bluuebunny/crossref_metadata_2025 huggingface dataset:
EPID-05. THE INCREASED RISK OF MENINGIOMA AMONG INDIVIDUALS WHO ARE NON-HISPANIC BLACK IS MAGNIFIED AMONG MALES AND AMONG THOSE DIAGNOSED WITH GRADE 2-3 TUMORS
Authors: Walsh Kyle , Price Mackenzie , Raleigh David R , Kruchko Carol , Barnholtz-Sloan Jill S , Ostrom Quinn T
Published: November 2024

BACKGROUND

Demographic factors associated with elevated meningioma incidence include older age, female sex, and Black race. There are limited data exploring how meningioma risk in Black persons varies across the lifespan, interacts with sex, and differs by tumor grade.

METHODS

The Central Brain Tumor Registry of the United States (CBTRUS) is a population-based registry combining data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, covering the entire U.S. population. Meningioma diagnoses from CBTRUS (2004-2019) were used to calculate incidence rate ratios (IRRs) for non-Hispanic Black individuals (NHB) as compared to non-Hispanic White individuals (NHW) across 10-year age intervals, and stratified by sex and WHO tumor grade (grade 1 versus grades 2/3, combined).

RESULTS

From 2004-2019, a total of 53,890 NHB individuals and 322,373 NHW individuals were diagnosed with a primary meningioma. The NHB to NHW IRR was elevated, beginning in the third decade of life (IRR=1.19; 95%CI: 1.11-1.28), peaking in the seventh decade (IRR=1.29; 95%CI: 1.26-1.31), and persisting throughout the lifespan. The IRR peaked in the seventh decade of life across strata of tumor grade, but, within this age group, NHB race/ethnicity was associated with substantially higher risk of grade 2/3 tumors (IRR=1.59; 95%CI: 1.48-1.70) than grade 1 tumors (IRR=1.27; 95%CI: 1.24-1.29). Meningioma risk was elevated in NHB females compared to NHW females (IRR=1.16; 95%CI: 1.15-1.18) and among NHB males compared to NHW males (IRR=1.22; 95%CI: 1.19-1.25), revealing synergistic interaction between NHB race/ethnicity and male sex (PInteraction=0.001).

CONCLUSIONS

This study identifies an elevated risk of meningioma in NHB relative to NHW, beginning shortly after puberty and continuing across the lifespan. NHB race/ethnicity conferred higher risk of meningioma among men than among women, and higher risk of developing WHO grade 2/3 than grade 1 tumors. These results highlight meningioma as a major potential source of racial disparities in neuro-oncology.
EPID-06. ACROMEGALY AND THE RISK OF CANCER: A NATIONWIDE POPULATION-BASED LONGITUDINAL COHORT STUDY IN KOREARUNNING TITLE: ACROMEGALY AND THE RISK OF CANCER
Authors: Kim Yeo Song , Yun Jae-Seung , Kim Hyunho , Jeun Sin Soo , Lee Jung Eun , Kim Bongseong , Ko Seung-Hyun , Ahn Yu-Bae , Han Kyungdo , Yang Seung-Ho
Published: November 2024

INTRODUCTION

Previous reports on cancer risk in patients with acromegaly have inconsistent findings. Using a nationwide population-based cohort, we primarily investigated whether overall and site-specific cancer risk are increased in patients with acromegaly.

MATERIALS AND METHODS

The study included 2,382 acromegaly patients and 11,910 controls aged above 20, from 2006 to 2016. Cox hazards regression analysis was used, adjusting for baseline covariates.

RESULTS

Among the 2,382 patients with acromegaly, overall cancer occurred in 244 (10.2%), while the 11,910 controls had 707 (5.9%) occurrences (HR: 1.90 (95% CI: 1.63-2.22). Acromegaly patients had the highest relative risk for brain cancers with an HR of 6.80 (95% CI: 2.83-16.38) and significantly higher risk of lymphoma, thyroid cancer, multiple myeloma, pancreatic cancer, and colorectal cancer. Even after five years from the diagnosis of acromegaly, patients with acromegaly had a significantly higher incidence of cancer. Risk of cancer in general and stomach cancer in specific was significantly higher in patients under the age of 50 compared to older patients. There was no sex difference.

CONCLUSIONS

This nationwide longitudinal cohort study shows an increased risk of cancer in acromegaly patients. Active and long-term cancer screening is necessary to improve the prognosis in patients with acromegaly.
EPID-11. RATES OF CRANIOTOMIES FOR BRAIN METASTASES AFTER INTRODUCTION OF IMMUNOTHERAPY
Authors: Pelcher Isabelle , Begley Sabrina , Sreenivasan Sanjeev , Ziemba Yonah , Travaglia Isabella , Ratra Avi , Schulder Michael
Published: November 2024

