tbuckley/cabot-search huggingface dataset:
QOLP-30. SURVIVAL, LOCAL CONTROL, AND HEALTH RELATED QUALITY OF LIFE IN OLIGOMETASTATIC AND POLYMETASTATIC SPINAL TUMORS: A MULTICENTER, INTERNATIONAL STUDY
Authors: Ori Barzilai, Anne Versteeg, Arjun Sahgal, Laurence Rhines, Mark Bilsky, Daniel Sciubba, James Schuster, Michael Webber, Peter Varga, Stefano Boriani, Chetan Bettegowda, Michael Fehlings, Yoshiya Yamada, Michelle Clarke, Paul Arnold, Ziya Gokaslan, Charles Fisher, Ilya Laufer
Journal: Neuro-Oncology (2018)

Oligometastatic disease (5 metastases) is considered an intermediate cancer state of limited metastatic capacity and improved prognosis. Hence, in recent years, treatment of oligometastatic spinal disease has trended towards more definitive, ablative therapies. Little is known about the actual prognosis of patients presenting with oligometastatic spinal disease. The focus of this study was to compare oligometastatic spine patients to those with polymetastatic disease (>5 metastases). This is an international, multicenter analysis of prospectively collected data. Data collected included demographics, survival, local control, histology, number and location of spine metastases, epidural spine cord compression (ESCC), the Spinal Instability Neoplastic Score (SINS), systemic disease burden, and treatment details. Health-related quality of life (HrQOL) measures included; numeric rating scale (NRS) for pain, EuroQol-5D (EQ-5D-3L), short form 36 version 2 (SF-36v2) and the spine oncology study group outcomes questionnaire (SOSGOQ). A total of 393 patients were included, of which 215 presented with oligometastatic disease and 178 with polymetastatic disease. A significant survival advantage was found for patients presenting with oligometastatic disease compared to those with polymetastatic disease at time of initial treatment of spinal metastases. This survival advantage was noticeable in both operative and non-operative patients. Local control rates were higher in the oligometastatic group for the spinal level treated. Furthermore, both groups experienced significant improvement in multiple HrQOL measures at 6 months post-treatment with no differences in these outcome measures between the two groups. At time of treatment of spinal metastatic disease, oligometastatic disease offers a significant survival advantage compared to polymetastatic disease, regardless of treatment choice. Local control can be achieved in both groups. HrQOL measures improve in both groups post-treatment, thus demonstrating a palliative treatment benefit for all treated patients. Our results support the oligometastatic theory and the current trend of ablative treatment for oligometastatic spine disease.
ATIM-06. PHASE 2 TRIAL OF SL-701 + BEVACIZUMAB IN PATIENTS WITH PREVIOUSLY TREATED GLIOBLASTOMA (GBM) MEETS PRIMARY ENDPOINT OF OS-12, WITH PRELIMINARY CORRELATION BETWEEN LONG-TERM SURVIVAL AND TARGET-SPECIFIC CD8+ T CELL IMMUNE RESPONSE
Authors: David Peereboom, L Burt Nabors, Priya Kumthekar, Michael Badruddoja, Karen Fink, Frank Lieberman, Surasak Phuphanich, Erin Dunbar, Tobias Walbert, David Schiff, David Tran, Lynn Ashby, Nicholas Butowski, Fabio Iwamoto, Ross Lindsay, John Bullington, Michael Schulder, Jonathan Sherman, Chris Brooks, David Reardon
Journal: Neuro-Oncology (2018)

SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM targets: interleukin-13 receptor alpha-2, EphrinA2 and Survivin. Updated Phase 2 data are reported. Patients with previously treated GBM, bevacizumab (bev)-naive, HLA-A2+, and KPS>60, were enrolled. SL-701 with adjuvant poly-ICLC was dosed biweekly with bev (10 mg/kg) for 6 months, then q28 days. Primary endpoint was OS-12, with statistical significance determined if lower bound of 2-sided 95% Clopper Exact confidence interval (CI) is >20%. Target-specific CD8+ T-cell frequency was assessed by flow cytometry. 28 patients received median of 13 SL-701 doses with bev. Most frequent treatment-related adverse events (TRAEs) were fatigue (39%) and injection site reaction (25%). Grade 3 TRAE was fatigue (3.6%); there were no other grade 3 TRAEs. Disease control rate (complete response [CR], partial response [PR], stable disease) was 54% (n=15), with 2 CRs and 2 PRs. Median duration of disease control was 8.8 months (95% CI 3.7, NE). Median OS was 11.7 months (95% CI: 7.1, NE). The primary endpoint was met with a 50% OS-12 (95% CI: 30.6, 69.4). Target-specific CD8+ T cell activity was detected at 8–24 wks, the majority occurring by wk 16. Long-term survivors were largely comprised of patients with target-specific CD8+ T-cell responses; median OS of these immune responders was not reached. The Phase 2 trial of SL-701 + bev in previously treated GBM met its primary endpoint with a 50% OS-12. The regimen was well-tolerated and demonstrated objective responses, including CRs. There was an even more pronounced survival signal, as well as an encouraging survival tail comprised largely of target-specific CD8+ T cell responders, and the median OS of these immune responders was not reached. Updates around next steps, including leveraging potential immune-related biomarkers in a registration-directed trial design, will be provided.
TMOD-23. DYNAMIC PATTERNS OF GLIOBLASTOMA CLONAL EVOLUTION IN RESPONSE TO CHEMORADIOTHERAPY
Authors: Maleeha Qazi, Chitra Venugopal, Parvez Vora, Allison Nixon, Kimberly Desmond, Mohini Singh, Savage Neil, Minomi Subapanditha, Amy Tong, David Bakhshinyan, Annie Mak, Nicholas Yelle, Naresh Murty, Kevin Brown, Nicholas Bock, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2018)

Despite aggressive multimodal therapy, glioblastoma (GBM) remains incurable and inevitably relapses. Recent data have implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in GBM. Models that capture the evolution of GBM biology in response to standard-of-care (SoC) chemoradiotherapy will allow for the identification of cellular mechanisms that govern GBM therapy failure. In this study, we coupled cellular DNA barcoding technology with our novel patient-derived xenograft SoC model (combined temozolomide and radiation treatment) to profile the clonal evolution of GBM stem cells (GSCs) through therapy. We report the successful barcoding of patient-derived primary, treatment-naive GSCs at a single cell resolution that were expanded into clonal populations, intracranially engrafted in immune-deficient mice, and treated with SoC therapy. We performed MRI imaging to identify spatial recurrence patterns of GSCs through the in vivo chemoradiotherapy model. We then interrogated the temporal fate of clonal barcoded GSC populations through SoC therapy model to identify differential barcode selection in response to treatment. Through this, we determined dynamics patterns of a pre-existing or a therapy-driven GSC subpopulation(s) seeding GBM tumour relapse. Profiling the dynamic nature of heterogeneous GBM subpopulations through disease progression and SoC treatment may lead to the identification of the modes of therapy resistance utilized by GBM to drive disease relapse.
ANGI-09. CIRCULATING MIR-10B AND MIR-21 IN PATIENTS WITH GBM TREATED WITH BEVACIZUMAB ARE SECRETED TO THE CIRCULATION BY PROTEINS AND THEIR HIGH QUANTIFICATION IS PROBABLY THE RESULT OF DRUG-INDUCED TUMOR HYPOXIA
Authors: Hanna Charbit, Anat Mordechai, Alexander Lossos, Iris Lavon
Journal: Neuro-Oncology (2018)

Bevacizumab is a one of the salvage therapy to patients with recurrent GBM. Antiangiogenic treatment such bevacizumab reduce blood supply and consequently increase hypoxia in the tumor microenvironment. We previously demonstrated that miR-10b and miR-21 are highly quantified in the circulation following bevacizumab treatment, and that the quantity of these miRNAs in the circulation is correlated negatively and significantly with tumor volume. miRNAs are selectively exported from tumors due to cellular signals or environmental cues and are selectively released to differential carrier such as exosomes, microvesicles, HDL or protein-associated miRNAs. The aim of the current study was to explore whether the upregulation of these miRNAs during the antiangiogenic treatment is induced by hypoxia, and via which carrier they are transported to the circulation. Three glioma and one endothelial cell line were exposed to hypoxic condition and the expression of VEGF and mir-10b and mir-21 were studied by quantitative-PCR. The cell medium as well as serum of patients treated with bevacizumab was fractionated by size-Chromatography-column (Izon’s qEV) and then the quantification of the miRNAs in each fraction was measured by quantitative-PCR. Hypoxia induction was confirmed by upregulation of VEGF in both endothelial and glioma cell-lines. mir-10b and mir-21 were upregulated in the glioma cells and the glioma medium culture after 24Hr of hypoxia, but not in the endothelial cell-line Moreover, these miRNAs were enriched in the size fraction of protein and not in the other fractions. The results of this study imply that the high quantification of mir-10b and mir-21 in the serum of patients treated with bevacizumab are induced by tumor hypoxia and that these miRNAs are selectively secreted to the circulation by proteins. Further study is needed to investigate whether these circulating miRNAs and their delivery mode have a role in treatment response of GBM to bevasizumab.
TMOD-02. DIFFUSE GLIOMATOSIS IN MOUSE MODEL OF GFAP TISSUE SPECIFIC KNOCK IN OF EGFRvIII AND KNOCK OUT OF p19 ARF
Authors: Mira Li, Sameer Agnihotri, Mark Wilson, Julie Metcalf, Olivia Singh, Shirin Karimi, Kelly Burrell, Severa Bunda, Suganth Suppiah, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

