bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDRE-39. REPURPOSING CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS WITH GUIDANCE BY METHYLATION PROFILES
Authors: Tran Anh , Wang Wenxia , Scholtens Denise , Zhang Lyndsee , Pokorny Jenny , Wang Yufen , Baran Aneta , Sahm Felix , Aldape Kenneth , James David , Horbinski Craig 
Published: November 2021

Abstract
Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas are categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter or longer PFS at FDR-adjusted p &lt; 0.05. Using Cytoscape/Reactome FI software, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the seventeen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. As monotherapy, the effects of docetaxel on meningioma were attenuated by multidrug resistance protein 1 (ABCB1) and Cytochrome P450 1B1 (CYP1B1). Docetaxel at 2µM augment double-stranded DNA damage caused by irradiation in vitro, leading to increased cell death. In animal model, low doses of docetaxel and radiation therapy had synergistic effects, increasing survival of mice intracranially implanted with human meningioma cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.
DDRE-50. INVESTIGATING THE ROLE OF LonP1 IN GLIOBLASTOMA TUMOR PROGRESSION
Authors: Douglas Christopher , Bota Daniela , Di Kaijun , Das Bhaskar , Lepe Javier 
Published: November 2021

Abstract
Glioblastoma (GBM), a WHO grade IV brain cancer, exhibits strong treatment resistance and a high rate of reoccurrence, which gives it a dismal prognosis, a 5% survival rate in the first 5 years. LonP1, a mitochondrial master regulator, can drive metabolic transformation, cytokine production, EMT, and treatment resistance in various cancer types, but its role in GBM remains unexplored. Our research group has previously shown that LonP1 is overexpressed in human malignant gliomas, particularly glioblastoma, and that this is associated with disease prognosis. Here, we present findings that demonstrate that LonP1 seems to drive enhanced tumor progression, invasiveness, angiogenesis in different high grade glioblastomas based on TCGA-subtype. Furthermore, in collaboration with Professor Bhaskar Das, we have validated a lead compound, BT317, with on-target inhibition of LonP1 protease activity. BT317 has enhanced activity against glioma stem cell lines (GSC) and has demonstrated low toxicity and efficacy in an intracranial xenograft model. This preliminary data highlights the potential of using combinatorial, pharmacological LonP1 and proteasome inhibition as a novel strategy for targeting specific subtypes of GBM.
EPID-04. THE NATURAL HISTORY OF NEUROFIBROMATOSIS-1, THE MONTEFIORE EXPERIENCE
Authors: Lin Tiffany , Dalvi Nagma 
Published: November 2021

Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder with varying phenotypes that can affect many organ systems. Notably, it has significant clinical variability involving different systems in each individual. Manifestations may also develop and evolve with age. Although current literature has looked into the prevalence of the manifestations of NF1, few have compared the prevalence in populations of diversity. The objective of our study is to describe the clinical manifestations of NF1 seen in an urban neurocutaneous clinic that serves a diverse ethnic and socioeconomic population. We intend to see how the clinical manifestations of our patients compare to what is reported and to better understand the clinical impact and prognoses of NF1 in this population. We performed a retrospective study of patients in our neurocutaneous clinic from May 2014 to December 2020. Of the 89 that fit study criteria, we had a majority of Hispanic and Black patients. We compared our data to two recent NF1 natural history studies, Boulanger et al. and Cnossen et al., using chi-square or Fisher exact test. Results showed that we had a lower incidence of cutaneous neurofibromas (23.6% vs the reported 40%) and lisch nodules (32.6% vs the reported 50%), but a higher incidence of symptomatic plexiform neurofibromas (48.3% vs the reported 25%) and CNS tumors requiring intervention (4.5% vs estimated 2% in compared studies). This may indicate that our population is at higher risk for more serious complications. We speculate that socioeconomic and ethnic diversity may be the driver behind these differences. Our center has also initiated treatment using MEK inhibitors in indicated patients. Due to the differences in clinical manifestations and more severe complications, we recommend closer surveillance in diverse populations. We also advocate for further research in the application of MEK inhibitors beyond second-line therapy.
EPID-06. ASSOCIATIONS BETWEEN GERMLINE GENETIC VARIANTS AND OVERALL SURVIVAL IN PATIENTS WITH GLIOMA
Authors: Potnis Kunal , Ostrom Quinn , Claus Elizabeth 
Published: November 2021

Abstract

BACKGROUND
In addition to somatic genetic variation in tumors, germline genetic variation can better define cancer susceptibility risk, guide therapy, and predict survival. Most prior research into associations between germline genetic variants and survival outcomes in patients with glioma has been limited by small sample sizes and to high-grade glioma only. This study is the first to use data from Brigham and Women’s Hospital (BWH) and to include both low-grade and high-grade glioma cases to explore associations between germline genetic variants and overall survival.