Immunotherapy has revolutionized the treatment paradigm for patients with brain metastases and has been found to prolong overall survival. We sought to determine whether rates of craniotomies for the treatment of brain metastases has decreased since the introduction of immunotherapy into routine treatment regimens. Pathology records were queried at our institution from 2011-2022 to include all patients surgically treated for brain metastases. A total of 885 samples from 789 unique patients were analyzed. National data was queried from the NSQIP database from 2011-2022 to include patients surgically treated for brain metastases with a total of 14,494 cases. A Craniotomy for Metastases Index (CMI) was generated to reflect the total number of craniotomies performed over time. The most common institutional primary cancers were lung (46.1%), breast (17.4%), and gastrointestinal (10.1%), with the most common lung cancers being adenocarcinoma (57.11%) and non-small cell carcinoma (11.52%). The institutional CMI demonstrated a non-significant decrease in the number of craniotomies (R2=0.0545, p=0.46) across all time ranges, as well as no significant change in CMI when comparing rates from 2011-2016 and 2017-2022 (p=0.37). The national CMI demonstrated a significantly positive slope of 0.03 (R2=0.544, p=0.006), as well as a significant increase (p=0.005) in craniotomies when comparing rates from 2011-2016 and 2017-2022. Despite the growing use and efficacy of immunotherapy in the treatment of brain metastases and increasing overall survival, the rates of craniotomies had no change institutionally and increased nationally. Several reasons for these findings may include: longer overall survival of patients with systemic cancer can lead to the development of metastatic brain tumors later in their disease course, improvement of surgical techniques making resection safer, and variable response of patients to stereotactic radiosurgery (SRS). Further studies should be conducted to determine the effect of SRS on these findings. Surgical resection remains the mainstay in the treatment of brain metastases.
EPID-19. INTERACTION BETWEEN GERMLINE AND SOMATIC GENETICS TO ELUCIDATE RISK OF ADULT DIFFUSE GLIOMA
Authors: Eckel-Passow Jeanette , Kosel Matthew , Decker Paul , Kollmeyer Thomas , Drucker Kristen , Molinaro Annette , Francis Stephen , Wiencke John , Wrensch Margaret , Lachance Daniel , Tobin W Oliver , Jenkins Robert
Published: November 2024

Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.
EPID-25. A SEER-MEDICARE ANALYSIS OF EXPOSURE TO COMMONLY USED MEDICATIONS AND 1-YEAR SURVIVAL IN GLIOBLASTOMA
Authors: Shah Roshani , Moeller Patrick , Keith Scott , Hass Richard , Shi Wenyin , Maio Vittorio , Alnahhas Iyad
Published: November 2024

OBJECTIVES

Despite of research efforts, glioblastoma (GBM) remains a deadly disease. We aimed to evaluate the effects of commonly used medications on survival in GBM.

METHODS

We performed a retrospective cohort study and utilized the Surveillance, Epidemiology, and End Results (SEER) national cancer registry database linked with Medicare data to identify patients 66 years and older diagnosed with GBM between 1/1/2008 and 12/31/2019. Patients were excluded if they did not receive treatment after diagnosis. We evaluated several medication groups including metformin and oral hypoglycemics, insulin, fluoxetine, statins, beta-blockers, ACE inhibitors and NSAIDs. Mortality was captured within 1 year after diagnosis. Patients were identified as exposed to the medications if they filled at least 1 prescription between 3 months prior to and 9 months after diagnosis.

RESULTS

9,641 GBM patients were included. 54.4% were male and the mean age was 73.8 ± 5.8 years. As expected, patients 66-70 years of age had the best survival compared to the older age groups. Similarly, patients diagnosed between 2017-2019 had the best survival compared to patients diagnosed in prior years. Moreover, patients with the highest Charlson Comorbidity Index scores had the worst prognosis. Obesity specifically had no effect on survival. Patients who underwent any resection had better survival and patients who received both radiation and chemotherapy had better survival compared to patients who received only one treatment modality. 15.5% of patients were exposed to insulin at 1 year and had worse prognosis (OR 1.65, CI 1.42-1.91). 3.4% of patients were exposed to fluoxetine at one year and surprisingly had worse prognosis (OR 1.35, CI 1.03-1.76). None of the other medication groups had significant effects on survival.

CONCLUSION

Our study suggests that exposure to insulin and fluoxetine negatively affects survival in GBM. Stratification of patients per molecular subgroups is necessary for more accurate conclusions.
EPID-26. STEREOTACTIC RADIOSURGERY FOR CRANIAL NERVE METASTASES: A SINGLE INSTITUTION EXPERIENCE
Authors: Persad Amit , Shahsavari Nastaran , Ahmad Maleeha , McCleary Tamra-Lee , Park David , Hori Yusuke , Emrich Sara , Ustrzynski Louisa , Tayag Armine , Gu Xuejun , Rahimy Elham , Pollom Erqi , Solyts Scott , Meola Antonio , Chang Steven
Published: November 2024

Cranial nerve metastases (CNM) can be primary via leptomeningeal metastasis or secondary by spread due to head and neck cancers or due to distant tumor metastasis to the skull base. In addition, they may cause cranial nerve-related symptoms that can impact patient quality of life. We performed a single-center retrospective cohort study of all patients with CNM treated with SRS at our institution between April 2003 and February 2021. Demographic and clinical information were retrieved from the electronic medical record. Median follow-up was 12.9 months. Our study cohort consisted of 9 patients with primary CNM and 8 with secondary CNM – for a total of 17 patients, with a total of 33 lesions (23 primary, 10 secondary). Eleven patients (64.7%) had symptoms caused by cranial nerve metastases. Symptoms were resolved in 5 of 11 patients (45.5%) after SRS. Patients with secondary CNM were more likely to have cranial nerve symptoms and more likely to have resolution of symptoms following SRS. The median time between SRS and symptom improvement was 3 months. Local tumor control was achieved in 30 of 33 lesions (90.9%). Local tumor control at 6 months and at 1 year were 100%. Our study suggests that SRS may be a safe and effective treatment for cranial nerve metastasis providing 90.9% local tumor control at final follow-up, and symptomatic stability or improvement in 90.9% of symptomatic cases. Patients with secondary CNM may stand to benefit more from a symptom management standpoint.
EPID-33. EPITHELOID SARCOMA IN A LONG-TERM SURVIVOR OF AN ATYPICAL TERATOID / RHABDOID TUMOR WITH RHABDOID TUMOR PREDISPOSITION SYNDROME
Authors: Vanan Magimairajan Issai , Brizini Meziane , Shawyer Anna , Wilkes Courtney , Min Suyin Lum , Stefanovici Camelia , Hamza Sate , Drimes Tina , Bourne Catherine , McDonald Patrick
Published: November 2024

