bluuebunny/crossref_metadata_2025 huggingface dataset:
DDDR-23. DECODING GLIOBLASTOMA DRUG RESISTANCE DYNAMICS USING NOVEL MICROFLUIDIC EX VIVO MODELS
Authors: Pun Sirjana , Krummel Daniel Pomeranz , Sengupta Soma , Barrile Riccardo
Published: November 2024

Glioblastoma (GBM) is clinically challenging due to its aggressive nature and limited treatment options. Current standard of care involves surgical resection and chemoradiation with temozolomide (TMZ). GBM, however, often returns post-treatment fueled by its complex biology and the presence of resilient GBM stem cells. Compounding the issue is the blood-brain barrier, which poses a formidable obstacle to drug delivery into the brain. Understanding the molecular dynamics post-therapy within the brain, influenced by the tissue microenvironment, is key for developing more effective therapeutic strategies. Unfortunately, existing research models have fallen short in capturing the complexity of GBM and its response to treatment. While animal models have been a mainstay in GBM research, their ability to predict human responses has been called into question, highlighted by the disappointing results seen in clinical trials. We are therefore advancing bioprinting-based approaches for modeling various components of the tumor microenvironment to gain insight into mechanisms of drug resistance. We report on the development of three novel microfluidic platforms to investigate and interrogate GBM biology. First, we have developed a novel microfluidic model of GBM, termed GlioFlow-3D, produced through a combination of 3D printing methods. GlioFlow-3D mimics specific aspects of the perivascular niche, including protection from circulating TMZ. Second, we have adapted GlioFlow-3D as part of a platform to investigate advanced ultrasound techniques for delivering novel therapeutics into the human brain. Third, we are developing a novel approach aimed at exploring the relationship between the brain extracellular matrix and tumoral cells using bioprinting of living tumor organoids obtained from patients with a history of recurrence. By integrating bioprinting technologies with patient-derived models to create novel ex vivo platforms, we aim to obtain new insights into the intricate dynamics of drug resistance in GBM, ultimately paving the way for more effective therapeutic strategies. Funding: The Brain Tumor Center Research Award (UCGNI) The ARC Project - CCHMC and UC joint Research Award
DDDR-24. REAL WORLD EXPERIENCE USING THE IDH INHIBITOR IVOSIDENIB IN IDH MUTANT GLIOMA: TOLERABILITY AND OUTCOMES
Authors: Lanman Tyler , Youssef Gilbert , Huang Raymond , Rahman Rifaquat , DeSalvo Matthew , Flood Thomas , Hassanzadeh Elmira , Lang Min , Lauer Jason , Potter Christopher , Miller Julie , Cahill Daniel P , Botero Juan Pablo Ospina , Nakhate Vihang , Stec Natalie , Shi Diana , Bi Wenya Linda , McBrayer Samuel , Arrillaga-Romany Isabel , Lee Eudocia , Chukwueke Ugonma N , Nayak Lakshmi , Forst Deborah , Gerstner Elizabeth , Jordan Justin T , Dietrich Jorg , Batchelor Tracy T , Reardon David A , Wen Patrick , Castro Luis Nicolas Gonzalez
Published: November 2024

BACKGROUND

Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel therapeutic strategy for treating IDHm glioma, though their optimal use outside of clinical trials remains undefined. This study describes real world utilization of the IDH1 inhibitor, ivosidenib, in patients with IDHm glioma.

METHODS

We retrospectively reviewed clinical and radiographic data from IDHm glioma patients treated with ivosidenib monotherapy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2020-2024. Patients with a baseline MRI at ivosidenib initiation and at least 2 subsequent scans while on ivosidenib were included in radiographic response analysis (452 scans).

RESULTS

This cohort included 77 patients (39 males) age 17-75 years (median 41). Thirty-eight patients (49%) had astrocytomas and 39 (51%) had oligodendrogliomas; 48 (62%) had grade 2, 26 (34%) grade 3, and 3 (4%) grade 4 gliomas. Twenty-four patients (31%) received ivosidenib as first-line therapy and 53 (69%) received ivosidenib after failing prior treatments. Among those in the radiographic analysis, 4 (6%) demonstrated partial response, 4 (6%) minor response, 44 (62%) stable disease, and 19 (27%) progressive disease (PD). Significantly higher PD rates were seen in those with enhancing disease (p<0.001) or received ivosidenib as subsequent-line therapy (p=0.002); PD rate was similar between grades 2 and 3 in the first-line group (p=0.64). One-year progression free survival was 100% in the first-line group and 66% in the subsequent-line group. At the time of our analyses, 4 patients (5%) had died (all in the subsequent-line group). Infrequent side effects included CK elevation, QTc prolongation, transaminitis, and diarrhea. One patient (1%) was dose reduced and 3 (4%) discontinued drug due to side effects.

CONCLUSIONS

In this real world IDHm glioma cohort, ivosidenib was well-tolerated. Better response rates were seen in patients without enhancing disease at ivosidenib initiation and those who received the drug as first-line therapy.
DDDR-32. EXPLORING ANDROGENIC MODULATION IN GLIOBLASTOMA: POTENCY AND SELECTIVITY OF NOVEL NORETHINDRONE DERIVATIVES
Authors: Dudley Richard , Schneider Ryan , Shoemaker Carson , Stitzlein Lea
Published: November 2024

BACKGROUND

Glioblastoma (GBM) represents the most frequently diagnosed malignant CNS tumor in adults and remains incurable. Despite the identification of several oncogenic drivers contributing to tumor formation, targeted therapy with brain-penetrant inhibitors has afforded little progress in survival outcomes. Interestingly, gender has been shown to increase the incidence of GBM, with men having roughly a 50-60% increase in incidence compared to women in the US. This statistic led to research on the involvement of and subsequent inhibition of androgen synthesis and signaling in cell culture models and tumor samples.

METHODS

To further investigate the potential involvement of steroidal hormones in GBM proliferation, our lab synthesized a series of norethindrone (NE) derivatives with varied molecular weights, steric bulk, and lipophilicity to modulate the androgenic activity of NE. The small library was tested in several GBM cell lines, including U87, A172, and T98G cells, using cell viability assays.

