bluuebunny/crossref_metadata_2025_split huggingface dataset:
GENE-47. A 3D ATLAS TO EVALUATE THE SPATIAL PATTERNING OF GENETIC ALTERATIONS AND TUMOR CELL STATES IN GLIOMA
Authors: Hilz Stephanie , Hong Chibo , Jalbert Llewellyn , Mazor Tali , Martin Michael , Kumar Anupam , Shelton Samuel , Wong Karen , Hayes Josie , Yu Yao , Zhang Michael , Luks Tracy , Olson Marram , Lafontaine Marisa , Shai Anny , Bengtsson Henrik , Olshen Adam , Molinaro Annette , McDermott Michael , Chang Edward , Hervey-Jumper Shawn , Berger Mitchel , Lim Daniel , Diaz Aaron , Lupo Janine , Phillips Joanna , Chang Susan , Nelson Sarah , Oldham Michael , Costello Joseph 
Published: November 2019

Abstract

BACKGROUND
Previous studies of solid tumors have been restricted in their ability to map how heterogeneous cell populations evolved within the tumor in three-dimensional (3D) space due to insufficient sampling, typically one sample per tumor, and a lack of knowledge of where within the tumor the sample was obtained. Knowledge of the extensivity of heterogeneity and how it is spatially distributed is crucial for assessing whether a therapeutic target is truly tumor-wide, and for exploring how mutations relate to heterogeneity in the local microenvironment.

METHODS
We developed a novel platform to integrate and visualize in 3D multi-omics data generated from each of 8–10 spatially mapped samples per tumor. Together, the 171 samples collected using this approach from 16 adult diffuse glioma at diagnosis and recurrence form a novel resource – the 3D Glioma Atlas.

RESULTS
By maximally sampling the tumor geography without excluding samples based on low cancer cell fraction (CCF), we identify a subpopulation of glioblastoma with pervasively lower CCF likely excluded by other atlases, such as the TCGA, that used stringent CCF cutoffs. Exome sequencing of 3D-mapped samples from lower-grade tumors revealed that clonal expansions are typically spatially segregated, implying minimal tumor-wide intermixing of genetically heterogenous cells. Heterogeneity is less spatially segregated for faster-growing high-grade tumors, suggesting that cell populations expand in these tumors differently. Recurrent low-grade tumors have greater intratumoral mutational heterogeneity than newly diagnosed tumors, though this did not translate into greater dissimilarity in gene expression profiles for recurrent tumors, suggesting minimal functional impact of this additional mutational diversity on gene expression.

CONCLUSIONS
The delineation of spatial patterns of heterogeneity that our work provides enables more informed interpretation of biopsies and greater insight into the factors shaping intratumoral variation of gene expression patterns. Ongoing work is exploring the spatial patterning of amplification events and the tumor microenvironment.
GENE-52. ANALYSIS OF RECURRENT MUTATIONS WITHIN CANCERS REVEALS PATTERNS OF DIRECTIONAL EVOLUTION IN BRAIN TUMORS
Authors: Küçükosmanoglu Asli , L Van Der Borden Carolien , Noske David , Wurdinger Tom , Westerman Bart 
Published: November 2019

Abstract

INTRODUCTION
Intratumor genetic heterogeneity is commonly caused by a stochastic evolution, but can also show remarkable selectivity resulting in directional evolution. We hypothesized that directional evolution is driven by its genetic onset-stage. This process could enforce already existing traits resulting in an enhancement of linear pathways rather than the complementary/parallel evolution.

METHODS
We generated a prediction model for directional evolution based on its genetic onset-stage. We performed a comprehensive analysis of 16 different tumor types of ~10,000 patients of whole-exome sequencing and copy number variation, obtained from The Cancer Genome Atlas.

RESULTS
We found in 5% of the patients that directional evolution occurs on a fixed genetic onset stage. There is a strong relationship between the frequencies of directional evolution and the frequencies of commonly co-occurring mutations in the onset stage. These co-occurring mutations are frequently observed in the same chromosomal region and occasionally in the same pathway. Brain tumors show a frequent directional evolution towards EGFR mutations and to a lesser extent PIK3CA mutations.

