bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-08. TUMOR-IMMUNE INTERACTIONS ARE DYNAMIC AND INFLUENCE THE EVOLUTIONARY TRAJECTORY OF ADULT DIFFUSE GLIOMA
Authors: Varn Frederick , Johnson Kevin , Barthel Floris , Kim Hoon , Wade Taylor , Lodha Disha , Ajaib Shoaib , Ahmed Nazia , Garofano Luciano , D’Angelo Fulvio , Stead Lucy , Noushmehr Houtan , Iavarone Antonio , Verhaak Roel ,   The GLASS Consortium
Published: December 2020

Abstract
Diffuse glioma is an aggressive brain cancer that is characterized by a poor prognosis and a universal resistance to therapy. The evolutionary processes behind this resistance remain unclear. Previous studies by the Glioma Longitudinal Analysis (GLASS) Consortium have indicated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single cell studies have revealed that malignant glioma cells are highly plastic, and capable of changing their cell state in response to diverse challenges in their microenvironment. The tumor immune response has been implicated as a major driver of these malignant cell state transitions, and is known to be affected by the administration of therapy, but the extent to which tumor genetics, therapy, and the different components of the immune response interact to influence a glioma’s evolutionary trajectory are poorly understood. To further investigate these factors, we collected DNA and RNA sequencing data on pre- and post-treatment tumor pairs from over 150 glioma patients that have received chemotherapy, radiotherapy, and/or immune checkpoint blockade agents. By integrating mutation, copy number, and in silico deconvolution analyses of bulk transcriptome data across the three molecular subtypes of diffuse glioma, we show that longitudinal increases in chromosomal instability and gene fusions associate with decreased immune infiltrate and altered cell states at recurrence. We additionally find that specific molecular alterations and malignant cell states associate with unique inflammatory and immunosuppressive programs in tumor-associated macrophages and microglia. Lastly, we show that the abundance of T cells in the tumor microenvironment does not associate with changes in neoantigen depletion and the acquisition of antigen presentation machinery defects, suggesting minimal immunoediting activity over time. Collectively, our results indicate that the administration of therapy can alter the dynamics of tumor-immune interactions in glioma, resulting in new steady-states at recurrence that can be subsequently targeted.
EPCO-28. SPHEROID STUDY OF A GLIOBLASTOMA TUMOR IDENTIFIED A SUBCLONAL MUTATION OF EGFR T790M
Authors: Rosenberg Shai , Steinberg Eliana , Yaacov Adar , Lutati Ranel , Mordechai Anat , Linetsky Eduard , Lossos Alexander , Paldor ido , Benny Ofra 
Published: December 2020

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common and the most devastating primary brain cancer in adults. Precision genetic medicine approach does not provide benefit to majority of GBM patients. A major reason for this is tumor heterogeneity harboring potential resistance mechanisms. Here, we describe an approach to grow spheroids of GBM, containing tumor, stroma and vascular tissues. We show that this approach can identify undetected subclonal driver mutations that can potentially cause drug resistance later in the disease course.

METHODS
We grew spheroids of a GBM patient in a multi-well array and monitored them visually. Exome sequencing of the parental tumor (coverage of 557X) and of spheroids after 10 days (n=3) and 20 days (n=5) of growth was performed. In addition, we sequenced six spheroids that were grown for 10 days and treated by Temozolomide for the next 10 days.

RESULTS
70 somatic mutations were detected in the parental tumor. 42/70 of the tumor’s somatic mutations were also detected in the spheroids. 192 somatic mutations were detected in the spheroids only and not in the parental tumor despite high coverage sequencing of the parental tumor. In cancer genes: six somatic mutations were identified in the parental tumor, 5/6 were also detected in the spheroids and 13 mutations were detected only in the spheroids. EGFR V774M mutation was detected in both tumor and spheroids. However – EGFR T790M was independently detected in 7/11 of the spheroids sequenced after 20 days or growth but not in the parental tumor.

