bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDRE-12. DETERMINATION OF TOTAL AND UNBOUND LEVELS OF A POTENT INHIBITOR OF FIBROBLAST GROWTH FACTOR RECEPTOR, INFIGRATINIB, IN HUMAN PLASMA, CEREBROSPINAL FLUID AND BRAIN TUMOR BY A VALIDATED LC-MS/MS ASSAY
Authors: Margaryan Tigran , Sanai Nader , Tovmasyan Artak 
Published: November 2021

Abstract

BACKGROUND
Infigratinib is an orally available potent inhibitor of fibroblast growth factor receptor (FGFR) under investigation in a Phase 0 clinical trial for recurrent high-grade gliomas harboring oncogenic FGFR mutation or translocation (NCT04424966). Here, we report on our development and validation of an LC-MS/MS method for determination of total and unbound levels of infigratinib in human plasma, cerebrospinal fluid (CSF) and glioblastoma tissue.

METHODS
Infigratinib was extracted from human plasma, CSF and glioblastoma homogenate samples by protein precipitation with methanol. Unbound fractions of infigratinib in plasma and brain tissues were determined by equilibrium dialysis. Validation was performed using Sciex ExionLC UHPLC system coupled with Sciex QTRAP 6500+ MS/MS detector using positive electrospray ionization mode. The method was validated according to FDA guidelines and CAP/CLIA regulations.

RESULTS
The method was validated for 0.2-1000 nmol/L concentration range using plasma as matrix for all biospecimens. The analytical separation was optimized on Phenomenex Kinetex™ F5 column with total run time of 3.5 min using isocratic mode. Maximum coefficient of variation for intra- and inter-day precision was 12.7% and the accuracy was within 88.5-115.0% in all matrixes. The analyte is stable in plasma for at least 19 hours at room temperature (RT). Plasma stability at -20°C was demonstrated for at least 119 days. Stability of stock and working solutions was demonstrated for at least 15 hours (RT) and 60 days (2-8°C). The unbound fraction of infigratinib in pooled human plasma and brain were determined to be 0.01.

CONCLUSIONS
A sensitive and rapid bioanalytical method is successfully developed and validated to quantify total and unbound infigratinib levels in human plasma, CSF and glioblastoma tissue. The method is presently employed to evaluate plasma pharmacokinetics and CNS penetration of infigratinib in recurrent glioblastoma patients in an ongoing Phase 0 clinical trial.
DDRE-23. PRECLINICAL EVALUATION OF BRAIN PENETRATION PROPERTIES OF NEW FIRST-IN-CLASS LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INHIBITOR, SP-2577
Authors: Jiang Jun , Hopkins Barbara , Hook Garry , Melendez Ernesto Luna , Tovmasyan Artak , Mehta Shwetal , Li Jing , Sanai Nader 
Published: November 2021

Abstract

BACKGROUND
Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation gene programs that give rise to a number of cancers. SP-2577 is a first-in-class selective and reversible inhibitor of LSD1. Here, we evaluated the ability of SP-2577 to cross blood-brain barrier in mouse brain.

METHODS
Fifteen BALB/c mice were treated with 50 mg/kg SP-2577 twice daily intraperitoneally for 4 days. At 2, 6, and 12 hours after the last treatment dose was delivered, plasma and brain samples were collected for analysis of SP-2577 bound and unbound fractions (5 mice/time point). An LC–MS/MS method was developed to measure the drug levels in mouse plasma and brain. The unbound fractions of SP-2577 in plasma and brain tissue were determined using equilibrium dialysis.

RESULTS
Total plasma levels of SP-2577 at the 2, 6, and 12-hour time points following the last dose were 1353 nM, 1209 nM, and 560 nM, accordingly. Total drug levels in brain measured at the same time points were 276 nM, 183 nM, and 168 nM. SP-2577 is highly bound to plasma proteins and brain tissue components with an average plasma unbound fraction value of 0.009. Unbound levels of SP-2577 were undetectable in brain tissue, potentially due to instability of the drug in brain homogenates. The total brain-to-plasma ratio (Kp) was determined as 0.032 (range, 0.027–0.046) in mice.

