bluuebunny/crossref_metadata_2025 huggingface dataset:
EXTH-57. IDENTIFICATION OF NOVEL IMMUNE CHECKPOINT MOLECULE IN GLIOMA, LAIR1
Authors: Tao Haipeng , Chen Dongjiang , Yang Changlin , Jin Linchun , Von Roemeling Christina , Mendez-Gomez Hector , Liu Ruixuan , Nguyen Duy , Hou Alicia Y , Pepe Alfonso , Weidert Frances , Ghiaseddin Ashley , Mitchell Duane , Deleyrolle Loic , Sayour Elias , Sawyer W , Tran David , Huang Jianping
Published: November 2022

BACKGROUND

In recent years, emerging evidence indicates that tumor-associated myeloid cells (TAMCs) affect cancer progression. But the molecular mechanisms and signaling pathways involved in the TAMCs’ interaction with extracellular matrix (ECM) and tumor stroma are incompletely understood. Checkpoint inhibition therapy targets immune inhibitory receptors, such as CTLA-4 and PD-1, which have become a major weapon in fighting cancer. These antibodies demonstrate apparent advantages such as being easy to use, broad applicability, and durable clinical response. Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), also called CD305, a collagen-binding immunoreceptor tyrosine-based inhibition motifs (ITIM)-bearing inhibitory receptor, was identified to present on almost all immune cell populations and overexpressed in cancers of human patients. However, LAIR1’s role and regulation in solid cancers are poorly defined.

OBJECTIVE

To identify LAIR1 as a new class of immune checkpoints in cancers that impacts TAMCs-associated tumor immunity. Further functional investigation warrants understanding the crosstalk between LAIR1-related immune checkpoint blocking agent(s), immune micro-environment, and its underlying mechanisms for targeted therapy development.

METHODS

Murine GBM cell line KR158-Luciferase cell line was used to set up the mouse model. Tumor-bearing mice were administered the Anti-LAIR1 blockade and IgG, followed by IVIS imaging for tumor growth and survival were recorded. The presentation and phenotype of immune cell populations in tumors and spleens were measured through scRNA-Seq.

RESULTS

GBM is one of these tumors that overexpress LAIR1 based on the TCGA analysis. LAIR1 molecules express highly on macrophages, monocytes, DCs, and activated T cells, not on the naive T cells. We found that LAIR1 blockade enhanced survival in preclinical GBM models. LAIR1 blockade reduced the presentation and function of TAMCs in tumors. What's more, LAIR1 blockade provided a synergetic antitumor effect with CD70 CAR T cells.

CONCLUSION

This study suggests that we identified a novel immune checkpoint molecule, LAIR1, which can limit tumor progression.
EXTH-74. ATR INHIBITION IN EXPERIMENTAL GLIOMA
Authors: Walter Bianca , Schnabel Leonard , Hirsch Sophie , Stahl Aaron , Haeusser Lara , Tsiami Foteini , Kuhlburger Laurence , Nahnsen Sven , Templin Markus , Schenke-Layland Katja , Merk Daniel , Tabatabai Ghazaleh
Published: November 2022

Glioblastoma are incurable primary tumors of the central nervous system. Novel treatment options are urgently needed. Recently, we investigated molecular effects of disrupting the (b)HLH network, a frequently altered and tumor-promoting transcriptional network in glioma, by introducing a dominant-negative variant of the E47 protein. The identified downstream anti-tumor effects included the DNA damage response pathway. In the present study, we aimed at investigating the anti-glioma effects of ATR inhibition in vitro and in vivo with a particular focus on treatment-induced vulnerabilities and potential combination therapies. We performed acute cytotoxicity, clonogenic survival assays, flow cytometry-based determination of cell cycle status and apoptosis induction in human and murine glioma cell lines in vitro, and investigated tumor growth in the SMA560/VMDk syngeneic mouse model in vivo. Furthermore, we applied RNA sequencing, DigiWest protein profiling analyses and genome-wide CRISPR/Cas9 loss-of function and activation screens to determine potential combination therapies. Combination treatments were further analyzed for synergism by the Bliss and ZIP synergy models. ATR inhibition in glioma cells resulted in reduced viability and clonogenic survival. However, differential patterns of gene expression deregulation (e.g. p53 signaling) and differing modes of cell cycle arrest in distinct glioma model systems argue for a substantial heterogeneity with regard to response to ATR inhibition. Based on our data we designed combinatorial treatments. We will present novel insights into promising combinatorial treatments using ATR inhibition and their underlying molecular mechanisms.
EXTH-79. HIJACKING A NEURODEVELOPMENTAL EPIGENOMIC PROGRAM IN METASTATIC DISSEMINATION OF MEDULLOBLASTOMA
Authors: Zou Han , Poore Bradley , Brown Emily , Yash Patel , Hu Zhongliang , Li Xuejun , Pollack Ian F , Friedlander Robert M , Hainer Sarah , Taylor Michael , Hu Baoli
Published: November 2022