CONCLUSION
Analysis of GBM spheroids enables detection of rare subclonal mutations not detected in parental tumor. We hypothesize that this is due to positive selection of the ex vivo growth conditions. This analysis enabled detection of EGFR T790M – an important targetable resistance mutation in lung cancer not previously described in primary GBM.
EPCO-36. GENOMIC INSTABILITY AND TRANSCRIPTOMIC SIGNATURES UNDERLYING EPIGENETIC MENINGIOMA SUBGROUPS REVEALS MECHANISMS OF IMMUNE INFILTRATION AND THERAPEUTIC VULNERABILITIES
Authors: Choudhury Abrar , Magill Stephen , Prager Briana , Eaton Charlotte , Lam Tai-Chung , Pu Jenny Kan-Suen , Li Lai Fung , Leung Gerald , Vasudevan Harish N , Lucas Calixto-Hope G , Chan Jason W , Wendt Jake , Guerra Geno , Susko Matthew S , Braunstein Steve , Villanueva-Meyer Javier , Bush Nancy Ann Oberheim , Sneed Penny K , Berger Mitchel , Perry Arie , Solomon David , McDermott Michael W , Costello Joseph , Francis Stephen , Rich Jeremy , Raleigh David 
Published: December 2020

Abstract

BACKGROUND
Meningioma treatments are limited due to incomplete understanding of meningioma biology. To address this, we performed multiplatform molecular profiling on 565 meningiomas with comprehensive clinical data to define genomic drivers and identify therapeutic vulnerabilities.

METHODS
DNA methylation profiling was performed on meningiomas from UCSF (n=200, discovery) and Hong Kong University (n=365, validation). Median follow-up was 5.6 years, and there were 388/142/35 WHO grade I/II/III meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on UCSF meningiomas. Cell type deconvolution, metagenomics, CRISPR, and pharmacology were used for mechanistic and functional validation.

RESULTS
Unsupervised hierarchical clustering of differentially methylated DNA probes revealed that meningiomas were comprised of 3 epigenetic subgroups associated with good, intermediate, and poor outcomes, with representation from all WHO grades in each subgroup. Meningiomas from the subgroup with the best outcomes (52% WHO grade I) were distinguished by recurrent gain of Chr5. Meningiomas from the subgroup with intermediate outcomes (31% WHO grade II) were distinguished by genomic stability, enrichment of innate immune genes, and immune infiltration in the setting of endogenous retroviral gene re-expression, a mechanism of immune recruitment. The most aggressive subgroup of meningiomas (57% WHO grade III) was distinguished by genomic instability, including recurrent loss of Chr22q harboring NF2, and decreased immune infiltration. Consistently, NF2 suppression in primary meningioma cells derived from immunogenic meningiomas decreased expression of innate immune genes critical for immune recruitment, suggesting a novel immunostimulatory function of NF2. The most aggressive subgroup of meningiomas were further distinguished by activation of the mitogenic FOXM1 transcriptional program, and recurrent loss of Chr9p harboring CDKN2A/B, which rendered primary meningioma cells from this subgroup susceptible to CDK4/6 inhibitors.

CONCLUSIONS
Meningiomas are comprised of 3 epigenetic subgroups defined by genetic mechanisms driving immune infiltration in the tumor microenvironment and meningioma cell proliferation.
EPCO-37. USING SINGLE-CELL RNA SEQUENCING TO IDENTIFY CELLULAR HETEROGENEITY WITHIN NON-FUNCTIONING PITUITARY ADENOMAS
Authors: Jain Saket , Babikir Husam , Shamardani Karin , CatalanSaavedra Francisca , Diaz Aaron , Aghi Manish 
Published: December 2020

Abstract
Pituitary adenomas (PA) are one of the most common primary brain tumors and comprise approximately 15% of brain neoplasms. Most PA are histologically benign but can cause significant morbidity. Previous studies utilized whole-genome and exome sequencing to identify a few somatic variants, but no recurrent mutations were observed. Further studies are warranted to identify driver mutations occurring at low frequencies. We used single-cell RNA sequencing (10X Genomics) to investigate cellular heterogeneity in three non-functioning pituitary adenomas. Our analysis identified discrete clusters of cells associated with specific functional pathways. One of these clusters corresponded to cells expressing genes related to metabolic pathways, primarily lipid metabolism. Another cluster consistent amongst the three patients comprised of cells involved in antigen presentation and processing. In addition, the copy number variation analysis highlighted distinct chromosomal alterations within our samples. Interestingly, we were able to identify clonal variations within each tumor based on chromosomal aberrations. For example, in our first patient, we observed a gain of chromosome 19 and loss of chromosome 2. Our analysis showed three different clonal populations within this tumor. All three populations harbored the loss of chromosome 2, one population exhibited gain of chromosome 19, while a third population exhibited loss of chromosome 19. These early results indicate the loss of chromosome 2 as an early event in tumorigenesis and gain/loss of chromosome 19 as late events. We are currently in a process of identifying somatic variations within these tumors by variant calling. Currently we are expanding our analysis to 20 non-functional PA. Mapping the single-cell gene expression profiles with mutational phylogeny will reveal the differences in clonal evolution within the tumor subtypes. This study will help us define the molecular fingerprint of pituitary adenomas and provide insights which could be utilized in the clinic for better management of these tumors.
EPID-04. THE SINGLE CENTER STUDY FOR BRAIN METASTASES OF UNDIAGNOSED PRIMARY TUMOR AND THE ROLE OF SURGICAL REMOVAL
Authors: Shimizu Yuzaburo , Suzuki Mario , Akiyama Osamu , Kondo Akihide 
Published: December 2020

