bluuebunny/crossref_metadata_2025 huggingface dataset:
DDDR-31. THE CHEMOTHERAPEUTIC ACTIVITY OF TEMOZOLOMIDE IS ANTAGONIZED BY ITS HYDROLYSIS PRODUCT, AIC
Authors: Sowers Mark L , Baljinnyam Tuvshintugs , Tang Hui , Herring Jason L , Hatch Sandra , Valdes Pablo , Zhang Kangling , Sowers Lawrence C
Published: November 2024

Temozolomide is the only FDA-approved drug that has demonstrated improved overall survival in patients with Glioblastoma. Despite the clinical impact it has had, overall survival today largely remains less than two years with current standard-of-care. Temozolomide is a prodrug that undergoes hydrolysis releasing 5-amino-4-imidazole carboxamide (AIC) before it can alkylate DNA. The DNA damage response invoked by TMZ depletes NAD+ levels. We present evidence from mass spectrometry LC-MS/MS studies that AIC released from TMZ can be aberrantly incorporated into the purine synthesis pathway, augmenting purine, and NAD+ synthesis and contributing to chemo- and radiation- resistance. The chemotherapeutic efficacy is therefore antagonized by its own hydrolysis product. TMZ analogs that do not generate AIC will likely have greater activity.
DDDR-37. OHSV AND RADIATION THERAPIES SENSITIZE GLIOBLASTOMA TO IGF1R-TARGETED THERAPY AND SYNERGIZE IN TRIPLE COMBINATION THERAPY
Authors: Miller Alexandra A , Noh Min Hye , Kang Jin Muk , Nguyen Grace , Huang Min Xin , Otani Yoshihiro , Nakashima Hiroshi , Chiocca E Antonio , Lee Tae Jin , Yoo Ji Young
Published: November 2024

Glioblastoma (GBM) continues to have a dismal prognosis despite remarkable advances in the field due to both tumor-intrinsic factors (i.e., IDH1 or EGFRvIII mutations) and extrinsic factors (i.e., relating to the tumor microenvironment (TME)), necessitating therapeutic innovation. Oncolytic herpes simplex virus-1 (oHSV) is an FDA-approved therapy that has shown promising results in clinical trials; however, therapeutic efficacy is limited to a small subset of patients. Thus, elucidating both the tumor-TME interplay and feedback/feedforward tumor-cell signaling in the context of viro-immunotherapy is essential in augmenting therapeutic outcomes. We recently discovered a novel mechanism of resistance to oHSVs, in which infection increases secretion of Insulin-like growth factor 2 (IGF2), activating the Insulin-like Growth Factor-1 Receptor (IGF1R). Upregulation of the IGF1R signaling pathway in GBM is correlated with poor prognosis and has been implicated in resistance to conventional therapies including radiotherapy (RTx). Herein, we further elucidate the impact of oHSVs on IGF1R activation, demonstrating a dose-dependent enhancement of downstream signaling. While IGF1R targeting therapies (e.g., OSI-966, Picropodophyllin (PPP)) have displayed limited efficacy in clinical trials, they significantly increased oHSV-induced cytotoxicity in all tested primary GBM cells compared to either agent alone in vitro and in vivo, resulting in a dose-dependent increase in PARP and caspase 3 activity by western blot and immunohistochemistry. We further found that RTx-induced IGF1 secretion and subsequent IGF1R activation were enhanced when combined with oHSV treatment. Triple combination therapy with oHSV, IGF1R inhibition, and RTx significantly increased tumor cell killing in vitro and improved survival of orthotopic GBM tumor-bearing mice. Collectively, our study provides preclinical evidence of enhanced therapeutic efficacy of oHSVs and RTx in combination with IGF1R blockade, supporting future use of IGF1R inhibitors in combination with the standard of care and FDA-approved oHSV therapies in patients with GBM.
DDDR-39. PI3 KINASE AND CHECKPOINT INHIBITION: A POTENTIALLY NOVEL THERAPEUTIC STRATEGY FOR GLIOBLASTOMA (GBM)
Authors: Jalali Ali , Siddik Abu Bakar , Yu Kwanhu , Tobin Richard P , Hay Charles E , Aminkeng Folefac , Fonkem Ekokobe , Newell-Rogers M Karen
Published: November 2024

Glioblastoma is the most common and aggressive malignant brain tumor with a median survival of less than 2 years, highlighting the need for more effective therapeutics. Dual pathway synergism between PI3K inhibitors and check-point inhibitors is a promising therapeutic avenue that has not been explored. Based on this possibility, we hypothesized that the combination of PI3K and checkpoint inhibitors will improve survival in our native glioblastoma mouse model. Treatment with GCT-007, a small molecule PI3K inhibitor, induces growth arrest of GBM cells that is accompanied by increases in the cell surface expression of molecules targeted by the immune system and immunotherapy drugs, including MHC Class II and PD-L1. Treatment of mouse GL261 and human U251 GBM cell lines with GCT-007 caused growth arrest, increased the cell surface expression of PD-L1 and MHC class II, and synergized with radiation to cause growth arrest and cell death. We compared GCT-007 to Paxalisib in our in vitro studies and observed that GCT-007 outperformed Paxalisib at increasing MHC class II and PD-L1 expression on the tumor cells at equivalent doses. We then performed in vivo animal studies using our native mouse GBM model. We treated mice orally with GCT-007 and observed a significantly prolonged survival compared to placebo. Mice treated with anti-PD1 resulted in a sexually dimorphic response consisting of prolonged remission of all female mice, now surviving beyond 1 year, but no improvement in the survival of male mice compared to placebo. Adding GCT-007 to anti-PD1 did not alter the prolonged remission outcome in female mice, it did result in prolonged remission of 25% of the male mice, now beyond 1 year. In conclusion, these results indicate that GCT-007 treatment alone improves survival in our native GBM mouse model and it may also improve the response to immune checkpoint inhibitor therapy in at least a fraction of GBM tumors. These data warrant further investigation as a potentially novel therapeutic approach to GBM.
DDDR-40. TARGETING BCL-XL WITH MIRZOTAMAB CLETUZOCLAX (ABBV-155) AND STANDARD OF CARE THERAPIES OVERCOMES APOPTOTIC RESISTANCE IN GLIOBLASTOMA
Authors: Fernandez Elizabeth , Mai Wilson , Young Pauline , Young William , Rodriguez Fausto , Souers Andrew , Cloughesy Timothy , Nathanson David
Published: November 2024