Normal brain development relies on precise genetic and epigenetic spatiotemporal regulation of gene expression. How dysregulation of neurodevelopment relates to medulloblastoma, the most common pediatric brain tumor, remains elusive. Here, we uncovered a novel neurodevelopmental epigenomic program that regulates Purkinje cell migration in developing cerebellum is hijacked to induce tumor metastatic dissemination in medulloblastoma. Integrating publicly available datasets with our in-house data, unsupervised analyses revealed that BAF60C/SMARCD3, a subunit of SWI/SNF chromatin remodeling complex, promotes tumor cell migration in vitro and metastasis in vivo. Based on analyzing the single-cell RNAseq data of cerebellum developmental trajectory in mice and humans, aligning with the medulloblastoma patients’ datasets, we found that BAF60C/SMARCD3 regulated DAB1-mediated Reelin signaling is involved in Purkinje cell positioning during cerebellum development and medulloblastoma metastasis by orchestrating the cis-regulatory elements (CREs) at the DAB1 gene locus. Moreover, analysis of spatiotemporal gene expression and chromatin architecture in the human and mouse cerebellum demonstrated that transcription activity of the BAF60C/SMARCD3-DAB1 circuit is downregulated in a mature state of cerebellar development, however, is upregulated in metastatic medulloblastoma. We further identified that a core set of transcription factors, enhancer of zeste homolog 2 (EZH2) and nuclear factor I X (NFIX), bi-directionally control BAF60C/SMARCD3 transcriptional regulation by coordinating with the CREs at the BAF60C/SMARCD3 gene locus to form a chromatin hub during developing cerebellar development and medulloblastoma metastatic dissemination. Highly expressed BAF60C/SMARCD3 activates the Reelin/DAB1 signaling pathway downstream Src kinase, which was validated in the pair-wised primary and metastatic tumors from medulloblastoma patients. Preclinical medulloblastoma mouse models revealed that inhibiting Src activity reduces tumor cell migration and metastatic dissemination at a lower and safe dose. Together, these data deepen our understanding of how the developmental program influences disease progression and provide an opportunity for the development of therapeutics for this devastating brain cancer in children.
EXTH-80. THE MOLECULAR FUNCTION AND THE THERAPEUTIC POTENTIAL OF MICRORNA-211 IN GROUP 3 MEDULLOBLASTOMAS IN CHILDREN
Authors: Yuan Menglang , Katsushima Keisuke , Pokhrel Rudramani , Lee Bongyong , Stapleton Stacie , Jallo George , Raabe Eric , Eberhart Charles , Perera Ranjan
Published: November 2022

Medulloblastoma is a central nervous system tumor that primarily affects children and requires aggressive therapy. Patients often suffer from treatment-related side effects, and treatment-resistant recurrences are common, with high mortality rates. There are four major molecular MB subgroups (Wnt- and Shh-activated MBs G3 and G4 MBs). G3 MB is the most aggressive subtype, and the diagnosis and management remain challenging. Medulloblastomas develop through various genetic, epigenetic, and noncoding (nc) RNA-related mechanisms. However, the roles played by ncRNAs, (microRNAs, long noncoding RNAs, circular RNAs, etc.) in MB development remain poorly defined. Here we address this knowledge gap with an exemplar microRNA, microRNA 211 (miR-211) implicated in G3 MB development and progression. Our preliminary results support that miR-211 is an attractive therapeutic agent to treat this aggressive MB subtype. miR-211 is significantly downregulated in medulloblastoma cell lines compared to normal cerebellum, underscoring its important role as a therapeutic agent and a biomarker. miR-211 ectopic expression in G3 MB cells significantly reduced cell proliferation and 3D colony formation and induced apoptosis. In vivo, miR-211force-expression in G3 MB cells injected into mouse cerebellum produce smaller tumors than those derived from parental cells. We identified that Long-chain-fatty-acid—CoA ligase 4 (ACSL4), and the oncogene Ras-related protein Rab22A are miR-211 targets genes for G3 medulloblastomas. The preliminary results of this study are encouraging and will provide a pre-clinical foundation for further therapeutic testing.
EXTH-84. A NOVEL DUAL-SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELL WITH HIGH SPECIFICITY FOR EGFR AND EGFRVIII IMPROVES SURVIVAL IN EGFR EXPRESSING MEDULLOBLASTOMA
Authors: Wilson Joseph , Wilkinson Daniel , Ryan Katherine , Bigner Darell , Chambramohan Vidya , Fecci Peter
Published: November 2022

BACKGROUND

Medulloblastoma is the most common malignant brain tumor in children 0-19 years of age and current treatment requires surgical resection, followed by high dose chemotherapy and radiotherapy. Therapy carries high morbidity, with late effects including neurocognitive decline, endocrine dysfunction, and subsequent malignancies. Chimeric antigen receptor (CAR) T cell therapy presents the potential for less toxic and more effective treatment for medulloblastoma. Epidermal growth factor (EGFR) is expressed in medulloblastoma derived cell lines and appears to serve an important role in the metastatic potential of this tumor type. D2C7 is a recombinant monoclonal antibody short chain variable fragment (scFv) with dual specificity, binding to wild type EGFR (EGFRwt) and its mutant EGFR variant III (EGFRvIII). We previously developed a novel, third-generation chimeric antigen receptor T-cell construct utilizing the D2C7 scFv and performed analysis on both glioblastoma and medulloblastoma tumor models.

METHODS

U87 and U87vIII glioblastoma and DAOY medulloblastoma cell lines were characterized by flow cytometry to evaluate for EGFRwt and EGFRvIII expression. Cytotoxicity assays were performed utilizing flow cytometry on serially diluted effector: target ratios of U87, U87vII, and DAOY mixed with D2C7 CAR. DAOY was orthotopically implanted into the frontal lobe of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. After tumor implantation, D2C7 CAR was introduced within the tumor bed.

RESULTS

EGFR was detected in U87, U87vIII, and DAOY on flow analysis. EGFRvIII was expressed only on U87vIII. D2C7 CAR demonstrated effective in vitro cytotoxicity against all three cell lines with >90% cytotoxicity achieved at an effector: target ratio of 2.5:1. In vivo, D2C7 CAR treatment significantly prolonged survival compared to treatment with mock CAR.