Abstract

BACKGROUND
The diagnosis of a brain metastases is generally made during the follow up examinations of patients with primary known cancer. However, there are some patients presenting brain metastases as the first manifestation of a previously undiagnosed primary tumor (UDP) pathological confirmation of the diagnosis. The timing of a subsequent neurosurgical intervention is influenced by the distribution of primary tumors in UDP patients. The purpose of this study was to investigate the optimal diagnostic approach and the role of surgery for UDP patients.

METHODS
In a retrospective study, 35 patients admitted to our institution and underwent brain tumor removal from 2017 to 2019 with the diagnosis of cerebral metastases and diagnosed lung cancer as primary tumor subsequently, or previously diagnosed lung cancer.

RESULTS
UDP patients represented 46% of the whole group. Primary tumor subtype was the adenocarcinoma (n=13, 81%), small cell carcinoma (n=2, 13%), and neuroendocrine carcinoma (n=1, 6%). They did not have bronchoscopy nor excision of lung cancer. On the other hand, the patients previously diagnosed lung cancer represented 54% and subtype was adenocarcinoma (n=14, 74%) and small cell carcinoma (n=5, 26%). EGFR mutation was detected from 7 patients (44%) in UDP group and treated by EGFR tyrosine kinase inhibitor.

CONCLUSION
The significance of surgical intervention in metastatic brain tumors has been limited. However, active surgical intervention in UDP patients could identify not only histological diagnosis but also molecular biological characteristics. Our study suggests the possibility to avoid whole brain radiation in UDP patient by the active surgery.
EPID-20. NOVEL GLIOBLASTOMA POPULATION-BASED HISTOLOGIC STAIN NORMALIZATION
Authors: Agraz Jose , Grenko Caleb , Viaene Angela , MacLean Nasrallah , Feldman Michael , Akbari Hamed , Bakas Spyridon 
Published: December 2020

Abstract
Histopathologic evaluation has been an integral part of clinical diagnosis for central nervous system tumors, providing information essential for classification, management, and treatment of the disease. Hematoxylin and eosin (H&E) staining is routinely used in histology, providing detail of tissue morphology, structure, and cellular composition. MOTIVATION: Slide staining is rife with color intensity variations, mainly due to differences in materials and staining protocols among others. These variations introduce inaccuracies in downstream computational analysis and quantification of disease, disabling the generalization of computational models. To overcome these variations, current approaches arbitrarily select a slide within the cohort to normalize all slides of the cohort, leading to non-reproducible results in other cohorts. We develop a population-based whole slide image (WSI) normalization method based on overall region driven stain vectors and color histogram, weighted by corresponding percent contribution to overall slide (PCOS). METHODS: We identified a cohort of 509 H&E stained WSIs with corresponding anatomical annotations from the Ivy Glioblastoma Atlas Project. These WSIs and annotations were reviewed by two neuropathologists for correctly annotated regions. Each region was weighted according to PCOS, WSIs with PCOS &lt; 0.05% were discarded. Then, the optical densities and histograms calculated. Resulting color histogram and optical density was applied to the WSI cohort. Finally, stain intensity variability pre- and post- normalization was compared. RESULTS: Normalizing WSIs based on our approach, results in a significant (p &lt; 0.01, Wilcoxon) improvement in color intensity variation for eight of nine regions tested, with the exception of “Pseudopalisading Cells with no visible Necrosis” (p = 0.8). DISCUSSION: This novel transformative technique is insensitive to artificially staining background density and straightforward to apply. Furthermore, the approach shows promise towards a viable and robust tool for stain normalization in large WSIs cohorts, with the potential towards a stain normalization standard generalizable to other diseases.
EPID-21. EPIDEMIOLOGY OF MALIGNANT GLIOMAS IN KOREA USING NATIONWIDE BIG DATA FROM 2007 TO 2017
Authors: Ho Yang Seung 
Published: December 2020

