bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction
Authors: Strong SI
Published: December 2020

This chapter provides an introduction to a new, multi-faceted empirical study on legal reasoning in commercial disputes by describing existing scholarship on legal reasoning as well as best practices in empirical legal studies.. In so doing, the discussion not only provides novel insights into general practices involving legal reasoning but also lays the foundation for further analysis by considering standard assumptions about differences in reasoning arising along the judicial–arbitral, domestic–international, and common law–civil law divides. These assumptions are tested throughout the book to determine whether and to what extent legal reasoning differs according to the nature of the decision-maker, the scope of the dispute or the legal tradition in which the matter is set.
Conclusion
Authors: Strong SI
Published: December 2020

This chapter concludes the analysis by putting the new empirical research discussed earlier in the book into a larger practical and scholarly context. The chapter begins by considering how the empirical data measures up to theoretical studies in this area of law, pulling together select elements from the three research strands (i.e. the international survey, semi-structured interviews, and coding exercise) and focusing on particular issues of interest across the three major areas of comparison (i.e. the judicial–arbitral, domestic–international, and common law–civil law divides). While this summation is not intended to be comprehensive, it nevertheless provides a high-level overview of general research outcomes. Next, the chapter discusses certain unanticipated data that was generated during the course of the study and seeks to situate that information within the academic understanding of legal reasoning. Finally, the focus turns to the various ways that studies in legal reasoning might develop in the future as a result of the research reflected herein.
The shift from pulmonary colonization to Pneumocystis pneumonia
Authors: Le Gal Solène , Bonnet Pierre , Huguenin Antoine , Chapelle Célia , Boulic Pierrick , Tonnelier Jean-Marie , Moal Marie-Christine , Gut-Gobert Christophe , Barnier Aude , Nevez Gilles
Published: December 2020

Pulmonary specimen pairs from five patients who presented with pulmonary colonization and later developed Pneumocystis Pneumonia (PcP) were retrospectively examined for P. jirovecii genotyping. A match of genotypes in pulmonary specimen pairs of three patients was observed, whereas a partial match and a mismatch were observed in the fourth and fifth patients, respectively. The genotyping results suggest that the colonization state can differ from PcP but can also represent the incubation period of PcP. Clinicians should not systematically rule out the treatment of putative colonized patients and should at least discuss the initiation of prophylaxis on a case-by-case basis.
Planet Hunters TESS II: findings from the first two years of TESS
Authors: Eisner N L , Barragán O , Lintott C , Aigrain S , Nicholson B , Boyajian T S , Howell S , Johnston C , Lakeland B , Miller G , McMaster A , Parviainen H , Safron E J , Schwamb M E , Trouille L , Vaughan S , Zicher N , Allen C , Allen S , Bouslog M , Johnson C , Simon M N , Wolfenbarger Z , Baeten E M L , Bundy D M , Hoffman T
Published: December 2020

We present the results from the first two years of the Planet Hunters TESS (PHT) citizen science project, which identifies planet candidates in the TESS (Transiting Exoplanet Survey Satellite) data by engaging members of the general public. Over 22 000 citizen scientists from around the world visually inspected the first 26 sectors of TESS data in order to help identify transit-like signals. We use a clustering algorithm to combine these classifications into a ranked list of events for each sector, the top 500 of which are then visually vetted by the science team. We assess the detection efficiency of this methodology by comparing our results to the list of TESS Objects of Interest (TOIs) and show that we recover 85 per cent of the TOIs with radii greater than 4 R⊕ and 51 per cent of those with radii between 3 and 4 R⊕. Additionally, we present our 90 most promising planet candidates that had not previously been identified by other teams, 73 of which exhibit only a single-transit event in the TESS light curve, and outline our efforts to follow these candidates up using ground-based observatories. Finally, we present noteworthy stellar systems that were identified through the Planet Hunters TESS project.
Tracing the Genetic Legacy of the Tibetan Empire in the Balti
Authors: Yang Xing-Yan , Rakha Allah , Chen Wei , Hou Juzhi , Qi Xue-Bin , Shen Quan-Kuan , Dai Shan-Shan , Sulaiman Xierzhatijiang , Abdulloevich Najmudinov Tojiddin , Afanasevna Manilova Elena , Ibrohimovich Khudoidodov Behruz , Chen Xi , Yang Wei-Kang , Adnan Atif , Zhao Ruo-Han , Yao Yong-Gang , Su Bing , Peng Min-Sheng , Zhang Ya-Ping
Published: December 2020

The rise and expansion of Tibetan Empire in the 7th to 9th centuries AD affected the course of history across East Eurasia, but the genetic impact of Tibetans on surrounding populations remains undefined. We sequenced 60 genomes for four populations from Pakistan and Tajikistan to explore their demographic history. We showed that the genomes of Balti people from Baltistan comprised 22.6–26% Tibetan ancestry. We inferred a single admixture event and dated it to about 39–21 generations ago, a period that postdated the conquest of Baltistan by the ancient Tibetan Empire. The analyses of mitochondrial DNA, Y, and X chromosome data indicated that both ancient Tibetan males and females were involved in the male-biased dispersal. Given the fact that the Balti people adopted Tibetan language and culture in history, our study suggested the impact of Tibetan Empire on Baltistan involved dominant cultural and minor demic diffusion.
BIOM-09. MULTIPLEX ANALYSIS OF CSF EXTRACELLULAR VESICLES OF INTRASPINAL TUMORS
Authors: Ricklefs Franz , Stevic Ines , Mende Christian , Welsh Joshua , Jones Jennifer , Westphal Manfred , Lamszus Katrin , Eicker Sven
Published: December 2020