Conventional GBM therapies (e.g., temozolomide (TMZ), irradiation (IR)) transiently halt tumor growth of glioblastoma (GBM) but fail to induce apoptosis, inevitably leading to disease progression and poor patient survival. Targeting apoptotic blocks with BH3 mimetics can be an efficacious strategy to trigger apoptosis; however, these therapies can prevent high exposures in patients due to on-target, off-tumor toxicity in normal tissues. Mirzotamab Cletuzoclax (ABBV-155) is a first-in-class antibody-drug conjugate (ADC) that is specific for the highly expressed cell surface protein B7-H3 (CD276) and delivers a selective and potent BCL-XL inhibitor warhead. Here we identified that both TMZ and IR leave p53 WT GBM tumors exclusively dependent on the apoptotic block, BCL-XL, for survival. ABBV-155 negated the BCL-XL apoptotic block in both cell culture and orthotopic xenograft GBM models. Consequently, ABBV-155 combined with TMZ or IR initiates apoptosis and is synergistically lethal in GBM cells. Moreover, these combinations decrease tumor burden and extend survival in patient derived orthotopic xenografts. Taken together, these results demonstrate that the combination of DNA damaging therapy and ABBV-155 can have a synergistic anti-tumor impact in p53 WT GBM.
DDDR-43. ERAS-801 IS A SELECTIVE BRAIN-PENETRANT EGFR INHIBITOR WITH IMPROVED ACTIVITY AGAINST EGFR EXTRACELLULAR DOMAIN-MUTANT GLIOBLASTOMA
Authors: Okobi Quincy , Cadet Dimitri , Urner Lorenz , Jung Michael , Cloughesy Timothy , Nathanson David
Published: November 2024

Epidermal growth factor receptor (EGFR) is a driver of nearly 50% of glioblastoma (GBM), yet EGFR inhibitors have failed in GBM (e.g., erlotinib, lapatinib, neratinib, gefitinib, and afatinib) due to poor CNS penetration and/or an inability to inhibit EGFR in its wildtype and extracellular domain (ECD) mutated forms (e.g., EGFRvIII). Here we describe ERAS-801, a reversible and selective EGFR tyrosine kinase inhibitor with unique binding properties that enable potent activity for amplified and ECD mutant EGFR. ERAS-801 demonstrated the highest nonclinical CNS penetration out of all tested EGFR inhibitor comparators. Accordingly, relative to other EGFR inhibitors tested in GBM trials (e.g., erlotinib, lapatinib, and osimertinib), ERAS-801 showed superior survival benefit in EGFR altered orthotopic PDX models. Finally, further characterization of ERAS-801 in a preclinical trial of glioma orthotopic PDX models that capture the molecular heterogeneity of GBM, ERAS-801 demonstrated a significant survival benefit at a 25 mg/kg QD dose in the vast majority of EGFR-driven orthotopic GBM PDX models, with FDG-PET imaging serving as a non-invasive biomarker of response. Based on these nonclinical data, ERAS-801 is currently under clinical investigation for GBM.
DDDR-44. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO OVERCOME RESISTANCE TO CDK9 INHIBITORS IN DIFFUSE MIDLINE GLIOMA
Authors: Murdaugh Rebecca L , Eberl Brittany R , Richard Rosemary U , Tremblay Jack , Dei-Ampeh Alfred , Anastas Jamie N
Published: November 2024

Diffuse midline glioma (DMG) is a subset of aggressive brain tumors with few effective therapies. Cyclin-dependent kinase 9 (CDK9i) inhibitors such as zotiraciclib (ZTR) are in clinical trials for glioma, but CDK9i treatment alone may be ineffective due to the development of resistance. To identify CDK9i resistance mechanisms, we analyzed the transcriptomes of DMG xenograft tumors after three weeks of treatment with ZTR, which revealed that transcripts encoding synaptic signaling regulators such as glutamate receptors were overexpressed in surviving cells, suggesting that altered regulation of synaptic signaling may mediate CDK9i resistance. We also performed drug synergy screens using a library of FDA-approved and bioactive compounds and found that drugs that modulate neurotransmitter signaling, such as SSRIs and SNRIs (selective serotonin and serotonin/norepinephrine reuptake inhibitors), increased DMG sensitivity to an IC25 dose of ZTR. Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres by BLISS analysis and show that co-treatment with CDK9i and SSRI/SNRI strongly induces the apoptotic marker cleaved caspase 3 and reduces the CDK9 target phos-Pol2Ser2. Additional phospho-proteomic analyses identified differentially phosphorylated proteins following CDK9i+SSRI treatment, including chromatin regulators, Pol2 elongation factors, and splicing regulators. Further RNAseq studies reveal that CDK9i+SSRI treatment resulted in more robust transcriptional changes than either drug alone, including the downregulation of transcripts associated with ZTR resistance such as GRIA3/4, and SYT12. These observations suggest that CDK9i +SSRI/SNRI drug combinations may overcome some of the transcriptional changes underlying CDK9i resistance. Finally, preclinical studies show that co-treatment with low doses of AZD4573 and sertraline reduces the growth of orthotopic DMG xenografts and prolongs overall survival. Taken together, these data suggest that SSRI/SNRI and CDK9i might be used in combination to synergistically reduce DMG growth and overcome CDK9i resistance.
DDDR-47. TARGETING HTR2B SUPPRESSES NON-FUNCTIONING PITUITARY ADENOMA GROWTH AND SENSITIZES CABERGOLINE TREATMENT VIAINHIBITING GΑQ/PLC/PKCΓ/STAT3 AXIS
Authors: Lin Shaojianlin , Wang Liangbo , Han Changxi , Dai Yuting , Xue Li , Wu Zhe Bao
Published: November 2024

BACKGROUND

Managing non-functioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline’s (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential.

