bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-29. THE PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF PARTIAL MGMT PROMOTER METHYLATION FOR IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Torre Matthew , Iorgulescu Bryan 
Published: November 2022

Abstract

BACKGROUND
Glioblastoma patients showing hypermethylation of the promoter of the O6-methylguanine-methyltransferase (MGMT) gene have significantly improved survival when treated with temozolomide compared to patients with hypomethylated MGMT promoters. However, the prognostic and predictive significance of partial MGMT promoter methylation is unclear.

METHODS
The National Cancer Database was queried for patients newly diagnosed in 2018 with histopathologically-confirmed IDH-wildtype glioblastoma. MGMT promoter methylation status was correlated with overall survival (OS) using multivariable Cox regression with Bonferroni correction for multiple testing (p&lt; 0.008 was significant).

RESULTS
3,663 patients were identified with newly diagnosed, histopathologically-confirmed IDH-wildtype glioblastoma and known MGMT promoter methylation. Of the 2,807 patients who received single agent chemotherapy (i.e. likely temozolomide), the MGMT promoter was unmethylated, partially methylated, hypermethylated, and methylated not otherwise specified (NOS) in 57.9%, 5.0%, 3.1%, and 34.0% of cases, respectively, with the later group likely consisting predominantly of hypermethylated cases. Multivariable analysis demonstrated that among patients receiving temozolomide, those with unmethylated MGMT promoters had significantly worse OS than patients with partially methylated MGMT promoters (hazard ratio (HR) 1.94; 95% confidence interval (CI), 1.54-2.44; p&lt; 0.001). However, the OS of hypermethylated patients (HR 1.02; 95% CI, 0.72-1.46; p=0.9) and methylated NOS patients (HR 0.99; 95% CI, 0.78-1.26; p=0.928) were not statistically different from the OS of partially methylated patients.

CONCLUSIONS
IDH-wildtype glioblastoma patients with partial methylation of the MGMT promoter treated with temozolomide have improved OS compared to their unmethylated counterparts, supporting the use of temozolomide therapy in these patients.
BIOM-35. A NEW PRECISION-MEDICINE APPROACH TO PREDICT TUMOR TREATMENT RESPONSE IDENTIFIES IN GLIOBLASTOMA A 17 GENE SIGNATURE PROGNOSTIC OF TMZ RESPONSE AND SURVIVAL WITH ROBUST PREDICTIVE VALUE
Authors: Morelli Mariangela , Stefano Anna Luisa Di , Picca Alberto , Lessi Francesca , Santonocito Orazio , Menicagli Michele , Pasqualetti Francesco , Franceschi Sara , Aretini Paolo , Sanson Marc , Mazzanti Chiara Maria 
Published: November 2022

Abstract
The Glioblastoma (GB) field has been experiencing a therapeutic standstill since 2005, primarily due to ineffective preclinical approaches to test anti-cancer treatments. Therefore, better treatment screening approaches are required. We developed a NADH FLIM-based functional precision medicine approach, that within one week after surgery identified two groups of TMZ Responder and Non-Responder tumors. A 17 gene molecular signature able to classify with 100% precision the TMZ responder and non-responder samples was discovered and identified by Kaplan Meier analysis, a Low-Risk and a High-Risk survival group, interrogating the TCGA GB database (Hazard Ratio = 1.87 p=0.00098,n=148) and TCGA LGG database (Hazard Ratio = 7.66 p=1.197e−35, n=660). Same results were obtained in the CCGA datasets. The 17 gene signature power for independently predicting prognosis (Hazard Ratio = 1.9, p=0.002) was then confirmed by direct RNAseq analysis of a separate clinically characterized cohort of 235 GB patients. Then, we combined the methylation status of the MGMT promoter to analyze the survival status of patients. The survival analysis based on the 17 gene risk signature and MGMT promoter methylation status demonstrated remarkable stratification of the clinical courses into four subgroups. Patients with MGMT promoter unmethylation and 17 gene High-Risk score had the worst prognosis, while patients with MGMT promoter methylation and 17 gene Low-Risk score had the best prognosis. In the latter group, a significant 24-month increase in survival was observed with 10% of 100 months Long Survivors with a difference of 35 months compared to the other groups. Our data indicate a new statistically strong RNAseq-based prognostic survival and TMZ response tool for patients with malignant glioma. The accuracy of this functional precision medicine approach allowed the development of a new prognostic gene signature that can improve the clinical management of GB patients. The approach could be implemented on other cancers as well.
BIOM-43. THE GENOMIC, TRANSCRIPTOMIC, AND EPIGENOMIC LANDSCAPE OF ISOCITRATE DEHYDROGENASE WILD TYPE GLIOBLASTOMA ACROSS THE AGE CONTINUUM
Authors: Johnson Margaret , Bell April , Shah Yajas , Viets-Layng Kayla , Mauer Elizabeth , Xiu Joanne , Elemento Olivier , Glantz Michael , Walker Phillip , Chen Clark , Dunbar Erin , Fonkem Ekokobe , Kesari Santosh , Brenner Andrew , Newton Herbert , Low Justin , Sumrall Ashley , Korn Wolfgang , Ashley David , Wainwright Derek 
Published: November 2022