BACKGROUND: Extracellular vesicles (EVs) play an important role in cell-cell communication in different types of tumors, carrying multiple layers of biological functional molecules, including proteins, RNA, DNA and lipids. We previously demonstrated that extracellular vesicles (EV) from central nervous system tumors reflect the molecular subtype of the original tumor and mediate an exchange of pro-oncogenic signals. Their implication as biomarkers in tumor disease is under current investigation. It is unclear, however, to what extent cerebrospinal fluid (CSF) EVs from intraspinal tumors are utilizable for diagnostical purposes and how their marker profiles overlap with EVs derived from non tumorous EVs. We analyzed CSF EVs of intraspinal tumors to define CSF EV profiles that allow tumor subtype classification. METHODS: EVs were isolated from CSF of patients suffering from intraspinal meningioma (n=5), ependymoma (n=7) and neurinoma (n=5). Patients suffering from normal pressure hydrocephalus were used as controls (n=5). EVs were analyzed by multiplex bead based assay, immunoblotting, electron microscopy and NTA. RESULTS: CSF EVs were 97.21 ± 3.37nm (intraspinal tumor patients) and 101.6 ± 3.68nm (controls) in sizes and showed vesicular structures by electron microscopy. Particle number were not significantly different between both groups (p = 0.103). Using our 37 protein mutliplex EV profiling kit we found 29 proteins to be expressed in a sufficient manner on CSF EVs. CSF EVs of intraspinal meningioma showed elevated CD62P, HLA-DR, CD40, CD42a and CD45 expression levels, while ependymoma showed decreased levels of CD9, CD63, CD81, whereas neurinomas had elevated levels of SSEA-3 and CD25. CONCLUSION: This is the first comprehensive analysis of CSF EV of intraspinal tumor patients. CSF EV display distinct subpopulations that may allow tumor classification and long-term surveillance. However as tumor-specific EVs may be rare, there is still the need to identify markers that can enrich tumor-specific EVs for molecular profiling.
BIOM-11. ENZYMATIC ASSAY USED TO MONITOR CHANGES IN ONCO-METABOLITE, D2HG, IN RESPONSE TO THERAPY
Authors: Saber Rehan , Rahman Masum , Olson Ian E , Rajani Karishma , Burns Terry C
Published: December 2020

INTRODUCTION

Gliomas are the most common and deadly adult brain cancers with a median survival time of less than 18 months. Many therapeutics have failed translating into effective therapies due to incomplete understanding of the disease and heterogeneity of tumors between patients. There is a need for methods that allow for continual access and analysis of glioma biomarkers. We sought to establish a reliable method for quantifying the onco-metabolite, D2HG. After optimizing this method, we used microdialysate and microperfusate to test our hypothesis that analysis of D2HG in response to therapy can indicate therapeutic efficacy sooner than current methods permit.

METHODS

Microdialysate and microperfusate were collected from the tumor centers and lateral ventricles of athymic nude mice implanted with IDH1 mutant PDX line GBM196. We performed microdialysis and microperfusion on consecutive days to determine baseline D2HG concentration. Following a five day period of TMZ treatment, we collected another round of microdialysis and microperfusion one week after treatment and again two weeks after treatment. We then used our optimized D2HG enzymatic assay to quantify the changes in D2HG in response to therapy.

RESULTS

Using our enzymatic D2HG assay, we were able to quantify D2HG as low as 30nM (30fmol/uL). We found a ~20% decrease in D2HG concentration in the tumor center and right lateral ventricle after 1 week of TMZ treatment (n=2), and ~36% decrease after 2 weeks of TMZ treatment (n=2).

CONCLUSION

Using a D2HG quantification assay to monitor changes in concentration of D2HG in microdialysate/microperfusate can predict sensitivity to therapy.
BIOM-13. DNA METHYLATION MARKS GLUCOCORTICOID PATHWAY RESPONSE IN DEXAMETHASONE-TREATED BRAIN TUMOR PATIENTS
Authors: Wiencke John , Molinaro Annette , Warrier Gayathri , Rice Terri , Clarke Jennifer , Taylor Jennie , Wrensch Margaret , Tamaki Stanley , Lee JiYoon , Hansen Helen , McCoy Lucie , Bracci Paige , Salas Lucas , Koestler Devin , Christensen Brock , Kelsey Karl
Published: December 2020