CONCLUSION

D2C7 CAR demonstrates efficacy in vitro and in mouse models of medulloblastoma and glioblastoma. Future steps in our work will set out to assess the D2C7 CAR in NSG mice with DAOY in the posterior fossa.
EXTH-89. EXPLORING ANTI-TUMOR EFFECTS OF SMALL MOLECULE INHIBITORS OF CDK4/6, FAK, AND RAF/MEK IN PRECLINICAL MODELS OF MENINGIOMA
Authors: Ijad Nazanin , Waller Katie L , Nayyar Naema , Larson Juliana M , Spear Joshua , Cahill Daniel , Barker Frederick G , Galanis Evanthia , Sarkaria Jann , Wakimoto Hiroaki , Vaubel Rachael , Brastianos Priscilla
Published: November 2022

BACKGROUND

Adequate treatment options are limited for patients with meningiomas once they have exhausted surgery and radiation. As our molecular understanding of meningiomas and their progression has improved, CDK, FAK, and RAF/MEK pathways have emerged as potential avenues for therapeutic intervention. However, patient-derived cell and xenograft models of meningiomas are difficult to establish, presenting a challenge in preclinical testing and validation of new therapeutic targets. The objective of this study is to develop informative preclinical models of meningiomas and use those to evaluate the activity of potent and selective inhibitors of CDK4/6, FAK, and RAF/MEK.

METHODS

We used CellTiter-Glo assay to assess the anti-tumor effects of CDK4/6 inhibitor abemaciclib, FAK inhibitor defactinib (VS-6063) and dual RAF/MEK inhibitor RO5126766 (VS-6766) in BEN-MEN-1 (WHO Grade I, NF2-mutant), CH157-MN (WHO Unknown, NF2-mutant), and IOMM-Lee (WHO Grade III, CDKN2A loss) cell lines. Additionally, we used CyQUANT assays to quantify anti-proliferation activity of these inhibitors in a newly established patient-derived cell line MN14 (WHO Grade II, NF2 mutant). In parallel, we continue our attempts to establish patient-derived cell and xenograft models using freshly isolated surgical specimens of progressive meningioma.

RESULTS

Defactinib monotherapy significantly decreased cell viability across a 10nM-10μM range for all three established cell lines. RO5126766 showed improved efficacy (by 10-fold) in IOMM-Lee, compared to CH157-MN and Ben-Men-1. Abemaciclib showed potent effects at 10nM in IOMM-Lee and BEN-MEN-1, compared to 100nM for CH157-MN. In the MN14 patient-derived cell line, established from an NF2-mutant atypical meningioma, we observed a significant decrease in cell proliferation with defactinib. A decrease in cell proliferation was also observed with RO5126766 and abemaciclib.

CONCLUSION

Selective inhibitors of CDK4/6, FAK, and RAF/MEK showed anti-meningioma activity against traditional and patient-derived cell models in vitro. Molecular characterization and establishment of patient-derived models that encompass the diversity of clinical meningiomas are ongoing.
EXTH-99. SYSTEMIC AND BRAIN PHARMACOKINETICS OF A GABAA RECEPTOR AGONIST, AMLAL-101, AS AN INVESTIGATIONAL THERAPEUTIC FOR THE TREATMENT OF PRIMARY AND METASTATIC BRAIN CANCERS
Authors: Karve Aniruddha , Ahmed Taukir , Desai Janki , Bhattacharya Debanjan , Toukam Donatien Kamdem , Gadgil Sidharth , Pemberton Merissa , Plas David , Gudelsky Gary , Sallans Larry , Cook James , Desai Pankaj , Krummel Daniel Pomeranz , Sengupta Soma
Published: November 2022

PURPOSE

AMLAL-101 is a novel agent which preferentially targets α3, α5 subtypes of ɣ-amino butyric acid receptors and shows anti-tumor activity against disparate cancer types. AMLAL-101 is being advanced as an ‘add-on’ to potentiate treatment of primary and metastatic brain cancers. However, AMLAL-101 must penetrate the blood-brain barrier (BBB) and show sufficient brain retention. The primary purpose of this study was to determine the plasma pharmacokinetics (PK) and quantitative estimate of the BBB permeability of AMLAL-101.

METHODS

We performed intracranial microdialysis, employing jugular vein cannulated Sprague-Dawley rats which facilitated simultaneous serial blood and brain extracellular fluid (ECF) sampling. AMLAL-101 was injected i.p. at 5 mg/kg and serial blood and brain ECF samples collected up to 10 h post-dosing. Plasma and ECF samples were analyzed by LC/MS-MS and plasma and ECF concentration vs time PK profiles determined. In vivo recovery analysis was performed using retrodialysis and rapid equilibrium dialysis employed to determine the extent of protein binding.

RESULTS

AMLAL-101 plasma protein binding was 85% and in vivo recovery from ECF was 25%. AMLAL-101 peak concentration (Cmax) in plasma and brain ECF were 15 µM and 13.8 µM, respectively. The plasma and brain ECF area under the concentration (AUC0-10) were 27.5 h.µg/mL and 24.10 h.µg/mL, respectively. The brain partitioning of unbound AMLAL-101 (Kp,uu; determined either as a ratio of brain ECF Cmax:unbound plasma Cmax or brain ECF AUC: unbound plasma AUC), were 6.13 and 4.13, respectively. The elimination half-life of AMLAL-101 was 3 h for both brain ECF and plasma.

CONCLUSIONS

These results suggest that AMLAL-101 has the requisite BBB permeability required for brain cancer therapeutics. AMLAL-101 shows significant brain retention when compared to a chemically similar agent that does not show anti-cancer activity, which may contribute to efficacy of AMLAL-101 as an anti-tumor agent for treatment of brain cancers.
EXTH-101. MECHANISTIC INSIGHTS INTO CYTOTOXIC EFFECTS OF LETROZOLE AGAINST GLIOBLASTOMA CELLS
Authors: Karve Aniruddha , Desai Janki , Dave Nimita , Phoenix Timothy , Gudelsky Gary , Plas David , Dasgupta Biplab , Wise-Draper Trisha , Desai Pankaj
Published: November 2022

PURPOSE

Despite significant advances in multimodal approaches for the treatment of glioblastoma (GBM), the outcome for the patients remains dismal. Previous research from our lab has shown that aromatase (CYP19A1), an enzyme that catalyzes in situ production of estrogens, is markedly elevated in GBM tissues. Additionally, letrozole (LTZ), an aromatase inhibitor with extensive record of efficacious use in breast cancer, exhibited significant activity against GBM in preclinical studies. The purpose of this study was to investigate the mechanism(s) of LTZ activity in GBM.