Abstract

BACKGROUND
Older age is a poor prognostic factor for glioblastoma (GBM) patients. We tested whether the intrinsic molecular landscape of the tumor may contribute to this poor prognosis.

METHODS
In accordance with the 2021 WHO classification scheme, we included only isocitrate dehydrogenase (IDH) wild type GBM. Based on published literature, we defined older as age &gt; 65. RNA expression, gene amplification, tumor mutational burden (TMB) and mutational profiles were analyzed in three unique datasets: Tempus (n = 1,410), Caris (n = 1,432), and TCGA (n = 557). Comparison were made between &lt; 65 and ³ 65 year olds using Pearson’s Chi-squared tests, Fisher’s exact tests, or Wilcoxon rank-sum where appropriate.

RESULTS
From our evaluable gene sets, TERT promoter mutations were more prevalent in patients ³ 65 years old (Caris 82.64 vs 77.27%, p = 0.016; Tempus 58.0 vs 49.0%, p = 0.002). There were no significant differences in PDCD1, CD274, CD3E, TNFRSF18, CD40, CD8A, TNFRSF4, CTLA4, HAVCR2, TNFSF9, CD274, or CDKN2A; PDL-1 (by IHC); dMMR/MSI-H, TMB; CDK6 amplification, EGFR amplification, EGFR, EGFRvIII, EGFR fusions, MET fusions, PTEN, TP53, or NF-1. MGMT promoter methylation (Caris data) was more common in the older group (49.73 v 34.14%, p &lt; 0.001). TGCA data demonstrated that gene expression, TMB, and methylation did not change significantly with age. Additionally, PCOLCE2 and SLC10A4 were differentially methylated, and missense mutations, of any type, were more common in the older group (p=0.006).

CONCLUSION
Despite worse survival outcomes for older patients with IDHwt GBM as compared to younger counterparts, the molecular landscape is similar at the genomic, transcriptomic and epigenomic levels. The key exception is TERT promoter mutations that are more common in older GBM patients. Poorer survival is therefore not likely to be attributable solely to intratumoral factors.
BIOM-45. DETERMINANTS OF GBM VULNERABILITY TO INHIBITORS OF NEDD8 ACTIVATING ENZYME (NAE)
Authors: Tang Nanyun , Hao Yue , Berens Michael 
Published: November 2022

Abstract
Advancing new therapeutics to FDA approval for GBM is hampered by intra- and inter-tumoral heterogeneity. Design of clinical trials to enroll patients likely to respond to a new treatment seems critical to build the arsenal of agents against this disease. Neddylation is a protein modification pathway aligned to protein degradation and cytological localization within the ubiquitin/proteasome system. Components of the neddylation pathway are frequently overexpressed or hyperactivated in GBM, and whose upregulation has been associated with glioma progression and worse survival. Among glioblastoma cell lines and patient-derived stem cells, subsets were found to be selectively susceptible to NAE inhibitors. We previously showed that PTEN signaling, DNA replication, and chromatin instability pathways are the most significant differentiators between MLN4924 sensitive vs. non-sensitive models. To test a candidate molecular “signature of vulnerability”, two subsets of PDX models (PTEN wildtype and PTEN del or mutated) were treated with a panel of 3 NAE inhibitors. 5 GBM PTENwt models were shown vulnerable to MLN4924 and TAS4464 with average EC50 values 5-10 folds lower than 6 PTENmt/del models. CDC activity was greater against PTENwt, but only 2-fold different vs PTENmt/del. Transcriptomic data mining uncovered additional determinants of response to NAE inhibitors. To disclose the relationship between constitutive expression of three gene sets: DNA Replication Fork Progressing, Replication Fork Protection, and Replication Fork Protection Complex, we found that the genes involved in these are significantly under expressed in PTENmt models when comparing to PTENwt models. The molecular determinants of drug response to NAE inhibitors will be further verified in the extended preclinical models and lead to a patient-enrollment “signature of vulnerability” to increase the likelihood of demonstrating therapeutic efficacy in the early stage of clinical trials.
BIOM-63. IDENTIFICATION OF MIRNA IN CEREBROSPINAL FLUID AND PLASMA AS A BIOMARKER TO SUPPORT MRI EVALUATION AND MONITORING OF PEDIATRIC BRAIN TUMORS
Authors: Coyle Anne , Familiar Ariana , Zhao Chao , Rathi Komal , Hollawell Madison , Choudhari Namrata , Foster Jessica , Naqvi Ammar , Bagheri Sina , Anderson Hannah , Vidal Lorenna , Vossough Arastoo , Storm Philip B , Madsen Peter , Resnick Adam C , Nabavizadeh Ali , Koptyra Mateusz 
Published: November 2022

