bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPID-34. GEODEMOGRAPHIC CLASSIFICATION OF GLIOBLASTOMA RISK IN A RURAL HOSPITAL SYSTEM: RELATIONSHIP TO TUMOR INCIDENCE AND OVERALL SURVIVAL
Authors: Haadi Ali , Kosman Justin , Bross Shane , Manikowski Jesse , Hinger Bradley , Conger Andrew , Vadakara Joseph , Tosha Gatson Na 
Published: November 2019

Abstract
In 2019, a projected 86,000 persons in the US will be diagnosed with a primary brain tumor, with an estimated prevalence of 700,000. Glioblastoma (GBM) is the deadliest and most common of these tumors in adults with an overall survival ~15 months. Exposure to ionizing radiation is the single known environmental risk factor for GBM. Most research in the field is directed at treatment and tumor biology/classification. There is growing interest in geodemographics, disease prevention, and measuring quality-survival in GBM. We evaluated 622 GBM patients (2006 to 2018) in Northeastern/Northcentral Pennsylvania treated at one of the nation’s largest rural hospital systems. Each patient was geocoded (plotted longitude/latitude) address at time of diagnosis and we used medical records, projected 2015 Census, and Environmental Protection Agency data to develop risk maps. Preliminary evaluation of overall survival (OS) and incidence related to distance from hospital, age, sex, level of education, insurance, income, and income disparity (Gini coefficient measure of income inequality) was completed. Interestingly, all significant clusters of high GBM incidence lay along water-ways or overlapped with high coal mine reprocessing. Contrary to recent studies, there was no significant sex or distance (0mi to 150mi) impact on survival. However, each age-decile increase resulted in an average 9mo decrease in OS (37mo[< 40yo], 26mo [41-50yo], 17mo [51-60yo], 12mo [61-70yo], and 3mo [>71yo]). Counties with the lowest OS shared geodemographic characteristics such as fewer insured and lower incomes (low income inequality), and counties with more college educated persons had longer survival. Counties with higher GBM incidences had better insured percentages, lower incomes (high income inequality), and large polarity between high school uneducated and college educated persons. Rural populations potentially demonstrate unique geodemographic characteristics that might better predict disease outcomes. Studies in this area could influence improvements in public policy and prevention-focused health literacy opportunities.
EXTH-02. THE BLOOD BRAIN BARRIER (BBB) PERMEABILITY IS ALTERED BY TUMOR TREATING FIELDS (TTFIELDS) IN VIVO
Authors: Schulz Ellina , Kessler Almuth F , Salvador Ellaine , Domröse Dominik , Burek Malgorzata , Tempel Brami Catherine , Voloshin Sela Tali , Giladi Moshe , Ernestus Ralf-Ingo , Löhr Mario , Förster Carola , Hagemann Carsten 
Published: November 2019

Abstract

OBJECTIVE
For glioblastoma patients Tumor Treating Fields (TTFields) have been established as adjuvant therapy. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Therefore, the BBB may block delivery of drugs for treatment of brain tumors. Here, the influence of TTFields on BBB permeability was assessed in vivo.

METHODS
Rats were treated with 100 kHz TTFields for 72 h and thereupon i.v. injected with Evan’s Blue (EB) which directly binds to Albumin. To evaluate effects on BBB, EB was extracted after brain homogenization and quantified. In addition, cryosections of rat brains were prepared following TTFields application. The sections were stained for tight junction proteins Claudin-5 and Occludin and for immunoglobulin G (IgG) to assess vessel structure. Furthermore, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent was performed before and after TTFields application.

RESULTS
TTFields application significantly increased the EB accumulation in the rat brain. In TTFields-treated rats, the vessel structure became diffuse compared to control cryosections of rat brains; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue. Serial DCE-MRI demonstrated significantly increased accumulation of Gadolinium in the brain, observed directly after 72 h of TTFields application. The effect of TTFields on the BBB disappeared 96 h after end of treatment and no difference in contrast enhancement between controls and TTFields treated animals was detectable.

CONCLUSION
By altering BBB integrity and permeability, application of TTFields at 100 kHz may have the potential to deliver drugs to the brain, which are unable to cross the BBB. Utilizing TTFields to open the BBB and its subsequent recovery could be a clinical approach of drug delivery for treatment of brain tumors and other diseases of the central nervous system. These results will be further validated in clinical Trials.
EXTH-08. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION
Authors: Feng Xi , Gupta Sonali , Chen David , Boosalis Zoe , Liu Sharon , Gupta Nalin , Rosi Susanna 
Published: November 2019

Abstract
Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits.
EXTH-09. FIRST-IN-HUMAN DOSING CONSIDERATIONS OF A BISPECIFIC ANTIBODY FOR TREATING GLIOBLASTOMA
Authors: Schaller Teilo , Foster Matthew , Spasojevic Ivan , Gedeon Patrick , Sanchez-Perez Luis , Sampson John 
Published: November 2019