METHODS
This study included 211 patients enrolled at BWH from April 2010 to January 2020. Ninety-two candidate germline genetic variants were identified via literature review. Fifty-five variants with minor allele frequency &gt;0.05 were included preliminarily, for which bivariate Cox proportional hazards regression models were employed. Twenty-two variants with P&lt; 0.5 were included in the final multivariable model, adjusted for patient sex, age, race, and glioma grade. Stratified sub-analyses were also conducted by sex. Associations were considered statistically significant at P&lt; 0.05.

RESULTS
Among all patients, homozygous C/C genotype at rs17655 (ERCC5 gene) was significantly associated with worse overall survival (hazard ratio=2.61, P=0.0095). Among females only, worse survival was associated with homozygous T/T genotype at rs1381057 (POLQ, hazard ratio=2.58, P=0.046). Among males only, heterozygous status for the A genotype at rs487848 (POLQ, hazard ratio=0.31, P=0.018) and the A genotype at rs1468923 variant (PIK3CA, hazard ratio=0.51, P=0.016) were associated with improved survival.

CONCLUSION
We identified statistically significant associations between overall survival and four variants in genes involved in DNA repair and the PIK3 pathway, three of which were sex-specific. Our results contribute to improving patient stratification in glioma and may lead to increased targeting of treatment strategies.
EPID-09. VARIATION IN GLIOMA INCIDENCE AMONG US HISPANICS BY GEOGRAPHIC REGION OF ORIGIN
Authors: Walsh Kyle , Bondy Melissa , Kruchko Carol , Huse Jason , Amos Christopher , Barnholtz-Sloan Jill , Ostrom Quinn 
Published: November 2021

Abstract

BACKGROUND
Glioma incidence is 25% lower in U.S. Hispanics than in White non-Hispanics. The US Hispanic population is diverse and registry-based analyses may mask incidence differences associated with geographic/ancestral origins.

METHODS
County-level glioma incidence data in U.S. Hispanics were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS), which includes data from the Centers for Disease Control’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results program and covers ~100% of the U.S. population. American Community Survey (ACS) data were used to determine county-level proportion of the Hispanic population of Mexican/Central American origin, Caribbean origin (Puerto Rican, Cuban, Dominican), or other origin. Incidence rate ratios (IRRs) were generated to assess the association of glioma incidence in Hispanics with predominant origin group.

RESULTS
Compared to Hispanics living in predominantly Caribbean-origin counties, Hispanics in predominantly Mexican/Central American-origin counties were at lower age-adjusted risk of glioma (IRR=0.83; P&lt; 0.0001), glioblastoma (IRR=0.86; P&lt; 0.0001), diffuse and anaplastic astrocytoma (IRR=0.78; P&lt; 0.0001), oligodendroglioma (IRR=0.82; P&lt; 0.0001), ependymoma (IRR=0.88; P=0.0121), and pilocytic astrocytoma (IRR=0.76; P&lt; 0.0001). Associations were consistent in children and adults, and when using more granular regions of origin. However, Central American origin was associated with modestly increased incidence of several lower-grade glioma histologies. Associations were only partially attenuated after adjusting for state-level estimated of European admixture in Hispanics using 23andMe data.