RESULTS

One derivative, a lipophilically modified version of NE synthesized via a one-pot click reaction, was shown to have improved potency compared with parental NE (>5-fold). The lipophilic NE derivative had IC50 value of 22 uM, 15 uM, and 35 uM in the U87, A172, and T98G cells, respectively. This molecule was tested in immortalized normal human astrocyte (NHA) cells and found to have an IC50 value of 34 uM suggesting some selectivity.

DISCUSSION

Given this derivative’s activity in GBM models and modest selectivity, we plan to screen it in additional GBM cell lines (LN-18 and U251) and eventually in glioma stem cell models. Future research will focus on identifying key targets involved in the mechanism of action, including the impact of lipophilic addition to the steroid nucleus and its effect on androgenic activity and downstream signaling. We will investigate these effects using RPPA and co-treatments with androgen receptor antagonists and 5-alpha reductase inhibitors.
EPID-09. THE NATURAL HISTORY AND MOLECULAR ARCHITECTURE OF INCIDENTAL MENINGIOMAS
Authors: Nguyen Minh , Chen William , Mirchia Kanish , Magill Stephen , Morshed Ramin , Raleigh David
Published: November 2024

The prevalence of asymptomatic, incidental meningiomas is increasing due to greater frequency of brain imaging. This retrospective cohort study of adult patients presenting at a single institution from 1996-2020 integrated clinical data, serial magnetic resonance imaging (MRI) volumetrics, DNA methylation profiling, and targeted gene expression profiling to define the natural history and molecular architecture of incidental meningiomas. Volumetrics were calculated from contrast-enhanced brain MRIs at time of diagnosis compared to serial surveillance MRIs (average 3 MRIs per patient pre-intervention, range: 1-12) DNA methylation groups and gene expression risk scores were defined for 123 samples that underwent resection. Time-to-event analyses were performed for progression-free survival (PFS), symptom-free survival (SFS), and treatment-free survival (TFS). The cohort included 238 meningiomas from 207 patients. Median age at diagnosis was 59 years and 81.5% of patients were female. Median clinical and imaging follow-up were 9.1 and 6.7 years, respectively, during which time 50.8% progressed. Median maximum diameter and volume at diagnosis were 2.20 cm and 4.25 cm3, respectively, and median pre-treatment volumetric growth rate was 19.2% per year. Median pre-treatment PFS and TFS were 3.10 and 1.27 years, respectively, and median SFS and post-treatment PFS were not reached. Cox proportional hazards regression identified maximum diameter at diagnosis as a significant predictor of worse pre-treatment PFS (multivariate HR 1.65 per 1 cm [95% CI 1.19–2.28], p=0.0027) and worse TFS (multivariate HR 1.44 per 1 cm [95% CI 1.17–1.76], p<0.001). Skull base tumors had with worse SFS (multivariate HR 2.48 [95% CI 1.02–6.00], p=0.045). Molecular and histological features among incidental meningiomas that ultimately underwent resection (n=176, 74.0%) were reassuring (89.2% WHO grade 1, 10.2% WHO grade 2). These findings suggest maximum diameter at diagnosis of incidental meningiomas is significantly associated with earlier progression and eventual treatment, and skull base tumors have earlier symptom development.
EPID-14. PATTERNS OF CARE AND PROGNOSTIC FACTORS FOR PATIENTS WITH BRAIN METASTASES FROM COLON CANCER: A REAL-WORLD STUDY
Authors: Jayram Diya , Hodgson Lydia , Bellur Shreyas , Ahmad Shahzaib , Sommer Samuel , Ozair Ahmad , Frias Numa , Ahluwalia Manmeet
Published: November 2024

BACKGROUND

Brain metastases (BMs) from colon cancer (CC) have limited published literature. This work sought to examine patterns of care and prognostic factors for patients with CC BMs.

METHODS

A retrospective study was conducted on patients with CC BMs in the National Cancer Database between 2010-2020 and reported using STROBE guidelines. Treatment was stratified into receipt of stereotactic radiosurgery only (SRS), whole brain radiation only (WBRT), systemic therapy only (Sys), combination therapy, and no brain-directed treatment (NoTx). Median overall survival (mOS) and prognostic factors were determined using multivariate cox proportional hazards adjusting for age, sex, race/ethnicity, insurance, Charlson-Deyo score (CDS), concurrent metastases (CMs), and treatment. Outcomes were reported as hazard ratio (HR) and 95% confidence intervals.

RESULTS

Among 1,383 BMs patients, median age was 64.0 years (IQR 56.0-73.0). 46.4% were female and 81.2% were White. Overall mOS (95% CI) was 5.6 months (4.5-6.2). 26.1% had bone, 71.5% had lung and 72.4% had liver CMs. 24.4% underwent WBRT+Sys, 22.6% NoTx, 18.5% Sys, 14.8% SRS+Sys, 14.7% WBRT, and 5.0% SRS. Patients who underwent SRS+Sys had the highest mOS of 14.4 months (12.8-16.3) followed by Sys: 11.6 months (8.6-13.4), WBRT+Sys: 9.5 months (8.5-10.9), SRS: 3.2 months (2.5-4.4), WBRT: 2.5 months (2.2-2.8), and NoTx: 2.5 months (2.2-2.8) (P<0.001). Patients treated with WBRT+Sys (HR:1.2, 1.0-1.5, P=0.028), SRS alone (HR:1.8, 1.4-2.5, P<0.001), WBRT alone (HR:3.6, 2.9-4.4, P<0.001), NoTx (HR:2.5, 2.0-3.0, P<0.001) was associated with significantly lower survival than SRS+Sys. Patients treated at non-academic facilities (HR:1.1, 1.0-1.3, P=0.038), with Medicare-insurance (HR:1.2, 1.1-1.5, P=0.013) and with left-sided mCC (HR:0.8, 0.7-0.9, P<0.001) had lower survival.