CONCLUSION
SP-2577 is well tolerated in mice and achieves reasonable total drug levels in mouse brain, yet is highly-bound to plasma proteins and brain components. Taken together, these data indicate that SP-2577 cannot reach pharmacologically-relevant drug concentrations across the mouse blood-brain barrier.
DDRE-38. MAGMAS INHIBITION IN MEDULLOBLASTOMA CELL CULTURES AND PATIENT-DERIVED XENOGRAFT MODELS: POTENTIAL THERAPEUTIC IMPLICATIONS
Authors: Hoerig Clay , Plant-Fox Ashley , Lepe Javier , Douglas Christopher , Lomeli Naomi , Di Kaijun , Das Bhaskar , Bota Daniela 
Published: November 2021

Abstract

BACKGROUND
Brain tumors are the second most common type of pediatric cancer and are the leading cause of all cancer-related deaths in children. Medulloblastoma (MB) is the most common type of malignant pediatric brain tumor and has a five-year overall survival ranging from 40-75%, depending on the patient’s age and other prognostic features. There are current anti-cancer therapies against medulloblastoma, but the treatment of recurrent disease remains a challenge. Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) overexpression has been reported in multiple types of metabolically active tissue and cancer cells, including prostate cancer, pituitary adenoma, and glioma. Limited data suggest that specific subgroups of medulloblastoma may also overexpress Magmas. This study aims to examine whether Magmas inhibition by compound “BT#9” could be beneficial for the treatment of medulloblastoma.

METHODS
We studied the ability of a Magmas inhibitor (BT#9) as a therapeutic agent in stable medulloblastoma cell lines (DAOY and D283) and patient-derived primary cultures with MTT assays, migration assays, and invasion assays.

RESULTS
Similar to the adult GBM studies, Magmas inhibition by BT9 had signiﬁcant cytotoxic eﬀects, causing both decreased cell proliferation and blocked cell migration in medulloblastoma cell lines DAOY and D283. IC50s determined for each during different time points demonstrated an average range of less than 3μM compared to the average range seen in adult glioblastoma cell cultures (&lt; 10 μM). These findings suggest that the inhibition of Magmas warrants further investigation as a potential therapeutic target to optimize clinical outcomes in medulloblastoma. Our future studies will include the determination of IC50s for primary cell cultures and in vitro testing with patient-derived xenograft models.
DDRE-43. SCREENING OF FDA-APPROVED COMPOUNDS FOR THE TREATMENT OF CHORDOMA, WITH IN VIVO VALIDATION USING THREE DIFFERENT XENOGRAFT MODELS, IDENTIFIES BRIGATINIB AS A POTENTIAL TREATMENT
Authors: Tatman Philip , Wroblewski Tadeusz , Fringuello Anthony , Scherer Sam , Foreman William , Damek Denise , Youssef Samy , Lillehei Kevin , Ormond David , Graner Michael 
Published: November 2021

Abstract

BACKGROUND
Chordoma is a rare malignant tumor with poor surgical control and no existing pharmacotherapies. Therefore, these tumors require additional research into novel therapeutics for their treatment.

METHODS
In this study we created a high-throughput drug screen and culture system to evaluate the efficacy of existing FDA-approved compounds in 10 chordoma cell lines and primary tumors. The cell lines were graciously donated by the Chordoma Foundation. Primary tumors were collected from our operating room. In vivo validation using three separate chordoma xenograft models was also performed through the Chordoma Foundation. One model was a primary clival pediatric tumor, the second was a metastatic sacral tumor, and the third model was a recurrent skull base tumor.

RESULTS
Using a 127 FDA-approved compound library, we screened 6 donated chordoma cell lines and 4 tumors resected from our institution. 5 of the chordomas were primary, 3 were recurrent, and 2 were metastatic. 6 chordoma were located in the sacrum, three were located in the mobile spine, and one was located in the clivus. Five tumors came from female patients and five came from male patients. After a single 72-hour 1um dose of brigatinib, the average tumor viability in our drug screen was reduced to 81.5% +/-9.5SD (p=1.61x10-13). In the in vivo studies, brigatinib achieved a full response in the metastatic sacral chordoma xenograft model (TGI=100%, p&lt; 0.0001), a partial response in the recurrent skull base xenograft model (TGI=54%, p=0.3048), and no response in the primary clival pediatric xenograft model (TGI = 0%, p &gt;0.9).