INTRODUCTION

Rhabdoid tumor predisposition syndrome (RTPS) predisposes to a high risk of developing Rhabdoid tumors in Brain, kidney; and is defined by a germline mutation in SMARCB1 (rarely SMARCA4) gene. The most frequent pediatric tumor associated with RTPS is atypical teratoid/rhabdoid tumor (ATRT), commonly diagnosed in children < 3 years of age. Epitheloid Sarcoma (ES) is a rare soft tissue sarcoma, arising in any age group and histologically defined by loss of SMARCB1 in tumor cells.

METHODS

We describe a long- term survivor of ATRT with RTPS presenting 12 years later with ES. Data was collected from medical chart review.

RESULTS

Our patient was diagnosed with ATRT and RTPS (SMARCB1) at 6 months of age and treated with chemotherapy as per ACNS0333 at diagnosis; by chemotherapy / focal radiation at first relapse and with alisertib on second relapse. At 10yrs of age she presented with multiple firm, skin-colored dermal nodules in both her hands (palms and fingers). She was diagnosed to have palmar warts and treated with topical cantharidin with a waxing and waning course. Subsequently the hand lesions were diagnosed as granuloma annulare and followed up with no therapy. At 12 years of age, lesion in tip of the right thumb increased in size and a punch biopsy was done which revealed ES with IHC showing loss of SMARCB1 in tumor cells. Staging CT of the chest showed multiple bilateral (b/l) small (<1cm) axillary lymph nodes with a negative PET scan. Bilateral axillary lymph node biopsies were negative for ES. She underwent excision of all the hand lesions with negative margins with no further therapy.

CONCLUSION

Based on our case and single case report in literature, we hypothesize that ES is likely a primary malignancy of RTPS and should be included in the spectrum of malignancies of RTPS.
EPID-37. PROGNOSIS OF BRAIN METASTASES PATIENTS WITH WHOLE BRAIN RADIATION THERAPY (WBRT) VS NON-WBRT AT THE NATIONAL CANCER CENTER OF INDONESIA, DHARMAIS HOSPITAL
Authors: Andriani Rini , Susilodinata Alfred , Wilopo Siswanto Agus
Published: November 2024

BACKGROUND

Limited treatment options for brain metastases (BM) remain a challenge for many cancer centers in Indonesia. To improve overall survival, Whole Brain Radiation Therapy (WBRT) is still widely used in many Indonesian cancer centers This study aims to evaluate the effectiveness of WBRT vs non-WBRT for overall survival of brain metastases patients.

METHOD

This retrospective study observed 148 brain metastasis patients admitted to our hospital from January 1st, 2021 to December 31st, 2022 and we followed their overall survival up to July 1st, 2023. The brain metastasis is confirmed by brain MRI. In addition to overall survival, we collected information on age, sex, primary tumor types, sides of metastasis, and treatment received (WBRT, non-WBRT, and surgery). To examine the overall survival among treatment received and tumor characteristics, we present median survival time, Kaplan-Meier curves, and its log-rank statistics using Stata program version 17. Additionally, we use Cox regression for further analysis.

RESULTS

The overall median survival of these patients was 4.3 months. Patients receiving WBRT exhibit higher survival rates than non-WBRT as presented in their median survival rates (1.5 months vs 6.9 months). The primary tumors (breast, lung, and others) have no difference in the median survival rates. The survival rate trends using Kaplan-Meier showed a significant difference between patients with WBRT vs non-WBRT (log-rank p=0.0). A Cox regression shows hazard rates(HR) for patients receiving WBRT =0.40 and it shows only a small change when adjusted for surgery and other variables.

CONCLUSIONS

Brain metastasis patients who received WBRT have better survival than non-WBRT patients who could reduce HR to 0.4. This means that WBRT patients are protected 60% of the risk for overall survival.
DISP-07. CURRENT NEURO-ONCOLOGY CAPACITY IN SUB-SAHARAN AFRICAN COUNTRIES: A QUESTIONNAIRE-BASED SURVEY
Authors: Odukoya Lateef , Ghomsi Nathalie , Kabare Gloria , Kamson David , Eckel-Passow Jeanette , Jenkins Robert , Kitange Gaspar , Akinjo Andrea , Badmos Kabir , Bankole Olufemi , Idowu Olufemi , Karekazi Claire , Darko Kwadwo , Edrick Elias , Ekhator Chukwuyem , Katasi Victoria , Lachance Daniel , Brown Desmond , Huse Jason , Llewellyn Henry , Magambo Margreth , Magoha Michael , Ngaiza Advera , Nyalundja Arsene , Higgins Dominique , Okenwa Minda , Osei-Tutu Lawrence , Petershie Bernard , Yevudza Elorm , Anunobi Charles , Tiamiyu Liadi , Gankpe Gbetoho , Heronima Kashaigili , Shroeder Kristin , Fonkem Ekokobe , Teddy Totimeh , Balogun James , Cheserem Beverly , Zerd Francis
Published: November 2024

Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). There is no previous large-scale effort focusing on brain tumor genetics in SSA. This project aims to map out the current neuro-oncology capacity in terms of workforce and available services in SSA. This is an ongoing online survey among a cross section of neuro-oncology practitioners spread across SSA countries to capture information on the distribution, number of available neuro-oncology care practitioners, capacity for neuropathology and molecular diagnosis, management of brain tumors, cancer registration, and tumor biobanking. The survey was disseminated by the Society for Neuro-oncology in SSA (SNOSSA). There were 83 respondents representing 15 countries and 52 health institutions: 46 tertiary, 4 secondary, 1 private and 1 other. Here, we present data on the 52 institutions. The prevalence of specialties was 87% neurosurgery, 75% anatomic pathology, 69% medical oncology, 64% neurology, 60% radiation oncology, and 39% neuropathology. For radiologic evaluation, 81% of institutions were reported to have both CT and MRI, 17% CT only, and one institution neither. For molecular testing, 46% have access to IHC or NGS testing, whereas 52% were reported to have neither. A neuro-oncology tumor board was reported at 58% of institutions. A general cancer registry is available in 64% of institutions, 31% have a brain tumor specific registry and 10% have a brain tumor biorepository. This study shows that SSA has substantial potential in neuro-oncology care practice capacity and facilities. Most significant gaps remain in areas such as neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes is also difficult due to low number of brain tumor registries and biobanks in SSA. The present findings reveal strategic opportunities, especially in neuropathology, tumor registries, biobanks, and infrastructure for IHC and NGS in SSA.
DISP-12. AN ECONOMIC STUDY OF NEURO-ONCOLOGICAL PATIENTS IN A LARGE DEVELOPING COUNTRY – A COST ANALYSIS
Authors: Campos Paiva Aline Lariessy , Araujo João Luiz Vitorino , Lovato Renan Maximillian , Daoud Alex Michel , de Oliveira Jean Gonçalves , Veiga José Carlos Esteves
Published: November 2024

BACKGROUND

Neuro-oncological patients require specialized medical care. However, the data on the costs incurred for such specialized care in developing countries are currently lacking; these data are relevant for international cooperation.

OBJECTIVE

This study aimed to estimate the direct cost of specialized care for an adult neuro-oncological patient with meningioma or glioma during hospitalization in the largest philanthropic hospital in Latin America.

METHODS

This observational economic analysis describes the direct cost of care of neuro-oncological patients in Santa Casa de São Paulo, Brazil. Only adult patients with a common primary brain tumor were included.

RESULTS

Due to differences in the system records, the period analyzed for cost estimation was between December 2016 and December 2019. A group of patients with meningiomas and gliomas was analyzed. The estimated mean cost of neurosurgical hospitalization was US$4,166. The cost of the operating room and intensive care unit represented the largest proportion of the total cost. A total of 17.5% of patients had some type of infection, and 66.67% these occurred in nonelective procedures. The mortality rates during emergency procedures were 12.7% and 92.3%.

CONCLUSIONS

Emergency surgeries were associated with an increased rate of infections and mortality. The findings of this study could be used by stakeholders and policymakers for resource allocation and to perform economic analyses to establish the value of neurosurgery in achieving global health goals. KEY WORDS: costs; brain tumor; glioma; meningioma.
DISP-18. RACIAL DISPARITY IN THE UTILIZATION OF MOLECULAR DIAGNOSTIC AS A PROXY FOR SUB-OPTIMAL CLINICAL CARE IN GLIOBLASTOMA PATIENTS
Authors: Zhu Ping , Do Huy , Chen Clark
Published: November 2024

BACKGROUND

Molecular characterization of IDH mutation and MGMT-promoter methylation (MGMTm) are standard-of-care (SOC) diagnostics and essential to diagnosis, treatment, and prognosis of glioblastomas. Here, we determined the extent to which racial disparity occurs in this dimension of oncologic care.

METHODS

31,439 glioblastoma patients were derived from the National Cancer Database (NCDB,2018-2021), with 20,736 IDH-wildtype patients with defined MGMT-status. Accessibility to SOC diagnostics was defined as whether patients got IDH/MGMT testing or not. Race/Ethnicity was grouped into Non-Hispanic White (NHW), Non-Hispanic Black, Asian/Pacific Islander, Hispanic, and Others. Receipt of SOC diagnostics and treatments, post-operative outcomes, and overall survival (OS) were explored using multivariable logistic regression, Kaplan-Meier method, and Cox proportional hazards models.

RESULTS

Relative to NHWs, all racial minority groups were less likely to have undergone IDH or MGMT-testing. These effects remain robust after adjusting for economic status, insurance, and facility type. Patients who received neither IDH nor MGMT-testing were 38% less likely to undergo SOC concurrent chemo-/radiation therapy (cCRT) relative to those having both testing. Further, patients having neither IDH nor MGMT-testing showed significantly higher risk of 30-day mortality (aOR:2.20), 90-day mortality (aOR:1.60), and hazard of death (median OS:8.9-mon,aHR:1.09,p=0.002) than those having both testing (median OS:12.9-mon). Of those tested for both IDH/MGMT, the odds of bearing a methylated MGMT-promoter remained relatively constant across five racial groups. Non-NHW glioblastomas patients were significantly less likely to receive SOC-modality. Of the patients who underwent IDH/MGMT-testing and cCRT, median OSs were 23.7 and 14.4-mon for MGMT-methylated and unmethylated glioblastoma, respectively. No significant difference in hazards of death for racial/ethnic minorities compared to NHWs was detected, regardless of MGMT-methylation status.

