bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDDR-28. SPHINGOSINE AND N,N-DIMETHYLSPHINGOSINE MODULATE CHOLESTEROL HOMEOSTASIS IN IDH1MUT GLIOMAS, CAUSING PRO-APOPTOTIC MEMBRANE DEGRADATION
Authors: Dowdy Tyrone , Vilamu Helena Muley , Lita Adrian , Li Aiguo , Zhang Lumin , Gilbert Mark , Larion Mioara 
Published: November 2024

Abstract

BACKGROUND
Previous work in our team revealed a therapeutic potential for metabolic reprogramming along the sphingolipid pathway within IDH1mut gliomas. The dosing of various IDH1mut glioma subtypes with sphingosine and sphingosine kinase inhibitor (SphKi), N,N-dimethylsphingosine (NDMS) led to the enrichment of pro-apoptotic ceramides and sphingosines while suspending the proliferation of the IDH1mut neurospheres. However, the mechanism of drug action (MOA) was not well understood. We postulated that suppressing the production of S1P production with SphKi treatment combined with the global accumulation of sphingosine and certain ceramides triggers apoptotic membrane stress in highly susceptible IDH1mut gliomas.

METHODS
We cultured and treated IDH1mut (TS603, BT142 & NCH1681) and IDH1wt (GSC923) glioma cell lines with a combination of NDMS and C17-sphingosine. We used a comprehensive multi-omics approach involving LC-MS lipidomic, RNA sequencing, immunoblotting, flow cytometry, and fluorescent microscopy.

RESULTS
Following combination treatment, a global increase in sphingosines, ceramides, and their derivatives was accompanied by a decline in cholesterol levels. The transcriptomic expression was elevated for NR1H3, MYLIP, ABCA1, and ABCG1, which regulate the trafficking and biosynthesis of membrane-associated cholesterol. In contrast, total gene expression for catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis was negatively impacted. In addition, early onset changes included an elevation in the expression of ROCK (a marker for apoptotic membrane blebbing). Moreover, fluorescent microscopy revealed that sphingosine and cholesterol tend to become associated within the cellular membranes. This interaction then saturates the plasma membrane (PM), causing apparent vesiculation, permeation, and disruption of membrane integrity.

CONCLUSION
The MOA involved concomitant attenuation of cholesterol metabolism and influx in response to membrane saturation with sphingosine-associated cholesterol. As a result, PM stress was incurred, leading to PM disintegration in a blebbing fashion. Our study revealed how reprogramming sphingolipid metabolism increases the susceptibility of IDHmut gliomas to sphingosine-associated cholesterol-induced blebbing and resulting cell death.
DDDR-36. LOOKING AROUND THE CORNER: PREDICTING SYNERGY OR FUTILITY TO COMBINATION OF ARSENIC TRIOXIDE PLUS MNK1 INHIBITORS IN GLIOBLASTOMA
Authors: Shaffer Charles , Tang Nanyun , Hao Yue , Baker Angela , Berens Michael 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. The five-year survival rate of 6.8% highlights the challenges inherent to exceptionally heterogeneous tumors that grow behind the blood brain barrier. The protracted dearth in new agents approved for GBM begs innovative strategies by which to approach clinical trials. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. ATO has an idiopathic mechanism of action, but has shown beneficial effects in other solid tumors. Across six GBM PDX models a 10-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. This resistance has been previously shown to correlate with MNK1 expression. In order to sensitize PDX models innately resistant to ATO we utilized combination therapy with the MNK1 inhibitor AUM001 (AUM Biosciences, Singapore; NCT05462236). In high MNK1 expressing PDX models the combination of ATO + AUM001 induces cytotoxic synergy. Additionally, when narrowly measuring effects on the glioma stem cell population (ELDA), strong synergy was observed in models, including those failing to show such using bulk cell population viability assay. GSEA analysis revealed differential high enrichment in gene sets related to oxidative phosphorylation in the models failing to show synergy. Such criteria could act as exclusionary criteria (futility) for clinical trials by excluding such putative non-responder patients from the treatment population. Synergistic models showed enrichment in gene sets related to epithelial/mesenchymal transition, skeletal and sensory organ development, and regionalization. These signatures could serve to prioritize patient inclusion in clinical trials of ATO in combination with AUM001, enriching the fraction of responsive glioma patients. Such molecular signatures may bring precision medicine in early-stage clinical trials to advance promising new agents and combinations of agents to full FDA approval.
DDDR-38. TRANSLATIONAL STEPS OF THE ANTITUMOR PEPTIDE TAT-CX43266-283 AS A TREATMENT FOR GLIOBLASTOMA: EGFR AS A TREATMENT RESPONSE BIOMARKER AND RESULTS OF COMBINATION THERAPY IN A PRECLINICAL RESECTION MODEL
Authors: Álvarez-Vázquez Andrea , Volovetz Josephine , San-Segundo Laura , Cerveró-García Pilar , Flores-Hernández Raquel , Ollauri-Ibáñez Claudia , Segura-Collar Berta , Hubert Christopher G , Sánchez-Gómez Pilar , Pollard Steven M , Lathia Justin D , Tabernero Arantxa 
Published: November 2024