We generated a transgenic mouse harboring EGFRvIII knock in and homozygous p19 ARF deletion restricted to glial cells. The mice developed diffuse glioma with some tumors showing classical histological pseudopalisading necrosis and hyper vascularity. Transgenic mice develop tumors as early as 1 month and 53% of mice die by 6 months of age. MRIs reveal that mice develop ventriculomegaly and external hydrocephalus when tumor cell infiltration grows exophytic and presents with accumulations of neoplastic cells in association with leptomeninges, in addition to the brain and spinal cord parenchyma. Immunohistochemical analysis shows a strong glial component; tumors display positive GFAP, S100 staining and negative NeuN, synaptophysin staining. Three primary cell cultures were isolated as adherent and neurospheres from mice with tumors. During in vitro culture, EGFRvIII expression was lost in 2 of 3 lines, similar to seen in humans GBMs. Results were confirmed by Western blot and RT-PCR. Intracranial injection with EGFRvIII positive lines resulted in tumors in NODSCID mice. Immunohistochemistry staining of xenografts show that cells retained EGFRvIII expression, thus reinforcing that the importance of tissue microenvironment in maintaining genomic drivers. We present phenotype and genomic profile of a new transgenic model of glioma, with a prominent phenotype of leptomeningeal spread, potentially serving as a model for this important manifestation of human tumors.
EPID-04. LEVERAGING GENOMIC DATA TO IDENTIFY RISK FACTORS FOR CHILDHOOD EPENDYMOMA
Authors: Chenan Zhang, Helen Hansen, Julio Gonzalez-Maya, Ivan Smirnov, Joseph Wiemels, Kyle Walsh
Journal: Neuro-Oncology (2018)

SNPs identified by previous GWAS can serve as instrumental variables for exposures of interest using a process known as Mendelian randomization. We sought to identify risk factors for childhood ependymoma using a Mendelian randomization approach. We identified 390 Californian children born after 1982 and diagnosed with intracranial ependymoma before age 19, and retrieved their archived newborn bloodspots from the state. DNA from 360 cases and 2176 controls was successfully extracted and genotyped on the Affymetrix Axiom array which, coupled with whole-genome imputation, yielded 4.5M SNP genotypes per subject. We constructed polygenic scores of anthropometric traits, telomere length, and immune cell profiles using SNPs discovered in prior GWAS. Case-control comparisons were adjusted for ancestry-informative principal components. A polygenic score for adult height (416 unlinked SNPs) indicated that a 2.5cm increase in predicted height was associated with a 1.23-fold increased risk of ependymoma (P=0.041). No associations were observed for birth length, pre-pubertal height, or head circumference. A polygenic score for inter-individual variation in telomere length (8 unlinked SNPs) indicated that longer predicted telomere length increases risk of ependymoma (P=0.037), particularly adolescent-onset ependymoma (P=7.1x10-3). A polygenic score for lymphocyte count (156 unlinked SNPs) was not associated with ependymoma risk (P=0.14). However, a one standard deviation increase in the score for myeloid cell count (191 unlinked SNPs) was associated with a 0.79-fold decreased risk of ependymoma (P=9.0x10-3). Within the granulocyte lineage, increased neutrophil count was associated with decreased risk of ependymoma (OR=0.82, P=0.027), while neither eosinophil count nor basophil count showed evidence of association (P=0.22 and 0.99, respectively). Because ependymoma therapy can affect height attainment, telomere length, and immune parameters, these exposures are ill-suited for traditional case-control study designs. Using a Mendelian randomization approach, we observe that genetic predisposition to taller height, longer telomere length, and decreased circulating myeloid cell counts may increase risk of ependymoma.
Erratum: Corrigendum: The transcription factor IRF4 is essential for TCR affinity–mediated metabolic programming and clonal expansion of T cells
Authors: Kevin Man, Maria Miasari, Wei Shi, Annie Xin, Darren C Henstridge, Simon Preston, Marc Pellegrini, Gabrielle T Belz, Gordon K Smyth, Mark A Febbraio, Stephen L Nutt, Axel Kallies
Journal: Nature Immunology (2014)
Abstract 19909: Beneficial Immune Modulation Post-Cardiac Infarction in Mice
Authors: Isabella Imhof, Holly Hoover, Luyi Li, Guanying Wang, Boqing Zhu, Norman Honbo, Matthew Bell, Erene Niemi, Christine Hsieh, Mary C Nakamura, Joel Karliner
Journal: Circulation (2017)