METHODS

Patient-derived GBM cells with varying aromatase expression and other genotypic/phenotypic characteristics were employed including aromatase expressing G43, G75, G76, BT-142-gfp-luc and aromatase-null G80 cells. The effects of LTZ on cell viability, neurosphere growth, DNA damage (assessed by measuring phosphorylated histone product ỴH2A.X using flow cytometry) and induction of apoptosis (caspase3/7 activity) were assessed. The effects of exogenous addition of estradiol (E2) was also examined.

RESULTS

LTZ treatment (72 hours) caused a marked reduction in viability and growth of all GBM cells (IC50 ranging from 0.08 to 0.7 µM) except in G80 cells where LTZ had no effects. LTZ treatment also resulted in inhibition of E2 synthesis in a time and dose-dependent fashion. Furthermore, in aromatase expressing cells LTZ treatment induced apoptosis as measured by increase in Caspase-3/7 activity and triggered significant DNA double strand break as determined by ỴH2A.X formation. The addition of exogenous E2 (250 pg/ml) abrogated the effects of LTZ on cell viability, DNA damage and induction of apoptosis.

CONCLUSIONS

Our study suggests that the cytotoxic effects of LTZ against GBM are mediated, at least partially, by the inhibition of aromatase activity which results in estrogen deprivation. These mechanistic insights are important to facilitate repurposing LTZ as a novel anti-GBM drug.
EXTH-103. DISCOVERY AND PHARMACOLOGICAL CHARACTERIZATION OF SKL27969, A NOVEL BRAIN-PENETRATING PRMT5 INHIBITOR WITH STRONG ANTITUMOR ACTIVITY, IN GLIOBLASTOMA AND BRAIN METASTASIS PRECLINICAL MODELS
Authors: Moon Mijin , Shin Yongje , Lee Ho Yeon , Hong Beomjin , Kim Jinhee , Lee Jun , Laramy Janice K , Vashi Vijaykumar , Park Sook-Kyung
Published: November 2022

Protein arginine methyltransferase 5 (PRMT5), a type II methyltransferase, regulates cellular processes such as survival, proliferation, and apoptosis by inducing symmetric arginine dimethylation of multiple cellular proteins involved in the regulation of cellular transcription and RNA splicing. Elevated tumor PRMT5 protein level has recently been correlated with poor prognosis and poor patient survival in various human cancers, including glioblastoma multiforme (GBM), lung cancer, breast cancer, and ovarian cancer. SKL27969 is a highly selective and potent PRMT5 inhibitor that is designed for brain penetration. It strongly binds to S-adenosylmethionine (SAM)-bound PRMT5/MEP50 (methylosome protein 50), leading to potent cellular symmetric dimethylarginine (SDMA) inhibition with an IC50 of 3.4 nM. Cell line panel profiling of SKL27969 revealed a broad spectrum of anti-proliferative activity in various cancer cell types, including CNS tumors, solid cancers prone to spread to brain, other solid cancers, and hematologic cancers. SKL27969 showed excellent brain exposure, with total and unbound partition coefficient (Kp and Kpuu) values of 6.57 and 1.08, respectively, and high tumor-to-plasma ratio, which resulted in significant survival benefit in orthotopic GBM xenograft models and metastatic brain cancer models such as intracranial xenograft models of non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC). Administration of SKL27969 showed strong tumor growth suppression in subcutaneous xenograft models of GBM, NSCLC, or TNBC. High correlation between tumor and plasma SDMA levels after SKL27969 treatment were observed in the preclinical models. Furthermore, SKL27969 showed potentiation of DNA damage when used in combination with DNA-damaging agents, which may suggest possible benefit as a combination therapy. Given the therapeutic target potential of PRMT5 in glioblastoma and other brain metastatic cancers, and the preclinical efficacy of SKL27969, these results have enabled the initiation of Phase 1/2 open-label, multicenter dose-finding study in patients with advanced solid tumors (NCT05388435).
QLTI-04. USING VARIANT ALLELIC FRACTION OF DRIVER MUTATIONS IN ADULT-TYPE DIFFUSE GLIOMA TO IMPROVE MGMT PROMOTER METHYLATION TESTING
Authors: McCord Matthew , Galbraith Kristyn , Jamshidi Pouya , Lukas Rimas , Zhang Hui , Jennings Lawrence , Snuderl Matija , Horbinski Craig
Published: November 2022

Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter predicts favorable response to temozolomide in adult-type diffuse gliomas. Accurate MGMT results require adequate tumor cellularity. Too many admixed non-neoplastic cells (which are always MGMT unmethylated) may cause false-negative results. Currently, ~70% tumor cellularity, based on estimation by microscopy, is recommended for reliable testing. However, this is subjective, and few cases are actually excluded from testing, so there is a risk of false-negative MGMT results. Since adult-type diffuse gliomas usually have heterozygous driver mutations in nearly all tumor cells, including IDH1, IDH2, and/or TERT, we determined whether the variant allelic fraction (VAF) of these mutations could serve as a better quality control metric in MGMT assays. A discovery cohort consisted of 175 gliomas (112 IDH-wildtype, TERT-mutant GBMs, 34 IDH-mutant astrocytomas, and 29 oligodendrogliomas). A validation cohort consisted of 50 gliomas (32 GBMs, 11 IDH-mutant astrocytomas, 7 oligodendrogliomas); all cases had MGMT pyrosequencing and NGS data. Gliomas with average ≥ 10% methylation of 4 measured CpG sites on the MGMT promoter were considered positive, as per standard cutoffs. The discovery cohort showed positive correlation between VAF and MGMT methylation among all gliomas (slope=0.26, R2=0.034, P=0.014). The largest drop-off in MGMT methylation occurred with VAF < 13% (average MGMT of 4.77% versus 18.65% for VAF ≥ 13%, P=0.037). Among GBMs, only 1/7 (14.0%) with TERT VAF < 13% met the cutoff for MGMT promoter methylation, versus 39/105 (37.0%) with VAF ≥ 13%. Based on our previous study (PMID 33830235), approximately 36.5% of GBMs should be positive. The validation cohort showed a similar pattern, wherein gliomas with driver mutation VAF < 13% had average MGMT of 5.75% versus 14.94% for VAF ≥ 13%. In summary, our results suggest that glioma samples with driver mutation VAF below 13% are at higher risk of false-negative MGMT promoter methylation.
QLTI-11. IMPROVING ACUTE STROKE RESPONSE AT A COMPREHENSIVE CANCER CENTER: A MULTIDISCIPLINARY HOSPITAL-BASED QUALITY IMPROVEMENT PROJECT
Authors: Quashie Wayne , Avila Edward , Barzola Melissa , Buchholz Tara , Majeed Jibran , Maria Nicole Santa , Schaff Lauren
Published: November 2022

BACKGROUND

Stroke is common in patients with malignancy, but cancer patients in treatment have contraindications to intravenous (IV) tissue plasminogen activator (tPA). Advancements in endovascular therapy (EVT) has expanded options for acute stroke management . Memorial Sloan Kettering (MSK) is a cancer center without a public emergency room. Acute stroke management occurs inpatient or in urgent care center (UCC). We determined a need for rapid identification and management for acute strokes in our patient population.

METHODS

We developed a multidisciplinary Acute Stroke Pathway relying on activation of our hospital’s rapid response team (RRT), neurology, radiology, nursing support, patient escort services, and pharmacy. We initiated hospital-wide education around stroke symptoms and the pathway. All stroke activations are reviewed by Neurology bi-weekly for real-time feedback. Metrics include the times of symptom identification (“door time” = UCC check in or symptom discovery for inpatients), evaluation, head computed tomography (CT), labs, and administration of IV tPA. Times are compared to our 2016 institutional baseline data and National Institute of Neurological Disorders and Stroke (NINDS) benchmarks.

RESULTS

Since implementation of the pathway (6/11/2018) through Q1 2022 (3/31/2022), there were 551 acute stroke activations, 13 IV tPA administrations, and 48 patients transferred to a comprehensive stroke center for consideration for EVT. Average 2021 door-to-evaluation time: 8 mins (baseline: 18 mins, NINDS: 10 mins), door-to-stroke team: 11 mins (baseline: unknown, NINDS: 15 mins), door-to-CT: 33 mins (Baseline: 95 mins, NINDS: 25min), door-to-CT interpretation: 34 mins (baseline: 251 mins, NINDS: 45 mins), door-to-labs: 50 mins (baseline: unknown, NINDS: 45 min), door-to-IV tPA: 62 mins (baseline: unknown, NINDS: 60min).

DISCUSSION

The patient population at MSK is distinct from most hospitals. Patients with cancer have a higher incidence of stroke but are unlikely candidates for intervention. Inter-professional collaboration resulted in early stroke care in oncology patients consistent with NINDS benchmarks.
QLTI-15. VENOUS SINUS THROMBOSIS AFTER BRAIN TUMOR RESECTION
Authors: Regis Patrick , Cavaliere Robert , Sauvageau Eric , Hanel Ricardo
Published: November 2022

Post-operative venous sinus thrombosis (POVST) is an uncommon complication from a craniotomy for brain tumor resection. There are few data in how to treat POVST, including the use of anticoagulation and follow-up. It has been found that POVST is more common in dural-based lesions especially located on or near a sinus, however treatment has not been standardized. We retrospectively reviewed our POVST cases between January 2018 to December 2020 for brain tumor resection, whether we chose to start anticoagulation or not, and the eventual outcome. We also performed a literature review on the topic to compare findings and management. We identified 14 cases of POVST; 8 of the cases were for extra-axial masses. Of the 14, 6 POVST had clot involving the superior sagittal sinus (SSS), with 3 being discharged with a direct oral anticoagulant (DOAC) and one being discharged on warfarin. With transverse sinus involvement, 6 cases were noted (with no SSS clot), with 2 started on a DOAC and 2 being started on ASA 81mg. In the sigmoid sinus there were 2 cases and did not receive anticoagulation. Of the 14 total cases, 1 was symptomatic (new-onset seizures) necessitating surgical recanalization and no other cases had symptoms attributed to the POVST. Two patients died from unrelated reasons prior to receiving any outpatient imaging, and all other patients had recanalization of their involved sinuses within 2-5 months. There were no complications in patients receiving anticoagulation. Our literature review didn't show a standardized method in POVST treatment. There is also disagreement in what anticoagulation should be used, and if it is necessary. Based on our retrospective analysis and literature review, if the clot is symptomatic, involves the SSS, or propagates, we recommend anticoagulation. Outside the SSS, it should be determined on a case-by-case basis, but anticoagulation may not be necessary.
QLTI-19. EVALUATION OF INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSTIC SERVICES – A LARGE TERTIARY UK CENTRE EXPERIENCE
Authors: Digby Richard , Ramakrishnan Piravin , Moughal Saad , Chakrabarty Arundhati , Mathew Ryan
Published: November 2022

INTRODUCTION

Brain tumour intraoperative diagnosis (smear cytology, frozen section) is a commonly performed, routine diagnostic service. Currently, samples must be transported from the operating room (OR) to pathology, impacting turnaround time (TAT), carbon emissions (if cross-site), and motivation for repeat sampling. We performed a broad evaluation of current practice in a large, tertiary, UK brain tumour centre, to identify potential gains in real-time tissue diagnosis.