Abstract
Glioblastomas (GBM) are the most malignant primary brain tumors, and they remain incurable. Despite the current standard of care (surgical resection of the tumor and administration of chemotherapy and radiotherapy) some GBM stem cells (GSCs) remain in the brain parenchyma causing tumor recurrence. The Src-inhibitory peptide TAT-Cx43266-283 has shown promising antitumor results in GBM preclinical models, reducing GSC viability and increasing survival in GBM-bearing mice. Here we have investigated some of the main gaps to overcome when translating preclinical results to the clinic, to promote the progress of TAT-Cx43266-283 as a clinical therapy to fight GBM. First, we investigated biomarkers of treatment response to design a more targeted therapy. We assessed cell viability after treatment with TAT-Cx43266-283 in 13 patient-derived GSC lines and we found a stronger treatment response in those GSCs that had alterations in the Epidermal Growth Factor Receptor (EGFR). This was further confirmed in several murine GBM lines. Importantly, we found that treatment with TAT-Cx43266-283 was more effective in vitro than temozolomide or the classical EGFR inhibitor, erlotinib. Moreover, we showed that EGFR participates in TAT-Cx43266-283 response together with Src, by decreasing EGFR and EGFRvIII activity in some GSCs and increasing survival in mice bearing tumors with EGFR alterations. Next, we studied the effect of TAT-Cx43266-283 in a clinical context by administering it in a murine model of tumor resection. We analyzed the histopathology of this GBM model, uncovering histological features typical of human GBM. We found that resection alone improved, although not significantly, GBM-bearing mice survival. However, tumors that regrew after resection exhibited more aggressive features. Importantly, the combination of tumor resection and TAT-Cx43266-283 achieved better survival outcomes and showed reduced invasive features. Altogether, these results serve as a base for future clinical investigations and support the therapeutic potential of TAT-Cx43266-283 as a treatment for GBM.
DDDR-42. LEVERAGING GENOME-WIDE CRISPR/CAS9 KNOCKOUT DRUG SCREENS TO IDENTIFY SENSITIZERS FOR PROTEOSOME INHIBITORS IN GLIOBLASTOMA
Authors: Anand Alisha , Shaikh Muhammad Vaseem , Chokshi Chirayu , Brakel Benjamin , Maich Will , Grewal Shan , Venugopal Chitra , Singh Sheila 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis despite aggressive treatment. Patient outcomes remain abysmal with 95% of patients relapsing and a median overall survival of 15 months. This necessitates the rapid search for personalized therapeutics and agents to enhance current treatments. One pathway that demonstrates dysregulated functioning is the ubiquitin-proteasome pathway (UPP). Literature has shown that UPP dependent proteolysis remains constitutively upregulated in cancer cells leading to the rapid degradation of proteins that regulate oncogenic pathways. Despite robust preclinical evaluations for the usage of proteasome inhibitors against GBM, most proteasome inhibitors failed in clinical trials, indicating resistance. We conducted an unbiased genome wide CRISPR-Cas9 screen in HAP1 cells treated with the proteasome inhibitor, Bortezomib (BTZ), to identify genes leading to a BTZ-resistant phenotype. We identified several genes that when perturbed, sensitized cells to BTZ including N-glycanase-1 (NGLY-1), Nuclear factor Erythroid 2-Like-1 (NFE2L1), and DNA damage inducible 1 homolog 2 (DDI2). Herein, we sought to evaluate the effects of perturbing these identified genes in our patient derived GBM cell lines by utilizing CRISPR/Cas9 knockout technology in vitro and in vivo. The generation of NGLY-1, DDI2, and NFE2L1 KO cell lines demonstrated functional sensitivity to the proteasome inhibitor Marizomib (MZB) as observed through a significant reduction of the IC50 in the KO cell lines compared to an adeno-associated virus integration site 1 (AAVS1) control. Functional evaluation also demonstrated reduced proliferation capacity and sphere formation in our KO GBM lines. Ongoing in vivo work will aim to evaluate the mitigation of this resistant pathway in our NSG mouse models orthotopically transplanted with our patient derived KO cell lines. In an ongoing collaborative effort, we aim to functionally assess a novel small molecule NGLY-1 inhibitor for preclinical sensitivity to MZB in our in vitro and in vivo models.
EPID-15. INPATIENT CARE COSTS AND ASSOCIATED REIMBURSEMENTS FOR PATIENTS WITH LEPTOMENINGEAL DISEASE: A REAL-WORLD ANALYSIS
Authors: Ozair Ahmad , Mansouri Alireza , Grossman Stuart 
Published: November 2024