Abstract
The purpose of the study of the study is to investigate the incidence, prevalence, and survival of malignant glioma (MG) using population-based Korean National Health Insurance Database (NHID) data. We identified patients with MG as C71 codes in KCD 5–7 according to ICD-10 from 2007 to 2017. Epidemiological characteristics of MG, including annual incidence, prevalence, mortality rates, and survival rates, were collected and analyzed according to socioeconomic state (SES) and treatment modalities. 45,066 new patients with MG were identified from 2007 to 2017. An age-adjusted incidence of 7.47 per 100,000 people. The mean age at diagnosis was 54 years. The male to female ratio was 1.11. Mortality and survival probability were analyzed among total subjects and in subgroups. The mortality of female patients was lower than that of male patients (hazard ration, 0.69; 95% CI, 0.67–0.71), and younger age and higher income had significantly lower mortality rate. The 1-, 3-, 5-, and 10-year total relative survival rates were estimated at 63.4%, 46.2%, 39.4%, and 34.8%, respectively. This is the first population-based study to determine the incidence and prevalence of MG according to epidemiological characteristics in Korea using NHID data. Our study found that female sex and high SES were factors that significantly lowered the mortality rate in MG, and younger groups and operated patients showed significantly higher survival rates.
EPID-24. OBESITY IN MALES WITH MENINGIOMA: A U.S. POPULATION-BASED STUDY
Authors: Shahin Maryam , Rae Ali , Ramos Christian Lopez , Bagley Jacob , Bowden Stephen , Bullis Carli , Cetas Justin , Han Seunggu 
Published: December 2020

Abstract

BACKGROUND
The female predominance of meningiomas may reflect a hormonal influence on tumorigenesis. Obesity alters steroid synthesis and chronically exposes men to hyperestrogenemia.

OBJECTIVE
Identify differences in males undergoing craniotomy for meningioma compared to other tumors or aneurysms.

METHODS
The National Surgical Quality Improvement Program was retrospectively queried from 2013–2018 for cases of craniotomy for resection of meningioma, other tumor, and aneurysm by CPT code in male patients and confirmed with postoperative ICD-10 code. Height and weight data were used to create body mass index (BMI): underweight (&lt; 18.5), normal (18.5 to&lt; 25), overweight (25 to&lt; 30), class I obesity (30 to&lt; 35), class II obesity (35 to&lt; 40), and class III obesity (40+).

RESULTS
We identified 2,458 males who underwent craniotomy for meningioma, 9,889 for other tumor, and 386 for aneurysm. Using multivariable logistic regression, age (OR 1.01 per year, 95% CI 1.01-1.01, p&lt; 0.001), diabetes mellitus (OR 1.32, 95% CI 1.17–1.48, p&lt; 0.001), and increasing BMI (overweight: OR 1.55, 95% CI 1.36–1.76, p&lt; 0.001; class I: OR 2.00, 95% CI 1.75–2.30, p&lt; 0.0001; class II: OR 2.05, 95% CI 1.24–1.76, p&lt; 0.001; class III: OR 1.47, 95% CI 1.24–1.76, p&lt; 0.0001) were significantly and independently associated with craniotomy for meningioma compared to other tumor or aneurysm. For other tumor, higher BMI was associated with lower likelihood (overweight: OR 0.70, 95% CI 0.62–0.79, p&lt; 0.001; class I: OR 0.55, 95% CI 0.49–0.63, p&lt; 0.001; class II: OR 0.52, 95% CI 0.44–0.62, p&lt; 0.001; class III: OR 0.74, 95% CI 0.63–0.87, p&lt; 0.001). For aneurysm, there was no significant difference (overweight p=0.70; class I p=0.65; class II p=0.76; class III p=0.57).

CONCLUSIONS
BMI independently predicts having craniotomy for meningioma when compared to other tumor or aneurysm amongst US male patients.
EPID-26. CLINICAL AND HISTOLOGICAL CHARACTERIZATION OF PRIMARY CENTRAL NERVOUS SYSTEM SARCOMA IN PEDIATRICS. A SINGLE INSTITUTION EXPERIENCE IN A MIDDLE-INCOME COUNTRY
Authors: Cabrera Edgar , Aponte Nelson , Garcia Johnny , Salazar Fredy , Bouffet Eric , Bartels Ute , Jaramillo Lina , Fonseca Adriana 
Published: December 2020

Abstract

INTRODUCTION
Primary central nervous system (CNS) sarcomas are rare mesenchymal non-meningothelial tumors accounting for less than 0.2% of intracranial lesions. Diagnosis and management are challenging due to the current lack of substantive clinical, histological and molecular data.