CONCLUSIONS
Brigatinib may be a viable treatment option for recurrent and metastatic chordomas.
EPID-01. THE EPIDEMIOLOGY OF BRAIN METASTASES IN ADOLESCENT AND YOUNG ADULT (AYA) PATIENTS DISTINCTLY DIFFERS FROM THE ADULT POPULATION
Authors: Lamba Nayan , Iorgulescu Bryan 
Published: November 2021

Abstract

INTRODUCTION
Few data exist regarding the epidemiology of brain metastases (BMs) in adolescent and young adult (AYA) patients. Herein we use national cancer registry data to dissect their epidemiology and compare to the adult population.

METHODS
AYA patients (15 ≤ age ≤ 39) who newly presented with a BM between 2010 and 2017 were identified in the National Cancer Database (comprising &gt;70% of all newly-diagnosed cancers in the U.S.). The epidemiology of BMs was analyzed by primary cancer of origin, and compared between AYA and adult patients. Overall survival was analyzed with multivariable Cox regression.

RESULTS
2,773 AYA patients presenting with BMs were identified (98% with histopathological diagnosis), compared to 156,103 adult patients (94% with histopathological diagnosis). Whereas 39.6% of newly-diagnosed brain tumors with histopathological confirmation were BMs in adults, BMs represented only 5.8% of such tumors in AYA patients. Additionally, the distributions of primary cancer types differed substantially between adults and AYA patients: notably, NSCLC dominated in adults (64.2%) vs representing only 31.6% of BMs in AYA patients. AYA patients were more likely to present with BMs from melanoma (13.0% of AYA BMs vs 3.7% in adult), soft tissue (4.5% vs 0.3%), testicular (in males 26.2% vs 0.1%), and breast (in females 29.5% vs 7.8%) primaries. Among breast BMs in females, AYA patients were less likely to have HR+/HER2- primaries (40.2% vs 47.8%) and more likely to have HER2+ (25.2% vs 20.1%) and triple positive (11.1% vs. 9.8%) primaries than adults. Overall survival was significantly longer for AYA patients with BMs (HR=0.61 compared to adult patients, 95%CI:0.58-0.64, p&lt; 0.001) even after adjusting for primary cancer type, patient sex.

CONCLUSIONS
The epidemiology and cancer types of BMs in AYA patients differ substantially from adult patients. Future research aimed at understanding the unique differences in pathophysiology and outcomes of BMs in AYA patients is warranted.
EPID-10. GLIOMA INCIDENCE AND SURVIVAL BY INCOME LEVEL IN THE UNITED STATES GENERAL POPULATION AGES AND ABOVE FROM 2000-2018
Authors: Murillo Jennifer , Anyanda Elizabeth , Huang Jason 
Published: November 2021

Abstract
Gliomas are the most common primary malignant brain tumor in the United States with previous studies showing the incidence varied by age, sex, and race or ethnicity. Survival after diagnosis has also been shown to vary by these factors. Also, socioeconomic status and its association with various cancers have also been studied at length over time. PURPOSE: The purpose of our research was to quantify the differences in incidence and survival rates of gliomas in 15 years and older by income level. METHODS: This population-based study obtained incidence and survival data from the Incidence-SEER Research Database the general population. Average age incidence were generated by glioma groups and grouped by income levels. Survival rates were generated by overall glioma diagnosis grouped by observed survival at 12, 24, 36, 48 and 60 months and by again by income levels. The analysis included 94,207 patients with glioma diagnosed in those aged 15 years or older. RESULTS: Overall, 94, 207 patients diagnosed with glioma were analyzed. Of these, 1,089 (1.16%) fell into the &lt; $35k group, 1,684 (1.79%) in the $35k-$40k group, 3,473 (3.69%) in the $40k-$45k group, 5,647 (5.99%) in the $45k-$50k group, 7,138 (7.58%) in the $50k-$55k group, 6,468 (6.87%) in the $55k-$60k group, 15,348 (16.29%) in the $60k-$65k group, 13,216 (14.03%) in the $65k-$70k group, 9,035 (9.59%) in the $70k-$75k group, and 31,109 (33.02%) fell in &gt; $75k group. The data was also broken further down into survivability showing average survival. CONCLUSION: Incidence of glioma and 12, 24, 36, 48 and 60 month survival rates after diagnosis vary significantly by income level with higher income level greater than $75,000+ having higher incidence and higher survival rates compared with lower income levels. Further research is needed to help determine risk factors and barriers to care to help reveal health disparities.
EPID-26. ALIGNING THE CBTRUS HISTOLOGY GROUPS WITH 2016 WHO CLASSIFICATION OF TUMORS OF THE CENTRAL NERVOUS SYSTEM
Authors: Kruchko Carol , Patil Nirav , Cioffi Gino , Brat Daniel , Bruner Janet , McLendon Roger , Tihan Tarik , Barnholtz-Sloan Jill , Ostrom Quinn 
Published: November 2021

