabri Siham , Shenouda George , Sarkaria Jann , Rak Janusz , Abdulkarim Bassam
Published: December 2020

Glioblastoma (GBM) is invariably fatal due to failure of current chemoradiation (Stupp) regimes. Biomarkers such as MGMT have proven to predict response to Temozolomide (TMZ). An equivalent biomarker for radiation (RT) has not yet been identified. Transglutaminase-2 (TGM2) has been implicated in driving radiation resistance; but the mechanism is poorly understood. We have investigated how exposure to neoadjuvant TMZ in glioma stem cells (GSCs) with different levels of TGM2 would affect the response to RT. MATERIALS/METHODS: Primary GSCs lines with different TGM2 levels (high: 1123, 83; low: 528, OPK49) were used to explore the role of TGM2 in RT response and modulation of expression by TMZ in vitro and in-vivo. RESULTS: We showed that TGM2 drives radioresistance in GSCs through restriction of p53 mediated repression of RAD51 expression. We demonstrate that exposure of GSCs to TMZ drives rapid downregulation of TGM2 in vitro and this phenomenon is recapitulated in vivo. Interestingly, we confirm that RT is able to drive reciprocal changes in TGM2 and promotes reactivation of TGM2 in TGM2-high tumours but not TGM2-low tumours. Given these observations, we hypothesized that exposure to neoadjuvant TMZ in TGM2-low tumours would increase the efficacy of subsequent RT in these tumours. Comparison of the effect of standard treatment consisting of 3 weeks of concurrent TMZ and RT (Stupp) to a novel regime (neo-Stupp) consisting of 1 week of neoadjuvant TMZ followed by two weeks of TMZ and hypofractionated RT revealed a superior survival benefit of this novel regime in TGM2-low tumours but not in TGM2-high tumours. Utilization of the TGM2 inhibitor GK921 in combination with neo-Stupp prevented rapid relapse previously observed in TGM2-high tumours. CONCLUSION: We provide evidence that TGM2 is a biomarker of RT response and can be used to tailor chemoradiation protocols to the unique biology of each individual GBM patient.
EXTH-12. INHIBITION OF CBP/p300 HISTONE ACETYLATION ACTIVITY ENHANCES TEMOZOLOMIDE ACTIVITY IN GLIOBLASTOMA PATIENT DERIVED XENOGRAFTS
Authors: Kitange Gaspar J , Burgenske Danielle M , Bakken Katrina K , Hu Zeng , He Lihong , Carlson Brett L , Wilson Jonathan , Bommi-Reddy Archana , Conery Andy , Sarkaria Jann
Published: December 2020

There is an unmet need to identify novel targets that can sensitize temozolomide (TMZ) or prevent resistance in GBM. We have demonstrated that retinoblastoma binding protein 4 (RBBP4) interacts with p300 to modulate expression of genes involved in homologous recombination (HR), including RAD51. In vitro, RBBP4- or p300-shRNA significantly sensitized TMZ in patient derived xenograft (PDX) GBM43 cells (relative fluorescence for 100µM TMZ treated control shNT cells was 0.89 ± 0.1 vs 0.47± 0.09 and 0.39 ± 0.01 for shRBBP4 and shp300, respectively (p< 0.01)). TMZ sensitization increased DNA damage signaling through phosphorylation of KAP1 (p-KAP1) and p-CHK1. Moreover, RBBP4- or p300-shRNA delayed the repair of TMZ-induced DSBs evidenced by persistent gH2AX. Silencing RBBP4 or p300 reduced acetylation of lysine 27 of histone H3 (H3K27Ac) within promoters of HR genes regulated by RBBP4/p300 complex. Thus, RBBP4/p300 complex controls gene expression through p300-mediated histone acetyltransferase (HAT) activity, suggesting that p300 inhibitors could sensitize GBM to TMZ. Accordingly, CBP/p300 inhibitor CPI1612 significantly suppressed H3K27Ac and HR repair genes, including RAD51. Moreover, CPI1612 sensitized TMZ in GBM43 (synergy score = 258), and TMZ/CPI1612 significantly suppressed growth of GBM39 PDX cells compared with either drug alone (confluence (%) was 92 ± 1.0 (DMSO), 76.5 ± 4.6 (10 µM TMZ), 62 ± 3.4 (10 nM CPI1612) and 21.9 ± 3.2 (TMZ 10 µM/CPI-CPI1612 10 nM). CPI1612 enhanced TMZ-induced DSBs with increased damage signaling through p- KAP1 and persistent gH2AX. Pharmacodynamics studies in GBM39 orthotopic mice models revealed that oral CPI1612 penetrates the brain and accumulate in tumor regions and suppresses H3K27Ac without significant weight loss in mice that received placebo, TMZ, CPI1612 alone or combined TMZ/CPI-1612, demonstrating good animal tolerability. Collectively, these findings are encouraging that CBP/p300 inhibition by the brain penetrant CPI-1612 is a potential strategy for enhancing the efficacy of TMZ in GBM.
EXTH-14. A NOVEL LONG-ACTING INTERLEUKIN-7 AGONIST, NT-I7, INCREASES CYTOTOXIC CD8 CELLS AND ENHANCES SURVIVAL IN MOUSE GLIOMA MODELS
Authors: Ghosh Subhajit , Yan Ran , Thotala Sukrutha , Jash Arijita , Mahadevan Anita , Hu Tong , Lee Byung Ha , Yang Se Hwan , Hallahan Dennis , Chheda Milan , Thotala Dinesh , Campian Jian
Published: December 2020

