bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-75. A MACROPHAGE-BASED DRUG DELIVERY PLATFORM FOR GLIOMA TREATMENT
Authors: Sun Miaomiao , Bialasek Maciej , Rygiel Tomasz , Weller Michael , Krol Magdalena , Weiss Tobias 
Published: November 2023

Abstract
There is an urgent need for more effective treatment strategies against gliomas. Even though various drugs have potent anti-tumor activity in vitro, their application in vivo is limited by ineffective delivery and systemic toxicity. Therefore, novel strategies are needed to deliver these drugs effectively and safely to the tumor site. Here, we developed an adoptive transfer strategy against malignant brain tumors utilizing monocyte-derived macrophages that are loaded with ferritin-protein cages containing drugs or other proteins and transfer these nanocarriers effectively to cancer cells for intracellular release and cancer cell killing. Using flow cytometry and microscopy, we observed a high transfer efficiency of ferritin-cages from loaded macrophages into human and mouse glioma cells in vitro in co-culture assays. We also confirmed the transfer of ferritin-cages from macrophages to glioma cells in vivo upon intravenous or intratumoral treatment of GL-261 or CT-2A glioma-bearing mice using in vivo imaging and ex vivo flow cytometry and microscopy. To study the anti-glioma activity with therapeutically active payloads, we loaded murine/human macrophages with ferritin cages carrying cytotoxic auristatin. Co-culture of these loaded macrophages with murine or human glioma cells in vitro revealed a time- and concentration-dependent cytotoxicity to glioma cells. In vivo, intravenous or intratumoral administration of ferritin-drug protein cages was tolerated without toxicities and conferred a survival benefit in two orthotopic murine glioma models (GL-261 and CT-2A) leading to a large fraction of long-term surviving mice. Interactome studies of ferritin-cage-binding proteins revealed phagocytic and cytoskeleton re-arrangement pathways to be involved in uptake and transfer of ferritin-cages from macrophages to glioma cells. This ‘Trojan Horse’ approach based on macrophages-ferritin-protein cages constitutes a promising platform to deliver cytotoxic drugs effectively and safely to gliomas and provides a rationale for clinical translation.
EXTH-77. EXTENDED HALF-LIFE IL-2 SYNERGIZES WITH Α-PD-1 FOR TREATMENT OF PRECLINICAL MURINE GLIOBLASTOMA MODELS
Authors: Owens Carley , Tritz Zachariah , Ayasoufi Katayoun , Wolf Delaney , Parney Ian , Hanson Michael , Fang Jin , Johnson Aaron , Campian Jian , Fain Cori , Himes Benjamin , Malo Courtney , Goddery Emma , Yokanovich Lila , Wang Chensu , Vile Richard , Moynihan Kelly , Irvine Darrell J , Mercano Rosa , Wittrup Dane , Maynes Mark 
Published: November 2023

Abstract
α-PD-1 checkpoint blockade is a promising immunotherapeutic approach for many solid tumors; however, this strategy is minimally effective for GBM patients as a monotherapy. One potential reason why α-PD-1 checkpoint blockade is ineffective is the tumor microenvironment and systemic derangements of the immune system which are prevalent in GBM patients. We have successfully modeled peripheral immune derangements in experimental murine GBM models. These include low peripheral blood CD4 T cell counts, reduced MHC class II expression on monocytes, and atrophy of primary immune organs in animals harboring gliomas. We therefore hypothesized that extended half-life IL-2, a potent cytokine which promotes the proliferation, differentiation, and killing activity of T cells, could overcome immune derangements and could potentially synergize with α-PD-1 checkpoint blockade therapy. In cohorts of C57Bl/6 mice, we supplemented α-PD-1 checkpoint blockade with multiple bio-engineered extended half-life IL-2 molecules to treat GL261 and CT2A orthotopic glioma models which are normally resistant to monotherapy. We observe a statistically significant increase in survival in GL261-bearing animals receiving the combination of extended half-life IL-2 reagents and αPD-1 therapy relative to control-treated mice. Some animals receiving this combination therapy had a reduction in tumor burden to levels below detection. These long-term survivors underwent a rechallenge experiment with a second inoculation of GL261-Luc and effectively cleared tumor without further therapeutic intervention. This intervention causes a significant shift in the immune profile, including the formation of mature T cell responses, as well as restoring the diminished peripheral immune cell counts in GL261-bearing animals. Finally, combining extended half-life IL-2 with α-PD-1 checkpoint blockade is effective independently of the CD8 T cell response. Together, these data suggest that combination immunotherapies employing extended half-life IL-2 fusion proteins are translational to the clinic and do not require the identification of tumor specific antigens for efficacy
EXTH-78. CRISPROFF EPIGENOME EDITING AND FUNCTIONAL GENOMICS DEFINE MEDIATORS OF CHEMOTHERAPY RESISTANCE IN GLIOBLASTOMA
Authors: Lin Katie , Goudy Laine , Pak Joanna , Foster Kyla , Payne Emily , Ozawa Tomoko , de Groot John , Vasudevan Harish , Raleigh David , Gilbert Luke , Berger Mitchel , Liu John 
Published: November 2023