Abstract

INTRODUCTION
Leptomeningeal disease (LMD) is an increasingly significant cause of cancer-related morbidity, mortality, and economic burden. While healthcare costs associated with brain metastases (BMs) have been well-described, minimal economic literature exists for LMD. This study sought to evaluate inpatient care costs (IPCCs) and reimbursements for LMD patients using a contemporary US claims database.

METHODS
This retrospective study, reported following STROBE guidelines, included adult LMD patients (aged 18-65 years) receiving inpatient care during January 2016 to December 2021 in TruvenHealth MarketScan Commercial Claims and Encounters Database, currently the largest US commercial insurance database. Patient selection using ICD-10 codes, data management, and statistical analyses were performed in Stata/SE18.0. Demographic, clinical, and financial attributes were summarized through descriptive statistics. IPCC measures were adjusted using 2023 Consumer Price Index Medical Care component. Primary study outcome was adjusted gross total payments (total IPCC). Given skewness in IPCC, log-transformation was carried out, followed by multivariable linear regression using socio-demographic, clinical and insurance-related characteristics to identify significant covariates.

RESULTS
A total of 1047 inpatient admissions across 1010 LMD patients were included. 43.8% (N=442) had brain metastases (BM) concomitantly present while 56.2% (N=568) did not. Primary tumor associated with LMD comprised of: lung and/or lower respiratory tract cancer (18%), breast cancer (6.6%), and melanoma (6.1%). 54.8% (N=554) did not have any bone metastases and 78.6% (N=794) did not have any liver metastases. Per inpatient admission, median adjusted values of gross total payments were $32603.6 (IQR $19967-64960) and gross payments to principal physician $1119.26 (IQR $532.41-2919.78), being 3.4% of total payments. Covariates associated with significantly higher total IPCC included age, male sex, length -of-stay, whole brain radiotherapy, and admission year, while cancer from lung and melanoma, medical and psychiatric admission (versus surgical), and drug claims capture were associated with significantly lower IPCC.

CONCLUSIONS
Contemporary IPCCs for LMD patients in US are substantial but driven minimally by payments to principal physician for services rendered.
EPID-27. THE INCIDENCE OF BRAIN METASTASIS IN GASTROINTESTINAL CANCER ACCORDING TO PRIMARY SITE AND STAGE: A 15-YEAR SINGLE INSTITUTIONAL ANALYSIS
Authors: Barcelona Marc Vincent , Kataki Kaushik Jagannath , Rahman Fadwa Abdel , Schultz David , Millar Barbara-Ann , Conrad Tatiana , Taremi Mojgan , Kongkham Paul , Elimova Elena , Deng Yangqing , Yan Michael Ming 
Published: November 2024