CONCLUSION
Given these strong correlations and since directional evolution is apparently a highly selective process, our prediction model could predict more effective therapies by choosing therapies targeting both the mutated gene that is affected by directional evolution as well as the commonly occurring co-mutated genes.
GENE-55. GENE EXPRESSION SIGNATURE ASSOCIATED WITH AGGRESSIVE GLIOBLASTOMA GROWTH IS ENRICHED IN CHROMATIN MODIFICATION AND STEMNESS TRANSCRIPTIONAL REGULATION PROGRAMS
Authors: Berezovsky Artem , Nuga Oluwademilade , Meng Yuling , Poisson Laila , Noushmehr Houtan , deCarvalho Ana 
Published: November 2019

Abstract
Prognosis of patients diagnosed with IDHwt glioblastoma is influenced by known clinical and demographic factors, and likely by physiological characteristics. Our goal is to determine tumor-intrinsic gene expression signatures associated with aggressive tumor growth in patient-derived xenografts (PDXs). Cancer stem cell (CSC) lines established from 10 IDHwt glioblastoma tumors were implanted orthotopically in cohorts of 10 to 15 nude mice (3x10E5 viable cells/mouse), for development of PDX under uniform conditions. Mice were monitored and sacrificed when symptomatic. Five PDX lines, presenting median survival of 29 to 59 days were classified as short (S) survivors, and 5 lines with median survival between 111 and 134 days as long (L) survivors. RNA was isolated from terminal PDX tumors (n=3/line) and sequenced using Illumina HiSeq 2000. Differential gene expression analysis between tumors in S and L survival groups was conducted using the lmFit and eBayes, and genes were ranked by Benjamini-Hochberg adjusted P-values, set to adj.p< 0.05, resulting in 1663 genes upregulated and 1539 genes downregulated in the aggressive S group. Gene ontology analysis was performed using Metacore (Clarivate Analytics) and Metascape (http://metascape.org). Chromatin modification was significantly enriched in the aggressive tumor group (Metacore, p= 1x 10–12). Remarkably, 40% (654/1663) of the genes upregulated in the aggressive PDX tumors were co-expressed with an epigenetic master regulator in the TCGA glioblastoma RNAseq dataset (cBio Portal, q< 10E-15), and this subset was also highly enriched in chromatin modification, stemness transcriptional regulation and DNA repair (q=10E-45 to q=10E-13). These results indicate that novel host-independent prognostic gene expression signatures can be derived from the PDX models and underline the potential of epigenetic regulators as therapeutic target for aggressive glioblastomas. Our results further indicate that these models are suitable for testing a new generation of epigenetic drugs currently in pre-clinical and clinical development.
GENE-56. MENINGIOMA GENOMIC SUBGROUP AS A PREDICTOR OF POST-OPERATIVE PATIENT OUTCOMES: IMPLICATIONS FOR TREATMENT AND FOLLOW-UP
Authors: Youngblood Mark , Sheth Amar , Zhao Amy , Montejo Julio , Duran Daniel , Li Chang , Tyrtova Evgeniya , Özduman Koray , Peyre Matthieu , Boetto Julien , Omay Sacit , Kalamarides Michel , Zeynep Erson-Omay E , Günel Murat , Moliterno Jennifer 
Published: November 2019

Abstract

BACKGROUND
Meningiomas can be classified into six genomic subgroups based on mutations in NF2, SMARCB1, KLF4, POLR2A, or activating variants in the PI3K or Hedgehog signaling pathways. Previous work has identified specific associations of driver events with clinical and molecular features, such as tumor location. However, their utility in predicting post-operative patient outcomes is not well-explored. Similar to recently described epigenetic signatures, underlying genomic subgroup may provide prognostic value in meningioma management.

METHODS
Targeted sequencing data was used to classify over 500 meningiomas into established genomic subgroups, and available patient outcome data was assembled based on retrospective chart reviews. Collected data included recurrence (based on imaging), extent of resection (EOR), use of post-operative radiation, and radiologic follow-up period. Statistical associations between genomic subgroup and recurrence were assessed using Fisher’s exact, Kaplan-Meier, and Cox proportional hazards modeling, including stratification based on use of radiation, EOR, grade, and location.

RESULTS
Meningiomas in the PI3K subgroup exhibited higher rates of early recurrence during the first five post-operative years. This subgroup affiliation was found to be an independent predictor of recurrence free survival from Ki-67, grade, and other clinical features. By contrast, recurrence was rare in the POLR2A, SMARCB1, and KLF4 subgroups, and was typically associated with use of post-operative radiation in these cases. The longest average recurrence free survival was observed in POLR2A mutant meningiomas.

