bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-16. EPIDEMIOLOGICAL TRENDS FOR LONGER TERM GBM SURVIVORS POST STUPP
Authors: Forner Samantha , Al-Salihi Omar , Brazil Lucy , Swampillai Angela 
Published: December 2020

Abstract
Patients with Glioblastoma Multiforme (GBM) have a poor prognosis with few long-term survivors (&gt;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=&lt; 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

Abstract

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 &lt; 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 &gt;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 &gt;20 miles, non-whites, age &lt; 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

Abstract

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 &lt; 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

Abstract

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

Abstract

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 &gt; 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 &gt; 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

Abstract
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

Abstract
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

Abstract

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

Abstract
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

Abstract
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.