Abstract
Gastrointestinal (GI) cancers are a diverse group of cancers including pancreatic, gastric/gastroesophageal junction/esophageal (G/GEJ/E), colorectal (CRC), hepatocellular (HCC), biliary tract (BT), and anal origin cancers. The risk of developing brain metastasis (BrM) is not well characterized. The aim was to determine the incidence of BrM among all GI cancer patients at Princess Margaret Hospital (PM). We included patients diagnosed with GI cancer presenting from 2005-2020, captured prospectively in our institutional registry. These patients were cross-referenced with our radiotherapy database, where radiotherapy for brain metastases (BrM) was used as a proxy for the brain metastases development. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk. Overall survival (OS) was estimated using the Kaplan Meier method. The registry accounted for 22,188 patients. The median age of the cohort was 64. Most common primary sites are CRC adenocarcinoma, pancreatic adenocarcinoma, G/GEJ/E adenocarcinoma were 31.52%/11.71%/10.25%. The 15-year CI for BrM for the entire cohort was 1.65%, and for CRC, small bowel, anal, pancreatic, G/GEJ/E, HCC, and BT cancers were 2.69%/2.49%/1.30%/0.5%/3.52%/ 0.05% /0.4% (p &lt; 0.001) and Stage I-IV disease were 0.39%/0.81%/1.2%/3.1%, respectively (p &lt; 0.001). 5 year CI for HER2 positive G/GEJ/E patients was 19.5%. Median OS from initial presentation for those with BrM was 25.13 months. On univariable analysis, chemotherapy receipt [HR 1.916, p &lt; 0.001], Stage IV at presentation [HR 3.991, p &lt; 0.001], and G/GEJ/E primary [HR 1.357, p &lt; 0.001] predicted for higher risk of BrM. Multivariable analysis confirmed that receipt of chemotherapy and Stage IV disease predicted a higher risk for BrM and pancreatic, HCC, and BT cancers predicted for lower BrM. We observed that among patients diagnosed with GI cancers, Stage IV disease predicted higher risk for developing BrM and were more likely to receive chemotherapy.
EPID-29. EPIDEMIOLOGICAL CHARACTERIZATION OF BRAIN METASTASES IN MELANOMA: A LARGE POPULATION BASED-STUDY FROM 2014-2024
Authors: Kalluri Anita , Kramer Patrick , Parker Megan , Jiang Kelly , Materi Joshua , Azad Tej , Kamson David , Redmond Kristin , Warrier Govind , Lipson Evan , Ye Xiaobu , Bettegowda Chetan , Rincon-Torroella Jordina 
Published: November 2024

Abstract
Brain metastases (BM) are the second most common cause of mortality in metastatic melanoma. Despite increased screening, mortality remains substantial. Additionally, population-based studies of melanoma BM capture only synchronous metastases, therefore up-to-date epidemiological and survival studies may better inform screening and management strategies. Thus, we retrospectively analyzed the TrinetX Oncology dataset to study the prevalence and survival patterns of patients with melanoma BM. Data from 13,505 patients with histologically-confirmed melanoma was extracted. Demographic and clinical parameters were compared between patients with and without BM via t-test and chi-squared analysis. Overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses after cohorts were propensity-matched for age, sex, race, ethnicity, stage, extracranial metastases, excision of skin lesions, radiation, and antineoplastic utilization. In our study, the prevalence of BM was 7.3% (9.2% precocious, 22.5% synchronous, 68.3% metachronous). Compared to patients without BM, patients who developed BM were more often male (p&lt;0.0001), non-Hispanic (p&lt;0.0001), White (p&lt;0.02), and presented with advanced-stage disease (p&lt;0.0001). Patients with unspecified malignant melanoma (p&lt;0.0001) and nodular melanoma (p&lt;0.0001) were more likely to develop BM compared to those with other histological subtypes. Additionally, patients with BM were more likely to have ulceration (p&lt;0.0001) and extracranial metastases (p&lt;0.0001). Skin excision procedures were less common in patients with BM (p&lt;0.0001), whereas radiotherapy and antineoplastics were more common. When assessed from melanoma diagnosis, patients who developed BM any time along their disease course had reduced OS (HR(95% CI): 2.265(1.934-2.653)). When assessed from metastatic onset, patients with BM had reduced OS compared to those with only extracranial metastases (HR (95% CI): 2.197(1.883-2.563)). Synchronous BM were associated with decreased OS compared to metachronous BM when assessed from melanoma onset (HR(95% CI): 0.6(0.442-0.815)), but there was no survival difference after BM development. In conclusion, BMs decrease OS in melanoma. Our findings may inform screening and management of patients at risk for melanoma BM.
EPID-34. THE EFFECT OF ANTIDEPRESSANT THERAPY ON GLIOBLASTOMA SURVIVAL: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Sun Yifei , Hamo Mohammad , Hagan Emma O’ , Atchley Travis , Estevez-Ordonez Dagoberto 
Published: November 2024

Abstract

BACKGROUND
Symptoms of depression are highly prevalent among patients with glioblastoma (GBM) and have been associated with poor outcomes. In addition to managing depression symptoms, preclinical and clinical studies suggest that antidepressants may inhibit GBM progression and may be associated with improved outcomes. However, the effect of antidepressants on survival is unknown and results from existing studies are conflicting.