Abstract

BACKGROUND
The Central Brain Tumor Registry of the United States (CBTRUS) uses a histology grouping scheme modeled after the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) to classify cancer registry records for clinically relevant statistical reporting. Molecular studies have identified genetic features which precisely stratify tumor types, resulting in the 2016 update to the WHO Classification incorporating these markers. To continue providing clinically relevant statistics, the histology groupings have been aligned with the 2016 update. Resulting changes to groupings were assessed.

METHODS
In collaboration with four consulting neuropathologists the scheme was reviewed and realigned to the 2016 update. Obsolete histology nomenclature and ICD-O-3 codes were identified. Evaluation of the frequency of affected codes in the 2013-2017 data was conducted.

RESULTS
417,767 total cases of primary brain and CNS tumors were diagnosed during 2013-2017 in the US. After review of the CBTRUS grouping scheme, 67 codes were noted to be obsolete, 51 codes were re-classified and 12 new codes were incorporated. This reorganization could result in grouping assignment or reporting changes for 2,588 cases (0.6%). The histology groups most significantly affected were mesenchymal tumors and neuronal and mixed neuronal glial tumors.

CONCLUSIONS
The 2016 revision to WHO Classification has affected collection and reporting of CNS tumors. The CBTRUS data edits program is now undergoing revision, which will become the basis of reporting. Some histology-specific molecular markers require additional data to distinguish between cases. In collaboration with CBTRUS, the NAACCR SSDI Committee developed a new variable for collection of molecular information. This variable was included in Uniform Data Standards beginning on January 1, 2018 and will be available for reporting in 2021. A 2021 update to the WHO Classification is scheduled for release later this year, requiring further classification updates.
IMMU-01. CHARACTERIZATION OF TUMOR-INFILTRATING CD8+ T CELLS IN BRAIN METASTASES
Authors: Sudmeier Lisa , Hudson William , Hoang Kimberly , Nduom Edjah , Neill Stewart , Schniederjan Matthew , Olson Jeffrey , Ahmed Rafi 
Published: November 2021

Abstract

BACKGROUND
Use of immune checkpoint blockade (ICB) therapy has prolonged overall survival in patients with metastatic cancer. One potential strategy to improve the effectiveness of ICB is to target additional inhibitory receptors on exhausted CD8+ T cells, which may promote rescue of CD8+ T cells that do not respond to PD-1 pathway blockade alone. This therapeutic strategy requires knowledge of the inhibitory molecules expressed on tumor-specific CD8+ T cells. Toward achieving this goal, we characterized the phenotype of CD8+ T cells infiltrating brain metastases.

METHODS
We performed flow cytometry on 45 brain metastases samples, single cell RNA sequencing with T cell receptor (TCR) sequencing on 5 samples, and spatially-resolved transcriptomics on 8 samples.

RESULTS
Analysis of our scRNA-seq data revealed 4 populations of PD-1+ CD8+ T cells infiltrating brain metastases. One of these populations (cluster A) has a terminal effector exhausted phenotype suggesting that this population contains tumor-specific CD8+ T cells. Two of the other populations (clusters B and C) have a transcriptional profile that suggests they may contain stem-like CD8+ T cells. TCR sequencing shows that cells in cluster A do not express the same TCRs as cells in clusters B and C, suggesting that stem-like cells in clusters B and C are not the progenitors of the terminal effector cells in cluster A. Bystander cells expressing TCRs specific for viral antigens are found predominantly in clusters B and C, further supporting the hypothesis that cluster A contains tumor-specific cells. Spatial transcriptomics reveals that cluster A cells are infiltrating the tumor parenchyma while cluster B and C cells are predominantly in peri-tumoral inflammatory tissue.