CONCLUSIONS
Glioma incidence in U.S. Hispanics differs significantly in association with the geographic origins of the Hispanic community, with those of Mexican/Central American origin at significantly reduced risk relative to those of Caribbean origin. U.S. Hispanics are culturally, socioeconomically, and genetically diverse. Although classified as a single ethnic group in most registry data, more granular analytic approaches could advance cancer epidemiology and disparities research.
EPID-14. EPIDEMIOLOGY OF ADULT PITUITARY TUMORS IN THE U.S. ACCORDING TO THE 2017 WHO CLASSIFICATION OF ENDOCRINOLOGY TUMOURS
Authors: Castellanos Luz , Gutierrez Catherine , Smith Timothy , Iorgulescu Bryan 
Published: November 2021

Abstract

INTRODUCTION
Among adult intracranial tumors, the pituitary represents a frequent site of origin. We examine their contemporary epidemiology with a particular focus on uncommon pituitary tumor types.

METHODS
Adult patients presenting with pituitary or sellar tumors between 2004-2017 were identified from the U.S. National Cancer Database (comprising &gt;70% of newly-diagnosed cancers). Their epidemiology was assessed in the context of the 2017 WHO Classification of Endocrine Tumours.

RESULTS
12.5% of adult intracranial tumors arose in the pituitary region. 113,352 adults with pituitary tumors were identified. Histopathological diagnosis was obtained in only 59% of cases, in which 93% were pituitary adenomas and 6% were craniopharyngiomas. Among craniopharyngiomas, 71% were adamantinomatous and 29% were papillary, between which there were no differences in age, sex, or tumor size—however, papillary craniopharyngiomas were less common among Black nonHispanic patients (p&lt; 0.001). Among the remaining 1% (n=680) of pituitary tumors, posterior pituitary tumors comprised 21%, chordomas 16%, meningiomas 15%, pituitary carcinomas 11%, GCTs 10%, hematolymphoid 8%, other mesenchymal and stromal 7%, neuronal/paraneuronal 6%, and schwannoma 4%. Meningiomas (84%), mesenchymal/stromal (64%), and neuronal/paraneuronal (64%) tumors displayed a female predominance, whereas GCTs (75%) and pituitary carcinomas (62%) exhibited a male predominance. Age at diagnosis, tumor size, and race/ethnicity varied widely across uncommon tumor types. We further examined the subtypes of uncommon pituitary tumors: for sellar chordomas, 19% were chordoid and none were dedifferentiated; for sellar meningiomas, 94% were grade I; for pituitary GCTs, 79% were pure germinomas; for hematolymphoid, 52% were DLBCL, 11% were plasmacytomas, and 9% were Langerhans cell histiocytosis; for neuronal/paraneuronal, 64% were gangliocytomas; and for mesenchymal tumors, 53% were vascular and 16% were SFTs/HPCs.

CONCLUSIONS
Using national registry data, we provide a detailed dissection of the epidemiology of adult pituitary tumors, with a particular focus on examining uncommon pituitary tumor types in the context of WHO2017.
EPID-17. COMPARATIVE EPIDEMIOLOGY OF PRIMARY BRAIN TUMORS AMONG ADOLESCENTS AND YOUNG ADULTS (AYA)
Authors: Lamba Nayan , Iorgulescu Bryan 
Published: November 2021

Abstract

INTRODUCTION
We utilized national registry data to evaluate the unique epidemiology of primary adolescent and young adult (AYA) brain tumors according to the WHO2016 classification.

METHODS
AYA patients (15≤age≤39) presenting between 2004-2017 with a brain tumor were identified by ICD-O-3 coding from the National Cancer Database (comprising &gt;70% of newly-diagnosed cancers in the U.S.), and compared to pediatric and adult populations. Epidemiology and overall survival (estimated by Kaplan-Meier techniques and multivariable Cox regression) were assessed by WHO2016 tumor type.

RESULTS
108,705 AYA brain tumor patients were identified (56.9% female), compared to 23,928 pediatric (46.8% female) and 748,272 adult (55.6% female) patients. Among the 69.4% of AYA brain tumors with pathological diagnosis, diffuse gliomas (31.4%), sellar tumors (19.2%), and meningiomas (15.3%) predominated in both sexes. Diffuse glioma (31.4%), sellar (19.2%), cranial nerve (7.3%), and mesenchymal non-meningothelial (4.1%) tumors represented a greater proportion of AYA brain tumors than in either pediatric or adult populations. A majority of all intracranial GCTs (59.2%) and neuronal & mixed neuronal-glial tumors (51.6%) presented during AYA. Although the prevalence of diffuse gliomas was similar between AYAs and adults, AYA gliomas were more likely to be grade 2-3 astrocytomas (38.9% vs 14.3%) and oligodendrogliomas (19.3% vs 4.3%) than in adults. GBMs represented 76.0% of adult diffuse gliomas vs. only 25.7% of AYA diffuse gliomas, but with a similar prevalence of MGMT promoter methylation (40.8% vs 38.4%). Notably, 50.7% of AYA PCNSLs were associated with HIV/AIDS, vs only 7.1% in adults (p&lt; 0.001).