CONCLUSIONS

Our findings suggest that non-NHW glioblastoma patients are less likely to undergo SOC diagnostic (IDH/MGMT) testing, which serves as a proxy for receipt of sub-optimal clinical care. For glioblastoma patients who underwent SOC molecular testing and treatment, survival is similar across racial groups.
DISP-20. SEX DIFFERENCES IN MENINGIOMA AGGRESSIVE BEHAVIOR IN RURAL POPULATIONS: A GEO-ECOLOGICAL RISK ASSESSMENT OF MENINGIOMAS IN A SINGLE RURAL HEALTH CARE SYSTEM
Authors: Ali Haadi , Gatson Na Tosha
Published: November 2024

BACKGROUND

Cause for health outcome disparities in rural populations is multifactorial. These populations are potentially more vulnerable due to rural area environmental policies and practices. Environmental justice populations (EJP) are designated by the Environmental Protection Agency as at risk for generational exposer to environmental contaminants. We assessed these population for an association between EJP density and aggressiveness of indolent brain tumors. Meningiomas are the most common benign intracranial tumor and have a female predominance. We evaluated meningioma patients in a large rural health system for oncogenic risk associated geo-ecological factors.

METHODS

A retrospective review of 415 pathology confirmed CNS WHO grades 1-3 meningiomas cases between 2007 – 2017 within the Geisinger Health system in Pennsylvania. Cases were mapped by county for meningioma incidence, tumor grade, and tumor recurrence. Counties were rated for EJP density. We mapped geographic areas with a higher meningioma incidence, grade, and rates of recurrence, and evaluated sex-predilections.

RESULTS

Seventy-three percent of tumors were WHO grade 1 (n=303), 23.4% (n=97) were grade 2, and 3.6% (n=15) were grade 3. The highest incidence of meningiomas were localized to higher density EJP counties that bordered riverbeds, Lackawanna and Luzerne. Females had a 3.5:1 predominance as compared to males. The grade 1 10-year progression free survival rate was 54.7% in Luzerne, Columbia, and Montour counties (moderate to high density EJP). Males in high EJP counties had a 12% increased risk for developing high grade meningiomas. Males aged 51-60 were more likely to develop a grade 2 or 3 meningioma as compared to males aged 61-70 in these counties. Females aged 50-60 more likely had grade 1 meningiomas but demonstrated consistently increasing risk for recurrence every decile.

CONCLUSIONS

Pennsylvania high density EJP counties (especially along the Lackawanna River supply) have a disproportionate risk for aggressive meningiomas and lower progression free survival as compared to national averages. A sex-discrepancy exists for males in these areas to have the most aggressive tumors.
IMMU-10. IDENTIFICATION OF A NEW THERAPEUTIC ANTIGEN FOR GLIOBLASTOMA USING A MONOCLONAL ANTIBODY LIBRARY FROM PATIENT-DERIVED TUMOR SPHERES
Authors: Kuroda Hideki
Published: November 2024

Glioblastoma (GBM) has a poor prognosis despite intensive treatment by surgery, radiation, and chemotherapy, thus new treatment strategies are urgently needed. Various innovative cancer therapies targeting cancer-specific cell surface antigens, such as chimeric antigen receptor T cell therapy, are developed and more cell surface antigens that is highly specific for GBM cells are needed. Although extensive transcriptome analyses or proteomic analysis of GBM cells were performed, few transcripts specific for GBM cells have been identified. However, GBM cell-specific antigen epitopes formed by post-translational modifications of proteins may have been missed by transcriptome or proteomic analysis, and could still be discovered by thoroughly searching for cancer-specific monoclonal antibodies. In this study, we aimed to identify GBM-specific antigens using a monoclonal antibody library from patient-derived tumor spheres, create CAR-T cells against the antigen, and check antitumor efficiency of the CAR-T cells. Approximately 25,000 monoclonal antibody-producing hybridomas were establishment using BALB/c mice and patient derived tumor spheres. Among them, a antibodies that bind to plural glioblastomas and not to plural normal brain cells were selected and we identified the antigen as Prostaglandin F2 receptor negative regulator (PTGFRN) by the expression cloning method. PTGFRN witch is expressed in several cancers regulate migration, angiogenesis, and cell polarity and decreases the radiosensitivity of GBM cells. We created CAR-T cells against the antigen and co-cultured it with GBM cells, which significantly increased the production of IL-2 and INF-γ. Furthermore, the CAR-T cells injected intracranial in an orthotopic xenograft model with patient-derived GBM cells, significantly reduced tumor growth. PTGFRN CAR-T-cell therapy may be a potential novel therapeutic target for GBM.
IMMU-11. GUARDIANS OF INNATE IMMUNE ACTIVATION: CRUCIAL ROLES OF NONO AND CGAMP IN GLIOMA VIROTHERAPY
Authors: Gillard Andrew , Shin Dong Ho , Laspidea Virginia , Singh Sanjay , Jiang Hong , Xuejun Fan , Lopez-Rivas Andres , Parthasarathy Akhila , He Jiasen , Garcia-Moure Marc , Fueyo Juan , Gomez-Manzano Candelaria
Published: November 2024