CONCLUSIONS
Our analysis identifies divergence in meningioma patient outcomes based on genomic subgroup and suggests patients with PI3K activating events may require closer surveillance. These tumors, which often occur near and encase critical neurovascular structures along the sphenoid wing, may further benefit from consideration of radiation and emerging precision therapies. Conversely, other subgroups rarely recur, suggesting caution be invoked with use of potentially morbid adjuvant treatment.
HOUT-06. SYSTEMIC METABOLIC BIOMARKERS OBTAINED FROM COMPUTED TOMOGRAPHY (CT)-BASED BODY COMPOSITION AND SERUM GLUCOSE PREDICT SEX-SPECIFIC SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Naeem Muhammad , Jaswal Shama , Killeen Amy , Ballard David , Atagu Norman , Lancia Samantha , Salter Amber , Evans John , Mellnick Vincent , Dahiya Sonika , Chicoine Michael , Ippolito Joseph 
Published: November 2019

Abstract
In many cancers including glioblastoma, males have higher incidence and mortality. Although the mechanisms underlying this phenomenon have yet to be elucidated, there are inherent sex differences in metabolism. Males not only have higher glucose metabolism relative to females, but males also have higher amounts of abdominal visceral fat, a well-known metabolic biomarker for poor cardiovascular and cancer outcomes that could contribute to enhanced tumorigenesis. Previously, we identified that in renal cell carcinoma, females with male-pattern visceral fat did significantly poorly compared to all other patients (PMID 29558292) and that in lower grade gliomas, tumor glycolysis specifically stratified males (PMID: 28768910). We hypothesized that in glioblastoma, visceral fat would selectively stratify females and serum glucose would selectively stratify males. We retrospectively analyzed abdominal/pelvic computed tomographic (CT) datasets for the normalized relative visceral fat area (rVFA) and random glucose measurements at diagnosis from 159 males and 105 females with glioblastoma. Females with rVFA > 30.5% had significantly reduced median overall survival (OS) (11.6 months, n=63) vs females with rVFA < 30.5% (20.9 months, n=42, p=0.006), that was close to the median rVFA of 32.7%. For males, the optimized rVFA threshold was higher than the median (43.6%); males with rVFA > 58.9% had significantly reduced median OS (10.7 months, n=14) compared to males with rVFA < 58.9% (20.5 months, n=145, p=0.02). However, after adjusting rVFA for age and tumor size, it was an independent predictor in females, but not in males. Conversely, there was a male-specific survival effect of glucose: males with prediabetic random serum glucose greater than 179.5 mg/dL had shorter OS (9.9 months vs 20.9 months; p=0.007), where no glucose level could stratify females. These data support the use of metabolism to predict sex-specific cancer outcomes and suggest that interventions that target metabolism can improve sex-specific outcomes in glioblastoma.
HOUT-13. CLINICAL TRIALS IN GLIOBLASTOMA: LEARNING FROM PREVIOUS EXPERIENCES TOWARDS OPTIMAL DEVELOPMENT OF TRIAL DESIGN
Authors: Balasubramanian Adithya , Gunjur Ashray , Parakh Sagun , Cher Lawrence , Gan Hui 
Published: November 2019

Abstract

INTRODUCTION
We undertook a literature review testing the hypothesis that inefficiencies in the Phase 2/3 transition contributes to most GBM Phase 3 trials (P3T’s) being negative.

METHODS
Studies between 2005–2019 inclusive were identified though MEDLINE(R) using keywords and MeSH terms, and manual bibliography searches. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&AG). For each P3T, Phase 2 trial (P2T) data was “optimally matched” where same drug was used in similar schedule and GBM population; “partially matched” where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. Data were compared by Pearson Correlation, t-test or chi-square as appropriate.

RESULTS
18 relevant P3T’s and 15 P2T’s were identified. Median values for median progression free survival (mPFS) and median overall survival (mOS) in P3T’s were 7.9 and 17.9 mths respectively for first line studies; 2.2 and 7.9 mths for recurrent studies. These were 11.8 and 20.4 mths for 1st line P2T’s, suggesting selection bias, and 3.3 and 7.5 mths for recurrent studies. 50% of P3T had optimally matched P2D, with high concordance for mPFS (r2= 0.90, p< 0.01) and mOS (r2= 0.84, p< 0.01) between corresponding P3T and P2T. The remain 50% of P3T had ‘partially matched’ (22.2%) or lacked P2T data (27.8%). ‘Partially matched’ trials also had a high concordance for mPFS (r2= 0.92, p< 0.01) and mOS (r2= 0.83, p< 0.01). However, 80% of P3T planned for HR didn’t meet expected benefit. All first-line P2T with mPFS< 15 months and/or OS< 22 months had negative P3T. All recurrent P2T with mPFS< 5 months and mOS< 12 months had negative P3T. Impact of sponsors and molecular subtypes will be presented.