Abstract
MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors, however MRI measures are unable to fully relate to tumor biology and molecular stratification. Circulating in blood and cerebrospinal fluid (CSF), miRNAs are an abundant and stable nucleic acid which can be utilized as a tumor biomarker. Relating miRNA biomarkers and radiological tumor measurements may provide improved diagnostic and monitoring tools for pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close in proximity to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. We identified unique miRNA targets significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was identified to correlate with diagnosis and clinical features including tumor grade and survival status (p &lt; 0.05). In CSF, miRNA expression was correlated with MRI measurements including cystic core volume, non-enhancing tumor volume, leptomeningeal disease, tumor size and location (p &lt; 0.05). Combination of miRNA targets and radiomic tumor measurements improved diagnostic predictions between low- and high-grade tumors. In plasma, miRNA expression was correlated with MRI measurements including cystic core volume, location, and leptomeningeal disease (p &lt; 0.05). These results demonstrate utility of miRNAs as a pediatric brain tumor biomarker which combined with imaging features can improve minimally to non-invasive diagnostics and management of pediatric brain tumors.
BIOS-03. REAL WORLD CLINICAL OUTCOMES OF PATIENTS WITH DIFFUSE MIDLINE GLIOMA IN A LONGITUDINAL OUTCOMES REGISTRY
Authors: Stuhlmiller Timothy , Wasserman Asher , Quinn Jameson , Shapiro Mark , Kesari Santosh 
Published: November 2022

Abstract
We utilized the longitudinal clinical outcomes registry XCELSIOR (NCT03793088) to understand real world outcomes and treatment patterns among patients with diffuse midline glioma. A total of 74 patients were identified with a diagnosis of diffuse midline glioma by pathology or imaging (36 pediatric and 38 adult patients). Median age at diagnosis was 20 years. As of 6/1/2022, 45 patients had expired. Median overall survival (mOS) of the entire cohort was 16.2 months. Cox proportional hazard ratio analysis identified age as the only significant covariate for OS (pediatric HR = 1.59, p=0.04). Pediatric patients had a mOS of 12.9 months and adult patients a mOS of 18.9 months from diagnosis. Frequency of primary tumor location in this dataset was brainstem (35%), thalamus (23%), and pons (20%). Pons location was associated with worst survival (mOS 11.4 months, n=15 patients). The most common anti-cancer interventions among all patients were ONC201 (39 patients), temozolomide (37 patients), bevacizumab (23 patients), panobinostat (8 patients), and immune checkpoint inhibitors (3 patients each, pembrolizumab and nivolumab). In this dataset, no interventions were statistically significant in a Cox proportional hazard model, but both immune checkpoint inhibitors (HR = -1.24, p=0.11) and ONC201 (HR = -0.38, p=0.27) trended toward benefit in the entire population. The subpopulation of patients treated with ONC201 whose tumor also harbored a TP53 mutation displayed a tendency toward activity (n=8); TP53-mutant patients treated with ONC201 had a mOS of 25.0 months vs. TP53 wild-type patients treated with ONC201 had a mOS of 20.3 months. Annotation of data for additional patients is ongoing and updated analyses will be presented at the meeting.
CNSC-03. NEURONAL INTERMEDIATE FILAMENT (NIF) ANTIBODY POSITIVE PARANEOPLASTIC SYNDROME IN A PATIENT WITH METASTATIC NEUROENDOCRINE PANCREATIC CARCINOMA AND TREATMENT WITH IPILIMUMAB/NIVOLUMAB
Authors: Rodriguez Karla Mora , Peguero Edwin , Pina Yolanda , Strosberg Jonathan , Verma Neha , Mokhtari Sepideh 
Published: November 2022

