tbuckley/cabot-search huggingface dataset:
IMMU-25. PROGRAMMED CELL DEATH-LIGAND 1 (PD-L1) IS NOT EXPRESSED IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TUMOR CELLS
Authors: Preet Walia, Colleen D’Arcy, Cynthia Hawkins, Katherine E Warren
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is a pediatric high grade, infiltrative tumor that arises in the pons. It is the leading cause of brain tumor related death in children. Despite increased understanding of the genetics and epigenetics of DIPG, development of in vivo research models, and several clinical trials, standard of care and survival has not improved. One avenue that has yet to be explored in DIPG is the use of immune checkpoint inhibitors such as the anti-PD-1 and PD-L1 monoclonal antibodies, Nivolumab and Pembrolizumab, respectively. PD-1/PD-L1 checkpoint inhibition is currently being used to treat certain solid tumors, including melanoma and non-small cell lung cancer. In addition, two pediatric glioblastoma multiforme cases secondary to bi-allelic mismatch repair deficiency responded to treatment with Nivolumab. Evidence of immune infiltration and PD-1/PD-L1 expression was seen in these two tumors. Similarly, there may be a subset of DIPG that may respond to inhibiting the PD-1/PD-L1 axis. To test this hypothesis, immunohistochemistry was performed for PD-L1 (SP142 clone), CD4 and CD8 in DIPG tumor samples using formalin-fixed paraffin-embedded tissues from autopsy, and appropriate positive and negative controls. PD-L1 (n=31) was evaluated as percentage of positive tumor cells. CD4 and CD8 (n=20) expression was assessed from 0 to 3+ based on average number of positive lymphocytes in four high power fields. Membranous PD-L1 expression was negative in each of the 31 cases characterized. There was low expression of CD4 (1+) in 11 out of 20 cases and CD8 was moderately expressed in 19 cases (1–2+). Targeting the PD-1/PD-L1 axis may have limited efficacy against DIPG. However, since tumor infiltrating lymphocytes are present, alternate immune evasion mechanisms, such as IDO and CTLA-4, should be evaluated in order to further characterize the immune microenvironment and assess the potential of immunotherapy against DIPG.
Abstract 16287: Global Longitudinal Strain Provides Prognostic Value After Surgery for Severe Organic Mitral Regurgitation
Authors: Yasmine L Hiemstra, Anton Tomsic, Suzanne E van Wijngaarden, Meindert Palmen, Martin J Schalij, Jeroen J Bax, Victoria Delgado, Nina Ajmone Marsan
Journal: Circulation (2017)

Introduction: In patients with severe organic mitral regurgitation (OMR), appropriate timing of surgery is often challenging. Left ventricular ejection fraction (LVEF) is currently recommended in t...
DRES-17. ACTIVATION OF FGF SIGNALING PATHWAY CONFERS RESISTANCE TO EGFR INHIBITION IN GBM
Authors: Gao Guo, Ke Gong, Jann Sarkaria, Amyn Habib
Journal: Neuro-Oncology (2018)

Amplification and mutation of the EGFR gene is a signature lesion in GBM and occurs in 40–50% of GBM patients. However, EGFR inhibition has been ineffective in the treatment of GBM. Resistance to EGFR inhibition may be primary or secondary after an initial period of susceptibility suggesting that adaptive mechanisms may mediate resistance to EGFR inhibition The adaptive response to EGFR inhibition is multifaceted. We have recently reported that TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in GBM cells1. We now report that the FGF (fibroblast growth factor) signaling pathway is activated by EGFR inhibition in GBM. A number of studies have identified the FGF signaling pathways as important pro-oncogenic signals in cancer and in mediating resistance to treatment. Our data indicate that the FGFR pathway is an additional candidate for mediating the adaptive response to EGFR inhibition. We find that in glioma cells expressing either EGFRwt or the mutant EGFRvIII, EGFR inhibition with erlotinib induces FGF1 and FGF3 expression at both mRNA and protein levels. Additionally, erlotinib exposure leads to phosphorylation of FGFR1 in multiple GBM cell lines. Knockdown of FGFR1 sensitized GBM cells to EGFR inhibition. Moreover, combined treatment of erlotinib and FGFR selective inhibitors such as Debio-1347 or AZD4547 significantly increased cell death versus in either drug alone in multiple GBM cell lines. Our findings suggest that combined EGFR and FGF inhibition could be an effective alternative approach to treating GBM. 1. Guo G, et al. A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nat Neurosci. 2017;20(8):1074–1084.
TMIC-22. EXOSOMAL NON-CODING RNAS MEDIATE THE CROSS-TALK OF BRAIN METASTASIS CANCER STEM CELLS AND MICROGLIA
Authors: Simona Cazacu, Wei Jiang, Cunli Xiang, Zane Hammoud, Lisa Scarpace, Steven Kalkanis, Chaya Brodie
Journal: Neuro-Oncology (2018)