METHODS

We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays.

RESULTS

Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066.
DDDR-48. EZH2 INHIBITION AS A POTENTIAL THERAPEUTIC AVENUE IN THE TREATMENT OF MENINGIOMA
Authors: Casaos Joshua , Vitte Jeremie , Perryman Travis , Harary Maya , Shah Shilp , Na Brian , Everson Richard , Giovannini Marco
Published: November 2024

INTRODUCTION

High grade meningiomas provide challenges to treatment as these neoplasms are more likely to recur, exhibit invasion of brain parenchyma, and result in decreased long term survival. Recent works demonstrate the epigenetic modifier, EZH2, to be increased in higher grade meningiomas, and to correlate with poor survival. The selective targeting of EZH2 has shown promise in other malignancies with overexpression of or gain-of-function mutations in EZH2, leading to promising findings. Here we sought to investigate the effect of EZH2 inhibition on meningioma cell growth and viability, using a panel of in vitro models.

METHODS

Human immortalized meningioma cell lines, mouse meningioma cell lines and a panel of human primary cell cultures with varying baseline protein expression of NF2, SMARCB1, and EZH2, were selected for investigation. Cells were treated with several selective small molecule inhibitors of EZH2. Cell proliferation, cell cycle and cell death processes were assessed. RNAseq was used to assess transcriptional changes in response to EZH2 inhibition. Western blots were used to assess protein changes in response to EZH2 inhibition.

RESULTS

EZH2 inhibition significantly impairs meningioma cell proliferation, at varying IC50s, in all cell lines and primary cultures tested, utilizing a panel of EZH2 inhibitors. EZH2 inhibition resulted in significantly decreased colony formation in a high-grade cell line. Furthermore, EZH2 inhibition results in a reduction of Ki67+ cells, induction of cell cycle arrest, and apoptosis. Similar grouping of differential gene expression in immortalized cell lines and primary cell cultures is observed across cell lines and primary cell cultures, after EZH2 inhibition.

CONCLUSION

Our work demonstrates that EZH2 inhibition results in growth inhibition, cell cycle arrest, and cell death, across all cell lines, and cell cultures tested. Futhermore, modulation of protein levels of the EZH2 target H3K27 is observed upon treatment. RNA changes are broad and involve cell proliferative and migratory processes. This work provides the framework for further investigation of EZH2 inhibition in meningioma.
EPID-02. BLOOD-BASED CLASSIFICATION OF IDH-STATUS OF NON-ENHANCING GLIOMAS: A MACHINE LEARNING APPROACH
Authors: Hadad Sara , Warrier Gayathri , Mccoy Lucie , Hansen Helen , Chen Jiaying , Rice Terri , Wrensch Margaret , Taylor Jennie , Clarke Jennifer , Wiencke John , Molinaro Annette
Published: November 2024

BACKGROUND

Non-invasive determination of IDH mutational status in patients with glioma could offer significant therapeutic opportunities. While IDH wildtype (WT) tumors typically show enhancement on MRI, IDH mutant (MUT) tumors often lack this enhancement. However, relying solely on anatomic radiology may lead to misclassification, and currently, tissue acquisition is the primary method for assessing IDH-status in gliomas. These limitations hamper the development of neoadjuvant or intraoperative therapeutic strategies based on IDH-status; thus, more minimally invasive methods to determine IDH-status are needed. In this study, we assessed peripheral immune cell proportions, which vary by glioma subtype, from pre-surgery peripheral blood samples as an alternative method of classifying the IDH-status in gliomas without enhancement.

MATERIALS AND METHODS

We employed a highly accurate large language model (GPT-4-Turbo-128k) with over 99% accuracy to read radiology notes and exclude patients with enhancing gliomas. Then, we identified 12 immune cell subtypes from whole blood using deconvolution algorithms based on DNA methylation data. These immune cell subtypes, along with patient age, were integrated into a machine learning model (random forest) to predict IDH-status (WT vs. MUT), leveraging conditional Generative Adversarial Networks to generate synthetic data and mitigate bias in the datasets. Two independent datasets were included for training and validating the model.

RESULTS

The random forest model had an AUC of 0.90 and accurately identified IDH-status in 81% of a training set of 287 gliomas (65 WT and 222 MUT at varied time points after diagnosis). In an independent validation data set of 99 gliomas (6 WT and 93 MUT) from pre-surgery blood samples, the AUC was 0.93, and accurately predicted IDH-status in 92% of cases with a sensitivity of 93% and specificity of 83%.

CONCLUSIONS

We predicted the IDH-status of non-enhancing gliomas using patients’ age and immunomethylomic data from pre-surgical peripheral blood samples. This minimally invasive approach is a promising step toward reducing risk and enabling earlier therapies based on IDH-status.
EPID-03. BRAIN CANCER IN AFRICA: UNCOVERING THE HIDDEN EPIDEMIC THROUGH A SYSTEMATIC REVIEW
Authors: UWISHEMA Olivier
Published: November 2024

BACKGROUND

Cancer poses a significant public health threat globally, leading to substantial morbidity. While malignancies were previously thought to predominantly affect high-income countries, numerous studies indicate an increasing burden on resource-limited nations. Brain cancer, in particular, can be devastating due to treatment challenges and high mortality rates. Africa, with its resource-limited countries, must establish proper healthcare infrastructure to reduce cancer incidence and enhance patient survival. Additionally, the scarcity of data in this area in Africa presents a challenge to effective management. This study aims to explore the available evidence on the epidemiology and etiology of brain cancer in resource-limited African countries, highlighting the growing burden and advocating for further research.