Dexamethasone (DEX) is routinely prescribed in brain tumor patients to limit vasogenic edema but may also exacerbate immunosuppression and adversely affect survival. The wide spectrum of dosing and individual variation in glucocorticoid (GC) response makes it difficult to assess the impact of DEX exposures. A potential marker of steroid pathway activation and GC load affecting the immune system are induced changes in chromatin structure marked by DNA methylation. We identified DEX-responsive DNA methylation sites in blood leukocytes from glioma patients treated with the drug at various doses and times during the course of their disease. Using weighted co-methylation network analysis, we show that DEX-induced hypomethylation includes well-known regulators of GC receptor (GR) sensitivity (e.g., FK506 binding protein 51: FKBP5) and inflammation (e.g., myeloperoxidase: MPO) and is enriched at genomic locations containing glucocorticoid receptor (GR) binding sites. Elastic net regression modeling was used to train a multilocus GC methylation index (GCMI) that discriminates current DEX users and non-users. GCMI scores showed wide interindividual variation among cases and DEX naïve control subjects. Using independent samples of DEX naïve and exposed glioma patients we show that the GCMI is a sensitive and specific indicator of DEX exposure. GCMI measured in non-glioma controls indicated sensitivity to non-DEX steroid treatments (e.g. prednisolone, fluticasone). Subjects with elevated neutrophil and decreased lymphocyte counts demonstrated high GCMI scores, reflecting the clinically relevant in vivo impact of this marker. Among 195 IDH wildtype and hTERT non-mutant glioma subjects, the GCMI was associated with a HR of 1.11 (95% CI 1.06–1.17) p< 0.0001 in Cox survival models that included age and tumor grade. We conclude that epigenetic remodeling in the peripheral immune compartment in response to DEX exposures is a rich source of potentially powerful markers of individual response to GC pathway activation and associated alterations in the immune response.
BIOM-18. TUMOR LOCATION IS ASSOCIATED WITH CDKN2A STATUS IN IDH-MUTANT ASTROCYTOMAS
Authors: Graber Jerome , Cimino Patrick
Published: December 2020

BACKGROUND

Astrocytomas with isocitrate dehydrogenase (IDH) mutations have a better prognosis and response to therapy than matching tumors without IDH mutations. IDH-mutant tumors of any grade or histology that carry homozygous deletions in cyclin-dependent kinase inhibitor (CDKN2A) have a worse prognosis compared to tumors with intact CDKN2A. Within a retrospective cohort of IDH-mutant astrocytomas with known CDKN2A status, we examined whether there was any correlation of CDKN2A status with anatomic location.

METHODS

Astrocytomas of any grade carrying IDH mutations with further molecular sequencing that included CDKN2A status were identified from a tissue database, as well as a clinical cohort of patients seen at the neuro-oncology clinic who had genomic analysis by clinical request. Imaging was reviewed for tumor location. Fisher’s exact test was used to analyze differences between groups.

RESULTS

Six of 35 IDH-mutant astrocytomas (17%) had CDKN2A deletions. None of the six patients with CDKN2A mutant tumors had contact with the insula, whereas 16 of 29 tumors (55%) with intact CDKN2A contacted the insula (p=0.02). The majority of tumors in both groups were located completely or partially in the frontal lobe, as is common in IDH-mutant astrocytomas, and all CDKN2A deleted tumors were in the frontal lobe.

DISCUSSION

Astrocytomas with IDH mutations that also carry CDKN2A deletions have been shown to have a worse prognosis than similar grade tumors with intact CDKN2A status. This has important prognostic implications, but CDKN2A testing is not standard currently or used to stratify patients in clinical trials. Our sample size is small, but if confirmed in a larger cohort could help guide efficient testing for CDKN2A status and improve prognostication.
BIOM-20. PROTEOMICS PROVIDES POTENTIAL THERAPEUTIC APPROACHES TO GLIOBLASTOMA TREATMENT: RESULTS FROM THE CLINICAL PROTEOMICS TUMOR ANALYSIS CONSORTIUM (CPTAC)
Authors: Barnholtz-Sloan Jill S
Published: December 2020

Glioblastoma (GBM) is the most common type of primary malignant tumor in adults and contributes disproportionately to cancer morbidity and mortality. The ability to augment current knowledge based on the genome and transcriptome with information regarding protein abundance and post-translational modifications with small molecule and lipid abundance has provided novel biological insights into GBM tumorigenesis. In this presentation we will discuss results from proteogenomic and metabolomic investigations of prospectively recruited, newly diagnosed, treatment-naive glioblastomas (GBMs; N=99). Multiple key findings emerged that were not known from traditional genomic analyses as implemented in most currently available datasets. Analysis of protein phosphorylation identified key signaling intermediates in the RTK/RAS pathway common to multiple RTK genomic alterations, potentially offering common therapeutic targets for different oncogenic drivers in GBM. Phosphoproteomics also identified potential druggable targets based on kinase-substrate pathway analysis, as well as novel phosphoprotein targets associated with the regulation of telomere length by ATRX in IDH mutants. Identification of distinct Immune High and Immune Low phenotypes in GBM from whole genome interrogation of the proteome were driven by tumor-associated macrophage markers, and associated with distinct epigenetic modifications and histone acetylation patterns. Identification of key metabolic changes in IDH mutants facilitating the accumulation of oncometabolite 2-HG were also associated with lipidomic changes. Taken all together this work identifies additional therapeutic channels for GBM and novel information useful for more accurate stratification patients for effective treatment.
BIOM-21. CORRELATION BETWEEN EPHRIN-A2 EXPRESSION AND PROGNOSIS IN PATIENTS WITH GLIOBLASTOMA
Authors: Hirai Nozomi , Ichinose Toshiya , Tamai Sho , Nakajima Riho , Sabit Hemragul , Nakada Mitsutoshi
Published: December 2020