METHODS

All brain tumour samples (n=228) sent for intraoperative diagnosis in 2021 were analysed retrospectively. TAT was assessed by capturing different timepoints along the pathway. Concordance between diagnoses at the following stages was determined: preoperatively based on radiology, intraoperatively (frozen section or smear), provisional paraffin and final integrated. Additionally, we anonymously surveyed neurosurgeons’ opinions (n=18) on the current service.

RESULTS

The mean (±SD) specimen transportation time was 10.6±2.0 minutes, with an estimated total TAT of 30-60 minutes. Intraoperative diagnosis provided a slightly higher rate of concordance with provisional paraffin diagnosis than preoperative radiological diagnosis (89.5% vs 86.3%). Non-concordance was most commonly due to non-representative sampling (e.g., predominantly necrotic), with no repeat sample being sent/available intraoperatively. Prevailing neurosurgical opinion of the intraoperative diagnostic service was dissatisfaction or neutrality (50% and 39% of respondents), with a minority being positive (11%). Reasons for this included: intraoperative delay due to TAT (47%), perceived inaccuracy of results (41%), and perceived reduced out-of-hours availability (56%).

CONCLUSIONS

Current brain tumour intraoperative diagnostic practice relies on physical sample transportation and manual processing; the resultant long TAT causes surgeon dissatisfaction and dissuades repeat analysis in the case of non-representative sampling. Real-time tissue diagnostic technologies such as OR-sited probe-based confocal endomicroscopy, scanners and Raman spectroscopy should be considered to facilitate faster and repeated examination. The latter may have additional benefits in real-time expert pathology feedback, tumour margin-zone analysis and increased extent of resection.
QLTI-21. SAFETY OF THE UTILIZATION OF TELEMEDICINE FOR BRAIN TUMOR NEUROSURGERY FOLLOW-UP
Authors: Morell Alexis , Patel Nitesh , Higgins Dominique , Eatz Tiffany , Levy Adam , Eichberg Daniel , Shah Ashish , Kader Michael , Morell Alexis , Ivan Michael , Komotar Ricardo
Published: November 2022

BACKGROUND

There is a need to evaluate the outcomes of patients who underwent brain tumor surgery and were followed by telemedicine or in-person consults during the COVID-19 pandemic.

METHODS

We retrospectively included all patients who underwent surgery for brain tumor resection by a single neurosurgeon at our Institution from the beginning of the COVID-19 pandemic restrictions (March 2020) to August 2021. Outcomes were assessed by stratifying the patients using their preference for follow-up method (telemedicine or in-person).

RESULTS

Three-hundred and eighteen (318) brain tumor patients who were included. The follow-up method of choice was telemedicine in 185 patients (58.17%), and in-person consults in 133 patients. We found that patients followed by telemedicine lived significantly farther, with a median of 22.23 miles, compared to a median of 36.34 miles in the TM cohort (p = 0.0025). When comparing visits to the emergency department (ED) within 30 days after surgery, and we found no statistical difference between the TM and the IP group (7.3% vs 6.01%, p=0.72). Readmission rates, wound infections and 30-day mortality were similar in both cohorts. These findings were also consistent after matching cohorts using a propensity score. The percentage of telemedicine follow-up consults was higher in the first semester (73.17%) of the COVID-19 pandemic, compared to the second (46.21%) and third semesters (47.86%).

CONCLUSIONS

Telehealth follow-up alternatives may be safely offered to patients after brain tumor surgery, thereby reducing patient burden in those with longer distances to the hospital or special situations as the COVID-19 pandemic.
QOL-03. CLINICAL CHARACTERISTICS AND FACTORS ASSOCIATED WITH SEIZURES IN GLIOMA PATIENTS AT THE NATIONAL CANCER CENTER DHARMAIS HOSPITAL IN JAKARTA, INDONESIA
Authors: Suryawijaya Nathasia , Andriani Rini , Wilopo Siswanto Agus
Published: November 2022

BACKGROUND

Seizures are a common presentation of gliomas that substantially impact morbidity and quality of life. Little is known about the prevalence of seizures among glioma patients in Indonesia. Furthermore, there is no publication regarding clinical characteristics related to this prevalence.

OBJECTIVE

To measure the prevalence of seizures among glioma patients and its association with tumor grade (low or high), type, and location.

METHODS

This is a retrospective study based on the medical records of all patients diagnosed with glioma according to histopathology findings. There were 65 patients admitted to the National Cancer Center Dharmais Hospital, Jakarta between January 2019 and December 2020. The demographic characteristics and clinical data were extracted, including clinical and tumor characteristics. Using logistic regression, an odds ratio (OR) with 95% confidence intervals was used to investigate the association between factors related to seizures.

RESULTS

A total of 65 patients (39 males and 26 females) were included in the study. Most of the patients are ranging from 40 to 49 years old (39%). The prevalence of seizures is relatively high which is 42 out of 65 patients (64.6%). Headache (95%) is the most common complaint in patients. Our study shows that grading and location of tumor were significantly associated with seizure in glioma patients among clinical manifestations (headache, neurological deficits) and pathological classification (p=0.005 and p=0.022). Bivariate analysis using logistic regression showed that low-grade glioma had a 12.2-fold increase in the risk of developing seizures compared to high-grade gliomas with a 95% CI of 1.50 to 99.9 (P< 0.05). Moreover, the temporal location of the tumor had a 5.6-fold increase in the risk of developing seizures compared to the parietal location with a 95% CI of 1.01 to 30.9.