MATERIALS AND METHODS

We conducted a systematic review by searching PubMed and Scopus using a predefined approach. Additionally, we utilized the Global Cancer Observatory and Global Burden of Disease databases. Studies reporting on brain cancer epidemiology, etiology, and impact in Africa were included, with the level of evidence assessed according to Centre for Evidence-Based Medicine guidelines.

RESULTS

Brain cancer presents a significant healthcare challenge in many African developing nations due to poor survival rates, inadequate funding and resources for reporting, identification, and treatment, as well as limited comprehensive research.

CONCLUSION

This study underscores the urgent need to address brain cancer as a major public health crisis in Africa. Improved treatment options and access to screening are essential to mitigate the disease burden. Thus, substantial and comprehensive research on brain cancer within Africa is crucial for effective management and reducing associated morbidity and mortality.
EPID-07. MAJOR CONGENITAL ANOMALIES AND RISK OF CHILDHOOD BRAIN TUMORS IN 9 STATES
Authors: Hoang Thanh , Schraw Jeremy , Taylor Michael , Plon Sharon , Lupo Philip , Scheurer Michael
Published: November 2024

Children with congenital anomalies have a higher risk of developing a childhood brain tumor (CBT), but it remains unclear if associations vary by cancer histology, which could inform our understanding of these associations. Thus, we characterized co-occurrences of major congenital anomalies with six CBTs. We leveraged a population-based registry linkage study of live births, congenital anomalies, and cancer from nine states. Dates of birth and last follow-up varied by state, ranging between January 1, 1990 to December 31, 2018, for a total of 22,599,099 live births. CBT classification was based on the International Classification of Childhood Cancer for children diagnosed up to age 18 years. Major congenital anomalies were classified based on the National Birth Defects Prevention Network Surveillance Guidelines. Children with any genetic anomalies were excluded. We used Cox regression to evaluate associations between major congenital anomalies and astrocytoma, medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor (ATRT), primitive neuroectodermal tumors (PNET), and mixed and unspecified gliomas (“mixed gliomas”), adjusting for sex, state, maternal education, maternal race/ethnicity, and maternal age. Sensitivity analyses were conducted stratifying by number of major anomalies (0, 1, 2+) and age at cancer diagnosis (<1, 1-4, 5-9, 10+ years). There were 5,685 diagnosed with any CBT. Having any major congenital anomaly was significantly associated with astrocytoma, ATRT, medulloblastoma, mixed glioma, and PNET (aHR range: 1.79-5.78) but not ependymoma. When stratified by number of major anomalies, effect estimates were similar. Due to small numbers when stratified by age at cancer diagnosis, unadjusted analyses were conducted. Associations were strongest in children diagnosed with astrocytoma, ATRT, medulloblastoma, mixed glioma, or PNET before age 1 (HR range: 3.03-5.47) compared to other age groups (HR range: 1.25-3.07). Children with any major congenital anomaly have an increased risk of developing astrocytoma, ATRT, medulloblastoma, mixed glioma, or PNET, particularly by 1 year.
EPID-10. THE INCIDENCE OF PRIMARY BRAIN TUMORS IN JAPAN IN 2016-2019
Authors: Narita Yoshitaka , Ohno Makoto
Published: November 2024

The national cancer registries in Japan have started since 2016 and the actual number of cancer patients in including primary central nervous system (CNS) tumors in Japan was revealed. Average number of primary CNS tumors in 2016-2019 was 29,492 and the crude incidence rate per 100,000 people (CIR) was 23.30. Malignant and benign CNS tumors was 6,696 (22.7%) and 22,796 (77.3%) and each CIR was 5.29 and 18.00, respectively. Among 29,492 tumors, 10,537 (35.7%) meningioma, 5,217 (17.7%) pituitary adenoma, 4,537 (15.4%) neuroepithelial tumor, 2,730 (9.3%) neurinoma and 1,166 (4.0%) primary CNS lymphoma (PCNSL) were reported. Regarding to malignant brain tumors, 2,071 glioblastoma, 362 astrocytoma grade II, 390 anaplastic astrocytoma grade III, 138 pilocytic astrocytoma,182 oligodendroglioma grade II, 154 anaplastic oligodendroglioma grade III, 140 ependymal tumors, 128 embryonal tumors including 91 medulloblastoma, 211 germ cell tumor (GCT) were found. CIR of neuroepithelial tumor, glioblastoma, PCNSL, embryonal tumors and GCT were 3.64, 1.68, 0.93, 0.10 and 0.17, respectively. According to the Central Brain Tumor Registry of the United States (CBTRUS) (2016-2020), CIR in the US was 26.73, and age-adjusted incidence rates of primary CNS tumors per 100,000 population in the US based on the US population in 2000 (AIR) was 24.83 and AIR in Japan was 17.15. AIR of glioblastoma in the US and Japan was 3.27 and 1.05, AIR of PCNSL was 0.44 and 0.51, AIR of embryonal tumors was 0.21 and 0.16, AIR of GCTs was 0.08 and 0.27, and AIR of meningioma was 9.73 and 5.11, respectively. This report demonstrated that the incidence of neuroepithelial tumors and embryonal tumors in Japan was approximately half to one-third, whereas that of GCTs in Japan was approximately 3 times comparing to the US.
EPID-12. NEIGHBORHOOD SOCIOECONOMIC STATUS PREDICTS SURVIVAL IN GLIOBLASTOMA: A SINGLE CENTER COHORT STUDY
Authors: Sun Yifei , Estevez-Ordonez Dagoberto , Atchley Travis , Markert James , Nabors Burt
Published: November 2024

BACKGROUND

Glioblastoma (GBM) is the most common primary brain malignancy. Despite recent progress in treatments, prognosis for patients remain poor. Recent literature has suggested the association of GBM outcomes and socioeconomic status. However, there is limited evidence regarding the association of neighborhood-level socioeconomic status on GBM outcomes.