Despite aggressive therapeutic interventions, glioblastoma patients face a median survival of seven months after tumor recurrence. Alarmingly, there has been no improvement to the standard of care for two decades, and patients still receive toxic doses of radiation and chemotherapy, rendering many unable to perform daily functions. An emerging approach, oncolytic virotherapy (OV) using Delta-24-RGD, is gaining traction due to recent clinical trials (NCT00805376, NCT03178032, and NCT02798406) exhibiting robust responses in subsets of patients. While these studies demonstrated the therapeutic potential of OV, findings also indicate the early clearance of the virus, hindering the establishment of an effective anti-tumor immune response in most patients. We propose that mitigating the innate immune response against the therapeutic virus should result in improved intratumoral persistence, increasing the window of opportunity for developing an anti-tumor immune response. RNA-sequencing identified the non-POU domain containing octamer-binding (NONO) pathway as highly upregulated in syngenic glioma models and further amplified by OV treatment. In-vitro RNA sequencing and comparative analysis complemented these results to define a unique transcriptomic profile induced by adenovirus infection. LC-MS/MS identified host cGAS and adenoviral capsid proteins as candidate binding partners of NONO, which were validated using co-immunoprecipitation. Although the type I interferon cluster is deleted in most gliomas, tumor cells have a profound influence on their microenvironment through the secretion of the second messenger cGAMP. We show that NONO is required for cGAMP production, providing a mechanism to modulate antiviral responses in the tumor microenvironment during OV. Our findings underscore the significance of cGAMP shed from tumor cells in response to OV, and how NONO interacts with cGAS in the nucleus to sensor adenovirus infection. These findings uncover novel innate immunity mechanisms in gliomas and will inform the design of more efficacious oncolytic adenoviruses for glioma therapy.
IMMU-17. ADENOSINE DEAMINASE ACTING ON RNA (ADAR) SILENCES TUMOR-INTRINSIC INTERFERON RESPONSE IN DIFFUSE MIDLINE GLIOMA
Authors: Ramsoomair Christian , Castro Jesus , Seetharam Deepa , Shah Ashish , Reinberg Danny
Published: November 2024

INTRODUCTION

Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children and is currently incurable. Clinical trials using immune checkpoint blockade (ICB) therapy have failed to show efficacy due to multifactorial mechanisms including limited lymphocyte infiltration, low immune checkpoint (IC) expression, and a low mutational burden. Adenosine deaminase acting on RNA (ADAR) is an RNA editor, which limits anti-tumor immunity by editing/preventing the sensing of endogenous double-stranded RNA (dsRNA). We have found that ADAR protein levels are significantly elevated in DMG patients, suggesting that ADAR’s immune-silencing function is relevant to DMG immune suppression. The onco-histone driver H3K27M promotes epigenetic dysregulation in DMGs, de-suppressing retroelement transcription, a major source of endogenous dsRNA. By inhibiting ADAR, we expect that the increased levels of dsRNA will stimulate intracellular type-1 interferon (IFN) responses, induce chemokine secretion, and promote antitumor CD8+ cytotoxicity.

METHODS

Human DMG cells and patient-derived glioma spheres were treated with silencing RNA to transiently knockdown (KD) ADAR levels for assays involving in vitro viability and proliferation. Affected pathways were identified using immunoblotting and quantitative PCR.

RESULTS

Our data shows that ADAR protein levels are elevated in DMG patient proteomic datasets and cell lines. ADAR-depleted patient-derived DMG cell lines exhibit significantly less proliferation compared to control siRNA and ADAR-depleted hTERT-astrocytes (Mann-Whitney test, P-value <0.0001, ****).

CONCLUSION

Our results demonstrate that DMG tumor cells have an ADAR selective dependency in vitro. In ongoing studies, we aim to determine if ADAR-depletion improves in-vivo survival in both immunodeficient and immunocompetent models in combination with immunotherapies against DMG.
IMMU-18. IL-7 MEDIATED UPREGULATION OF VLA-4 INCREASES ACCUMULATION OF ADOPTIVELY TRANSFERRED T LYMPHOCYTES IN MURINE GLIOMA
Authors: Singh Kirit , Hotchkiss Kelly , Cook Sarah , Noldner Pamy , Zhou Ying , Moelker Eliese , Railton Chelsea , Blandford Emily , Puviindran Bhairavy , Wallace Shannon , Norberg Pamela , Archer Gary , Shaz Beth , Sampson John , Khasraw Mustafa , Fecci Peter
Published: November 2024