Abstract
Immune checkpoint inhibitors, such as ipilimumab (CTL-4) and nivolumab (PD-1) have shown effectiveness in many types of neoplasia. This combination has been used as salvage immunotherapy for high grade metastatic pancreatic carcinoma. Nevertheless, severe neurologic immune-mediated adverse effects can result from the use of this treatment. We present a case of a 64-year-old woman with metastatic neuroendocrine pancreatic carcinoma with abrupt left facial and oculomotor cranial nerve palsy as well spastic tetraplegia after one dose of ipilimumab/nivolumab. She had a history of sudden onset diplopia, fever and ground-level fall a few hours after her initial dose of immunotherapy. Initial laboratory assessment showed pronounced lymphocyte predominant leukocytosis and mild chronic hyponatremia. In the following hours, she developed right mydriasis, right sided fast phase nystagmus and right central facial paralysis along with weakness and spasticity in four extremities. Neuroimaging of brain, orbits and CTL spine showed enhancement of intra-orbital and intracranial optic nerves as well chiasm, linear enhancement from C4-C7 and cauda equina, as well as abnormal signal along thoracic spinal cord and conus medullaris. Routine EEG demonstrated non-etiology specific encephalopathy. Lumbar puncture had normal opening pressure, mild pleocytosis, hyper-proteinorrhachia and normal glucose. Viral panel and cytology in the CSF were negative, and myeline basic protein was elevated. She was treated with high dose steroids which improved overall strength and CN palsies. Twenty days after initial presentation, she suddenly developed hypotension, tachypnea, and altered cognition. The patient and family opted for comfort measures only. She passed away that same day. Late report of CSF antibody panels showed positive cell-based assay for heavy and light chain NIF with a titer of 1:512. This case emphasizes the importance of recognition of anti-body mediated paraneoplastic syndromes in patients treated with immunotherapy, their appropriate treatment and prognosis.
CNSC-04. CEREBROSPINAL FLUID-DERIVED CIRCULATING TUMOR DNA IS SUPERIOR TO PLASMA IN NSCLC PATIENTS WITH CNS PROGRESSION
Authors: Yang Hainan , Wen Lei , Zhou Caicun 
Published: November 2022

Abstract

Introduction
Central nervous system (CNS) metastases are devastating neurologic complications. However, the clinical value of cerebrospinal fluid (CSF) as liquid biopsy medium in EGFR-mutated or ALK-rearranged patients with brain metastases (BM) or leptomeningeal metastases (LM) remains unclear.

Patients and Methods
We retrospectively analyzed the gene map of 14/48 NSCLC-BM patients and 34/48 NSCLC-LM patients. Compare the clinical predictive value of CSF and matched plasma (PLA) for patients with single CNS progression (cohort 1) or intracranial progression simultaneously with extracranial disease progression (cohort 2). Circulating cell-free tumor DNA (ctDNA) in CSF and matched PLA underwent next-generation sequencing targeting 168 cancer-relevant genes.

Results
For patients with single CNS progression, the mutation rate of major driver genes is much higher than the rate in matched PLA. Besides, CSF also demonstrated higher levels of potential prognostic markers in comparison with matched PLA samples, showing EGFR-amp presented more than two times the rate compared to matched PLA, and the detection rate of TBX3, PTEN were almost double the rate in CSF than paired PLA samples. In addition, poor outcomes associated with makers including CDKN2A/B, PIK3CA/G, CDK4/6, and MET showed exclusively in CSF samples.Almost all mutations identified in the PLA could detect in matched CSF samples in NSCLC-LM patients with both intracranial and extracranial disease progression. In addition, detection rates of driver mutations, consisting of EGFR or ALK are much higher in CSF compared to matched PLA, and these potential survival marker genes like CDK4/6, CDKN2A/B, EGFR-amp, MET, and PIK3CA identified uniquely in CSF samples.