Brain metastases are the most common secondary brain tumors in adults. Despite their high frequency and patient poor prognosis, very little research has been performed on lung tumor brain metastases, mainly due to the lack of appropriate experimental models. In this study, we isolated cancer stem cells (CSCs) from fresh specimens of lung tumor brain metastases. The CSCs were analyzed for sphere formation and limiting dilution analyses, stemness markers, ability to generate xenografts and for their interaction with microglia cells. We found that CSCs derived from brain metastases had a high sphere forming capacity and self-renewal ability comparable to that of glioma stem cells. The CSCs expressed the stemness markers, CD133, Sox2, Klf4, Aldh2a, CD44 and the lung tumor markers, cytokeratin 7, and CD166. Transplantation of the CSCs or organoids generated from the brain metastases formed xenografts that recapitulated the parental tumors. These xenografts were infiltrated by a large number of amoeboid microglia that expressed high levels of M2 markers. Using co-culture experiments, we further found that CSCs derived from brain metastasis induced the polarization of microglia to the M2 phenotype via secreted exosomes. Similarly, M2 micrglia cells increased the self-renewal and stemness of the CSCs. RNA seq analysis identified specific miRNAs and lncRNAs that were associated with the CSC-microglia interactions. Using specific reporters, antagomiRs and CRISPR/Cas9 we demonstrated that miR-21, miR-1246 and the lncRNA TALNEC2 played a major role in the M2 polarization of microglia cells both in vitro and in vivo. In conclusion, we generated CSCs and organoids from lung tumor-derived brain metastases and identified potential therapeutic targets for these tumors. The established CSCs can serve as valuable in vitro and in vivo models for analyzing mechanisms involved in brain metastasis, for studying the tumor-microenvironment interactions and for personalized high throughput screening of new and repurposed drugs.
NCOG-10. EXECUTIVE DYSFUNCTION IN NEUROONCOLOGY: BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION IN ADULT PRIMARY BRAIN TUMOR PATIENTS
Authors: Sarah Braun, Ashlee Loughan, Autumn Lanoye
Journal: Neuro-Oncology (2018)

Adult primary brain tumor (PBT) survivors report persistent cognitive difficulties throughout treatment which are problematic for everyday functioning, employment capability, and quality of life. Cognitive domains often affected by cancer treatment appear to be attention and executive functioning (EF). One validated measure developed to assess an individual’s EF within daily living is the Behavior Rating Inventory of Executive Function – Adult (BRIEF-A). To date, no published research has investigated the EF profile of PBT patients using the BRIEF-A. Seventy-four patients from a NCI-designated cancer center completed the BRIEF-A, a validated self-report questionnaire that assesses executive functioning across nine subscales and provides three index scores: Behavioral Regulation, Metacognition, and Global Functioning. Descriptive analyses were conducted to determine the self-reported EF profile in PBT patients. MANOVA’s compared the performance of PBT patients to three diagnostic populations (comparison group data obtained from BRIEF-A manual): mild cognitive impairment (MCI), unmedicated attention-deficit/hyperactivity disorder (ADHD-U) and healthy controls (HC). PBT BRIEF-A group means were average across subscales and indexes, yet the prevalence of significant elevations ranged from 12–50%. The Metacognition Index demonstrated a 38% elevation prevalence compared to 22% in Behavioral Regulation. Approximately 61% of the sample had at least one clinically elevated scaled score. When comparing between group profiles, PBT reported significantly more impairment than HC and significantly less than ADHD-U across all subscales. No significant differences were found between PBT and MCI groups. CONCLUSIONS: Despite group means not reaching clinical impairment, a substantial proportion of patients with PBT endorse significant difficulty with executive dysfunction. Elevations were most prominent in metacognitive abilities (e.g., Working Memory), over behavioral dysregulation (e.g., Emotional Control). Notably, the EF profile of PBT patients was remarkably similar to that of MCI, increased when compared to HC, and well below ADHD-U.
Abstract 12078: Obese Girls With PCOS Have Evidence of Vascular Stiffening and Left Ventricular Hypertrophy Which Relate to Insulin Resistance
Authors: Melanie Cree-Green, Uyen Truong, Jennifer L. Dorosz, Kerri Moreau, Gregory Coe, Amy Baumgartner, Lindsey Newnes, Kristen J Nadeau
Journal: Circulation (2014)