We have previously described the development of a novel brain bi-specific T cell engager (BRiTE) targeting EGFRvIII in Glioma. Despite BRiTEs impressive potency, efficacy in solid tumors is dependent on tumor-infiltrating lymphocytes (TILs). We evaluated if peripheral adoptive lymphocyte transfer (ALT) increases TILs in immunocompetent mice, even during glioma-induced sequestration. C57/Bl6 mice were implanted with 3 x 10^4 cells syngeneic glioma (CT-2AvIII) and treated with 1 x 10^7 IV CD45.1+ ALT on Day 15. The brain was divided into tumor and non-tumor bearing hemispheres and analyzed each day for exogenous (CD45.1+) CD3/4/8 counts. We observed that IL-7-expanded ALT accumulated at a higher rate within tumor versus IL-2 ALT (72-hours IL-7 median 26.66x vs IL-2 median 4.291x, p=0.0159*). Exogenous T cell entry into tumor-bearing CNS overwhelmingly consisted of CD8+ T cells, and CD45.1+ IL-7 ALT cells made up ~20% of the CD3+ population in tumor 72-hours following administration (mean 19.4%, SD ±4.53%, n=5). Survival experiments used combination ALT and anti-4-1BB therapy in the same model. Mice were treated with IV ALT on Day 5, along with 200µg of IP anti-4-1BB. IP mAb Injections were given every 3 days for 4 total cycles (D5, D8, D11 & D14). Evaluation at these time points was selected as this correlated with peak sequestration of immune cells as evidenced by splenic involution. For survival studies, only combination ALT and anti-4-1BB produced significantly increased survival benefit in our CT-2AvIII model compared to ALT alone (median survival 45.5 days for combination versus 25 days in ALT only group, p=0.0134, chi-square test). These findings demonstrate the feasibility of combination ALT/antibody-based therapy in pre-clinical glioma, as well as outlining a novel approach for delivering both immune cells and antibody-based immunotherapy. Combination therapy with BRiTE and ALT will be explored in an upcoming clinical trial (NCT04903795).
IMMU-20. CIRCULATING CELL-FREE DNA DIRECTLY INHIBITS T CELL RESPONSES AND CONTRIBUTES TO SYSTEMIC IMMUNOSUPPRESSION IN GLIOBLASTOMA
Authors: Hoyt-Miggelbrink Alexandra , Reesman Rachael , Anani-Wolf Delaney , Hansen Michael , Pfaller Christian , Fain Cori , Johnson Aaron , Ayasoufi Katayoun
Published: November 2024

Glioblastoma (GBM) is an aggressive form of brain cancer with poor survival despite standard of care. Checkpoint inhibitors aimed to revive dysfunctional T cells have significantly improved outcomes in other cancers, but have failed GBM. GBM patients have severe peripheral immunosuppression, including severe lymphopenia, immune organ atrophy, and defective T cell responses. This immunosuppression is a critical barrier to patient survival and the success of immunotherapies. Using parabiosis, we demonstrated that serum-derived factors were sufficient to drive hallmark features of immunosuppression, including inhibition of ex vivo T cell proliferation. This factor was nonsteroidal in nature and had molecular weights greater than 100kDa. Mass-spectrometry and pathway analysis of the suppressive serum implicated proteins involved in DNA response elements, cell death, and DNA-histone complexes. We hypothesized that the factor is cell-free DNA (cfDNA). Confirming this, serum levels of cfDNA are increased in glioma-bearing mice. Moreover, exposure to cfDNA from serum of glioma-bearing mice was sufficient to directly and potently inhibit T cell proliferation ex vivo. Interestingly, exposure to genomic DNA was not sufficient to induce proliferation defects in T cells, highlighting the unique features of cfDNA. Importantly, reducing cfDNA content using DNaseI partially restored proliferation capacity. We determined that the T cell proliferation defects were independent of DNA sensing mechanisms through AIM2, implicating a novel pathway of DNA sensing in T cells. Finally, to determine the origin of the cfDNA, we employed methyl-seq. The chromatin signature most closely represented neutrophils. This highlights a potential role for neutrophils-derived cfDNA as a targetable strategy in GBM. Together, we contend that cfDNA induces immunosuppressive effects in GBM and devising strategies to reduce circulating cfDNA could be a therapeutic approach to improve T cell functions and outcomes in GBM patients.
IMMU-21. OVEREXPRESSING CAR T-CELL GLUCOSE TRANSPORTER TO ENHANCE ANTI-TUMOR ACTIVITY IN GLIOBLASTOMA
Authors: Sengupta Srabasti , Jin Linchun , Feier Diana , Silver Aryeh , Chakraborty Avirup , Tao Haipeng , Thomas Nagheme , Rahman Maryam , Flores Catherine , Castillo Paul , Sarkisian Matthew , Huang Jianping , Mitchell Duane A , Deleyrolle Loic P
Published: November 2024

INTRODUCTION

Despite aggressive interventions, Glioblastoma (GBM) remains as a challenge for neuro-oncologists. Standard treatments are often followed by disease recurrence. Adoptive cell therapies have emerged as a viable therapeutic for brain malignancies. CAR-T cell therapy has generated substantial interest because of its efficacy and specificity in treating various cancers. Despite these efficacies, studies reveal limitations of CAR-T therapy due to the altered metabolic environment in GBM. GBM tumors shift towards aerobic glycolysis, regardless of oxygen availability leading to massive glucose consumption. This results in impeding T-cell glycolysis and activation.

OBJECTIVE

The GBM microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T-cells. In our study, we manipulated the metabolic fitness of the therapeutic T-cells to enhance their tumoricidal activity, by overexpressing glucose transporter GLUT1 and GLUT3. We show that this manipulation can enhance their anti-tumor activity.

METHODS

The T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The functionality of metabolically modified T-cells was investigated in murine and human models.

RESULTS

We demonstrated that tumor cells impose glucose restriction when competing for glucose with T-cells leading to T-cell hypo responsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T-cell glucose utilization and provide survival advantage leading to enhanced T-cell activation in glucose-restricted conditions. The metabolic modifications regulate T-cell efficacy by enhancing intra-tumoral trafficking. We tested this approach in the context of CD70CAR T cell therapy. It was established that glucose transporter overexpression in CD70 CAR T-cells not only improves intracranial tumor invasion but also elicit functional anti-tumor cell response thus improving survival.