CONCLUSIONS

SRS+Sys was associated with the highest survival in patients with CC BMs, however only 14.8% received it. Notably, 22.6% of patients received NoTx. Further prospective studies exploring factors behind heterogeneity in clinical care are warranted.
EPID-16. GENOMIC ANCESTRY-RELATED RISK RATIOS FOR GLIOBLASTOMA INCIDENCE AMONG GLOBAL POPULATIONS AND RACIAL/ETHNIC GROUPS WITHIN THE UNITED STATES
Authors: Ballard Christine , Giang Minh Huy , Ostrom Quinn , Walsh Kyle
Published: November 2024

Glioblastoma (GBM) incidence varies globally, elevated rates in Europe and lower rates in Asia, Latin America, and Africa. While partially attributable to national differences in cancer diagnosis and reporting practices, analogous patterns exist within diverse Western nations. Ancestry-associated differences in GBM risk allele frequencies (RAFs) could contribute, a hypothesis supported by our prior multiethnic genome-wide association studies (GWAS). Leveraging variant effect estimates from large GBM GWAS datasets and ancestry-stratified allele frequency data from diverse reference populations (ALFA, GNOMAD, 1000 Genomes Project), we estimate the extent of GBM incidence differences across populations that can be attributed to underlying variation in RAF at the seventeen known GBM risk loci. Aggregate differences in RAF between global populations (Europe, West-Africa, East Asia) were associated with a >20% reduction in the normalized GBM risk-ratio (RR) in Africans compared to Europeans (RR=0.78) and a >50% reduction in East Asians compared to Europeans (RR=0.47). The frequency of GBM risk alleles was generally highest in Europeans, but four alleles found most commonly in Africans are at loci regulating telomere maintenance (TERC, TERT, OBFC1/STN1, RTEL1). We repeated analyses using RAF data from U.S. populations (African-Americans, Latinos, and non-Hispanic Whites). Compared to non-Hispanic Whites, aggregate differences in RAF were associated with a 15% reduction in GBM risk among African-Americans (RR=0.85) and a 28% reduction among Latinos (RR=0.72). We conclude that a sizable proportion of the reduced GBM incidence in Latinos and Asians, relative to non-Hispanic Whites, can be accounted for by population-level differences in RAF at known loci. However, registry-based analyses consistently report a two-fold lower incidence of GBM in African Americans relative to non-Hispanic Whites which is poorly explained by RAF differences at known loci. Further work is needed to identify structural, environmental, and biological factors contributing to unresolved differences in GBM incidence.
EPID-17. REAL-WORLD OUTCOMES OF BRAIN METASTASES FROM PANCREATIC CANCER: AN ANALYSIS OF 1266 PATIENTS
Authors: Jayram Diya , Bellur Shreyas , Ahmad Shahzaib , Ozair Ahmad , Steger Julia , Sommer Samuel , Frias Numa , Ahluwalia Manmeet
Published: November 2024

BACKGROUND

Brain metastases (BMs) from pancreatic cancer (PC) are uncommon. This study examined patterns of care and clinical outcomes for PC BMs.

METHODS

A retrospective analysis was conducted on PC BMs patients in the US National Cancer Database between 2010-2020, following STROBE guidelines. Treatments were categorized into systemic therapy (Sys) alone, stereotactic radiosurgery (SRS)±Sys, whole brain radiation (WBRT)±Sys, and no brain-specific treatment (NoTx). Primary outcome was median overall survival (mOS), with corresponding hazard ratio for death (HR) and 95% confidence intervals. Prognostic factors were determined using multivariable Cox proportional-hazards analysis including age, sex, race/ethnicity, insurance, Charlson-Deyo score (CDS), concurrent metastases (CMs), and treatment type.

RESULTS

Of 170,071 metastatic PC patients, 1,266 (0.7%) PC BM patients were included. 45.7% were female and 81.3% were White. Median age was 66.0 years (IQR:58.0-74.0). 34.4% had bone CMs, 45.4% had lung CMs, 60.2% had liver CMs. 48.1% of patients received NoTx, 22.6% Sys, 12.4% WBRT+Sys, 9.8% WBRT, 4.6% SRS+Sys, and 2.5% SRS. mOS (95% CI) was 2.4 months (2.2-2.5) in patients with BMs and 3.9 months (3.8-3.9) in those without BMs (P<0.001). Amongst BM patients, SRS+Sys had a significantly higher mOS of 7.8 months (6.1-14.3) followed by WBRT+Sys: 5.2 months (4.2-6.8), Sys: 4.8 months (4.2-5.8), WBRT: 2.0 months (1.6-2.2), SRS: 1.8 months (1.4-3.7), and NoTx: 1.2 months (1.0-1.3) (P<0.001). Patients treated with SRS alone (HR:2.9, 1.8-4.7, P<0.001), WBRT alone (HR:2.9, 2.0-4.0, P<0.001), and Sys alone (HR:1.5, 1.1-2.1, P=0.009) had significantly lower survival than with SRS+Sys. Patients treated in nonacademic facilities (HR:1.3, 1.1-1.4, P<0.001) and those with CMs (HR:1.4, 1.2-1.6, P<0.001) had poorer survival.

CONCLUSIONS

BMs in PC are rare and associated with lower survival. SRS+Sys was associated with the best prognosis, but <5% received it. 48% of patients receiving NoTx had mOS of 1.2 months. Future studies exploring care variations are warranted.
EPID-30. THE COST OF HOSPITAL-BASED CARE AMONG CANADIAN PATIENTS WITH MALIGNANT CENTRAL NERVOUS SYSTEM TUMOURS IN COMPARISON TO THOSE WITH LUNG AND COLORECTAL CANCERS IN THE YEAR PRECEDING THEIR CANCER DIAGNOSIS
Authors: Xu Linwan , Zhou Keyun , Yuan Yan , Walker Emily
Published: November 2024

BACKGROUND

Approximately 12% of the Canadian GDP was spent on healthcare in 2023. While hospital-based care (HC) constitutes a significant portion of this expenditure, the costs may vary depending on the cancer type. We investigate the HC cost of patients with malignant central nervous system tumours (CNS cancer) and compare it to patients with common cancers in Canadian provinces.