OBJECTIVE

To investigate the impact of neighborhood-level socioeconomic status on GBM outcomes.

METHODS

We retrospectively reviewed all adult GBM patients at a single institution from 2008 to 2023. Patient addresses underwent geospatial analysis and Area Deprivation Index (ADI) was extracted. Univariable and multivariable survival analyses were performed. A Cox proportional hazards model was used to assess the effect of ADI and other socioeconomic variables while controlling for a priori selected clinical variables with known relevance to survival.

RESULTS

In total, 1492 patients met inclusion criteria. The average age at diagnosis was 62±14.2 years with a median overall survival of 12.1 [Interquartile Range (IQR) 5-22] months. The median ADI was 66 (IQR 46-84). Patients with high socioeconomic deprivation (ADI>75) were less likely to receive chemotherapy (92% vs 96%, p=.03), and had worse overall survival compared to patients with low socioeconomic deprivation (10 vs 13 months, p=.001). In the multivariable model, patients with high ADI had worse overall survival (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.16-1.73, p<.001). To account for changes in WHO guidelines, we implemented the model on patients diagnosed between 2017-2023 and findings were consistent (HR 1.34, 95%CI 1.07-1.68, p=.011).

CONCLUSIONS

We present the largest study reporting the effect of neighborhood-level socioeconomic status on overall survival of GBM patients. Neighborhood-level socioeconomic status provides the most accurate capture of the patient-level socioeconomic determinants of health. Patients with higher ADI have worse overall survival after controlling for other socioeconomic and clinical variables. These results suggest significant association between neighborhood-level socioeconomic status and overall survival in GBM patients.
EPID-13. PREDICTORS OF HISTOPATHOLOGIC RESULTS OF BRAIN BIOPSY IN PATIENTS SUSPECTED OF SECONDARY CNS LYMPHOMA
Authors: Basit Khan A , Suki Dima , Goethe Eric , Fernandez Luis , Patel Rajan , Westin Jason , Chi T Linda , Weinberg Jeffrey
Published: November 2024

Patients suspected of secondary CNS lymphoma (SCNSL) often undergo brain biopsies. Recent studies doubt biopsy utility due to high SCNSL diagnosis rates. We sought to enumerate histopathologic biopsy results in suspected SCNSL patients to evaluate utility of biopsy. We furthermore assess clinical and radiographic factors based on ability to distinguishing SCNSL from non-SCNSL. 109 patients with non-CNS lymphoma who subsequently presented with brain lesions that underwent biopsy at MD Anderson Cancer Center were included. Histopathologic diagnoses were obtained. Pre-operative imaging was assessed for contemporary radiologic diagnoses by obtaining the leading differential reported at the time of the study. Subsequently, a staff neuroradiologist, blinded to biopsy outcomes and clinical considerations, provided a retrospective diagnosis. 61 patients had SCNSL whereas 48 did not. Non-SCNSL biopsy results included infection (n=16, 33%), glioma (n=12, 25%), nonspecific (n=12, 25%), and other metastases (n=3, 6%). Patients with non-indolent lymphoma (DLBCL, mantle cell, Burkitt’s, and lymphoblastic lymphoma) were more likely to have SCNSL on biopsy (p<0.001, OR 12.55). Patients with SCNSL had shorter time interval since initial diagnosis (median 18.1mo vs. 63.2mo, p=0.008). Systemic progression of disease at biopsy was not associated with SCNSL (p=0.35). There was no difference in age, stage, LDH, Albumin, ECOG, IPI, anatomic location, or B-symptoms at times of diagnosis or neurosurgery. No patient had positive CSF cytology prior to biopsy. Neither retrospective nor contemporary radiographic diagnoses had sufficient accuracy to replace biopsy. A positive retrospective diagnosis trended towards association with SCNSL pathology (sensitivity=0.94, specificity=0.23, PPV=0.65, NPV=0.70, p=0.08). A positive contemporary diagnosis was associated with SCNSL pathology (sensitivity=0.67, specificity=0.73, PPV=0.76, NPV=0.64, p<0.001). Similar biopsy proportions yielded SCNSL and non-SCNSL. Although some factors are associated with SCNSL, none can reliably distinguish patients. Given the divergent treatments for the reported pathologies, our study reiterates the necessity of biopsy in suspected SCNSL.
EPID-18. PATTERNS OF CARE AND CLINICAL OUTCOMES OF PATIENTS WITH GLIOBLASTOMA FROM 2005-2020: A REAL-WORLD ANALYSIS
Authors: Jayram Diya , Bellur Shreyas , Ozair Ahmad , Ahmad Shahzaib , Hodgson Lydia , Frias Numa , Podder Vivek , Ganiyani Mohammad Arfat , Ahluwalia Manmeet
Published: November 2024

BACKGROUND

Survival for glioblastoma (GBM) remains low, with disparities affecting outcomes. Standard of care (SoC) includes surgery and adjuvant chemoradiation. This study explores demographics, treatment patterns, and outcomes of GBM patients in the United States.