OBJECTIVE
We conducted a systematic review and meta-analysis to investigate the effect of antidepressant therapy on GBM survival.

METHODS
We searched PubMed, Embase, Scopus, PsycINFO, and Web of Science from inception to March 2024 for studies assessing the overall survival of patients with GBM treated with antidepressants. Prespecified Hazard ratios (HR), 95% confidence interval (CIs), median overall survival, and patient characteristics were extracted. Results were combined using a restricted maximum-likelihood estimation random-effects model.

RESULTS
We identified 6 observational studies meeting inclusion criteria with 8269 patients. Of these, 1093 (13%) were treated with antidepressant therapy at some point after their GBM diagnosis. Antidepressant therapy was not significantly associated with overall survival (HR 1.27, 95% CI 0.90-1.79, p=0.17). In a sub-analysis of studies that specified whether SSRIs were utilized, SSRI usage specifically was also not associated with overall survival (HR 1.08, 95% CI 0.58-2.03, p=0.81) We observed considerable heterogeneity (I2 = 92.7%, p&lt;.001).

CONCLUSIONS
Antidepressants were not significantly associated with overall survival in patients with GBM. However, our meta-analysis was limited by significant heterogeneity observed across studies. The effect of antidepressants on outcomes in patients with GBM remains uncertain. We observed conflicting results in the literature, with some studies suggesting decreased survival. Therefore, the role of antidepressants in patients with GBM warrants further investigation.
DISP-06. THE IMPACT OF SOCIAL DETERMINANTS OF HEALTH ON TREATMENT DELAYS FOR GLIOBLASTOMA
Authors: Cioffi Gino , Gratzl Samuel , Dmukauskas Mantas , Waite Kristin , Sloan Andrew , Mammoser Aaron , Stucky Nicholas , Barnholtz-Sloan Jill 
Published: November 2024

Abstract
Social determinants of health (SDOH) contribute to treatment delays for a variety of diseases. However, the impact of SDOH on delays in treatment for glioblastoma (GBM) is not well established. Utilizing the Truveta database, which includes electronic health records, claims, linked SDOH data, and medication dispense data for a collective of US health systems, we evaluated individuals diagnosed with GBM from 1/1/2018-5/16/2024 who received either surgery, radiation, or temozolomide. Univariable and multivariable logistic regression modeling was performed to assess the odds of experiencing a delay in surgery (&gt;7 days after diagnosis), radiation (&gt;30 days after diagnosis), or temozolomide (&gt;30 days after diagnosis). Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) are reported. Models were assessed for demographic (sex, age, race) and SDOH factors (education, income, social support, transportation, housing stability). At the univariable level, college attendance and single-member household were associated with delays in surgery but were not significant in the multivariable model. Individuals diagnosed with GBM at ages of 45-64 and 65+ were less likely to experience delays in surgery than individuals ages 18-44 (45-64 aOR (95%CI): 0.58(0.38-0.89), 65+ aOR (95%CI): 0.42(0.25-0.71)). Additionally, individuals with an estimated yearly income of $60,001-$120,000 were 61% more likely to experience delays in surgery compared to individuals with an estimated income of &lt;$40,000 (aOR (95%CI): 1.61(1.16-2.24)). In univariable analyses, male sex, age at diagnosis of 18-44, college attendance, and an estimated income &gt;$120,000 were associated with delays in radiation. However, no significant factors were associated with delays in radiation after adjustment. Individuals ages 45-64 and 65+ were less likely to encounter delays in temozolomide than individuals ages 18-44 (45-64 aOR (95%CI): 0.64(0.46-0.88), 65+ aOR (95%CI): 0.62(0.43-0.91)). Understanding how SDOH impact treatment patterns provides vital insight on diverse factors that impact patient care.