Abstract
Alkylating chemotherapies exhibit survival benefit for patients with glioblastoma (GBM). CRISPRoff is a programmable epigenetic memory writer that stably and heritably silences genes through DNA methylation. Epigenetic silencing of MGMT via promoter methylation predicts response to chemotherapy and is prognostic for overall survival. Here, we performed epigenome editing using CRISPRoff to stably silence MGMT through induced promoter methylation as a therapeutically tractable approach for potentiating GBM to chemotherapy. We then used genome-wide CRISPR interference (CRISPRi) screens to broadly define novel chemosensitizing targets of GBM cells. Epigenome editing was performed through electroporation of CRISPRoff mRNA and sgRNAs into MGMT hypomethylated GBM cell lines (LN18 and T98G) and primary GBM cells. Whole genome bisulfite sequencing, RT-qPCR, and western blot assessed gene silencing. Cell viability assays measured drug sensitivity. GBM xenografts with CRISPRoff-induced silencing of MGMT were intracranially transplanted in mice and treated with temozolomide. Genome-wide functional genomics screens were performed using CRISPR interference. CRISPRoff against MGMT reduced MGMT mRNA and protein levels by 99.97%, generating up to 150-fold sensitization to temozolomide and 9-fold sensitization to lomustine in GBM cells. Silencing remained stable and heritable in clonally isolated GBM cells at 145 days after transient delivery of CRISPRoff, and gene repression and drug sensitization were equivalent to Cas9-mediated homozygous deletion of MGMT in vitro and in vivo. CRISPRoff of MGMT in intracranial xenografts exhibited significant reduction in tumor growth with temozolomide treatment compared to temozolomide treatment with control CRISPRoff (p = 0.0047). CRISPRi screens validated MGMT and defined 266 and 238 additional modifiers of temozolomide and lomustine response, respectively, including the ATR (BRCA2), DNA repair (REV1), cell cycle (PSMD13), and Fanconi anemia pathways (FANCI, FANCD2). In summary, we integrate targeted epigenome editing with unbiased genome-wide approaches to establish a novel discovery and therapeutic platform against glioblastoma.
QLTI-03. FRACTIONATED PREOPERATIVE VS POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR PATIENTS WITH MELANOMA BRAIN METASTASES: A COST UTILITY ANALYSIS
Authors: Keister Alexander , Vignolles-Jeong Joshua , Kreatsoulas Daniel , Damante Mark , Elder J Bradley 
Published: November 2023

Abstract

INTRODUCTION
Stereotactic radiosurgery (SRS) followed by surgical resection is an emerging treatment paradigm for brain metastases. Preoperative SRS may improve outcomes such as rates of radiation necrosis (RN) and leptomeningeal disease (LMD) compared to postoperative SRS. However, the impact of this paradigm shift on metrics such as cost of care and hospital length of stay is unclear. In this study, we sought to categorize these metrics for melanoma metastases, specifically.

METHODS
A retrospective analysis identified patients who underwent surgical resection and fractionated stereotactic radiation therapy (FSRT) for melanoma brain metastases. Demographics, medical history, systemic and local treatment modalities, imaging, and postoperative course were collected. Perioperative cost of care was analyzed beginning two weeks preoperatively and concluded at four-weeks postoperatively. Continuous variables were analyzed via non-parametric two-sided t-tests and ANOVAs. Categorical variables were analyzed via Chi-squared tests.

RESULTS
Forty-two patients underwent 43 craniotomies for melanoma metastases. The mean age at surgery was 59.6 years-old and the male predominance was 65.1%. Total cost of perioperative care was more expensive among those treated with neoadjuvant (n = 11) FSRT compared to those who underwent postoperative (n = 32) FSRT ($262,072 vs $174,646; p = 0.0254). Mean length of stay for craniotomies was similar between groups (p = 0.1674), although trending down among the neoadjuvant FSRT group (4.5 days) among the neoadjuvant FSRT group versus the postoperative FSRT group (7.0 days).