The Eph receptor/ephrin ligand system is the largest family of tyrosine kinase with signaling modality through cell to cell adhesion. Eph/ephrin is involved in malignant phenotype such as cell proliferation, migration, and invasion in cancer cells. Although the functions of the Eph receptors in glioblastoma have been elucidated, little is known on ephrin ligands, especially ephrin-A2. Here, we analyze the expression of ephrin-A2 in gliomas using surgical specimens. The expression level of ephrin-A2 mRNA in 14 normal brains and glioma (WHO grade II 13, III 10, and IV 40) was measured by quantitative real-time PCR. Ephrin-A2 expression level was significantly lower in glioblastoma than in normal brain (p= 0.0127). When we divided the glioblastoma cases into high and low ephrin-A2 expression groups based on the median value, the overall survival (OS) was significantly longer in the high expression group compared with the low expression group (p= 0.034, median 24.0 and 14.0 months, respectively). Furthermore, multivariate analysis of factors related to OS with ephrin-A2 expression level and general prognostic factors (age, sex, preoperative KPS, surgical resection rate, radiochemotherapy, IDH1 mutation, MGMT promotor methylation) was performed. Ephrin-A2 expression level (p= 0.039), MGMT promotor methylation (p= 0.0001), and surgical resection rate (p= 0.017) were identified as independent prognostic factors. Taken together, ephrin-A2 is an independent favorable prognostic factor in glioblastoma.
BIOM-31. PROGNOSTIC VALUE OF MGMT METHYLATION IN IDH MUTANT GLIOMAS
Authors: Lam Keng , Eldred Blaine , Kevan Bryan , Ji Matthew , Lou Jerry , Pianka Sean , Yong William , Liau Linda , Nghiemphu Phioanh , Cloughesy Timothy , Green Richard , Lai Albert
Published: December 2020

BACKGROUND

Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those with IDH wildtype. Previous studies have also shown the predictive value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma. However, little is known in the prognostic value of MGMT methylation status for IDH mutant gliomas.

METHODS

We retrospectively identified IDH mutant gliomas patients from University of California Los Angeles and Kaiser Permanente Los Angeles that had been tested for MGMT methylation status. We performed Kaplan-Meier and Cox regression analyses of overall survival (OS) to compare the MGMT methylated versus MGMT unmethylated patients.

RESULTS

We identified a total of 375 IDH mutant gliomas with MGMT testing. Subgroups include 52 glioblastoma, 191 astrocytoma, and 132 oligodendroglioma. The median OS for all MGMT methylated patients was 20.0 years and for unmethylated patients 14.3 years (log-rank P=0.008). Cox regression analysis also confirmed patients with MGMT methylated to have better survival than those with MGMT unmethylated (hazard ratio of 0.47, P= 0.005). During subgroup analysis, MGMT methylated glioblastoma patients have a median OS of 13.7 years compared to MGMT unmethylated patients 3.2 years (log-rank P=0.004) with a hazard ratio of 0.14 (P=0.005). However, we see no difference yet for astrocytoma (hazard ratio of 1.09, P= 0.81) and oligodendrogliomas (hazard ratio of 0.36, P= 0.193), possibly as a result of immature survival data.

CONCLUSIONS

MGMT promoter methylation is associated with better outcomes in IDH mutant glioblastoma patients. Progression free survival will be analyzed to determine predictive benefit of MGMT methylation for other glioma subtypes.
BIOM-32. HIGH AFFINITY FLUORESCENT NANOPARTICLES FOR DETECTION IL13Rα2-POSITIVE EXTRACELLULAR VESICLES AND CELLS
Authors: Khristov Vladimir , Madhankumar Achuthamangalam , Zacharia Brad , Connor James
Published: December 2020

Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1%. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Despite advances in imaging technology, early identification of treatment failure or impending resistance remains problematic. A unique characteristic of GBM is the overexpression of the α2 variant of IL-13 receptor (IL13Rα2) in 78–96% of patients while virtually undetectable in normal brain tissue. We hypothesize that the blood of patients with GBM contains sufficient IL13Rα2-positive extracellular vesicles (EV) to inform the clinical picture regarding disease status such as tumor recurrence and response to therapy. To detect IL13Rα2 as a specific molecular target for diagnostic testing, we have developed a modified version of IL-13 with increased affinity and specificity for IL13Rα2, and conjugated this ligand to fluorescent/ magnetic nanoparticles using an 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) linker. Furthermore, we demonstrated that the EV plasma fraction of patients with GBM is enriched for the IL13Rα2 receptor. We also demonstrated the ability of the ligand-bound nanoparticles to aggregate with IL13Rα2-positive cells and EVs in vitro. This ligand-based affinity purification particle has the potential to both quantify IL13Rα2 EV levels in patient blood and isolate these EVs for further interrogation of genomic and proteomic molecular markers.
BIOM-43. GLUTAMATE RECEPTOR AND GLUTAMINE METABOLISM PROFILING BY GENE EXPRESSION ANALYSIS AMONG PATIENTS WITH HIGH GRADE GLIOMA (HGG)
Authors: Castro Michael , Badra-Azar Nilofar , Kessler Thomas , Schütte Moritz , Lange Bodo , Yaspo Marie-Laure
Published: December 2020

BACKGROUND

Glutaminolysis and excessive glutamate production are among the metabolic hallmarks of HGG. In addition to a probable role in causing seizures, autocrine stimulation of metabotropic and ionotropic (NMDA, AMPA, and kainate) receptors are capable of activating intracellular signaling pathways that are tumorigenic and contribute to drug and radiation resistance. While hints of a survival benefit from glutamate receptor targeting have occasionally emerged from the clinic, no single strategy has consistently demonstrated efficacy. Hence, we sought to characterize the magnitude of glutamate receptor overexpression and its diversity across a population of HGG patients.