METHODS

We obtained data between 2010 and 2014 from the Canadian Institute for Health Information’s in-patient and ambulatory care datasets. HC cost was estimated using a 12-month look back period prior to diagnosis date for each patient, including cost related to cancer diagnosis and general healthcare. Choosing colorectal (CRC) and lung (LC) cancers to be the common cancers, patients who were 15 years of age or older and had a diagnosis of one of these cancers were included. We used quantile regression to investigate the factors associated with HC cost.

RESULTS

A total of 4,498 (CNS), 41,028 (CRC) and 29,747 (LC) patients were included from Alberta and Ontario, Canada. Encounter type (in-patient/out-patient), province (AB/ON), and comorbidities (Yes/No) were the top three factors contributing to HC cost. Adjusting for encounter type, comorbidities and age, the HC costs for CNS patients were $0.7k and $2.4k higher than CRC patients at 50th and 90th percentile, respectively, and $1.0k higher than LC patients at 90th percentile in Ontario. While in Alberta, HC costs for CNS patients were $0.2k and $0.8k higher than CRC patients at 50th and 90th percentile, respectively, and $1.0k lower than LC patients at both 50th and 90th percentiles.

CONCLUSIONS

We compared HC cost among Canadian patients with different cancer types; significant HC cost differences between patients with CNS and common cancer were observed. Further investigations are warranted to understand drivers of the cost differences.
EPID-31. IMPACT OF THE COVID-19 PANDEMIC ON THE UTILIZATION OF STEREOTACTIC RADIOSURGERY AMONG RACIAL MINORITIES DIAGNOSED WITH BRAIN METASTASES
Authors: Zhu Ping , Chen Clark ,   N3C Consortium
Published: November 2024

OBJECTIVES

Brain metastases (BM) is the most common form of adult brain tumors and one of the devastating consequences of cancer. Stereotactic radiosurgery (SRS) is an established and effective treatment for oligometastatic BMs. We examined how COVID-19 pandemic impacted clinical utilization of SRS in BM treatment and generalize such impact to outpatient care for patients with all cancer types.

METHODS

Three national-scale datasets were used: National Cancer Database (NCDB,N=5,238), the National COVID Cohort Collaborative database (N3C, N=13,106 for BM, N=203,706 for all cancer types), and SEER. Multivariable logistic regression models were performed to determine whether the pandemic affected clinical utilization of SRS in BM treatment and chemotherapy initiation for all cancer types.

RESULTS

Prior to 2019 (pre-pandemic), we observed no racial disparity in the odds of receiving SRS between non-Hispanic white (NHWs) and non-Hispanic black (NHBs) BMs in both NCDB and N3C. Between 2020 and 2021 (pandemic), however, NHBs were significantly less likely to receive SRS comparing to NHWs in both NCDB (NHB:aOR-0.77,p=0.002) and N3C (NHB:aOR-0.78,p<0.001). In SEER, the age-adjusted incidence rate of BM remained unchanged when comparing pre- and post-pandemic periods. Further substantiating the impact of COVID-pandemic on racial disparity in outpatient care for all cancer patients, we showed that NHB patients were more likely to receive delayed chemotherapy (>60 days since diagnosis of cancer) compared to NHWs during the pandemic (aOR-1.10, p<0.001), but such association was not detected before pandemic. Ratio of odds ratio (ROR) analysis confirmed that NHB patients comparing to NHWs during pandemic experienced 1.11-fold difference in the odds of delayed chemotherapy between NHBs and NHWs before pandemic [ROR=1.11, p<0.001].

CONCLUSION

Racial disparity in SRS-receipt for BM patients has been exacerbated during COVID-19 pandemic and such impact could be generalized to outpatient care for all cancer types. Understanding the determinants giving rise to this disparity should augment the readiness of our cancer care infrastructure in anticipation of future pandemics or other public health crises.
EPID-32. ELEVATED SERUM IGE IS LINKED TO IMPROVED GLIOBLASTOMA SURVIVAL, PARTICULARLY AMONG FEMALES
Authors: Francis Stephen , Guerra Geno , Nakase Taishi , Kachuri Linda , McCoy Lucie , Hansen Helen , Wiemels Joseph , Wiencke John , Molinaro Annette , Wrensch Margaret
Published: November 2024

Prior epidemiological research shows a correlation between serum immunoglobulin E (IgE) levels and decreased risk of glioma. However, the relationship between IgE and the prognosis of glioma remains poorly understood. This study seeks to investigate how factors such as sex, tumor subtype, and IgE class influence the association of serum IgE levels with both glioma risk and survival outcomes. METHODS- In this investigation, we conducted a case-control study utilizing participants enrolled in the UCSF Adult Glioma Study from 1997 to 2010. We measured serum IgE levels for total, respiratory, and food allergy in adults diagnosed with glioma (n=1,696), and controls (n=1,135) matched based on age, sex, and race/ethnicity. Logistic regression, adjusted for patient demographics, was employed to evaluate the correlation between IgE levels and glioma risk. Multivariable Cox regression, adjusted for patient-specific and tumor-specific factors, was utilized to compare survival outcomes between the elevated and normal IgE groups. RESULTS- Increased levels of total IgE were linked to a decreased risk of both IDH wildtype (OR=0.65, 95% CI: 0.54-0.78) and IDH mutant glioma (OR=0.65, 95% CI: 0.50-0.85). In multivariable Cox regression analysis, heightened respiratory IgE levels were associated with enhanced survival among individuals with IDH wildtype glioma (HR=0.78, 95% CI: 0.67-0.91). Notably, this improved survival was more pronounced in females (HR=0.71, 95% CI: 0.53-0.96) compared to males (HR=0.80, 95% CI: 0.66-0.97), resulting in median survival improvements of 6.2 months (P<.001) and 1.6 months (P=0.003), respectively. CONCLUSION- Increased levels of serum IgE were associated with reduced risk of glioma overall, and improved prognosis for IDH wildtype glioma, which was particularly strong in females. These findings hint at potential sexual dimorphism in the antitumor activity of IgE-mediated immune responses, suggest an important role for IgE assessment in glioblastoma clinical trial design, and provide justification for investigations into IgE-based therapeutics.
EPID-35. COLLISION TUMORS AT THE SKULL BASE: UNVEILING A PETROCLIVAL MENINGIOMA COEXISTING WITH A GROWTH HORMONE-PRODUCING PITUITARY ADENOMA
Authors: Choi Yoon , Hsu Frank , Dai-Ju Jenny , Kuan Edward , Patel Vivek
Published: November 2024