CONCLUSIONS
The distribution, epidemiology, and survival outcomes of primary brain tumors in the AYA population are distinct from their pediatric and adult counterparts. Notably, AYA infiltrative gliomas were more often of lower grade than adults and AYA PCNSL were far more likely to be associated with HIV/AIDS. Primary brain tumors in AYA patients require specialized management.
EPID-19. CONDUCTING A NATIONWIDE BRAIN TUMOR EPIDEMIOLOGY STUDY IN AN LMIC: A MULTI-INSTITUTIONAL EXPERIENCE
Authors: Baig Erum , Shah Mashal , Bajwa Mohammad Hamza , Laghari Altaf Ali , Akhunzada Naveed Zaman , Bin-Anis Saad , Khalid Usman , Qadeer Namra , Lutfi Areeb , Tahir Izza , Bajwa Rameen , Rashid Huzaifa , Sadia Haleema , Ghazi Kinzah , Gillani Mishal , Siddiqi Sameen , Enam Syed Ather 
Published: November 2021

Abstract
Very little research has been conducted on brain tumor epidemiology in Pakistan and a few studies that do exist provide regional data only. Conducting population based epidemiological studies in low-and-middle income countries (LMICs) like Pakistan can be particularly challenging due to limited resources, poor clinical and research infrastructure, unreliable or incomplete hospital records and a lack of standardization across the health care system. Population-wide studies and registries play an important role in cancer epidemiology and can help identify the current magnitude of cancer burden and its likely future evolution, allowing for better planning of prevention, diagnosis, management, and rehabilitation. This paper describes our experience in designing and conducting Pakistan Brain Tumor Epidemiology Study (PBTES), a first-ever nationwide study carried out to assess the distribution of brain tumors in Pakistan. In addition to the aforementioned obstacles, we were also faced with the global health crisis caused by the COVID-19 pandemic and had to promptly adjust our study accordingly. Other investigators conducting epidemiological studies in LMICs with similarly challenging and constricting settings could benefit from our experiences.
EPID-20. THE RISING INCIDENCE AND PREVALENCE OF BRAIN TUMOURS: A CANADIAN EPIDEMIOLOGICAL STUDY
Authors: Voisin Mathew , Sasikumar Sanskriti , Mansouri Alireza , Zadeh Gelareh 
Published: November 2021

Abstract

BACKGROUND
Primary malignant brain tumours account for over one third of all brain tumours and are associated with high morbidity and mortality. The purpose of this paper is to estimate the rate and trends of incidence and prevalence for primary malignant CNS tumours in Canada from 1992 to 2017.

METHODS
An epidemiological study using publicly available data from Statistics Canada: Canadian Cancer Registry (CCR) from 1992 to 2017 for all of Canada was conducted. Incidence and prevalence per 100,000, age-standardized incidence, and age-standardized prevalence per 100,000 person-years of primary malignant CNS tumours were calculated and stratified by sex and age: pediatric (0-19), adult (20-64), and elderly ( &gt;64) populations.

RESULTS
During the study period, incidence and prevalence increased by 27.3% and 28.8%, respectively. Males accounted for 56% of all diagnoses and experienced decreased survival compared to females one year after diagnosis (p-value = 0.04). Age-standardized rates of incidence and prevalence were highest in elderly populations.