METHODS

A retrospective study was conducted on patients with GBM in the National Cancer Database for GBM patients between 2005-2020 according to ESMO Guidance for Reporting Oncology Real-World (GROW). Trends were analyzed with descriptive statistics and X2-test between time periods: 2005-08, 2009-12, 2013-16, and 2017-20. Predictors of SoC receipt were analyzed with multivariate logistic regression. Median overall survival (mOS) estimated using Kaplan-Meier and Cox regression models. Adjustment made using demographic, socioeconomic, and clinical factors. Outcomes reported as (Odds Ratio [OR]/Hazard Ratio [HR] 95% Confidence Interval) per STROBE guidelines.

RESULTS

Of 104,697 GBM patients, 42.5% were female. 91.2% White, 5.7% Black, and 2.0% were Asian. 5.3% were Hispanic. Median age was 65 years (IQR:57-73). Percentage of patients ≥65 years increased from 48.8% in 2005-08 to 54.0% in 2017-20. 56.5% of patients received SoC. SoC usage increased over time: 2009-12 (OR:1.26, 1.21-1.31, P<0.001) vs 2013-16 (OR:1.36, 1.31-1.41, P<0.001) vs 2017-20 (OR:1.51, 1.45-1.57 P<0.001). Females (OR:0.91, 0.89-0.93 P<0.001), Black (OR:0.81, 0.77-0.86 P<0.001), and Hispanics (OR:0.92, 0.86-0.97, P=0.004) were less likely to receive SoC than males, White, and non-Hispanics. Privately insured were more likely to receive SoC than Medicare (OR:0.83, 0.80-0.87, P<0.001), Medicaid (OR:0.68, 0.64-0.71, P<0.001), and uninsured patients (OR:0.60, 0.55-0.64, P<0.001). SoC recipients had mOS of 14.6 months (14.5-14.8) vs 4.8 (4.7-4.9) for non-recipients (P<0.001). Compared to 2005-08, survival improved over time: 2017-20 (HR:0.83, 0.82-0.85, P<0.001) vs 2013-16 (HR:0.88, 0.86-0.89, P<0.001) vs 2009-12 (HR:0.93, 0.91-0.94, P<0.001).

CONCLUSIONS

Receipt of SoC has risen with significant increase in survival. However, female, Black, and Hispanic patients were less likely to receive SoC. Targeted efforts are warranted to mitigate disparities.
EPID-20. PRIMARY INTRAMEDULLARY PILOMYXOID ASTROCYTOMA OF SPINAL CORD (PIPASC): A SYSTEMATIC REVIEW OF CASE REPORTS AND CASE SERIES OF TWO DECADES
Authors: Qadri Haseeb Mehmood , Bashir Asif
Published: November 2024

BACKGROUND

Pilomyxoid Astrocytoma (PMA), new variant of pilocytic astrocytoma, is more aggressive and relatively rare, mostly seen in children and commonly found in brain. Primary intramedullary pilomyxoid astrocytoma of spinal cord (PIPASC) is extremely rare. The distinct aggressive and pathological behavior, poor prognosis and the diversity in response to various treatment modalities makes the PIPASC an oncologic enigma. We aim to evaluate the clinical manifestations, histopathologic spectrum and onco-surgical management of this neoplasm.

MATERIALS AND METHODS

After an extensive literature search using PubMed Central and Google Scholar, eight case reports and one case series of patients with spinal PA were retrieved and included using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines without applying any filter of time, study type or place. Case presentations of 12 patients were analyzed in this review.

RESULTS

Pediatric preponderance of the neoplasm (75%) with the mean age of 7.90 ± 4.51 years was noted. Sensory deficits and scoliotic deformity were the most common presenting symptom and sign in 83.33% and 33.33% of patients, respectively. Thoracic spine (50%) was most commonly affected region. MRI showed the most consistent findings of cord compression in 100% cases and the lesion appeared hypointense on T1- weighted images (T1WI) and hyperintense on T2-weighted images (33.33%). The average post treatment survival duration was found to be more than 2 years.

CONCLUSIONS

Occurrence of PIPASC among pediatric population is rare. They have possibility of extraneural metastasis, can differentiate into more malignant glioma and get recurrent due to which they require a long-term follow-up of the patients. Further studies are required to investigate the utility of chemotherapy and radiotherapy in its management.
EPID-21. PRIMARY INTRAMEDULLARY LYMPHOMA OF SPINAL CORD (PILSC): A SYSTEMATIC REVIEW OF CASE REPORTS AND CASE SERIES FROM 2000 TO 2023
Authors: Qadri Haseeb Mehmood , Bashir Asif
Published: November 2024

BACKGROUND AND OBJECTIVE

Primary CNS lymphoma accounts for three percent of all newly diagnosed CNS tumours and 1-3% of all non-Hodgkin’s lymphomas. The oncologic origin of primary intramedullary lymphoma of the spinal cord (PILSC) is an enigma. We aim to determine the clinical manifestations, disease course and management of PILSC.

MATERIALS AND METHODS

A comprehensive literature search using PubMed Central and Google Scholar, was done, retrieving 17 case reports and two case series of 21 patients with PILSC and included using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, published between 2000 and 2023.

RESULTS

About 90.48% patients inflicted with PILSC were adult, with male predominance, 61.90%. The most common complaint at presentation was neurological deficit of motor type in 32.14% patients. MRI proved to be helpful in 76.19% cases, with spinal cord enlargement and high signal intensity in 19.04% cases. Adjuvant chemotherapy and radiotherapy was acquired by 52.38% and 38.09% patients. Non-Hodgkin type was reported in 90.47% cases and Hodgkin lymphoma was seen in 9.52% patients. Diffuse large B cell lymphoma was culprit in 41.10% cases. Five out of 21 cases had variable post-operative complications. The average follow-up was 16.16 months.