CONCLUSIONS
In this study, neoadjuvant FSRT had an increased cost of care in the perioperative period, and similar lengths of hospital stay for craniotomy. Preoperative FSRT for melanoma metastases may result in shorter LOS, however, comes with an increased cost of care. Further investigation of itemization of healthcare costs to identify areas of improvement for neoadjuvant therapy is warranted.
QLTI-04. LINKING DATA FROM A BRAIN CANCER CLINICAL REGISTRY (BRAIN) WITH THE STATE-BASED REGISTRY OF BIRTHS DEATHS MARRIAGES: IMPROVING THE QUALITY OF CLINICAL REGISTRY SURVIVAL DATA
Authors: Smith Samuel , Drummond Kate , Dowling Anthony , Bennett Iwan , Freilich Ronnie , Phillips Claire , Ahern Elizabeth , Reeves Simone , Campbell Robert , Collins Ian , Johns Julie , Dumas Megan , Gibbs Peter , Gately Lucy 
Published: November 2023

Abstract

BACKGROUND
Real-world data (RWD) collected routinely in clinical care forms the basis of cancer clinical registries. These registries are inclusive and provide valuable research outcomes, however missing data particularly survival compromise the accuracy of RWD. Here we explore the utility of data linkage to state-based registries to enhance the capture of survival outcomes.

METHODS
We reviewed prospectively collected data from consecutive patients with brain tumours in the Brain Tumour Registry Australia Innovation and Translation (BRAIN) database and included those treated in Victoria with no recorded date of death and no follow-up the preceding 6 months. Full name and birthdate were used to match patients in the BRAIN registry to those in the Victorian Births, Deaths and Marriages (BDM) Registry. Survival outcomes were compared, pre- and post-data linkage (DL).

RESULTS
Of the 7735 patients contained in BRAIN, 5435 patients (70.3%) met eligibility criteria and had no recorded date of death. 1611 (30%) of patients were matched with a date of death in BDM. More matches were found in tumours of highest malignant potential such as grade 4 glioma (67.2%), brain metastases (63.9%) and primary cerebral lymphoma (50.5%), compared with good-prognostic tumours such as meningioma (8.7%) and schwannoma (3.2%). Compared to post-DL, survival outcomes were significantly overestimated pre-DL for the entire cohort (30.3m vs 17m, p&lt; .0001). This difference was most pronounced for Grade-3 glioma (93.7m vs. 38.1 p = 0.008) but significant differences were seen across all tumour types.

CONCLUSION
Using an Australian brain-tumour population, this is the first study to demonstrate the importance of improved RWD accuracy through linking state-based registries to comprehensive cancer registries. This missing death data significantly compromises the potential quality of audit and research projects, driving a repeated over-estimate of survival. Routine periodic DL to pertinent registries should be considered to ensure accurate reporting and interpretation of RWD.
QLTI-05. COST TOXICITY OF ORAL CHEMOTHERAPY IN PRIMARY BRAIN TUMOR PATIENTS
Authors: Patel Mallika , Affronti Mary L , Buckley Evan , Herndon James , Lipp Eric , Mackowsky Emma , Johnson Margaret O , Friedman Henry , Ashley David , Kim Jung-Young , Peters Katherine 
Published: November 2023

Abstract

BACKGROUND
Costs associated with cancer treatments in the United States continue to rise as new therapies are approved. Financial toxicity describes both the quantifiable costs associated with cancer as well as the distressful effects related to the costs of treatment.

METHODS
The goal of this study is to better understand the financial burden of oral chemotherapies on patients with primary brain tumors from their perspective. Following one cycle of oral chemotherapy, we contacted patients per IRB-approved protocol to participate in a 20-question survey (COST-FACIT and other questions relevant to insurance and cost). With descriptive statistics, we summarized survey responses overall and within strata defined by on-label or off-label oral medication use.

RESULTS
Sixty surveys were completed (58 total patients; 2 completed surveys for a second treatment). Most surveys (n = 53, 88%) reflected on-label therapy use, with only 7 patients (12%) on off-label therapies. The mean overall financial toxicity score was 23.1 (range: 1 – 44); the lower the financial toxicity score, the greater the financial distress of study participants. When asked if their provider discussed treatment cost before initiation, 21 patients (35%) stated that they did, and 39 patients (65%) said they did not discuss cost or did not recall a discussion. However, in the off-label therapies cohort, all 7 patients stated that their provider discussed cost before prescribing. Majority of surveys (70%) noted patient copays associated with these medications. Nine patients (17%) in the on-label group and three patients (43%) in the off-label group had chemotherapy-associated costs that caused negative effects on quality of life.