CONCLUSIONS

Grading and location of the tumor were factors associated with seizures in glioma patients.
QOL-06. PREDICTING VENOUS THROMBOEMBOLISM IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMAS
Authors: Burdett Kirsten B , Unruh Dusten , Drumm Michael , Lamano Jonathan , Schwartz Margaret , Chandler James , Javier Rodrigo , Steffens Alicia , Amidei Christina , Lipp Eric S , Peters Katherine B , Lai Albert , Eldred Blaine , McCortney Kathleen , Heimberger Amy , Scholtens Denise , Horbinski Craig
Published: November 2022

Venous thromboembolism (VTE) is a common paraneoplastic complication in patients with adult-type diffuse gliomas. VTE greatly diminishes quality-of-life, and can even be life-threatening. While effective VTE prediction models exist for other cancers, those models do not work for gliomas. Thus, there are no standard guidelines for thromboprophylaxis in glioma patients. To address this deficiency, arterial blood, tumor tissue, and comprehensive clinical-pathologic data (including next generation sequencing) were obtained from 258 newly diagnosed WHO grade 2-4 adult-type diffuse glioma patients at Northwestern Memorial Hospital. Forty-six out of 258 grade 2-4 glioma patients (17.8%) experienced a subsequent VTE. Intratumoral expression of two proteins that have been associated with VTE risk in other cancers, thromboplastin and podoplanin, was higher in IDH wild-type than IDH mutant gliomas. Tissue expression of both markers was associated with increased VTE risk, but in the circulation, only thromboplastin positively correlated with VTE. LASSO time-to-event analysis showed that older patient age, elevated body mass index, elevated WBC count, hypertension, a preoperative history of VTE, asthma, and higher WHO grade predicted increased postoperative VTE risk, whereas hypothyroidism, IDH mutation, and MGMT promoter methylation were negative risk factors. Together, these 10 variables generated a receiver operating characteristic curve for 3, 6, 9, and 12 months from original surgery resulting in estimated AUC value of 0.82 in the Northwestern discovery cohort, 0.72 in the UCLA validation cohort (N=68), and 0.68 in the Duke validation cohort (N=157). We created an online prediction tool based on this model, which estimates VTE risk up to 1 year from original surgery. To the best of our knowledge, this is the first externally validated VTE risk prediction tool designed specifically for adult-type diffuse glioma patients. This tool, based on readily obtainable information, provides treating physicians with more objective risk estimates on which to base thromboprophylaxis decision-making.
QOL-15. VALIDITY AND RELIABILITY EVALUATION OF PRO-CTCAETM FOR ADULT DIFFUSE GLIOMAS PATIENT IN CHINESE POPULATION. (VERONICA): A PRELIMINARY DELPHI STUDY
Authors: Luo Chen , Wu Shuai , Cai Linbo , Chen Juxiang , Chen Song , Fei Zhou , Kong Lin , Li Sanzhong , Ma Hui , Mou Yonggao , Qiu Xiaoguang , Shu Kai , Song Sida , Sun Chongran , Tang Zhiwei , Wu Zanyi , Xiong Zhang , Xu Geng , Xu Jiankun , You Yongping , Zhang Jianmin , Zhang Wei , Zhong Chunlong , Zou Yourui , Wu Zhenyu , Wu Jinsong
Published: November 2022

OBJECTIVES

Given the increasing importance of patient’s perspective in adverse events reporting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) has been proposed as new PRO measures in oncology; however, its implementation has not yet been evaluated in glioma patients, and standardized selection process of priority symptom terms has not been applied.

METHODS

A total of 16 experts (13 neurosurgeons, 2 radiotherapists, 1 psychiatrist) from 14 medical centers in China were invited to participate in a consensus-seeking 2-round online Delphi survey. Participants rated the level of their agreement with each symptom term likely to occur during adult diffuse gliomas treatment on a 5-point Likert scale. Terms not reaching consensus over the first round were modified in the second rounds. Consensus was defined as content validity index (CVI) > 0.78，coefficient of variation (CV)< 0.35 and average Likert score > 3.00.

RESULTS

Experts reached a consensus on 21 PRO-CTCAE™ symptom terms in the first Delphi round, and 10 terms in the second round. Likert scale scoring among all experts showed significant consistency (Round 1: Kendall’s W= 0.415，p＜0.001; Round 2: Kendall’s W = 0.351，P＜0.001). The 31 terms (38.75%) screened out of all 78 terms covered neurological symptoms(n=7), psychiatric symptoms(n=6), dermatological symptoms(n=6), gastrointestinal symptoms(n=5) and other common postoperative systemic symptoms of glioma patients.

CONCLUSIONS

We identified a customized PRO-CTCAE™ questionnaire containing a core set of priority symptom terms for the adult diffuse glioma through a 2-round Delphi survey. Next, a prospective, multi-center, real-word study would be performed to assess the validity, reliability and responsiveness of the customized PRO-CTCAE™ for adult diffuse glioma patients in Chinese population (VERONICA).
QOL-21. REAL-WORLD QUALITY-OF-LIFE AND HEALTH UTILITIES FOR PATIENTS WITH CNS CANCERS ON THE XCELSIOR PLATFORM
Authors: Sabates Alanis , Wood Alayna , Lee Hope , Swain Andrew , Irizarry Sabrina , Hinton Chezney , Ginn Sarah , Cole Zac , Chavez Gordon , Tadic Kristina , Chuyka Don , Federowicz Bryan , Proescholdt Christina , Shapiro Mark
Published: November 2022

OBJECTIVE

xCures operates a direct-to-patient, real-world evidence platform according to the nationwide observational research protocol XCELSIOR (NCT03793088), which aggregates medical data in an FDA-compliant electronic database. There is a relative scarcity of published results on real-world Quality-of-Life (QoL) outcomes and resulting health state utilities for patients with Central Nervous System (CNS) cancers. We sought to use the xCures platform to help address this issue.