METHODS
We retrospectively identified all patients with diagnosis of primary CNS sarcoma at the Hospital Fundación Pediatrico la Misericordia (HOMI) in Bogota, Colombia. We collected patient demographics, disease characteristics, and outcomes for analysis.

RESULTS
Between 2008 and 2020, twenty-four consecutive patients were diagnosed at the HOMI representing 6% of all CNS tumors diagnosed over the same time period. The median age at presentation was 9.48 years (range:1.6–13.4). The median time of symptoms prior to diagnosis was 2 weeks (0.1–24). The most common presentation was headache (21/24- 89%) and vomiting (19/24- 79%). The frontal lobe was involved in 63% of patients (15/24) and only one patient presented with a cerebellar lesion. Histologically, these tumors were characterized by a pleomorphic spindle cell architecture and high mitotic activity. All samples lacked immunoreactivity to GFAP, CD34, EMA, and S100 and all samples had strong nuclear immunopositivity for TLE-1; BCL-2 was reactive in eighteen cases. Gross total resection was attained in fifteen patients, most patients received focal radiation therapy and ICE chemotherapy. Progression-free survival at 12 and 24 months was 57% and 31% respectively. Overall survival was 77% at 12 months and 39% at 24 months. Thirteen patients relapsed, 11 presented with local failures, and 2 with intracranial recurrences outside of the radiation field.

CONCLUSION
Our study identifies TLE-1 as a diagnostic marker of primary CNS sarcoma, a highly malignant supratentorial tumor of childhood. Further molecular studies are urgently needed to elucidate the biology of this disease and the unusually high incidence observed in the Colombian pediatric population.
EPID-27. THE VANISHING TUMOR PHENOMENON IN THE DIAGNOSIS OF PRIMARY CNS LYMPHOMA
Authors: Yim Eunji , Umemura Yoshie , Sun Yilun , Junck Larry 
Published: December 2020

Abstract

INTRODUCTION
Steroid is commonly initiated for newly recognized brain tumors. For primary CNS lymphoma (PCNSL), however, its lympholytic effect can partially treat the tumor and obfuscate the surgical-pathological diagnosis needed to initiate chemotherapy. Evidence for this remains controversial. In this study we investigated the incidence of the vanishing tumor phenomenon and its association with steroid use.

METHODS
Patients &gt; age 18 with PCNSL were identified from January 1, 2000 to April 30, 2020 within the University of Michigan Health System. Clinic and operative notes, pathology, imaging, and lumbar puncture results were reviewed. Inclusion required histopathologic diagnosis from brain tissue, cerebrospinal fluid, or autopsy, including diagnosis on repeat biopsy. Patients with prior/concurrent systemic lymphoma, HIV, organ transplant, or diagnosis established from primary ocular disease were excluded. Date(s) of biopsy, steroid initiation, and recurrence (by imaging) were abstracted. We defined vanishing tumor as a lesion whose radiographic improvement or disappearance resulted in deferred or nondiagnostic biopsy, with later confirmation of PCNSL. Steroid use and vanishing tumor were modeled using univariable logistic regression.

RESULTS
We identified 162 cases of PCNSL, of which 103 patients (63.6%) received steroids prior to biopsy. Twenty-three had vanishing tumor: 11 with deferred biopsies, 12 with non-diagnostic biopsies. Twenty-two of the 23 received steroid. Mean cumulative dose, in dexamethasone equivalents, was 555 + 704 mg prior to nondiagnostic/deferred biopsy (N=17) compared to 186 + 376 mg prior to successful biopsy (N=76) (Wilcoxon p&lt; .001). Median time to recurrence after deferred or non-diagnostic biopsy (N=21) was 53 days (range: 8–648); two cases never recurred. Steroid use increased the risk of vanishing tumor by 14% per 100 mg dexamethasone equivalent (95% CI of odds ratio [1.03–1.29], p=0.02).

CONCLUSION
Vanishing tumor phenomenon is common in PCNSL, delays diagnosis, and is driven by steroid use.