Collision tumors are rare occurrences characterized by coexistence of two histologically different tumor types within the same anatomical location. While collision tumors involving skull base meningiomas and pituitary adenomas are uncommon, they pose distinct diagnostic challenges. We report the case of a 57-year-old female initially diagnosed with petroclival meningioma WHO 1, subsequently found to harbor a collision tumor with a growth hormone-producing pituitary adenoma. The patient initially presented with aphasia, right-sided weakness, and gait instability, prompting a diagnosed of left petroclival mass with left temporal horn entrapment. Patient underwent craniotomy and partial resection of the tumor in 2022 and was diagnosed with meningothelial meningioma, WHO1. The patient had history of uncontrolled diabetes and physical features of large hands with hypertrophied terminal phalangeal tufts but patient reported that she has had similar hands since childbirths for decades. Screening pituitary function tests were ordered due to the petroclival meningioma involving suprasellar region, revealing significantly elevated growth hormone, and insulin-like growth factor-1(IGF-1) levels, raising suspicion for pituitary adenoma. Subsequent endoscopic resection of the sellar mass via a transsphenoidal approach in 2024 confirmed the presence of somatotroph pituitary neuroendocrine tumor. Retrospectively growth hormone producing pituitary adenoma likely contributed to patient’s uncontrolled diabetes and coarse, large hands. This case highlights the importance of a high index of suspicion for collision tumors, particularly in patients with skull base tumors involving supra sellar region, especially when presenting with atypical clinical features.
DISP-05. SUPERVISED MACHINE LEARNING PREDICTION OF THERAPEUTIC CLINICAL TRIAL ENROLLMENT FOR MINORITY PATIENTS AND WOMEN IN NEURO-ONCOLOGY
Authors: Mehari Mulki , Warrier Gayathri , Dada Abraham , Kabir Aymen , Haskell-Mendoza Aden , Reihl Sheantel , Jackson Joshua , Gonzalez Ariel , Reason Ellery , Flusche Ann , Dalton Tara , Negussie Mikias , gonzales Cesar Nava , Chukwueke Ugonma , Molinaro Annette , Porter Alyx , Fecci Peter , Hervey-Jumper Shawn
Published: November 2024

BACKGROUND

Despite changes in national policy, women and minority patients remain under-accrued in glioma clinical trials. Supervised machine learning may serve as a novel approach to understanding which variables and their complex interplay most influence enrollment for underrepresented patients. We aimed to design and externally validate machine learning models to predict therapeutic clinical trial enrollment for a) all patients, b) women, and c) NIH-designated minority patients with low- and high-grade glioma.

METHODS

In a 20-year retrospective cohort of 1042 adult patients with low- and high-grade glioma, boosted neural network (BNN) models for the whole, women, and minority cohorts were used to analyze the combined effects of demographic, socioeconomic, and oncologic variables on clinical trial enrollment. These models were validated using an external cohort (n=103).

RESULTS

In the development cohort (445 [42.7%] women; 151 [14.5%] minorities; median age, 51.5 [interquartile range: 39.4-62.5] years), 350 patients (33.6%) enrolled in a therapeutic clinical trial. The whole cohort BNN (AUC: 0.827, misclassification rate (MR): 0.175), the women cohort BNN (AUC: 0.895, MR: 0.125), and the minority cohort BNN (AUC: 0.983, MR: 0.053) models accurately predicted trial enrollment on external validation. For the whole cohort and women models, several demographic (race, ethnicity, minority status, sex), socioeconomic (insurance, employment status), and oncologic variables (seizure, chemotherapy, KPS, WHO grade, tumor lobe) were equally influential (Main effect (ME): 1.000, Total effect (TE): 1.000) on enrollment. For the minority model, socioeconomic variables including insurance status (ME: 0.089, TE: 0.417) and occupation classification (ME: 0.087, TE: 0.381) drove enrollment.

CONCLUSION

We designed and externally validated the first machine learning model for predicting therapeutic clinical trial enrollment for patients with diffuse glioma. Model features driving trial enrollment varied for underrepresented patients. These results may help prioritize personalized patient-specific initiatives to address barriers to equitable patient accrual.
DISP-08. GBM PATIENTS FACE TTF ACCESS AND INFORMATION INEQUITY THAT MAY IMPACT PATIENT OUTCOMES AND QUALITY-OF-LIFE
Authors: Ostrom Quinn T , Iwamoto Fabio M , Nayak Lakshmi , Duprey Kelli , Pilkington Ed , Ellen Jacob , Robles David
Published: November 2024