Conclusion
CSF is more comprehensive in genomic mutation profile than matched PLA in NSCLC -LM regardless of single intracranial progression or intracranial progression simultaneously with extracranial evolution.
SURG-38. ASSESSING THE ROLE OF FRAILTY IN CRANIAL NEUROSURGERY FOR PRIMARY CNS NEOPLASMS IN THE GERIATRIC POPULATION: SEVEN YEAR RETROSPECTIVE ANALYSIS USING THE NATIONWIDE READMISSION DATABASE
Authors: Shahrestani Shane , Brown Nolan , Singh Rohin , Gendreau Julian 
Published: November 2022

Abstract
Frailty is a clinical state of increased vulnerability due to age-associated decline and has been well established as a perioperative risk factor. Yet, literature describing the effects of frailty on short- and long-term complications in geriatric patients is limited. In this study, the authors evaluate the effects of frailty in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. For this purpose, we conducted a retrospective cohort study between 2010 and 2017 by using the Nationwide Readmission Database. Demographics and frailty were queried at primary admission, and readmissions were analyzed at 30-, 90-, and 180-day intervals. Nearest-neighbor propensity score matching for demographics was implemented to identify nonfrail control patients with similar diagnoses and procedures. The analysis used Welch two-sample t-tests for continuous variables and chi-square test with odds ratios. A total of 6713 frail patients and 6629 nonfrail patients were identified at primary admission. At primary admission, frail geriatric patients undergoing cranial neurosurgery had increased odds of developing acute posthemorrhagic anemia (OR 1.56, 95% CI 1.23-1.98; p = 0.00020); acute infection (OR 3.16, 95% CI 1.70-6.36; p = 0.00022); acute kidney injury (OR 1.32, 95% CI 1.07-1.62; p = 0.0088); urinary tract infection prior to discharge (OR 1.97, 95% CI 1.71-2.29; p &lt; 0.0001); acute postoperative cerebral infarction (OR 1.57, 95% CI 1.17-2.11; p = 0.0026); and mortality (OR 1.64, 95% CI 1.22-2.24; p = 0.0012) compared to nonfrail geriatric patients receiving the same procedure. In addition, frail patients had a significantly increased inpatient length of stay (p &lt; 0.0001) and all-payer hospital cost (p &lt; 0.0001) compared to nonfrail patients at primary admission. Frailty may significantly increase the risks of short-term acute complications in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. Long-term analysis revealed no significant difference in complications between frail and nonfrail patients.
TMET-03. STEAROYL-COA DESATURASE INHIBITOR SUPPRESSES IDH MUTANT GLIOMA GROWTH VIA ENHANCING LIPOLYSIS
Authors: Yamasaki Tomohiro , Lita Adrian , Zhang Lumin , Dowdy Tyrone , Koizumi Shinichiro , Kurozumi Kazuhiko , Gilbert Mark , Larion Mioara 
Published: November 2022

Abstract

BACKGROUND
Mutant isocitrate dehydrogenase (IDH) produces 2-hydroxyglutarate (D2HG) and causes metabolic reprograming, but so far, little is known about the role of mutant IDH and D2HG in de novo lipogenesis and fatty acids synthesis. In this study, to develop a feasible drug for IDH mutant glioma, we targeted Stearoyl-CoA desaturase 1 (SCD1) catalyzing the biosynthesis of monosaturated fatty acids (MUFA) to suppress IDH mutant glioma progression. Materials and

METHODS
We prepared genetically engineered glioma cell lines (U251 wild type: U251WT and U251 IDHR132H mutant: U251RH), normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH) and patient derived cell lines. Lipid metabolic analysis was conducted by using LC-MS, and functional analysis for the role of SCD1 expression was investigated by RNA sequence and Western-blotting.

RESULTS
LC-MS analysis of extracted Endoplasmic Reticulum revealed that there was significantly higher amount of MUFA in IDH mutant than wild type. SCD1 expression was increased in IDH mutant compared to wild type due to D2HG-mediated upregulation of SCD1 in IDH mutant. Therefore, IDH mutant in which SCD1 expression level was higher than wild type indicated high sensitivity to SCD inhibitor, and apoptosis was highly induced in IDH mutant compared to wild type. RNA sequencing was performed in U251RH treated with SCD inhibitor compared to U251RH treated with DMSO, and lipid droplet metabolism-associated RNA expression was significantly changed in SCD inhibitor-treated U251RH. Based on the RNA sequence data, we checked lipid droplet in U251RH with presence or absence of SCD inhibitor, and lipolysis was induced by SCD inhibitor treatment, suggesting that SCD inhibition is associated with the apoptosis in IDH mutant via enhanced lipolysis mechanism.

CONCLUSIONS
D2HG produced in IDH mutant glioma directly induces SCD1 expression and enhances sensitivity to SCD inhibitor, which suggests that SCD inhibitor would be IDH mutant glioma-specific treatment strategy.