Abstract
Current therapy for glioblastoma (GBM) is incapacitating and limited by non-specific toxicity to the surrounding brain. We have developed an immunotherapeutic approach that selectively targets GBM by redirecting the patients’ own T cells towards the tumor in an antigen-specific manner using a bispecific antibody. Our novel bispecific antibody (“BRITE”) binds GBM-specific surface marker EGFRvIII and the CD3 receptor on T cells, resulting in crosslinking and tumor-specific cell lysis. We previously showed in patient-derived and syngeneic murine glioma models, that treatment with BRITE leads to long-term survival in mice with glioblastoma. A pharmacokinetic analysis in a CD3 humanized mouse revealed that BRITE in plasma and whole blood has an initial half-life of ~8 minutes and a terminal half-life of ~2.5 hours. Given our preclinical success, we have initiated clinical trial-enabling studies, including studies of BRITE toxicology and GMP manufacturing of drug product. A crucial consideration for our proposed Phase 1 dose escalation trial is the starting dose in humans. To this end, we utilized the FDA-recommended minimum anticipated biological effect level (MABEL) of BRITE – a holistic approach that considers all available in vitro and in vivo data – to calculate the first-in-human starting dose of BRITE.
EXTH-16. HUMAN PLACENTAL HEMATOPOIETIC STEM CELL DERIVED NATURAL KILLER CELLS FOR GLIOBLASTOMA IMMUNOTHERAPY
Authors: He Shuyang , Gleason Joseph , Habboubi Nassir , Hariri Robert , Zhang Xiaokui 
Published: November 2019

Abstract
Taniraleucel (CYNK-001) is an allogeneic, off-the-shelf cell therapy enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. CYNK-001 exhibits in vitro cytotoxicity against various cancer cell types, including glioblastoma multiforme (GBM), and secretes cytokines during co-culture with cancer cells. To evaluate in vivo anti-GBM activity, safety and persistence of CYNK-001, we conducted two studies in the non-obese diabetic (NOD)-scid IL2Rgammanull (NSG) immune deficient mouse models. First, CYNK-001 in vivo anti-GBM activity was assessed in a U-87MG orthotopic NSG mouse model. Luciferase-expressing U-87MG cells were stereotactically injected into the cranium of NSG mice at Day 0. Repeated dosing of 0.5x106 CYNK-001 cells at Day 14 and Day 25 by intracranial (IC) injection showed a statistically significant reduction of Bioluminescence Imaging (BLI) compared to the PBS control. Furthermore, intravenous (IV) and intracerebroventricular (ICV) routes of administration were evaluated compared to IC. CYNK-001 administered with IC resulted in a greater reduction of BLI than IV and ICV. Second, a single-dose toxicity study was conducted in naïve NSG mice to assess the safety and persistence of CYNK-001 following an IC injection. IC administration of 1×106 CYNK-001 was well tolerated, and no adverse clinical symptoms were observed. Quantitative polymerase chain reaction (qPCR) analysis for the human telomerase reverse transcriptase (hTERT) gene revealed that CYNK-001 persisted in the brain up to seven days. Our studies demonstrated that CYNK-001with IC administration appears safe and well tolerated in naïve as well as U-87MG tumor bearing NSG mice. Furthermore, CYNK-001 anti-tumor activity was exhibited in a GBM orthotopic NSG mouse model. Taken together, our data support a safety and efficacy evaluation of CYNK-001 in patients with GBM. A Phase 1 study in adult patients with recurrent/refractory GBM is planned to start this year evaluating the safety and efficacy of CYNK-001 with both IV and IC administrations.
EXTH-20. HYPERPOLARIZED [2-13C] PYRUVATE TO [5-13C] GLUTAMATE AS BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO TEMOZOLOMIDE THERAPY
Authors: Subramani Elavarasan , Najac Chloe , Batsios Georgios , Viswanath Pavithra , Radoul Marina , Marie Gillespie Anne , Pieper Russell O , Ronen Sabrina 
Published: November 2019