We evaluated the quality and accessibility of healthcare for Glioblastoma (GBM) patients across the United States through an online survey distributed to the OurBrainBank community and partners and promoted on social media. A total of 297 patients or caregivers completed the survey (85% caregivers; 15% GBM patients). Median age at diagnosis was 57, lower than the national average. 78% described having some college education, and 69% reported commercial insurance coverage. Our preliminary findings highlight that 82% of respondents reported that their treating doctor recommended the standard-of-care for GBM consisting of tumor resection, 3-6 weeks of chemo/radiation, and 6 months of chemotherapy and sometimes Tumor-Treating-Fields (TTF), per the Comprehensive- Cancer-Network (2021) guidelines. 40% reported no discussion of TTF as an option. Of those offered TTF, nearly half (46%) received it as part of their initial treatment combined with standard chemotherapy and 36% received it as a subsequent option. For those attempting to access TTF, 29% encountered difficulties, often due to financial constraints linked to insurance denials. These findings illuminate significant concerns regarding dissemination of information on treatment options, as well as access to treatments. Access to these treatments can have a significant influence on survival and quality of life of GBM patients. The substantial number of patients not offered TTF, combined with challenges to accessing treatments due to insurance issues, highlight critical obstacles to engaging in informed and shared decision-making. Compared to the general GBM-affected population, our survey respondents tend to be younger and from urban areas, indicating a possible selection bias in survey participation. This skew could lead to an underrepresentation of the challenges encountered by patients facing additional barriers. We are adopting measures to engage a more diverse participant group, especially from rural communities Ongoing targeted recruitment will further elucidate barriers to patient-centered care in GBM, with the potential for significant improvements in survival and QOL.
DISP-13. TELEHEALTH UTILIZATION IN NEURO-ONCOLOGY: EXPERIENCE AFTER THE COVID-19 PANDEMIC
Authors: Sener Ugur , Uhm Joon , Haddad Tufia , Pritchett Joshua
Published: November 2024

BACKGROUND

Central nervous system (CNS) tumors are frequently characterized by physical disabilities, and treatment is often associated with side effects, as well as financial toxicity and loss of income owing to disease-related neurological deficits. Treatment at centers with specialized neuro-oncology care is associated with an overall survival benefit. However, access to such centers can be limited for many patients. Telehealth services represent an option for improving access to specialized care. During the COVID-19 pandemic public health emergency (PHE), regulatory and reimbursement changes provided patients improved access to neuro-oncology by telehealth.

METHODS

We retrospectively analyzed our institutional utilization of telehealth visits in the neuro-oncology vs solid tumor oncology practice after the COVID-19 pandemic.

RESULTS

Between July 2020 and April 2021, telehealth represented 24.1% of all neuro-oncology visits compared to 13.3% for all solid tumor groups. Between May 2021 and April 2023, telehealth visits remained frequent in neuro-oncology compared to solid tumor groups (34.6% vs 15.2%). Utilization rates declined across the practice in the year following expiration of the COVID-19 PHE in May 2023, though remained high for neuro-oncology at 34.1% vs 15.2% for solid tumor groups. Overall, telehealth visit utilization for neuro-oncology has remained more than double that of the oncology practice as a whole.

CONCLUSIONS

The striking difference between telehealth visit utilization in neuro-oncology compared with general medical oncology indicates that patients with CNS tumors, and those that provide care for these patients, have come to depend on this mode of care delivery. Even after expiration of the COVID-19 PHE, telehealth use remains high in neuro-oncology at our institution. Prospective evaluation to determine the safety of and clinical outcomes associated with telehealth visits for individuals with CNS tumors are critically needed. Such data may promote regulatory and reimbursement reform enabling broader adoption, service sustainability, and improved access to specialized care.
IMMU-23. NEOADJUVANT ANTI-PD-1 AND ANTI-CTLA-4 COMBINATION THERAPY INDUCED INTRATUMORAL IMMUNOLOGIC ALTERATIONS IN RECURRENT GBM PATIENTS
Authors: Markus Lauren , Wen Patrick , Sun Lu , Hugo Willy , Prins Robert
Published: November 2024

Glioblastoma (GBM) is a highly aggressive brain tumor that responds poorly to checkpoint blockade inhibitors (ICIs), such as anti-PD-1. We previously reported that neoadjuvant anti-PD-1 therapy activated and recruited T cells into recurrent GBM (rGBM) tumors, but also increased immune checkpoint interactions between T cells and myeloid cells. To overcome this resistance mechanism, we are currently conducting a phase 1B clinical trial of neoadjuvant anti-PD-1 (Nivolumab, BMS) +/- anti-CTLA-4 (Ipilimumab, BMS) combination therapy for rGBM patients (NCT04606316). To evaluate the local tumor microenvironment effects of these checkpoint inhibitors, we used multiplex immunofluorescence (mIF), bulk RNA sequencing, and T cell receptor sequencing to analyze the intratumoral immune profile of tumors. Using mIF, we are able to determine the density of key immune cell phenotypes within the section of tumor sample as well as the proximity between phenotypes to better understand their interactions. Patients who received the combination therapy (n=15) trended to have a higher median density of cytotoxic T cells (CD45+CD8+; median density of 27.13 cells/mm2 for combination therapy and 13.78 cells/mm2 for anti-PD-1), helper T cells (CD45+CD4+; median density of 33.73 cells/mm2 for combination therapy and 9.82 cells/mm2 for anti-PD-1), monocytes (CD14+), and HLA-DR+ macrophages (CD45+CD14+HLA-DR+) while patients treated with anti-PD-1 alone (n=16) trended to have densities similar to placebo treated patients (n=6). Patients treated with combination therapy are also trending to have a higher density of macrophages in close proximity (≤20μm) to T cells, particularly HLA-DR+ macrophages, suggesting a higher frequency of interactions within their tumor microenvironments. This data set is currently incomplete, but the final data set will be completed by the meeting. Nonetheless, these preliminary results, as well as the bulk RNA sequencing and T cell receptor sequencing, suggest distinct immunologic effects of monotherapy vs. combination neoadjuvant anti-PD-1 and anti-CTLA-4 therapy in the tumor microenvironment of rGBM patients.
IMMU-33. REPROGRAMMING OF MYELOID CELL METABOLISM VIA HEME OXYGENASE-1 INHIBITION POTENTIATES ANTI-TUMOR IMMUNITY IN A MURINE GLIOMA MODEL
Authors: Kim Lily , Choi John , Nitta Ryan , Pant Ayush , Schonfeld Ethan , Li Gordon , Jackson Christina , Wang Xinnan , Lim Michael
Published: November 2024