Immune cells play a significant role in cardiac repair post-ischemia. We examined the effects of the immunomodulating drug FTY720 on cardiac outcomes following myocardial infarction in a mouse mode...
CADD-30. A TREATMENT SIMULATOR FOR BRAIN CHEMOTHERAPY
Authors: William Broaddus, Raghu Raghavan
Journal: Neuro-Oncology (2018)

Dosing of systemically administered chemotherapies for brain tumors is generally designed without the benefit of quantitative estimates of spatial drug distribution in the brain, even though the integrity of the BBB varies spatially, and over time. We have designed a “Drug Entry Simulator” which displays a patient’s contrast enhanced MRI, a display of serum concentrations of drug over time, and an overlay of drug concentrations over time superimposed on the MRI. In addition, the area under the concentration time curve can be assessed for any region of interest. The mathematical modeling utilizes pharmacokinetic models with patient specific information on brain anatomy, BBB permeability incorporated via DCE studies and scaling hypotheses for different therapeutic agents. We have made and reported[1] preliminary assessments using results from clinical trials employing microdialysis or biopsies to determine the concentrations of agents within brain tumors. Simulations on data obtained from the individual patients shows 1) significant variability in spatial distribution, 2) poor penetration of the margins and 3) poor residence time of the agent in tissue. Studies of efflux of both small and large molecule agents infused directly into the brain have shown excellent agreement with direct measurements of their concentrations. Pretreatment estimates of drug entry, maximal concentration, time over effective concentration, and area under the concentration curve can help in planning systemic administration of therapeutic agents in patients with brain tumors. Future studies will address calibration issues with DCE, improvement of MR image acquisition, improved incorporation of characteristics of the drugs used, and continuing validation of the modeling approach. [1] Modeling the Entry of Systemically Administered Antineoplastic Agents into Brain Tumors, Brain Adjacent to Tumor, and Normal Brain. Stuart A. Grossman, Arati Desai, Marshall Pitz, Jaishri Blakeley, Jana Portnow, Martin Brady, Raghu Raghavan. Journal of Clinical Oncology, SNO Proceedings, 2008.
RTHP-04. TUMOR RECURRENCE OR RADIATION NECROSIS FOLLOWING CHEMORADIATION IN PATIENTS WITH GLIOBLASTOMA: DOES PATHOLOGY PREDICT OUTCOMES?
Authors: Anthony Patrizz, Phil Choi, Yuanqing Yan, Sohiel Zorofchian, Leomar Ballister, Yoshua Esquenazi
Journal: Neuro-Oncology (2018)

Chemoradiation following surgical resection of glioblastoma has improved overall survival (OS). Unfortunately, all patients develop progression of the disease, typically characterized as worsening radiographic appearance. Radiological imaging is limited in differentiating tumor progression from radiation-induced necrosis; therefore, re-resection is often needed to remove the abnormal tissue. There is little and contradictory data assessing the relationship between pathological evaluation (active tumor vs. radiation necrosis) and clinical outcomes. We performed a large retrospective study to analyze the prognostic value and clinical significance of the pathology evaluation following re-resection in patients with presumed tumor progression. Clinical, radiographic and pathological information was compiled from 675 patients with GBM from the Memorial Hermann Health Care System between 2010 and 2017. Second surgery was performed in 121 (18%) patients (mean age=56, median KPS=80) with presumed progression following chemoradiation. According to the pathology report following second surgery patients were classified into 2 groups (1: recurrent tumor- # of patients = 91 and 2: radiation necrosis # of patients = 30). A Kaplan-Meier survival analysis was performed comparing the OS of each group. No statistically significant differences in OS from initial diagnosis (median OS: active tumor 22.6 mo, radiation necrosis 21.3 mo, p=0.4) and suspected recurrence (median OS: active tumor 12.7 mo, radiation necrosis 13.7 mo, p=0.3) were found between the groups. The current study suggests that histopathologic findings following chemoradiation cannot predict outcomes. These findings are important and should be considered to guide treatment strategies and clinical trial endpoints.
MNGI-40. MENINGIOMA RESECTION SURGERY IN ELDERLY PATIENTS: AN ANALYSIS OF A NATIONAL DATABASE
Authors: Mina Lobbous, Sahil Gupta, Angela Shapshak
Journal: Neuro-Oncology (2018)