METHODS

A set of 41 genes related to glutamate metabolism was selected from the literature. RNA gene counts for TCGA glioblastoma multiforme (N=163) and Grade 3 glioma samples (Astrocytoma=82, Oligodendroglioma=47, Oligoastrocytoma=39) were downloaded from https://portal.gdc.cancer.gov/. Annotation on subtypes and PFS values were obtained from PMID: 24120142 and 26061751. Gene expression normalization as FPKM and hierarchical clustering were performed using R-3.6.0 genes.

RESULTS

A heatmap with hierarchical clustering for glutamate and glutamine-related genes for the TCGA GBM and grade III glioma samples cohort was generated including colored annotation for the subtype and progression free survival. The graph shows a rough separation into two groups, with grade III gliomas and proneural samples tentatively clustering together and showing higher expression for most of the glutamate related genes. The magnitude of glutaminolysis-related gene over-expression varied significantly across the cohort suggesting a wide variety in the extent of glutamine addiction.

CONCLUSION

Specific glutamate receptors are commonly upregulated in HGG patients, however the heterogeneity underlying this phenomenon suggests that uniform drug strategies are unlikely to succeed in a diverse population. However, gene expression analysis has utility to identify specific glutamate receptor and glutamine profiles and to inform the treatment strategies for discrete subsets of patients using drugs that are already in the armamentarium.
BIOM-48. PTEN MUTATIONS PREDICT BENEFIT FROM TUMOR-TREATING FIELDS THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Dono Antonio , Mitra Sonali , Takayasu Takeshi , Zhu Jay-Jiguang , Tandon Nitin , Esquenazi Yoshua , Ballester Leomar Y
Published: December 2020

BACKGROUND

Glioblastoma IDH-wildtype (GBM-IDH-WT) recurs despite the standard of care which includes surgical resection and concurrent chemoradiotherapy. Optimal treatment for recurrent GBM-IDH-WT (rGBM) is not standardized and multiple therapeutic approaches are utilized. Clinical trials have shown that Tumor-Treating Fields (TTF) provide equal benefits compared to physician’s chemotherapy choice for patients with rGBM. However, not all rGBM patients respond equally to TTF and understanding which patients will benefit from TTF therapy is critical.

METHODS

We reviewed clinical, molecular, and outcome characteristics of rGBM patients between 09/2009 to 2/2019 in our institution. Patients who received TTF-treatment at the time of 1st recurrence were selected for analysis. Tumors were analyzed for mutations in 315 cancer-related genes by next-generation sequencing. Post-progression survival (PPS) defined as the interval from 1st recurrence to death or the time of analysis, was examined using the Log-rank test and multivariable Cox-regression model.

RESULTS

149 rGBM patients were identified of which 29 (19%) were treated with TTF. Overall, no significant difference in survival was observed in rGBM patients who received TTF therapy (13.9-months vs 10.9-months, p= 0.06). However, among TTF-treated patients (n= 29), there was improved survival in PTEN-mutant (n= 14) patients compared to PTEN-wt (n= 15), (22.2-months vs 11.6- months, p= 0.017). No differences in TTF usage were observed between groups. Within the PTEN-mutant patients (70/149, 47%), those treated with TTF (n= 14) had longer PPS (22.2-months vs 9.3-months, p= 0.005). No survival benefit with TTF-treatment was observed in PTEN-wt patients (79/149, 53%).

CONCLUSIONS

Patients with GBM-PTEN-mutant tumors show a significant improvement in survival when treated with TTF at recurrence. Understanding the molecular mechanism underpinning the differences in response to TTF therapy could help elucidate the mechanism of action of TTF and identify patients that will benefit the most from this therapeutic option.
BIOM-52. A PROGNOSTIC GENE EXPRESSION RISK SCORE FOR MENINGIOMA
Authors: Chen William , Vasudevan Harish N , Choudhury Abrar , Lucas Calixto-Hope G , Magill Stephen , Susko Matthew S , Braunstein Steve , Boreta Lauren , Nakamura Jean , Sneed Penny K , Bush Nancy Ann Oberheim , Villanueva-Meyer Javier , Perry Arie , Solomon David , McDermott Michael , Theodosopoulos Philip , Raleigh David
Published: December 2020

BACKGROUND

Clinical biomarkers for identifying patients at risk for recurrence after resection of meningioma are lacking and are needed for guiding adjuvant therapy. The aim of this study was to identify a prognostic gene expression signature for meningioma.

METHODS

Targeted gene expression analysis was performed on a discovery dataset of 96 meningiomas with suitable tissue identified from a retrospective institutional biorepository. Recurrence was dichotomized based on the median time to local recurrence (TTR). With median follow-up of 6.4 years, the discovery dataset was enriched for clinical endpoints of local recurrence (58%), mortality (42%), and disease-specific mortality (49% of deaths). A 266 gene expression panel was used to interrogate the discovery dataset, and a prognostic gene signature and risk score was generated using prediction analysis for microarrays (PAM) and elastic net regression. The risk score was validated using gene expression data (GSE58037) from 56 meningiomas resected at an independent institution (20% local recurrence, 18% mortality, median follow-up 5.4 years).