Cancer cells exhibit a preference for aerobic glycolysis, a phenomenon known as the Warburg effect. Emerging evidence suggests that immune cells within the tumor microenvironment (TME) may employ a similar metabolic adaptation. Heme oxygenase-1 (HMOX-1), a metabolic regulatory gene, is elevated in myeloid cells of glioblastoma (GBM), yet its precise role in modulating immune suppression and energy utilization remains unclear. Our objective was to explore how targeting HMOX-1 activity in the GBM TME affects immune response and energy metabolism. We utilized syngeneic glioma models with C57BL/6J mice implanted with CT-2A cells, which were randomized into four treatment arms: intracranial (IC) injection of the HMOX-1 inhibitor zinc protoporphyrin (ZnPP), intraperitoneal (IP) injection of anti-PD-1, IC ZnPP + IP anti-PD-1, or IC saline (sham). For mechanistic studies, we developed a myeloid-specific knockdown model via adoptive cell transfer of myeloid-derived suppressor cells (MDSCs) transfected with Hmox-1 siRNA into CSF-1R myeloid-depleted mice. Immunophenotyping was conducted with flow cytometry. The Seahorse mitochondrial stress test was used for evaluation of energy dynamics. Downregulation of myeloid Hmox-1 expression and inhibition of HMOX-1 via ZnPP both led to heightened T cell activation, with increased IFN-γ expression in brain compared to untreated mice (P=0.039, 0.02, respectively). Notably, ZnPP treatment induced a compensatory elevation of PD-L1 in myeloid cells (P<0.0001). Both ZnPP monotherapy and anti-PD-1 + ZnPP combination therapy demonstrated enhanced median overall survival rates in comparison to sham and anti-PD-1 monotherapy groups, with the combined approach yielding the most significant survival advantage (P<0.0001). Metabolic analyses following Hmox-1 knockdown and ZnPP treatment revealed a shift away from cancer-like glycolytic shunting in MDSCs. Inhibiting the HMOX-1 pathway facilitated T cell activation and reversal of glycolysis-predominant metabolism in MDSCs, resulting in improved survival outcomes in a murine glioma model. Modulation of metabolic reprogramming in myeloid cells may potentiate anti-tumor immunity, especially in conjunction with checkpoint blockade.
IMMU-34. PREDICTION OF TUMOR-ASSOCIATED ANTIGENS USING RADIOGENOMICS
Authors: Ogando-Rivas Elizabeth , Paul Castillo , Reyes-Gonzalez Pablo , Lanzarin Abel , Binello Emanuela , Dasenbrock Hormuzdiyar , Fernandez-Abinader Jose , Holsapple James , Mitchell Duane , Lam Fred , Sayour Elias , Kasper Ekkehard
Published: November 2024

INTRODUCTION

Glioblastoma remains a disease with dismal prognosis. Immunotherapy demonstrated promising results against some refractory cancers. However, comparative results have not been accomplished in glioblastoma therapy due to lack of suitable tumor targets and considerable clonal heterogeneity.

OBJECTIVE

We propose leveraging radiogenomics using machine learning based on Pre-Op MRI to predict tumor antigen expression profiles displaying specific targets for immunotherapy.

METHODS

We collected RNAseq data and Pre-Op Axial T2-FLAIR images in 29 patients from IVY Glioblastoma Atlas Project. MRIs were segmented using LIFEx software as follows: 1) tumor + edema (T+E) and 2) whole brain (WB). The intended prediction was for tumor-associated antigens. H2O.ai software was used for prediction using an automated supervised machine learning algorithm. Antigens that achieved >55% area under the curve (i.e., prediction) were reanalyzed adjusting for reproducibility, time of analysis and maximum precision.

RESULTS

An average of 53.2 T2-FLAIR axial slices per patient were used for 3D reconstruction. We selected the following genes (ERBB2, TP53, IL10RA, CD163, EGFR and MGMT) for downstream analysis given their clinical, immunologic, and prognostic relevance. Regarding tumor-associated antigen prediction for ERBB2, TP53, IL10RA, CD163, EGFR and MGMT predicted 52%, 56%, 66%, 66%, 56% and 0%, on T+E segmentation respectively; The values were 49%, 93%, 87%, 47%, 37% and 0% for the respective WB group. Reanalysis revealed 100% prediction accuracy for the presence of mutant TP53 and IL10RA in both segmentation groups (T+E, WB). CD163 and EGFR prediction was 54% and 61% for the T+E group and 48% for both antigens in the WB group.

CONCLUSION

We successfully predicted the presence of two out of six antigens (i.e., mutant TP53 and IL10RA) in this patient cohort. Our approach can provide expeditious antigen identification to enable cellular therapy manufacturing for patients with unresectable newly diagnosed tumorsor those which relapsed geographically. Furthermore, this MRI-based methodology might provide a precision medicine approach to places that cannot afford costly testing (i.e., RNAseq).
IMMU-48. CRACKING THE ROLE OF ONCOMETABOLITES IN VIROIMMUNOTHERAPY FOR PEDIATRIC MALIGNANT BRAIN TUMORS
Authors: Moure Marc Garcia , Lopez-Rivas Andres R , Parthasarathy Akhila , Shin Dong Ho , Jiang Hong , He Jiasen , Tran Han Nhat , Yun Kyuson , Hernandez-Osuna Reyes , Alonso Marta M , Phoenix Timothy N , Wainwright Derek A , Fueyo Juan , Gomez-Manzano Candelaria
Published: November 2024