Meningiomas are often benign and mostly asymptomatic, and the treatment approaches may include open surgical resection, radiosurgery, and/or watchful waiting. Reported morbidity and mortality rates for elderly patients undergoing meningioma resection vary widely. We sought to investigate mortality rates for elderly patients undergoing craniotomy for meningioma resection using the Nationwide Inpatient Sample. The Nationwide Inpatient Sample (NIS) datasets from 2003 to 2013 were used to identify patient admissions for meningioma resection based on the ICD-9-CM code 01.51. Age categories were defined as 70 years of age. Primary outcomes were in-hospital mortality, poor outcomes (defined as death or discharge to a facility other than home), cost and length of hospitalization. A total of 24,953 patients were identified who underwent meningioma resection during 2003–2013 of which 20.4% were elderly (>70 years). Each of the primary outcomes was heavily influenced by the advancing age. In-patient mortality was higher in the elderly as compared to the younger patients (3.5% vs 1%), as was the rate of a poor outcome (64.8% vs 28.1%). Elderly patients also had a higher cost ($104425 vs $96012) and length of hospitalization (8.9 vs 6.8 days). In our study, age > 70 was strongly associated with adverse outcomes after meningioma resection. This increased risk should be taken into account when considering surgical intervention in this subgroup; closer perioperative monitoring may be warranted.
GENE-29. DLL3 AND ETV1 ARE INACTIVATED/METHYLATED IN CIC WILD-TYPE, IDH-MUTATED, 1p/19q-CODELETED GLIOMA
Authors: Matthew Kosel, Daniel Lachance, Paul Decker, Thomas Kollmeyer, Alissa Caron, Kristen Drucker, Gobinda Sarkar, Andrew Knight, Chandralekha Halder, Shulan Tian, Alexej Abyzov, Terry Burns, Caterina Giannini, Jeanette Eckel-Passow, Robert Jenkins
Journal: Neuro-Oncology (2018)

Adult diffuse glioma that harbor IDH mutation and 1p/19q codeletion commonly have CIC mutations; however, the functional and prognostic significance of CIC mutations remains unclear. We hypothesized that when CIC is not mutated, other genes may be inactivated by hypermethylation. Identifying such genes may help to further understand the biology of 1p/19q-codeleted glioma. To test our hypothesis, we utilized a two-stage design. In the discovery stage, 72 IDH-mutated 1p/19q-codeleted tumors were utilized from TCGA (40 CIC mutated, 32 wild-type); all via Illumina 450K methylation array. In the validation stage, 43 IDH-mutated 1p/19q-codeleted tumors were utilized from Mayo Clinic (33 CIC mutated, 10 wild-type); all via Illumina 850K methylation array. All tumors also had TERT promoter mutation. Genome-wide significance (p≤5x10-8) was used in the discovery stage to identify differentially methylated probes between CIC mutated vs wild-type tumors. Seven probes reached significance in TCGA; four validated at pCIC. DLL3, located on 19q, had a mean change in beta value between CIC wild-type and mutated tumors of 0.28 (p=1.29x10-8) and 0.24 (p=0.0024) in TCGA and Mayo, respectively. ETV1, located on 7p, had a mean change in beta value of 0.30 (p=1.37x10-8) and 0.15 (p=0.00011) in TCGA and Mayo, respectively. In the 72 TCGA tumors, we observed an inverse correlation between DLL3 methylation and gene expression amongst CIC mutated and wild-type tumors; -0.42 (p=0.0063) and -0.33 (p=0.069), respectively. There was also an inverse correlation between ETV1 methylation and gene expression amongst CIC mutated and wild-type tumors; -0.68 (pDLL3 and ETV1 was downregulated in CIC wild-type vs mutated tumors (p=0.000027 and 0.0000028, respectively). We confirm that ETV1 has higher gene expression in CIC mutated vs wild-type tumors. Our results suggest that DLL3 expression is inactivated by promoter methylation in CIC wild-type 1p/19q-codeleted oligodendrogliomas; thus, DLL3 may be an alternative target gene on 19q.