Abstract
Low-grade gliomas, driven by mutations in the cytosolic isocitrate dehydrogenase 1 (IDH1) gene, are less aggressive than primary glioblastoma, but nonetheless always recur and ultimately lead to patient death. The treatment of IDH1 mutant patients with Temozolomide (TMZ) improves survival, but there remains a need for complementary imaging methods to assess response to therapy at an early time point. The goal of this study was, therefore, to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic imaging biomarkers for detection of response to treatment. To this end we investigated NHA and U87 cells expressing IDH1 R132H mutant gene (NHAIDHmut and U87IDHmut) and first used 1H MRS combined with chemometrics to examined the metabolic alterations that occurred following treatment with the IC50 value of TMZ. We observed a significant increase in 2-hydroxyglutarate (2-HG), glutamate, and glutamine, and metabolic pathway analysis showed tricarboxylic acid (TCA) cycle and pyruvate metabolism to be significantly altered pathways following TMZ treatment compared to DMSO control. To confirm changes in TCA cycle flux and to assess the metabolic pathways contributing to the increase in 2-HG and glutamate/glutamine, cells were then labelled with [1-13C] glucose and [3-13C] glutamine. Our data indicated that both glucose flux via the TCA to glutamate and 2HG, and the contribution of glutamine to glutamate and 2HG were increased following TMZ treatment. Finally, we used hyperpolarized 13C-MRS to dynamically probe the metabolism of hyperpolarized [2-13C] pyruvate and its conversion to hyperpolarized [5-13C] glutamate via the TCA cycle. Consistent with our previous findings, we observed that hyperpolarized [5-13C] glutamate synthesis was significantly higher in TMZ-treated cells compared to controls. Collectively, our findings identify 1H MRS-detectable elevation of 2-HG and glutamate/glutamine as well as hyperpolarized 13C-MRS-detectable [5-13C] glutamate production from [2-13C] pyruvate as potentially translatable metabolic biomarkers of response to TMZ therapy in mutant IDH1 glioma.
EXTH-25. A MECHANICALLY-ENGINEERED SPRAY TO INCREASE BRAIN PENETRATION OF CHEMOTHERAPEUTIC NANOPARTICLES IN THE TREATMENT OF HIGH GRADE GLIOMAS
Authors: McCrorie Phoebe , Taresco Vincenzo , Ritchie Alison , Clarke Phillip , Scurr David , Marlow Maria , Rahman Ruman 
Published: November 2019

Abstract
Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib were chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.
EXTH-28. TARGETED POLYGIONS ENGINEERED WITH SURFACE miRNAs FOR COMBINED MULTIMODALITY IMAGING AND ENHANCEMENT OF TEMOZOLOMIDE TREATMENT: A NOVEL INTRANASALLY-DELIVERED THERANOSTIC STRATEGY AGAINST GLIOBLASTOMA
Authors: Sukumar Uday , Afjei Rayhaneh , Massoud Tarik , Paulmurugan Ramasamy 
Published: November 2019

Abstract

INTRODUCTION
We investigate intranasal targeted delivery of theranostic Polyfunctional Gold Iron Oxide Nanoparticles (PolyGIONs) surface loaded with therapeutic microRNAs to allow sensitizing of GBM cells to systemic temozolomide (TMZ), as well as multimodality molecular, anatomic and microscopic imaging.

METHODS
We synthesized PolyGIONs coated with b-cyclodextrin-chitosan hybrid polymer, loaded with miR-100 and antimiR-21, and decorated with PEG-T7 peptide. We characterized the PolyGIONs for microRNA loading efficiency, particle size, PDI, and charge using dynamic light scattering analysis; and for size and polymer functionalization using TEM. We studied PolyGIONs in GBM cells (U87MG and U373MG), and in nude mice orthotopically bearing GBMs after intranasal delivery, in combination with systemic TMZ. We also imaged mice bearing tumors using CT, MRI, bioluminescence, fluorescence, and by ex vivo microscopy.

RESULTS
The optimized PolyGIONs delivered to GBM cells showed efficient cellular uptake when imaged for intracellular Cy5-microRNAs, and therapeutic effects when investigated using MTT and FACS analysis. In a co-culture model of BMVEC (brain microvascular endothelial cells) and U87MG cells, we observed significant upregulation of p53 protein expression in U87MG cells after PolyGIONs treatment. The enhanced therapeutic potential of TMZ upon miR-100 and antimiR-21 sensitization by PolyGIONs was validated in both U87MG and U373MG cells. Mouse tumors revealed specific accumulation of PolyGIONs, and the highest upregulation of p53 expression within tumors of longest surviving mice, when co-treated with TMZ. Moreover, in vivo selective accumulation of PolyGIONs conjugated to T7 peptide within GBMs acted as a useful MRI and CT dual contrast agent, providing longitudinal multimodality imaging of PolyGION effects on GBMs.