CONCLUSION

PILSC is a multifaceted neoplasm in all its clinico-pathological aspects of presentation. Although rare, PILSC can involve adult and paediatric populations with a clear male preponderance. The MRI findings are not reliable to make a preliminary diagnosis. Like other lymphomas, the role of chemoradiotherapy is clearly more significant than surgical intervention in improving patient prognosis. Histopathologically, it can be Non-Hodgkin or Hodgkin, B-cell type or T-cell type and has a wide array of immunohistochemistry positivity.
EPID-23. HISTORY OF TYPE III IMMUNE HYPERSENSITIVITY IMPROVES SURVIVAL IN GLIOBLASTOMA
Authors: Neff Corey , Ballard Christine , Price Mackenzie , Liu Zhen , Cioffi Gino , Barnholtz-Sloan Jill , Walsh Kyle , Fecci Peter , Ostrom Quinn
Published: November 2024

Preexisting atopy, particularly allergic rhinitis, is consistently associated with decreased risk of glioma, and there is evidence that preexisting autoimmune conditions may also decrease risk. Glioblastoma is both locally and systemically immunosuppressive and, unlike many other forms of cancer, its initiation is not strongly linked with chronic inflammation. Therefore, history of immune hypersensitivity could be associated with improved anti-glioma immunosurveillance. We leveraged Surveillance, Epidemiology and End Results (SEER) data combined with Medicare claims to investigate the effect of preexisting immune hypersensitivities on overall survival of glioblastoma patients receiving resection, radiation, and temozolomide (standard of care, or SOC) from 2008-2019. Patients <66 years of age, enrolled in Medicare Advantage, not continuously enrolled in Medicare Part A/B, missing follow-up, reported by autopsy/death certificate only, or who did not receive surgery were excluded. Prior history of immune hypersensitivity (≥6 months prior to primary cancer diagnosis) was identified by ICD-9/ICD-10 codes. Treatment pattern was determined using ICD-9/ICD-10 and HCPCS/CPT codes. Conditions were classified into broad immune hypersensitivity types: type I (IgE-mediated, including atopy), type II (IgG- or IgM-mediated), type III (immune complex-mediated, including lupus and rheumatoid arthritis), and type IV (cell-mediated). Survival comparisons were made using Cox proportional hazard models adjusted for demographics, extent of resection, and Charlson comorbidity score (excluding immune conditions) to estimate hazard ratios, 95% confidence intervals, and p-values. Overall, 44% of 3,426 glioblastoma patients who received SOC had an immune hypersensitivity (type I: 33%, type II: 4%, type III: 8%, and type IV: 15%). These conditions were significantly more common in females (47% vs 41%, p<0.001). After adjustment, only type III immune sensitivity was associated with improved OS (HR=0.81, 95% CI:0.71-0.92, p=0.002). These results suggest that underlying immune-complex mediated hypersensitivity may improve treatment response and prognosis in glioblastoma, and that these pathways could potentially be exploited for therapy.
EPID-28. TRENDS IN LOW GRADE GLIOMA PROGNOSIS AND THE EVOLVING IMPACT OF GROSS TOTAL RESECTION ACROSS FIFTY YEARS: A MULTICOHORT ANALYSIS
Authors: Jin Michael , Young Jacob , Umbach Gray , Ravi Karthik , Lim Michael , Hervey-Jumper Shawn
Published: November 2024

OBJECTIVE

Significant advancements in neurosurgical planning, approach, and practice over the past five decades have improved the surgical management of diffuse low and high-grade gliomas. We sought to evaluate the extent to which LGG survival outcomes have evolved over the past fifty years using glioma registry datasets with histopathological groups defined by WHO diagnostic criteria and supplemented with next generation genome-sequencing.

METHODS

Three datasets (SEER, TCGA, and GENIE) were used to evaluate trends in prognosis following LGG diagnosis and resection between 1975 and present (GBM as a comparator cohort). The primary outcomes evaluated were longitudinal disease-specific survival and overall survival, with secondary fixed-timepoint outcomes evaluated at 12-months, 24-months, and 60-months. Subjects from SEER were categorized by histology, while subjects from TCGA and GENIE were included based IDH mutation status with available histopathology.

RESULTS

A total of 39,958 adult patients were included. Overall survival increased for both LGG and GBM between 1975 and 2010, however only LGG outcomes continued to improve following 2010 (2010-; HR=0.955, 95%CI 0.926 to 0.986). Evaluation of the interaction between resection extent and diagnosis year revealed a progressive increase in the survival benefit of GTR in recent years, particularly for LGG. Independent of other available clinical/molecular features and considering the interaction term between year of diagnosis and resection extent, the gap in independent prognostic benefit associated with GTR between LGG and GBM has significantly widened (2010-2020 vs 1990-2000, p<0.05).

CONCLUSION

Over the past three decades, consistent improvements in LGG outcomes were observed while prognosis following GBM diagnosis has remained largely unchanged following 2010. Notably, we observed increasing prognostic value of achieving GTR particularly in patients with LGG.
EPID-36. CLINICAL FEATURES OF 614 PRIMARY INTRACRANIAL GERM CELL TUMORS: AN 15-YEAR EXPERIENCE OF A SINGLE CENTER IN CHINA
Authors: Ge Jing-Jing , Li Cheng , Xue Feng-Jun , Qi Shao-Pei , Zhao Chi , Kong Chen-Chen , Zhao Chuan , Zhang Jun-Ping
Published: November 2024