CONCLUSIONS
Brain metastases are infiltrated by a population of terminally-differentiated effector CD8+ T cells which express co-inhibitory molecules that may be potential therapeutic targets to improve control of metastatic disease in the brain.
IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM
Authors: Miller Tyler , El Farran Chadi , Verga Julia , Couturier Charles , Chen Zeyu , Castro L Nicolas Gonzalez , D'Antonio Joshua , Petrecca Kevin , Suva Mario , Bernstein Bradley 
Published: November 2021

Abstract
Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.
IMMU-22. THE IMPACT OF MICROGLIA MODULATION ON GBM PROGRESSION IN SYNGENEIC MOUSE MODELS
Authors: Ritz Marie-Françoise , Shekarian Tala , Martins Tomás A , Schmassmann Philip , Hutter Gregor 
Published: November 2021

Abstract

BACKGROUND
The tumor immune microenvironment (TME) of Glioblastoma consists of almost myeloid-derived macrophages and microglia called TAMs. We have shown that the disruption of CD47-Sirpα-axis induces an antitumor activity of TAMs against GBM in immune-deficient mice, through increases of phagocytosis of tumor cells by TAMs. We have aimed to study the role of microglia and its activation/depletion on GBM progression, in the syngeneic GBM model in immune-competent mice. We have studied the interplay of innate and adaptive immune response after activation and depletion of microglia and the effect on tumor progression and outcome of the mice.

MATERIAL AND METHODS
We used different colonies of genetically modified immunocompetent mouse strains to genetically activate/deplete microglia in the tumor context. We generated Sall1 CreERT2/fl mice and Cre-negative littermates. The application of Tamoxifen in this constellation leads to the excision of the transcription factor Sall1 and subsequent enhanced microglia activity. Conversely, we generated Sall1 CreERT2 x Csf1r fl/fl animals and the respective heterozygous and Cre-negative littermates in which Tamoxifen treatment leads to inactivation of microglia through the deletion of Csf1r. Glioblastoma tumors were induced by intracerebral injection of GL261, CT2A, or retrovirus-induced PDGF-Akt in pups and Tamoxifen treatment was started once the tumors were detected.

RESULTS
We observed a survival advantage in tumor-bearing mice after activation of microglia in Sall1 CreERT/fl animals compared to Cre-negative littermates. Genetic depletion of microglia in this model resulted in a shorter lifespan in microglia-depleted animals compared to Cre-negative littermates. Furthermore, the iTME in these tumors is subjected to scRNAseq analysis to identify mechanistic insights.

CONCLUSION
Microglia are important players in tumor development and progression of glioblastoma in mouse models. These cells may be targeted in future immunotherapeutic approaches for patients.
IMMU-30. IDENTIFICATION OF COORDINATELY REGULATED IMMUNO-MODULATORY GENES USING SINGLE-CELL RNA SEQUENCING OF DECITABINE TREATED GLIOMA CELLS
Authors: Lai Thomas , Treger Janet , Rao Jingyou , Prins Robert , Everson Richard 
Published: November 2021

Abstract

INTRODUCTION
The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Our previous data has shown that the hypomethylating agent decitabine (DAC) is a strong sensitizer of GBM to NY-ESO-1 specific adoptive T-cell induced cytotoxicity. However, we hypothesized that DAC alters expression of other immuno-modulatory genes in addition to NY-ESO-1 that may also increase T-cell mediated killing in GBM. The extent of regulation of other immuno-modulatory genes to DAC demethylation has not yet been thoroughly investigated.

METHODS
We performed single-cell RNA sequencing on DAC and non-DAC treated glioma cells. We confirmed DAC treatment induced NY-ESO-1 expression with quantitative real-time PCR and demethylation using bisulfite sequencing. We analyzed our single-cell RNA sequencing data with Seurat and our customized R-based pipelines to identify coordinate differential expression of immuno-modulatory genes and their tumor subpopulations.

RESULTS
Using our single-cell data, we identified tumor subpopulations with coordinate differentially expressed immuno-modulatory genes including cancer testes antigens, antigen presentation proteins, and apoptosis regulators. Amongst these candidate genes, we validated their expression with qPCR and promoter demethylation with bisulfite sequencing and TA bisulfite cloning.

CONCLUSION
Exposure of glioma cells to DAC results in promoter demethylation of NY-ESO-1, with increased expression of CTA and other immunomodulatory genes. DAC treatment may therefore sensitize GBM to the immunotherapeutic targeting of these antigens and reveals a feasible strategy for clinical translation.