RESULTS

A 36-gene signature was identified achieving an AUC of 0.86 for TTR faster than the median in the discovery cohort. A risk score between 0 and 1 based on this signature was strongly associated with shorter TTR (F-test, P< 0.0001), and on multivariate Cox regression (MVA), was independently associated with recurrence (RR 1.56 per 0.1 increase, 95% CI 1.30–1.90, P< 0.0001) and mortality (RR 1.32 per 0.1 increase, 1.07–1.64, P=0.01) after adjusting for WHO grade, age, extent of resection, and sex. Similarly, in the validation dataset, the gene risk score was correlated with shorter TTR (P=0.002) and associated with mortality on MVA (RR 1.86 per 0.1 increase, 1.19–2.88, P=0.005) after adjustment for WHO grade.

CONCLUSIONS

The prognostic meningioma gene expression risk score presented here could be useful in identifying patients at higher risk of progression after resection.
BIOM-63. DIAGNOSIS AND PROGNOSTIC SIGNIFICANCE OF CIRCULATING miR-2276-5p IN PLASMA OF GLIOMA PATIENTS
Authors: Zhao Shiguang
Published: December 2020

Circulating microRNAs (miRNAs) in plasma have the potential to become diagnostic and prognostic biomarkers for various cancers. This study hopes to use plasma circulating miRNAs as biomarkers for diagnosis and prognosis of glioma patients. METHOD: In this study, the plasma circulating miRNAs of 124 patients with glioma and 36 controls was collected to detect the relative expression of miR-2276-5p, and the specificity and sensitivity of the diagnosis were verified by ROC curve. The follow-up survival status was analyzed by cox regression analysis. RESULT: In the GSE 139031 database, it was found that the expression of circulating miR-2276-5p in plasma of glioma patients was significantly lower than that of patients with non-gliomas. Using our plasma samples, and it is indicated that the expression of circulating miR-2276-5p in plasma is lower than that of healthy patients, and compared with low-grade gliomas, patients with high-grade gliomas have a lower expression of circulating miR-2276-5p. ROC curve analysis found that the AUC value was 0.851. The low expression of circulating miR-2276-5p in plasma of glioma patients indicates a poor prognosis of glioma patients, After univariate and multifactorial cox regression analysis, which can be used as an independent prognostic risk factor for glioma patients (P< 0.05). CONCLUSION: The expression of circulating miR-2276-5p in plasma of glioma patients was significantly lower than that of the control group, compared with low-grade gliomas, patients with high-grade gliomas have a lower expression of circulating miR-2276-5p. The lower the relative expression of circulating miR-2276-5p indicated that glioma patients had a worse prognosis.
CBIO-01. THERAPEUTIC IMPLICATIONS OF CONDITIONAL VULNERABILITIES CAUSED BY TTFIELDS EXPOSURE IN NOVEL COMBINATION THERAPIES FOR NON-SMALL CELL LUNG CANCER AND BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER
Authors: Kumar Karanam Narasimha , Story Michael
Published: December 2020

Tumor Treating Fields (TTFields) are low-intensity, intermediate frequency, alternating electric fields which are FDA-approved for glioblastoma and malignant pleural mesothelioma. Clinical trials are ongoing for other solid tumor cancers, including lung, pancreatic, and ovarian cancers. The initial mechanism for tumor cell killing identified for TTFields exposure was through the disruption of mitosis. Subsequently, it has been shown that TTFields causes replication stress and down-regulates DNA repair and cell cycle checkpoint genes. Here, relative quantitative proteomics were employed to elucidate the cause for the downregulation of DNA repair and cell cycle checkpoint genes. STRING database analysis of differentially expressed proteins revealed interaction networks that included cell cycle, DNA damage repair and replication, and transcriptional and translational regulation. Upstream analysis of key genes associated with cell cycle checkpoint and DNA repair identified reduced expression of the transcriptional activators E2F1 and E2F2 and increased expression of the transcriptional repressor E2F6, suggesting that TTFields affects the CDK–RB–E2F axis. This axis is known to control the transcriptional machinery of the key regulators of cell cycle progression and genome replication fidelity, hence may explain the reduced DNA repair capacity and replication fork maintenance in TTFields-exposed cells. The current study results suggest that TTFields-exposure causes a conditional vulnerability environment that renders cells more susceptible to chemotherapeutic agents that block interfere with the E2F-RB-CDK4/6 axis, inducing DNA damage and replication stress. TTFields-exposure synergistically enhanced the efficacy of the E2F inhibitor HLM006474 with or without the CDK4/6 inhibitor abemaciclib. TTFields plus either or combination of cisplatin and etoposide (known enhancers of replication stress) synergistically enhanced cell killing. These results suggest that the combination of cisplatin and etoposide together with TTFields would be beneficial for non-small cell lung cancer patients and patients with brain metastases from non-small cell lung cancer.
CBIO-03. ATRX LOSS IN GLIOMA RESULTS IN EPIGENETIC DYSREGULATION OF CELL CYCLE PHASE TRANSITION
Authors: Mullan Brendan , Qin Tingting , Siada Ruby , Ravindran Ramya , Thomas Chase , Harris Micah , Muruganand Ashwat , Pyaram Kalyani , Miklja Zachary , Reiber Mary , Garcia Taylor , Tran Dustin , Danussi Carla , Brosnan-Cashman Jackie , Pratt Drew , Zhao Xinyi , Rehemtulla Alnawaz , Sartor Maureen , Venneti Sriram , Meeker Alan , Huse Jason , Morgan Meredith , Lowenstein Pedro , Castro Maria , Yadav Viveka Nand , Koschmann Carl
Published: December 2020