BACKGROUND

Patients with glioblastoma (GBM) are treated with radiation (RT) and temozolomide (TMZ). These treatments can cause prolonged severe lymphopenia, which is associated with shorter survival. NT-I7 (efineptakin alfa) is a long-acting recombinant human IL-7 that supports the proliferation and survival CD4+ and CD8+ cells in both human and mice. We tested whether NT-I7 would protect T cells from treatment-induced lymphopenia and improve survival.

METHODS

C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days) and/or NT-17 (10 mg/kg on the final day of RT completion). We followed for survival and profiled CD3, CD8, CD4, FOXP3 in peripheral blood over time. In parallel, we assessed cervical lymph nodes, bone marrow, thymus, spleen, and the tumor 6 days after NT-I7 treatment.

RESULTS

Median survival in mice treated with NT-I7 combined with RT was significantly better than RT alone (GL261: 40d vs 34d, p< 0.0021; CT2A: 90d vs 40d, p< 0.0499) or NT-I7 alone (GL261: 40d vs 24d, p< 0.008; CT2A: 90d vs 32d, p< 0.0154). NT-17 with RT was just as effective as NT-I7 combined with RT and TMZ in both GL261 (40d vs 47d) and CT2A (90d vs 90d). NT-I7 treatment significantly increased the amount of CD8+ cells in the peripheral blood and tumor. NT- I7 rescued CD8+ T cells from RT induced lymphopenia in peripheral blood, spleen, and lymph nodes. NT-I7 alone or NT-I7 in combination with RT increased the CD8+ T cells in peripheral blood and tumor while reducing the FOXP3+ T-reg cells in the tumor microenvironment.

CONCLUSIONS

NT-I7 protects T-cells from RT induced lymphopenia, improves cytotoxic CD8+ T lymphocytes systemically and in the tumor, and improves survival. Presently, a phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957).
EXTH-17. LOCAL DELIVERY OF CYTOKINES AND SYNTHETIC IMMUNOMODULATORS INCREASES T CELL INFILTRATION AND SIGNIFICANTLY IMPROVES SURVIVAL IN A POORLY IMMUNOGENIC MODEL OF GLIOBLASTOMA
Authors: Haddad Alexander , Spatz Jordan , Collins Sara , Pereira Matheus , Gill Sabraj , Montoya Megan , Chuntova Polly , Young Jacob , Mummaneni Nikhil , Kasahara Noriyuki , Aghi Manish
Published: December 2020

BACKGROUND

Severe local and systemic immune suppression in glioblastoma (GBM) contributes to the failure of single-agent immunotherapies in clinical trials. In this study, we evaluated the efficacy of locally delivered combination immunotherapy in a poorly immunogenic murine GBM model.