Incidence of primary intracranial germ cell tumors (ICGCT) in Asian countries is higher than Western countries. This study aims to describe the characteristics of ICGCT patients in China. Data on all patients with ICGCT who were seen at the Department of Neuro-oncology, Sanbo Brain Hospital, Capital Medical University from 2007 to 2022 were collected retrospectively. Patient demographics, disease characteristics and treatment outcomes were analyzed. A total of 614 patients were identified, with 309 germinomas and 305 non-germinomatous germ cell tumors (NGGCT). The median age at diagnosis was 12.8 years. The male-female ratio is 2.4 to 1. The primary disease sites were mainly pineal gland and suprasellar region. Adults (age≥23) were more likely to develop germinomas (65.3%). 78% patients received radiotherapy after initial diagnosis. In M0 patients, whole brain radiotherapy was the most common approach, while in M+ was craniospinal radiotherapy. Whole ventricle radiotherapy was uncommon (4%). The most common chemotherapy regimen for germinoma was a combination of bleomycin, cisplatin and etoposide/tenipside; while for the NGGCT was ifosfamide combined with carboplatin/cisplatin and etoposide. For germinoma, the median recurrence-free survival (RFS) and overall survival (OS) were 150.3 months and 222 months; the 10 year RFS and OS were 58.2% and 85.1%, respectively. For NGGCT, the median RFS and OS were 80.4 months and 166.7 months; the 10 year RFS and OS were 46.9% and 60.5%. At relapse, four (0.65%) developed secondary malignancies. Seven (1.14%) developed extracranial dissemination. Chemotherapy and radiotherapy could improve the RFS and OS. Higher radiation dose was associated with better prognosis. The prognosis of focal radiotherapy alone was poor. M0 germinoma treated with focal radiotherapy alone were more likely relapse. This study suggested that treatment outcomes of our ICGCT patients are comparable with those in Western centers. Adjuvant chemotherapy and whole brain/craniospinal radiotherapy are pivotal treatment.
EPID-38. GLOBAL DISPARITIES AND PROJECTIONS IN PEDIATRIC BRAIN AND CNS CANCERS: A COMPREHENSIVE ANALYSIS THROUGH 2050
Authors: Sennani Sara , Erefai Ouassima , Hadrya Fatine , Soulaymani Abdelmajid , Mokhtari Abdelrhani , Hami Hinde
Published: November 2024

BACKGROUND

Brain and other central nervous system (CNS) cancers are the most prevalent solid tumors and the leading cause of death among children worldwide. This study investigates trends in the incidence, mortality, and global distribution of pediatric brain and other CNS cancers projected through 2050.

METHODS

Data on pediatric brain and other CNS cancer incidence and mortality were extracted from Globocan 2022 for children aged 0 to 14 years. Age-standardized incidence and mortality rates were calculated by continent, country, and Human Development Index (HDI) categories.

RESULTS

The Globocan dataset revealed 24,677 new cases and 12,249 deaths, corresponding to age-standardized incidence rates (ASIRs) of 1.3 and age-standardized mortality rates (ASMRs) of 0.62 per 100,000 population. Significant geographic disparities were observed: North America reported the highest incidence rate at 3.6, followed by Europe (2.2), Latin America (1.7), Oceania (1.4), Asia (1.3), and Africa (0.67). Europe recorded the highest mortality rate at 0.89, followed by Latin America (0.87), North America (0.70), Asia (0.66), and Africa (0.40). A country-specific analysis revealed that the highest incidence rates were in Montenegro (3.7), Estonia (3.4), and Austria (3.2), whereas the highest mortality rates were in Lithuania (2.1), Angola (2.0), and Honduras (1.7). Additionally, 37.82% of new cases and 40.71% of deaths occurred in high-HDI countries. Projections: The annual increase in incidence and mortality rates for brain and other CNS cancers is projected at 1.3% through 2050, with new cases expected to rise to 25,004 and deaths to 12,404.

CONCLUSIONS

The findings indicate a 23% decrease in brain and other CNS cancer cases in high-HDI countries by 2050, contrasted with a 45.3% increase in low-HDI countries. These disparities underscore the critical need for global health strategies that promote equitable healthcare access and advanced treatments to reduce the global burden of these cancers and address inequities in health outcomes.
DISP-02. SOCIOECONOMIC FACTORS INFLUENCE OVERALL SURVIVAL IN CHEMORADIATION-TREATED NEWLY DIAGNOSED WHO GRADE 4 GLIOBLASTOMA
Authors: Dada Abraham , Mehari Mulki , Kabir Aymen , Aabedi Alexander , Ore Cecilia Dalle , Hervey-Jumper Shawn
Published: November 2024

Social determinants of health are known to influence health outcomes, yet the interactive effects of patient-specific socioeconomic variables on overall survival remain poorly characterized in patients with glioblastoma (GBM). We aimed to assess socioeconomic factors associated with overall survival in a clinically homogenous GBM population. Patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, who underwent maximal safe resection of contrast-enhanced (CE) and non-contrast enhanced tissue (NC) tissue with adjuvant chemoradiation from 1997-2017 were selected for inclusion. Socioeconomic factors were collected through retrospective chart review. Variables associated with overall survival on univariate cox proportional hazards models (p<0.05) were selected for multivariate analysis. 272 patients (42.6% female, 14.3% minority) were included. On univariate logistic regression, older age (HR: 1.23, p<0.001), greater residual CE tissue (HR: 3.95, p<0.001), were associated with reduced survival. Greater extent of resection NCE tissue (HR 0.94, p=0.028), higher postoperative KPS (HR 0.89, p=0.034), and unemployment (HR: 0.67, p=0.022), were associated with longer overall survival. On multivariate analysis, age was associated with reduced survival (HR: 1.31, p<0.001), while unemployment (HR:0.69, p=0.049) was associated with longer overall survival. Subgroup multivariate analyses was performed dividing patients into those <65 (n=185, 45% female, 11.9% minority, 48% employed) and those ≥65 (n=87, 37% female, 14% minority, 20% employed). In the <65 cohort, protective factors included retirement (HR: 0.49 p=0.004), and unemployment (HR:.57, p=0.006). Older age (HR: 1.03, p=0.004), and greater residual CE tissue (HR: 1.16, p=0.03) continued to be associated with poorer survival. No variables correlated with outcomes in the ≥65 cohort. Active employment was associated with reduced survival in GBM patients treated with standard care, potentially serving as a proxy for access to subsequent treatment.