CONCLUSIONS
This review identified issues (selection bias, lack of appropriate P2T and possible underpowered P3T’s) at the Phase 2/3 interface and provides data for future trial design.
HOUT-21. CHARACTERISTICS OF SHORT-TERM SURVIVAL IN PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE ANALYSIS
Authors: Barbour Andrew , Healy Patrick , Lipp Eric , Herndon James , Thomas Leslie , Johnson Margaret , Ashley David , Desjardins Annick , Randazzo Dina , Friedman Henry , Kirkpatrick John , Peters Katherine 
Published: November 2019

Abstract
We sought to identify characteristics of glioblastoma (GBM) patients with short survival (< 10 months) in order to identify prognostic factors useful for guiding treatment management. This is an IRB-approved retrospective analysis of adult newly diagnosed GBM patients from 2008–2016 who survived < 10 months from diagnosis. We extracted demographics, tumor characteristics, and treatment details. We calculated survival from surgical diagnosis to date of death. The cohort includes 197 subjects (61% male) with a median age of 68 years (range 19–94). The majority (93%) are non-Hispanic white. The cohort has a median survival of 144 days (95% CI: 130–160). We focused on traditional prognostic indicators, including extent of surgical resection and KPS. A majority had biopsy only (n=92, 46.7%) rather than gross total (n=59, 29.9%) or subtotal (n=46, 23.4%) resection. Moreover, 160 out of 197 patients had a documented KPS with a majority being below 90 (KPS=70–80 (n=96); KPS < 70 (n=31)). Of 179 patients with data on RT course, 18% (n=32) received no RT or opted for hospice after diagnosis, 3% (n=6) received only RT, 54% (n=97) received RT+temozolomide (TMZ), and 24% (n=43) received RT+TMZ+bevacizumab. Of the 147 subjects receiving RT, 79% completed their RT course as prescribed. Most commonly, RT was prescribed as a 6- to 6-1/2-week course (85%), typically 59.4 Gy (45Gy primary, 14.4Gy boost) over 33 fractions or 60 Gy over 30 fractions. In contrast, 15% received a 3-week RT course, typically scheduled as 15 fractions of 2.667 Gy. We concluded that GBM patients with survival < 10 months were more likely to have biopsy only and a KPS < 90, notably associated with poorer prognosis. We continue to explore this dataset for further prognostic factors, particularly inability to complete planned RT course, and are comparing these traits to a larger cohort.
HOUT-25. PROGNOSTIC FACTORS FOR PROLONGED LENGTH OF STAY AND READMISSION FOLLOWING CRANIOTOMY FOR PRIMARY BRAIN TUMORS
Authors: Tran Nam , Amer Aboubakr , Alhazaimeh Mohammah , Tran Quan , Schroering Ashleigh , Agoris Corin , Clark Anthony , Imam Muhammad , Rao Gautam , Weisman Sydney , Dutta Mudit , Dhanashekar Anu , Etame Arnold , Sahebjam Solmaz 
Published: November 2019

Abstract

BACKGROUND
Escalating costs of healthcare has brought on a paradigm shift that links reimbursement to quality care. Important quality metric measures include hospital length of stay, 30-day readmission and re-operation rates. Identifying modifiable factors can provide information essential for reducing medical costs and improving the quality of medical care patients receive.

METHODS
The authors performed a retrospective chart review of all patients who underwent craniotomies for resection of primary brain tumors at the Moffitt Cancer Center from 2004–2014. Patient demographics (age, gender), clinical characteristics (comorbidities, steroid dose, seizure status, neurologic deficit, KPS), tumor characteristics (tumor type, location), surgical factors (primary or redo, length of surgery, blood loss), 30-day complications (infection, DVT/PE, seizure), 30-day readmission, and length of stay were assessed. Multivariate analysis was performed to determine risk factors associated with prolonged length of stay and 30-day readmission.

RESULTS
806 consecutive patients underwent craniotomies for primary brain tumors. High BMI (p< 0.001), CAD (p< 0.001), hyperglycemia (p< 0.04), peri-operative seizures (p< 0.03), low Karnofsky Performance Status score (p< 0.001), prolonged operative times (p< 0.001), and surgical blood loss (p< 0.001) contributed to prolonged length of hospital stay; whereas, preoperative hyperglycemia and perioperative seizures were associated with 30-day readmission.

CONCLUSIONS
This study identifies modifiable risk factors that contribute to poorer outcome following craniotomies for primary brain tumors and lays the groundwork for risk stratifying patients undergoing surgery.
HOUT-26. FACTORS ASSOCIATED WITH TREATMENT DELAY IN CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Barbaro Marissa , Pan Peter , Torres Sarah , Thakur Kiran , Welch Mary 
Published: November 2019

Abstract

OBJECTIVE
To identify clinico-radiographic characteristics associated with delayed treatment initiation in central nervous system lymphoma (CNSL).