METHODS

Immunomodulators used in these studies included: IL-15 and IL-7 (T cell activation), LIGHT (T cell tumor infiltration), FLT3L (dendritic cell maturation/proliferation), a surface T cell engager (T cell killing of tumor cells), and a bispecific PD-L1/T cell engager (T cell killing targeted to PD-L1-expressing cells). We first assessed T cell-mediated cytotoxicity in vitro against SB28, a poorly immunogenic murine GBM cell line, after expressing these immunomodulators in combination. Next, tumor growth inhibition in vivo was evaluated in syngeneic C57BL/6 mice, initially by establishment of intracranial tumors with pre-transduced SB28 cells, and subsequently by delivering these immunomodulators to pre-established naïve SB28 tumors using neural stem cells (NSCs) and retroviral replicating vectors (RRV).

RESULTS

SB28 cells transduced with immunomodulators activated dose-dependent T cell-mediated cytotoxicity in vitro. Mice with pre-transduced intracranial SB28 gliomas showed significantly longer survival (minimum survival: 60 days, long-term survival in 57% of mice) vs. control mice (median survival: 20 days) (p< 0.001), and significantly increased tumor infiltration of CD4+ and CD8+ T cells. NSC- and RRV-mediated immunomodulator delivery to pre-established SB28 gliomas also resulted in significantly increased survival of treated mice vs. controls (median survival: 31 days vs. 22 days, p< 0.001). Immunomodulator-treated tumors again showed significantly increased infiltration of CD4+ and CD8+ T cells, along with decreased CD11b+ cell infiltration.

CONCLUSIONS

A novel combination therapy for GBM immunotherapy activated T cell killing of SB28 GBM cells in vitro and achieved a significant survival benefit in vivo, associated with anti-tumor alterations to the GBM tumor microenvironment. Further studies to optimize the efficiency of combinatorial immunomodulator delivery are currently underway.
EXTH-20. SYNGENEIC B7-H3-SPECIFIC CAR T-CELLS HAVE POTENT ANTI-BRAIN TUMOR ACTIVITY VIA LOCAL OR SYSTEMIC DELIVERY
Authors: Haydar Dalia , Yi Zhongzhen , Houke Haley , Roussel Martine F , DeRenzo Chris , Gottschalk Stephen , Krenciute Giedre
Published: December 2020

BACKGROUND

We and others have identified B7-H3 (CD276) as a promising target for CAR T-cell-based immunotherapies for pediatric brain tumors. So far, B7-H3-CAR T cells have only been studied in xenograft models for brain tumors, which do not recapitulate the immunosuppressive tumor microenvironment (TME). To overcome this obstacle, we decided to adapt the immune competent GL261 murine glioma model which mimics human disease and host immune barriers.

METHODS

To evaluate their safety and efficacy, murine B7-H3-CAR T-cells were generated using retroviral particles encoding a 2nd generation B7-H3-CAR with a CD28.z signaling domain. Expansion, persistence, and anti-tumor activity were evaluated in vitro and in vivo. Components of the brain TME were then evaluated using flow cytometry and immunostaining.

RESULTS

B7-H3-CAR T cells only killed B7-H3+ tumor cells, secreted significant levels of IFNγ and IL-2 in an antigen-dependent manner and expanded an average of 85-fold in repeat stimulation assay with B7-H3+ tumor cells in contrast to control CAR T-cells. In vivo, intratumoral (2x106) or systemic (3x106) injection of syngeneic B7-H3-CAR T-cells into mice with orthotopic GL261 glioma induced complete regression in 60% of treated mice resulting in a significant survival advantage. Mice showed no evidence of acute or long-term toxicities related to CAR T-cell infusions. We confirmed this encouraging safety profile by systemic administration of a high dose (1x107) B7-H3-CAR T-cells and performing histological analyses of all major organs on day 14 post T-cell injection, which showed no notable signs of injury or on-target/off-tumor toxicities.

CONCLUSIONS

We successfully generated syngeneic B7-H3-CAR T-cells and have demonstrated that these cells have potent anti-tumor activity in the immune competent GL261 glioma model via local or systemic delivery without apparent toxicities. Our study paves the way for future testing of B7-H3-CAR T-cells in early phase clinical studies.