Diffuse midline gliomas (DMGs) are among the most frequent and lethal pediatric tumors. The standard of care for DMGs is palliative, resulting in a median survival of 12 months. Viroimmunotherapy is an emerging alternative treatment for these tumors. Our group developed a platform of oncolytic adenoviruses that was translated to the clinic. Specifically, Delta-24-RGD was recently tested in a Phase I clinical trial for patients with newly diagnosed DMG (NCT03178032) with encouraging results. To further stimulate the immune arm of this therapy, we developed Delta-24-RGDOX, expressing the T-cell activator OX40L (NCT03714334, NCT04714983). Using bulk RNAseq, we showed that treatment with Delta-24-RGDOX upregulated the immunosuppressive immunometabolic IDO-AhR pathway. Of importance, treatment with Th1-related cytokine IFNg resulted in the upregulation of IDO1 expression in a panel of human and murine DMG cells. In agreement with these data, we showed synergy between the oncolytic virus and several IDO1-AhR inhibitors in tumor and immune cell co-cultures, as indicated by T-cell activation and proliferation. To further dissect the reshaping of the TME in clinically relevant DMG models treated with Delta-24-RGD or Delta-24-RGDOX, we performed scRNA seq analysis. We showed a pronounced T-cell infiltration in virus-treated animals versus control-treated mice, further confirmed by flow cytometry. Additionally, Th1 and CD8 effector memory subsets were preferentially enriched in the Delta-24-RGDOX group, indicating an enhanced proinflammatory shift. Importantly, we detected, for the first time, upregulation of IDO-AhR downstream effectors in the myeloid compartment in the virus-treated groups. Interestingly, we detected IL4I1 in myeloid cells, a recently discovered checkpoint upstream of AhR never described in the context of virotherapy. Preliminary data using a combination of Delta-24-RGDOX and AhR inhibitors prolongs the survival of glioma-bearing mice. Collectively, our in vivo and in vitro data support the rationale to propel a future clinical trial combining Delta-24-RGDOX with AhR inhibitors for DMG.
IMMU-50. IMPACT OF SARS-COV-2 MRNA VACCINES ON PD-L1 EXPRESSION IN INTRACRANIAL TUMORS
Authors: Grippin Adam J , Copling Sage , Kim Andrew , Lohray Rishabh , Jiang Wen , Kim Yon Son Betty , Lin Steven H
Published: November 2024

Although immune checkpoint inhibitor (ICI) effectiveness is correlated with intra-tumoral PD-L1 expression, there are no clinically available methods to improve sensitivity to ICIs by modulating PD-L1 expression. mRNA vaccines stimulate robust interferon-dependent innate immune activation leading to four-fold increases in PD-L1 expression on peripheral and intratumoral myeloid cells and enhanced sensitivity to immune checkpoint blockade in preclinical models (Sayour, Grippin, et al., NanoLetters, 2018; Mendez-Gomez, et al., Cell, 2024). We hypothesized that mRNA vaccines targeting SARS-COV-2 would similarly enhance PD-L1 expression in intracranial tumors. To test this hypothesis, we utilized institutional databases to identify 5,524 patients at our institution with pathology reports including the term “PD-L1” from August 2020 to November 2023. Pathological data and dates of SARS-COV-2 vaccination were compiled for each patient. Across the entire cohort (n=5,524), receipt of a SARS-COV-2 mRNA vaccine within 100 days of biopsy was associated with a 55% increase in mean tumor proportion score (TPS) (14% vs 8.9%, p=0.029). In the subset of patients with intracranial tumors (n=187), receipt of a SARS-COV-2 mRNA vaccine within 100 days of biopsy was associated with a massive increase in TPS (57% vs 7.2%, p<0.001). To evaluate the impact of this change on clinical outcomes with immunotherapy, we utilized a second institutional database to assemble a cohort of patients with Stage IV melanoma with intracranial metastasis treated with immune checkpoint blockade during the period August 2020 through November 2023. Patients who received a SARS-COV-2 vaccine within 100 days of initiation of ICI (n=10) exhibited numerically improved overall survival compared to those without SARS-COV-2 mRNA vaccine (n=38) (HR 0.50, 95% CI 0.22-1.2, p=0.06). Median overall survival was 545 days among patients without COVID mRNA vaccination and was not met among those with COVID mRNA vaccination. This data supports further investigation of the immune modulating effect of SARS-COV-2 mRNA vaccines in patients with intracranial tumors treated with immune checkpoint blockade.
IMMU-59. AN IMMUNOSUPPRESSIVE PROGRAM ENCOMPASSING MULTIPLE IMMUNE CELL TYPES IN GBM TYPIFIED BY NOVEL MARKER LRRC25 ASSOCIATED WITH TYROBP SIGNALING
Authors: Zamler Daniel , Mathur Radhika , Chan Gary , Schupp Patrick , Shai Anny , Okada Hideho , Oldham Michael , Costello Joseph
Published: November 2024

Immunosuppression in glioblastoma is a powerful impediment to effective immunotherapy. We used maximal tumor sampling and genome-wide coexpression analysis of RNA sequencing, on 69 samples from 8 patients, to identify a module of 270 genes marked by LRRC25, determined by top fidelity score, that covaries with many immunosuppressive molecules. An immunosuppressive module was independently derived from an expanded cohort of 319 samples from 28 GBM also marked by LRRC25 by top fidelity score. Within the gene module, we observed strong co-variation of markers for monocytes, neutrophils, and NK cells with LRRC25. In published single-cell RNA-seq from glioma, we determined that LRRC25 is expressed by neutrophils and myeloid cells while absent from NK-cells. LRRC25 is also constitutively expressed in monocytes and neutrophils while being upregulated by microglia and DCs in the tumor core and necrotic regions. In addition to covariation with multiple cell-type specific markers we also discovered that LRRC25 expression is tightly associated with several members of the TYROBP causal signaling network in microglia. Thus, LRRC25 may play a novel role in TYROBP signaling which may, in turn, represent a novel mechanism of NK cell and neutrophil immunosuppression in glioma. We confirmed LRRC25 RNA expression in patient samples by RNAscope co-stained with an anti-CD163 antibody indicating myeloid expression, as well as tumor cell expression determined by histopathology. Although LRRC25 is known to mediate IFN and NFKb signaling in myeloid cells in-vitro, its function in glioma remains understudied. While significant efforts have focused on mechanisms of myeloid to T-cell immunosuppression, less focus has been given to mechanisms of myeloid to NK-cell and neutrophil immunosuppression, despite the fact they exist at levels comparable to T-cells in the tumor microenvironment. This work will be followed up with antibody validation as well as genetic manipulation of LRRC25 in-vitro and in-vivo.