INTRODUCTION
Clinical and radiographic characteristics of CNSL are often varied with a broad differential diagnosis, potentially leading to delays in diagnosis and treatment.

METHODS
A single-center retrospective review of clinico-radiographic data was performed at Columbia University Irving Medical Center in patients with pathologically confirmed CNSL diagnosed from 1/2010–12/2018. Descriptive statistics and univariate logistic regression were used to identify variables associated with delayed treatment. Using visual binning, delayed treatment time was designated as >33 days from first presentation to medical attention to first chemotherapy for CNSL. Variables of interest included demographic data, presenting symptomatology, radiographic characteristics, location of initial presentation, and diagnostic and therapeutic interventions performed before biopsy.

RESULTS
Seventy patients (36 men (51%); median age at diagnosis 70 years, IQR 14.75 years; median time from first presentation to treatment 21 days, IQR 41.25 days) were included. Presentation with cognitive deficits suggested a strong, but not statistically significant, association with delayed treatment (OR=1.93, p=0.20), whereas presentation with focal neurologic deficits suggested protection against delayed treatment (OR=0.25, p=0.05). Initial presentation to a hospital suggested a strong, but not statistically significant, trend against delayed treatment (OR=0.41, p=0.08). Multifocal disease on neuroimaging (OR=7.18, p=0.001), pre-biopsy cerebrospinal fluid (CSF) sampling (OR=5.18, p=0.002), and pre-biopsy immunomodulatory treatment (including high-dose intravenous corticosteroids) for suspected neuroinflammatory disease (OR=6.33, p=0.03) had statistically significant associations with delayed treatment. Antimicrobial treatment before biopsy for suspected CNS infection suggested a trend toward delayed treatment, but the association was not statistically significant (OR=5.1, p=0.06).

CONCLUSIONS
Multifocal disease and pre-biopsy CSF sampling and immunomodulatory therapy were associated with delayed treatment initiation for CNSL in our single-center cohort. Recognizing factors associated with delayed treatment may allow physicians to circumvent these factors and permit more rapid diagnosis through tissue sampling.
HOUT-27. HEALTHCARE RESOURCE UTILIZATION OF LEPTOMENINGEAL CARCINOMATOSIS IN THE UNITED STATES
Authors: E Hodges Sarah , Yang Zidanyue , Charalambous Lefko , M Adil Syed , Kiyani Musa , Musick Alexis , M Edwards Ryan , Parente Beth , Lee Hui-Jie , Peters Katherine , Fecci Peter , Lad Shivanand 
Published: November 2019

Abstract

INTRODUCTION
Leptomeningeal carcinomatosis (LC) represents a late complication of primary cancer spreading to the leptomeninges.

METHODS
The IBM MarketScan® Research databases were queried for adult patients diagnosed with LC between 2001 and 2015, secondary to four primary solid tumors (breast, lung, gastrointestinal, and melanoma). The primary outcome was overall healthcare resource utilization (HCRU) for each primary cancer subgroup, quantified as the total cost at baseline (1-year pre-LC diagnosis) and 30, 90, and 365 days post-LC diagnosis. The secondary outcome was interventional treatments for LC.

RESULTS
We identified 4,961 cases of LC (46% breast cancer, 35% lung cancer, 14% GI cancer, and 5% melanoma). The median baseline Elixhauser comorbidity index was lower for patients with LC secondary to breast cancer (19) relative to those with primary lung, GI, or melanoma (22). The overall median follow-up length was 66 days. The breast and lung cancer groups had the longest and shortest post-LC diagnosis follow-up at 84 and 51 days, respectively. Cost data demonstrated high baseline total costs for the year preceding LC diagnosis (median $117,219). Cumulative median service and medication costs at 365 days post-LC diagnosis were the highest for the GI subgroup ($167,768) and lowest for the lung cancer subgroup ($145,244). In the first 30 days post-diagnosis, 66.9% sought treatments of any kind: 40% radiotherapy, 28% therapeutic lumbar puncture (TLP), and 14% Ommaya insertion. Of the 747 (15%) patients surviving and continuously enrolled to 365 days post-diagnosis, 78.8% had at least one encounter for treatments: 58% radiotherapy, 30% TLP, and 15% Ommaya insertion.

CONCLUSION
In this large nationwide study of LC associated with four major primary cancers, breast cancer patients had the fewest comorbidities at baseline and the longest follow-up, while those with GI cancer had the highest cost both at baseline and one year after LC diagnosis.