CONCLUSIONS

This study integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.
IMMU-25. B-CELL BASED THERAPY (BVAX) PRODUCES ANTIBODIES TO SUPPRESS GLIOBLASTOMA TUMOR MIGRATION AND INVASION
Authors: Katz Joshua , Castro Brandyn , Wang Si , Arrieta Victor , Najem Hinda , Vazquez-Cervantes Gustavo Ignacio , Olson Ian , Hou David , Dapash Mark , Wan Hanxiao , Rashidi Aida , Arjmandi Tarlan , Shaikh Zainab , Jones Grace , Platanias Leonidas , McCortney Kathleen , Horbinski Craig , Stupp Roger , Zhang Peng , Ahmed Atique , Sonabend Adam , Heimberger Amy , Lesniak Maciej , Riviere-Cazaux Cécile , Burns Terry , Miska Jason , Fischietti Mariafausta , Lee-Chang Catalina
Published: November 2024

Glioblastoma (GBM) presents as a highly aggressive and malignant brain tumor with limited treatment options. Despite the availability of existing therapies, the invasive characteristics of GBM frequently result in tumor recurrence and poor prognosis. We previously developed a B-cell-based therapy (BVax) that has shown promising results in its ability to induce therapeutic responses in preclinical models of GBM. Our research revealed potency of BVax can be attributed to its robust antigen-presenting capability, cognate antigen specificity with T cells, and ability to generate tumor-reactive antibodies. The present study aims to characterize the unique antigenic reactivity of BVax-derived antibodies by evaluating their immunological effects and therapeutic potential in both murine models and GBM patient-specific samples. Leveraging CD45.1 and CD45.2 congenic mouse models, we first revealed that BVax preferentially migrated to glioma-bearing brains upon intravenous injection, resulting in a CD38+CD20-CD19+ plasmablast phenotype. To further characterize the reactivity of BVax-derived immunoglobulins (Ig), we utilized proteomic analysis and identified preferential targets of Gelsolin, Fibronectin, Versican, Fibrinogen, and collagen type IV alpha, commonly associated with cell motility and the extracellular matrix. Microdialysis data confirmed the increased presence of many of these BVax-derived Igs-recognized antigens in tumor regions compared to normal brain regions in GBM patients. Utilizing purified BVax-derived antibodies from patient specimen, in vitro cell motility assays demonstrated a significant prevention of the invasion and migration of cell lines from patient derived xenograft (PDX). In this study, we concluded that BVax elicits antitumor activity through targeted migration to tumor-bearing regions, differentiation into plasmablasts, and robust secretion of specific Igs that retain the ability to inhibit functionalities associated with cell invasion and migration. Here, we present the first in-depth study that characterizes GBM patients’ antibody reactivity, specifically a subset of inflammatory B cells (BVax) with therapeutic effects that offer an indication for a new direction of immunotherapies.
IMMU-27. INHIBITION OF THE EXTRACELLULAR MATRIX PROTEIN EFEMP1/FIBULIN-3 REDUCES IMMUNOSUPPRESIVE SIGNALING IN TUMOR STEM CELLS AND INCREASES MACROPHAGE ACTIVATION AGAINST GLIOBLASTOMA
Authors: Kundu Somanath , Mitra Soham , Arivazhagan Roshini , Longo John , Longo Sharon , Venskus Abigail , Babu Harish , Viapiano Mariano
Published: November 2024

Glioblastoma tumors remain a formidable challenge for immune-based treatments because of their molecular heterogeneity, poor immunogenicity, and growth in the largely isolated and immunosuppresive neural environment. As the tumor grows, GBM cells change the composition and architecture of the neural extracellular matrix (ECM), affecting the mobility, survival, and function of immune cells such as tumor-associated microglia and infiltrated macrophages (TAMs). We have previously described the unique expression of the ECM protein EFEMP1/fibulin-3 in GBM compared to normal brain and demonstrated that this secreted protein promotes growth and resistance of the GBM stem cell (GSC) population. Here, we describe a novel immunomodulatory role of fibulin-3 and the immuno-boosting effects of targeting this ECM protein. Mice carrying fibulin-3-deficient intracranial tumors showed increased myeloid infiltration and reduced expression of TAM pro-tumoral markers (Arginase, CD206) compared to controls. The opposite was observed in orthotopic tumors overexpressing fibulin-3. In silico dataset analysis revealed positive correlation of fibulin-3 with an immunosuppresive signature in GBM, which was validated in GBM stem cells (GSCs). Accordingly, expression of fibulin-3 by GSCs promoted anti-inflammatory polarization of co-cultured macrophages. We further demonstrated that fibulin-3 regulated the expression of immunosuppresive signals (CSF-1, TGFbeta) and the innate immune checkpoint CD47 in GSCs via autocrine activation of NF-kB signaling. Immunosuppresive signals in GSCs were downregulated by knockdown of fibulin-3 or inhibition of this protein with an anti-fibulin-3 antibody (mAb428.2). Genetic or antibody-mediated targeting of fibulin-3 in GSCs co-cultured with macrophages (U937 and THP1 lines) increased macrophage phagocytosis and reduced the viability of the tumor cells. Furthermore, local delivery of mAb428.2 in mice carrying intracranial GBM resulted in increased infiltration of TAMs expressing pro-inflammatory markers and reducing tumor viability. Our findings show that anti-fibulin-3 approaches, which impact the tumor ECM, can diminish immunosuppression in GBM and boost innate immune responses against the tumor.