METHODS

XCELSIOR participants were invited weekly to complete the EuroQol 5-Dimension (EQ-5D-5L) QoL survey. A EuroQol-endorsed model was used to estimate health state utilities from patient surveys. Survey results, utility estimates, and clinical information were analyzed to understand the influence of common mutations in glioma on patient reported outcomes.

RESULTS

30 patients (21 glioblastoma, 4 oligodendroglioma, 2 diffuse midline glioma, 2 diffuse astrocytoma, 1 Schwannoma) completed at least one EQ-5D-5L survey over the course of 9 weeks. Health state utilities were positively correlated (p< .03) with Karnofsky Performance Score (KPS). The average utility for EGFR-mutated patients (N=6) was .578 (SD=.334) while for EGFR-wildtype patients (N=7) it was .747 (SD=.227). The average utility for MGMT-methylated patients (N=13) was .816 (SD=.139) while for non-methylated patients (N=10) it was .583 (SD=.379). The average utility for IDH-mutated patients (N=9) was .789 (SD=.153) while for non-mutated patients (N=17) it was .685 (SD=.324). The average utility for patients with a 1p/19q co-deletion (N=4) was .837 (SD=.126) while for those without a co-deletion (N=8) it was .744 (SD=.244).

CONCLUSION

The xCures platform has enabled the study of real-world QoL outcomes for patients with CNS cancers. This is the first report studying the influence of genetic mutations on QoL collected through patient reported outcomes. Future research aims to perform similar studies with larger number of patients.
QOL-24. SILVER LININGS: THE EXPERIENCE OF POSTTRAUMTIC GROWTH IN NEURO-ONCOLOGY CAREGIVERS
Authors: Willis Kelcie , Lanoye Autumn , Kleva Christopher , Reid Morgan , Fox Amber , Sadicario Jaclyn , Brechbiel Julia , Loughan Ashlee
Published: November 2022

BACKGROUND

Posttraumatic Growth (PTG) refers to positive psychological changes resulting from a traumatic event. A brain cancer diagnosis may be experienced as traumatic—not only for patients, but also for their caregivers. While caregivers in neuro-oncology consistently report significant emotional distress throughout the disease trajectory, their experience of PTG is unknown.

METHODS

Cross-sectional data were obtained from patients (N = 101, Mage = 50 years, 59% female, 86% White, 47% high-grade) diagnosed with primary brain tumors and their caregivers (N = 62, Mage = 50 years, 79% female, 92% White, 58% spouses) during routine clinic visits or online following the precautions of COVID-19. Patients and caregivers completed the Post Traumatic Growth Inventory, where > 46 and > 3 represent the clinical cutoffs for high versus low PTG. We compared caregiver and patient PTG using descriptive statistics and independent samples t-test.

RESULTS

Caregivers’ total PTG score was in the low range (M = 44.58, SD = 20.95) and significantly lower than patients’ total PTG (M = 51.78, SD = 21.96, p = .04). All five of caregivers’ subscale scores were also considered to be in the low range. Nevertheless, 45% of caregivers demonstrated moderate-to-high total PTG (compared to 67% of patients), and 65% reported moderate-to-high PTG in at least one subscale (compared to 85% of patients). Similar to patients, caregivers reported the most growth in Appreciation for Life (M = 2.98, SD = 1.05) and the least growth in New Possibilities (M = 1.71, SD = 1.17).

CONCLUSIONS

Results mirror previous findings in neuro-oncology, where caregivers consistently demonstrate greater emotional distress than patients. The current study suggests caregivers may also experience fewer positive changes. Overall, caregivers would benefit from increased support to process traumatic experiences associated with the disease. Future research should continue to investigate predictors of PTG in this vulnerable sample.
QOL-25. IMPACTS OF IMPLEMENTING A PROSPECTIVE TREATMENT AND SURVEILLANCE PROTOCOL FOR THE MANAGEMENT OF NF2-ASSOCIATED VESTIBULAR SCHWANNOMAS ON TUMOR GROWTH, HEARING OUTCOMES, AND QUALITY OF LIFE
Authors: Rousseau Julien , Dahoud Andrea , Labidi Moujahed , El Haffaf Zaki , Florescu Marie , Saliba Issam , Gosselin Marie-Hélène , Lapointe Sarah
Published: November 2022

Neurofibromatosis type 2 (NF2) is an autosomal dominant neurocutaneous syndrome associated with the development of nervous system tumors, including vestibular schwannomas (VS), meningiomas, and ependymomas. Although considered a rare illness, it is a source of significant morbidity, mainly due to early hearing loss leading to decreased autonomy and productivity among young adults. Bevacizumab, a monoclonal antibody against VEGF, has been shown to improve audition and tumor size in observational studies on NF2-associated VS. The most common limitations in the literature include the lack of reliable control groups, the paucity of data on quality of life, and the lack of detailed audiology testing guidelines. Moreover, the cost of bevacizumab is a limiting factor in access to care. In our Canadian tertiary care center, bevacizumab has been offered to NF2 patients with VS complications without specific indications on optimal treatment initiation time or duration. We present a hybrid cohort study protocol with retrospective and prospective arms aimed at measuring the impacts of introducing a standardized treatment and surveillance protocol on tumor growth, hearing outcomes, and quality of life. Patients from the multidisciplinary neurofibromatosis clinic at the University of Montreal Health Center, Canada, will be evaluated for inclusion in the prospective arm through regular audiological evaluations and imaging. Eligible individuals will receive bevacizumab at an initial dose of 5 mg/kg every 2 weeks for a year while participating in serial audiological, radiological, and quality of life assessments. The results will be compared to those of our historical cohort. Our primary outcomes will be tumor growth rate (% per year) for vestibular schwannomas, meningiomas and ependymomas, audiological test results, and quality of life and subjective hearing estimated through standardized questionnaires (SF-36, SSQ). We hypothesize that patients enrolled in the prospective arm will show improved clinical response compared to our historical cohort.