CONCLUSION
Our preliminary results indicate the potential for targeting the p53 pathway in GBM using therapeutic miR-100 and antimiR-21 via intranasally delivered PolyGIONs, to enhance the chemotherapeutic effects of systemically delivered TMZ. PolyGIONs also allow simultaneous multimodality imaging to track cancer growth in response to treatment.
EXTH-33. RECEPTOR PHARMACOLOGY OF ONC201: THE FIRST BITOPIC DRD2 ANTAGONIST FOR CLINICAL NEURO-ONCOLOGY
Authors: Benjamin Free R , Cuoco Caroline , Prabhu Varun , Willette Blair , Day Marilyn , Anantharaman Lakshmi , Sulli Chidananda , Davidson Edgar , Deacon Sean , Rucker Joseph , Charter Neil , Doranz Benjamin , Oster Wolfgang , Stogniew Martin , Robert Lane J , Sibley David , Allen Joshua 
Published: November 2019

Abstract
ONC201 has exhibited durable tumor regressions in midline high grade glioma patients. G protein-coupled receptor (GPCR) dopamine receptor D2 (DRD2) is overexpressed in high grade gliomas, controls several oncogenic mechanisms, and its antagonism causes tumor cell apoptosis. Using bioinformatic and GPCR screens, we previously demonstrated selective DRD2/3 antagonism by ONC201 at therapeutic concentrations that translates into a wide therapeutic window, unlike antipsychotics that also target other dopamine receptors and GPCRs (Prabhu et al. CCR 2019 and Madhukar et al. Nat Comm in press). Here, we identify hallmarks of non-competitive DRD2 antagonism by ONC201 in β-arrestin, cAMP and radioligand competition assays. ONC201 caused both a shift in the IC50 and repression of Emax in the dopamine-dose-response curves for DRD2. Schild analysis and fitting these data to an operational model of allostery were consistent with non-competitive antagonism. Alanine scanning mutagenesis of DRD2 identified 6 orthosteric and allosteric residues that are critical for ONC201-mediated antagonism. The residues identified were predominantly conserved in DRD2/3 and were not relevant for antagonism by antipsychotics further explaining the unique selectivity of ONC201. Molecular docking revealed orthosteric interactions at TM-II and an extended binding pocket into an allosteric site. Other critical residues were clustered at an allosteric area at the interface of TM-IV and –V that has been shown to mediate the DRD2 homodimer interface. Point mutations at either site decreased the affinity of ONC201 in competition assays with radiolabeled methyl-spiperone, suggesting cooperativity between these topographically distinct sites. In summary, ONC201 causes a mixed non-competitive and competitive antagonism of DRD2 consistent with a bitopic mechanism of action that may explain its unique selectivity, safety, and anti-cancer activity in clinical trials as the first compound to target this receptor for clinical neuro-oncology. Non-competitive DRD2 antagonism may be critical for ONC201 anti-tumor efficacy in dopamine-rich microenvironments such as midline gliomas.
EXTH-35. LASER INTERSTITIAL THERMAL THERAPY INCREASES BLOOD-BRAIN BARRIER AND BLOOD-TUMOR BARRIER PERMEABILITY IN A MOUSE MODEL OF GLIOBLASTOMA
Authors: Paturu Mounica , Salehi Afshin , Caine Matthew , Mahlokozera Tatenda , Yano Hiroko , Leuthardt Eric , Klein Robyn , Schmidt Robert , Kim Albert 
Published: November 2019

Abstract

INTRODUCTION
A central challenge in glioblastoma treatment is the presence of the blood-brain barrier (BBB) and blood-tumor barrier (BTB), which prevent access of drugs to the brain and tumor respectively. Recent evidence in patients suggests laser interstitial thermal therapy (LITT), used clinically for tumor ablation, locally disrupts BBB integrity, potentially creating a therapeutic window to deliver otherwise brain-impermeant agents.

METHODS
A mouse model for LITT, established using a Nd-YAG laser coupled to a 600 mm fiber optic and thermocouple probe, was inserted via burrhole to target the somatosensory cortex. Syngeneic GL261 tumor cells were stereotactically implanted prior to LITT. BBB and BTB permeability were assessed through measurement of fluorescein and doxorubicin after IV injection. Permeability of IV dextran (10 and 70 kDa) and human IgG was monitored by immunohistochemistry (IHC) analysis. Mechanisms of BBB breakdown in vivo were explored utilizing electron microscopy and IHC.

RESULTS
By fluorescein assay, LITT-induced BBB and BTB permeability began one day post-treatment and was sustained for at least 2 weeks. Additionally, both normal brain and brain tumors demonstrated an increase in Dextran 10 kDa, Dextran 70 kDa, and human IgG extravasation after IV injection in vivo. Mechanistically, we provide evidence that LITT triggers both a decrease in tight junction integrity and an increase in brain endothelial cell transcytosis. As proof-of-concept that LITT can enhance tumor delivery of systemic drugs, LITT increased IV doxorubicin permeability in brain in vivo. Moreover, LITT plus doxorubicin significantly increased survival in brain tumor-bearing mice compared to doxorubicin or LITT alone.

CONCLUSIONS
Our data suggest that LITT increases BBB and BTB permeability over a defined time window to large molecular weight agents, including antibodies, through multiple cellular mechanisms. Our preclinical results with LITT plus doxorubicin, which mirror a current clinical trial, indicate LITT can enhance the efficacy of systemically delivered drugs.