CONCLUSIONS
Although the groups are disproportionate, a higher percentage of financial distress occurred in the off-label therapy group. While cost discussions are challenging, they remain an important part of therapy initiation that may decrease undue stress; this will be an area of improvement.
QLTI-08. THE COLUMBIA NEURO-ONCOLOGY RESEARCH DASHBOARD: A WEB-BASED TOOL TO ASSESS CLINICAL TRIAL RECRUITMENT AND ACCRUAL METRICS
Authors: Welch Mary , Pan Peter , Haggiagi Aya , Donovan Laura , Diaz Maria , Iwamoto Fabio , Lassman Andrew 
Published: November 2023

Abstract

BACKGROUND
Insufficient trial participation is a recognized barrier to drug development. Research has focused on patient and physician-associated factors, yet few institutions assess the impact of trial availability, referral patterns, and patient eligibility. Screening logs provide a rough estimate of candidate pools but tell us nothing about patients who are not screened, let alone why. To better understand site-specific barriers and effectively assess efforts to overcome them, real-time, data-driven metrics are essential.

METHODS
To address this need, we created The Columbia Neuro-Oncology Clinical Research Dashboard (CRD), a web-based tool designed to capture all patients presenting to our faculty practice with newly diagnosed or recurrent CNS tumors and track their participation -- or lack thereof -- in interventional trials. From 7/2022 - 9/2022, we experimented with several iterations of the CRD, adjusting the platform and variables in response to user feedback. To pilot the final design, we started with a limited sample of high-grade glioma patients seen at Columbia University Irving Medical Center's Neuro-Oncology Faculty Practice from 9/1/2022 - 1/1/2023. During this period, 62 patients were tracked, allowing for further refinements to improve functionality and data capture. When populated, the CRD was easily queried for important quality improvement metrics including accrual rates, time from presentation to study initiation and grounds for screen failure. It also captured the percentage of patients who were not offered a trial and the cited reasons. Inclusion of demographics and referral patterns provided additional dimensions to the data. NEXT STEPS: The CRD has met its preliminary aims. It provides a user friendly and accessible interface for data capture. With appropriate staffing and implementation processes in place, it has real potential to inform our efforts to improve patient accrual and diversity with real-time metrics. Subsequent efforts will focus on these aspects of the project.
QLTI-11. TIMELINE FROM INITIAL MRI TO INTERVENTION IN NEWLY DIAGNOSED HIGH GRADE GLIOMA
Authors: Cevering Colby , Kaur Maninder 
Published: November 2023

Abstract

OBJECTIVE
Prompt treatment of high-grade glioma is crucial for prolonging life. In an attempt to identify factors that lead to delays in treatment, we evaluated the amount of time between initial MRI and treatment start date for our patients with newly diagnosed high grade glioma.

METHODS
This was a retrospective chart review study. Adults over the age of 18 years of age with newly diagnosed high grade glioma were included if they were seen by the neuro-oncology department at Loma Linda University Medical Center. Reviewed charts were dated from November 2020 to August 2022. We evaluated the amount of time between initial MRI and several important milestones in the diagnosis and treatment of high grade glioma, including resection; biopsy results; neuro-oncology consult; radiation-oncology consult; date that chemotherapy was ordered, received by the patient, and initiated; and radiation therapy start date.

RESULTS
Twenty-two patients with new diagnosis of high-grade glioma were identified. Six patients were excluded due to complicated treatment courses involving outside facilities. Sixteen patients were included in the study. Thirteen patients (81%) had a diagnosis of glioblastoma, 2 (12%) had a diagnosis of diffuse midline glioma, and 1 (6%) had a diagnosis of anaplastic astrocytoma. The mean number of days between initial MRI and chemotherapy start date was 88. Prolonged timelines were seen in all analyzed metrics.

CONCLUSIONS
There is a significant delay in chemotherapy initiation for patients with high grade glioma at our facility. We also provide a framework for other institutions to evaluate their system processes in order to improve care delivery.
QLTI-13. RETROSPECTIVE REVIEW OF THE DIAGNOSTIC YIELD OF CEREBROSPINAL FLUID (CSF) ANALYSIS IN DIAGNOSIS OF CENTRAL NERVOUS SYSTEM (CNS) LYMPHOMA IN A COMMUNITY NEURO ONCOLOGY CENTER
Authors: Lu-Emerson Christine , Lawlor Donna , Deborah Cushing , Rughani Anand , Christman Robert , Florman Jeffrey 
Published: November 2023