Gliomas are a leading cause of cancer mortality in children and adults, and new targeted therapies are desperately needed. ATRX is a chromatin remodeling protein that is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and IDH-mutant grade 2/3 adult glioma. We previously showed that loss of ATRX in glioma results in tumor growth and additional tumor mutations. However, the mechanism driving these phenotypes has not been fully established. We found that in ChIP-Seq/ChIP-qPCR of mouse neuronal precursor cells (NPCs) and GBM cells with isogenic ATRX loss, ATRX binds regulatory elements for cell cycle phase transition gene sets, and ATRX loss subsequently results in reduced expression. Furthermore, human GBM cells with ATRX knock-out demonstrate higher rates of cells in S and G2/M phases, with clusters of cells demonstrating reduced expression of cell cycle regulatory gene sets by single-cell sequencing (scSeq) analysis. In human and mouse GBM in vitro models, ATRX-deficient cells exhibit a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation and enhanced activation of the master cell cycle regulator ATM with radiation. Treatment of ATRX-deficient gliomas with ATM inhibitors results in a selective increase in dysfunctional cell cycling and increased radio-sensitization in ATRX-deficient glioma cells. Using an ATM-luciferase reporter in orthotopically-implanted human GBM cells, both AZD0156 and AZD1390 demonstrate in vivo pathway inhibition. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate a doubling of median survival compared to radiated controls (p=0.0018) when treated with AZD0156 combined with radiation; this is not seen in ATRX-sufficient models. This study demonstrates that ATRX-deficient high-grade gliomas display epigenetic dysregulation of cell cycle phase transitions, which opens a new window for therapies targeting this unique phenotype.
CBIO-14. ELUCIDATING THE MECHANISM OF TEMOZOLOMIDE-INDUCED ATR ACTIVATION IN MGMT-METHYLATED GLIOBLASTOMA MULTIFORME
Authors: Ganesa Sachita , Sule Amrita , Sundaram Ranjini , Bindra Ranjit
Published: December 2020

Glioblastoma multiforme (GBM) is an aggressive, malignant brain tumor in adults. The current standard of care for GBM is surgical resection, radiation therapy and chemotherapy with temozolomide (TMZ). It is well established that GBM patients with a methylated MGMT promoter (MGMT-) who are treated with TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ GBM cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. It is known that MMR proteins are involved in ATR activation, however, this project aims to unravel the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions. To accomplish this, we treated an shMSH2 MGMT- GBM cell line with TMZ and an ATR inhibitor (ATRi) compared to treatment in an MSH2-proficient MGMT- GBM cell line. We observed decreased cell death in the shMSH2 setting compared to the MSH2-proficient cells, suggesting that MSH2 is integral in the activation of ATR upon TMZ treatment in the MGMT- setting. This study elucidates a potential role for MSH2 in ATR activation. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain in the treatment of patients with GBM.
COVD-04. REAL-WORLD PERSPECTIVES: TUMOR TREATING FIELDS (TTFIELDS) UTILITY TO OPTIMIZE TREATMENT OF PATIENTS WITH GLIOBLASTOMA (GBM) AMIDST COVID-19 PANDEMIC
Authors: Frongillo Peggy , Shackelford Melissa , Rain Lindsay
Published: December 2020

INTRODUCTION

Due to the unprecedented, COVID-19 pandemic and resulting health/safety guidelines, rapid-adjustments to treatment plans for patients battling glioblastoma (GBM; debilitating, aggressive cancer) were critical. Tumor Treating Fields (TTFields; FDA-approved for GBM; antimitotic device) are alternating electric fields (200 kHz) delivered through scalp-placed transducer arrays to target rapidly dividing GBM cells. Visitor restrictions at cancer-centers and often overburdened healthcare teams provided obstacles to cancer therapy. Health and safety of patients/caregivers, healthcare providers (HCPs), and patient Device Support Specialists (DSS) were prioritized. We evaluated the impact of Novocure® (device manufacturer) implemented strategies on overcoming limitations/restrictions to treatment-access during COVID-19.

TREATMENT/PROTOCOL

TTFields (Optune) offers a viable noninvasive, built-in-care system for convenient at-home use. TTFields provides survival benefit with continuous, portable-usage and is tolerable (no-related systemic effects) without overall impact on quality-of-life (except itchy skin). Novocure adopted/amended protocols to meet health guidance/regulation (ie, World Health Organization, Centers for Disease Control and Prevention, local, hospital/clinic directives).

PERSPECTIVES

COVID-19 forced a change in treatment patterns imposed by quarantine limitations. This, coupled with the vulnerabilities of immunocompromised patients with GBM, necessitated new-access to TTFields. A COVID-19 task force was created to monitor developments, providing directives to minimize risks to patients/caregivers and employees. Hygiene-practices/full-personal protective equipment were applied for live patient-appointments with DSS. Virtual education appointments were executed to guide patients/caregivers through treatment-initiation. New, no-contact, monthly-usage data downloads were employed. Communication measures were implemented, informing HCPs of process changes impacting patients. To date, no observed differences were noted for virtual to non-virtual patient starts, demographics, time-to-start (42-days), treatment discontinuations, percentage continuing therapy (90%), and overall complaints. No new safety signals were observed utilizing new approaches.