CONCLUSIONS
Overall, the incidence of primary malignant CNS tumours has increased from 1992 to 2017 with males and the elderly disproportionately affected. Increased healthcare resources and awareness are needed to better identify and deliver evidence-based care for these patients.
EPID-25. DISTANCE TRAVELED FOR BRAIN TUMOR CARE IN PAKISTAN: AN LMIC PERSPECTIVE
Authors: Bajwa Mohammad Hamza , Shah Mashal , Baig Erum , Tahir Izza , Ghazi Kinzah , Bajwa Rameen , Laghari Altaf Ali , Bin-Anis Saad , Akhunzada Naveed Zaman , Gilani Jaleed , Jawed Noyan , Khalid Usman , Qadeer Namra , Lutfi Areeb , Rashid Huzaifa , Sadia Haleema , Gillani Mishal , Consortium Pakistan Brain Tumor , Siddiqi Sameen , Enam Syed Ather 
Published: November 2021

Abstract

INTRODUCTION
Global oncology development within LMICs (low- and middle-income countries) requires bridging gaps in healthcare systems. Brain tumor care in Pakistan is currently sparse and concentrated in urban centers. Distance traveled to a hospital dictates a patient’s access to care, neurosurgical access, and continuity of care through adjuvant chemoradiotherapy and primary care providers can be disrupted if patients cannot overcome the barriers due to extensive distances traveled.

METHODS
Data was collected as part of the Pakistan Brain Tumor Epidemiology Study (PBTES) regarding patients with brain tumors who underwent surgical procedures in 2019 at private and public major neurosurgical centers across Pakistan. Using patient addresses, we used a mapping software to calculate the distance traveled by each patient to the primary hospital. Analysis was done using appropriate statistical methods.

RESULTS
Out of 2403 patients, the mean distance traveled across the country was 240 km. The longest distance traveled within Pakistan was from Skardu to Karachi (2002 km) for resection of a pituitary adenoma (28 hours via car). Only 48% of patients were able to reach their primary hospital within 50 km. 52% of patients had to travel more than 50 km, and 18% had to travel upwards of 500 km to reach their primary hospital. Additionally, 101 patients traveled to Pakistan from other countries for brain tumor surgery (98 patients from Afghanistan [mean distance traveled: 723.6 km], 3 patients from Syria, Oman, and Sudan).

CONCLUSION
Prior studies have described a cut-off of 50 km as an acceptable limit for distance from the primary hospital in cancer patients for optimal follow-up and outcomes, which is achieved by only 48% of brain tumor patients in Pakistan. Most patients have poor access to surgical care for brain tumors, further compounded by repeat traveling for follow-ups and chemoradiotherapy.
IMMU-06. COMBINATORIAL IMMUNE CHECKPOINT INHIBITORS FOR TARGETED INTRATUMORAL DELIVERY IN GBM
Authors: Sanders Stephanie , Herpai Denise , Debinski Waldemar 
Published: November 2021

Abstract
Glioblastoma (GBM) is an immunologically cold tumor. Using single cell sequencing of CD45+ cells we confirmed that T cells are present within GBM samples. These T cells are positive for exhaustion markers such as LAG3 and TIGIT, as well as CTLA4 and PD1 checkpoint receptors. Modulating T cell activity through use of immune checkpoint inhibitors (ICIs) has shown efficacy in the treatment of a variety of solid tumors, and the combination of anti-CTLA4 and anti-PD1 ICIs has shown increased efficacy over use of a single therapeutic. Additionally, targeting ICIs to the tumor cells may increase efficacy of this treatment. We therefore constructed a combinatorial ICI redirected to GBM via interleukin 13 receptor alpha 2 (IL13RA2), a receptor over-expressed on the majority of GBM cells but not normal brain. The first component of the construct, labeled with a histidine tag, targets CTLA4 while the second component, tagged with a StrepII tag, targets PD1. The tags added to the constructs will allow for purification of a combinatorial heterodimer simultaneously targeting PD1, CTLA4 and IL13RA2. We purified individual components via fast protein liquid chromatography (FPLC) using a proteinG column followed by a HisTrap or StrepTrap column. We obtained a recombinant, targeted multivalent ICI at &gt; 95% purity. We found that these constructs are able to bind their target receptors via ELISA in which the Kd values ranged from picomolar to low nanomolar range. Additionally, our constructs bind their target on live cells by flow cytometry. We next designed a heterodimeric construct which can combinatorially target CTLA4 and PD1 while also directing the ICI therapy to GBM. These constructs in conjunction with other immune stimulants like cytotoxic therapies are intended to facilitate the interaction between T cells and GBM tumor cells directly in a tumor microenvironment.