Abstract
Central nervous system (CNS) lymphoma can be a challenging disease to diagnose. Both primary and secondary CNS lymphoma often result in poor outcomes rendering early diagnosis and treatment essential. Traditionally, diagnostic modalities include surgery, cerebral spinal fluid (CSF) cytologic analysis, vitrectomy, and chorioretinal biopsy. Radiographic and clinical presentation can widely vary between patients, further enhancing diagnostic dilemma. We present a retrospective study from a community neuro oncology center analyzing the utility of CSF analysis in the diagnosis of CNS lymphoma. Between 2018-2022, 26 CNS lymphoma patients were identified of which 22 (85%) were primary CNS lymphoma patients. Median age of diagnosis was 68.5 years, and 21 (81%) of the patients were immunocompetent. 13 (50%) of the patients underwent CSF analysis, including cytology and flow cytometry), prior to biopsy and none (0%) yielded a positive diagnosis of CNS lymphoma. While mean CSF volume for cytology was slightly more than 3 cc of fluid, patients who had 5-10 cc of fluid sent for cytology also yielded a negative result for CNS lymphoma. For all patients, median duration from presentation of symptoms to surgery was 10.5 days. However, when divided between patients who proceeded straight to biopsy (CSFsecond) versus those who underwent CSF analysis prior to biopsy (CSFfirst), the duration from presentation of symptoms to surgery was 6 days versus 11 days, respectively. 10 patients in the CSFfirst group were not on steroids at the time of lumbar puncture whereas only 4 patients in the CSFsecond group were not on steroids at time of biopsy suggesting that steroid use did not seem to influence the yield of either diagnostic modalities. Our experience suggests that CSF analysis in community settings should be reserved only for staging and that surgical biopsy should be pursued as soon as the diagnosis of CNS lymphoma is considered.
QLTI-14. CAN VARIANT ALLELIC FREQUENCIES OF DRIVER MUTATIONS PREDICT FALSE NEGATIVE MGMT PYROSEQUENCING RESULTS IN ADULT-TYPE DIFFUSE GLIOMAS?
Authors: McCord Matthew , Jamshidi Pouya , Thirunavu Vineeth , Santana-Santos Lucas , Vormittag-Nocito Erica , Parker Stephanie , Baczkowski Joseph , Jennings Lawrence , Walshon Jordain , McCortney Katy , Galbraith Kirstyn , Zhang Hui , Lukas Rimas , Stupp Roger , Dixit Karan , Kumthekar Priya , Heimberger Amy , Snuderl Matija , Horbinski Craig 
Published: November 2023

Abstract
MGMT promoter methylation predicts favorable temozolomide (TMZ) response in gliomas. Accurate test results depend on adequate tumor cellularity in analyzed samples, which is usually estimated (with sub-optimal accuracy) via light microscopy. We evaluated driver mutation variant allelic frequency (VAF) as a quantitative metric for tumor cellularity in MGMT promoter methylation testing. In a cohort of 691 adult-type diffuse gliomas, MGMT promoter methylation was tested by either pyrosequencing (N = 445) or DNA methylation array (N = 246). VAF of TERT and IDH driver mutations was quantified by next generation sequencing (NGS). We compared frequency of methylated (positive) and unmethylated (negative) results (Fisher’s exact test) and promoter methylation levels (unpaired t-test) according to VAF. We correlated MGMT promoter methylation, VAF, visually estimated tumor cellularity, and cellularity inferred from VAF via linear regression. We assessed survival (Log-Rank test) for 201 patients with IDH-wildtype GBM treated with TMZ. In samples with VAF &lt;0.325 (identified by CutoffFinder), pyrosequencing yielded fewer positive results (37% versus 56%, p &lt; 0.0001) and lower methylation levels (13% versus 19%, p &lt; 0.0001) than samples with VAF≥0.325. Methylation array showed less frequent positive results at low VAF for IDH-mutant astrocytoma, but not for IDH-wildtype GBM. Microscopic examination tended to overestimate tumor cellularity, especially when VAF was low (R2 = 0.558). GBMs with unmethylated MGMT by pyrosequencing and TERT VAF &lt;0.145 showed better responses to TMZ versus cases with VAF≥0.145 (median survival = 16.8 versus 13.3 months). Twelve pyrosequencing samples were re-tested by DNA methylation array and droplet digital PCR (ddPCR). RESULTS: changed for 2/6 samples with TERT VAF≤0.1, and 0/6 samples with VAF &gt;0.1. Driver mutation VAF is useful for quality assurance in MGMT promoter methylation testing. Tumor samples with low VAF are at greater risk of false-negative results by pyrosequencing, which can be corrected by DNA methylation array and ddPCR.