CONCLUSIONS

TTFields care-delivery has been transformed during COVID-19 and preemptively in regards to other future access-limiting events, with adoption of virtual-platforms/protocols, resulting in enhanced access and education for patients/caregivers and healthcare teams.
COVD-08. THE DIVIDED PRINCIPLE OF JUSTICE: ETHICAL DECISION-MAKING IN CANCER CARE DURING THE COVID-19 PANDEMIC
Authors: Brenna Connor , Das Sunit
Published: December 2020

The four-principle approach to medical ethics, balancing prima facie obligations to beneficence, nonmaleficence, autonomy, and justice, has supplied a common language for the application of ethical analysis to medical practice for the last four decades. The frayed edges of this edifice are made visible, however, by the ongoing COVID-19 pandemic (and other historical circumstances of severe resource limitation in the healthcare system). We interrogate ethical considerations involved in the state of medical care during the COVID-19 pandemic, as demonstrated by reconsiderations of cancer care, in which the pillar of justice is exposed as internally divided. Specifically, we identify both patient-oriented and system-oriented principles of justice constituting a broader collective, unique among the classical four principles. This leads us to suggest a formal recognition of justice as a divided category, and a reclassification of the term into two subcategories which serve fundamentally different interests. The result is a more cohesive four principle approach in which all principles favour the deontological relationships fostered between patients and providers, which exists in constant balance with the utilitarian interests of the broader medical system.
COVD-12. THE LONGITUDINAL IMPACT OF COVID-19 PANDEMIC ON NEUROSURGICAL PRACTICE
Authors: Alatar Abdullah , Bajunaid Khalid , Alqurashi Ashwag , Ajlan Abdulrazag
Published: December 2020

OBJECTIVE

This observational cross-sectional multicenter study aimed to evaluate the longitudinal impact of the coronavirus disease 2019 (COVID-19) pandemic on neurosurgical practice.

METHODS

We included 29 participating neurosurgeons in centers from all geographical regions in the Kingdom of Saudi Arabia. The study period, which was between March 5, 2020 and May 20, 2020, was divided into three equal periods to determine the longitudinal effect of COVID-19 measures on neurosurgical practice over time.

RESULTS

During the 11-week study period, 474 neurosurgical interventions were performed. The median number of neurosurgical procedures per day was 5.5 (interquartile range [IQR]: 3.5–8). The number of cases declined from 72 in the first week and plateaued at the 30’s range in subsequent weeks. The most and least number of performed procedures were oncology (129 [27.2%]) and functional procedures (6 [1.3%]), respectively. Emergency (Priority 1) cases were more frequent than non-urgent (Priority 4) cases (178 [37.6%] vs. 74 [15.6%], respectively). In our series, there were three positive COVID-19 cases. There was a significant among-period difference in the length of hospital stay, which dropped from a median stay of 7 days (IQR: 4 – 18) to 6 (IQR: 3 - 13) to 5 days (IQR: 2 - 8). There was no significant among-period difference with respect to institution type, complications, or mortality.

CONCLUSION

Our study demonstrated that the COVID-19 pandemic decreased the number of procedures performed in neurosurgery practice. The load of emergency neurosurgery procedures did not change throughout the three periods, which reflects the need to designate ample resources to cover emergencies. Notably, with strict screening for COVID -19 infections, neurosurgical procedures could be safely performed during the early pandemic phase. We recommend to restart performing neurosurgical procedures once the pandemic gets stabilized to avoid possible post-pandemic health-care system intolerable overload.
COVD-14. TELEMEDICINE REVIEW IN NEURO-ONCOLOGY: COMPARATIVE EXPERIENTIAL ANALYSIS FOR BARROW NEUROLOGICAL INSTITUTE AND GEISINGER HEALTH DURING THE 2020 COVID-19 PANDEMIC
Authors: Fonkem Ekokobe , Gatson Na Tosha , Tadipatri Ramya , Azadi Amir
Published: December 2020

Coronavirus disease 2019 (COVID-19) has grossly impacted how we deliver healthcare and how healthcare institutions derive value from the care provided. at increased infectious risk on immunosuppressive therapies and often have mobility limitations. Adapting to new technologies and reimbursement patterns were challenges that had to be met by the institutions while patients struggled with decisions to prioritize concerns and to identify new pathways to care. With the implementation of social distancing practices, telemedicine plays an increasing role in patient care delivery, particularly in the field of Neurology. This is of particular concern in our cancer patient population given that these patients are often at increased infectious risk on immunosuppressive therapies and often have mobility limitations. We reviewed telemedicine practices in neurology pre-/post-COVID-19 and evaluated the neuro-oncology clinical practice approaches of two large care systems, Barrow Neurological Institute and Geisinger Health. Practice metrics were collected for impact on clinic volumes, institutional recovery techniques, and task force development to address COVID-19 specific issues. Neuro-Oncology divisions reached >67% of pre-pandemic capacity (patient visits and slot utilization) within 3-weeks and returned to >90% capacity within 6-weeks of initial closures due to COVID-19. The two health systems rapidly and effectively implemented telehealth practices to recover patient volumes. While telemedicine will not replace the in-person clinical visit, telemedicine will likely continue to be an integral part of neuro-oncologic care. Telemedicine has potential for expanding access in remote areas and provides a convenient alternative to patients with limited mobility, transportation, or other socioeconomic complexities that otherwise challenge patient visit adherence.