Introduction: Women with polycystic ovarian syndrome (PCOS) have evidence of greater plaque formation and vascular disease by the third decade of life compared to women without PCOS. We previously reported that obese girls with PCOS have a more atherogenic lipoprotein particle size profile compared to controls. It was unknown these youth also already had evidence of cardiac or vascular disease and plaque development. Hypothesis: We hypothesized that adolescent girls with PCOS have evidence of vascular stiffness and plaque formation. Methods: Sedentary, non-diabetic, obese girls with PCOS (OBP; N=38, age 14.9±0.2 years, BMI% 98.1±0.3) and without PCOS (OB; N=14, age 14±0.5 years, BMI% 97.4±0.7) were enrolled. Girls with clinical hypertension, renal disease or structural cardiac abnormalities were excluded. Measures included carotid IMT (CIMT), resting echocardiogram, blood pressure, serum lipid profile, and insulin sensitivity assessed with a hyperinsulinemic euglycemic clamp. Calculated measures included carotid beta- stiffness index and distention. Results: Resting blood pressures were normal for age and similar between groups. OBP had greater carotid vascular stiffness than OB (βstiffness 1.91±0.08U OB vs 2.19±0.09 OBP, p=0.01; Distention 0.23±0.17mm OB vs 0.18±0.01 OBP, P=0.0007), and there was evidence of greater left ventricular posterior wall thickness (0.79±0.03cm OB vs 0.88±0.02 OBP; P=0.02) and intraventricular wall thickness (0.77±0.04cm OB vs 0.86±0.02 OBP; P=0.04). There was no difference in CIMT between OBP and OB (0.45±0.02cm OB vs 0.48±0.01 OBP, P&gt;0.1). However, OBP were also more insulin resistant than OB (glucose infusion rate 18.3±2.3 mg/leankg/min OB vs 10.4±1.6 OBP, P=0.0007), which correlated with left ventricular posterior wall thickness (R=-0.50, P&lt;0.001). Conclusions: Obese normotensive girls with PCOS have vascular stiffening and left ventricular remodeling which relate to insulin resistance. They do not yet have increased CIMT, however, they have insulin resistance and a more atherogenic lipid profile, indicating that the substrate for imtimal-medial thickening and plaque formation is present. Interventions to prevent cardiovascular disease should begin in adolescence.
Abstract 11025: Insertable Cardiac Monitors Reveal Progression of 1st Degree AV-block to Higher Grade Block Requiring Pacemaker Implant
Authors: Thorsten Lewalter, Guido Rieger, Lorenza Mangoni
Journal: Circulation (2015)

Introduction: In the past, 1st degree AV-block has generally been considered a benign condition. A few recent studies have shown that 1st degree AV-block is associated with an increased risk for he...
NIMG-40. NON-INVASIVE IN VIVO SIGNATURE OF IDH1 MUTATIONAL STATUS IN HIGH GRADE GLIOMA, FROM CLINICALLY-ACQUIRED MULTI-PARAMETRIC MAGNETIC RESONANCE IMAGING, USING MULTIVARIATE MACHINE LEARNING
Authors: Spyridon Bakas, Saima Rathore, MacLean Nasrallah, Hamed Akbari, Zev Binder, Sung Min Ha, Elizabeth Mamourian, Jennifer Morrissette, Donald O’Rourke, Christos Davatzikos
Journal: Neuro-Oncology (2018)

PURPOSE: Mutational status of isocitrate dehydrogenase (IDH1) is a defining feature of the World Health Organization classification scheme for high grade gliomas (HGGs). IDH-mutant HGGs confer significantly improved prognoses when compared with IDH-wildtype, which typically describe the most common malignant primary HGGs in adults, namely glioblastoma. HGGs are densely cellular, pleomorphic tumors with high mitotic activity, with glioblastoma having either microvascular proliferation, or necrosis, or both. We hypothesize that integrative analysis of multi-parametric magnetic resonance imaging (mpMRI) via multivariate machine learning (ML), will enhance subtle yet important radiographic HGG characteristics, and reveal imaging signatures determinant of IDH1 mutational status. 86 HGG patients were retrospectively identified with available pre-operative clinically-acquired mpMRI data (T1, T1-Gd, T2, T2-FLAIR, DTI, DSC-MRI). Each HGG was delineated into sub-regions of enhancement, non-enhancement, and peritumoral edema/invasion. 342 quantitative imaging phenomic (QIP) features extracted across sub-regions from all mpMRI, comprising descriptors of size, morphology, texture, intensity, and biophysical growth modeling. Cross-validated sequential feature selection determined the most discriminative QIP features for our integrative ML predictor of IDH1 status. The predicted classifications, following a 10-fold cross-validation, were compared with the IDH1 status obtained by next generation sequencing, or immunohistochemistry. 61 QIP features, primarily descriptive of tumor texture, were determined as most important for an IDH1 imaging signature. Using this signature, our predictor classified IDH1 mutational status with an accuracy of 88.4% (sensitivity=66.7%, specificity=92.9%). Quantitative analysis of clinically-acquired mpMRI reveals subtle/visually-imperceptible, yet informative features, which integrated via ML yield a non-invasive in vivo IDH1 imaging signature in HGG. Knowledge of IDH1 mutational status at initial presentation can influence therapeutic decision-making, which will have a significant impact on patient care. Particularly in this precision medicine era, as mutant-IDH enzyme inhibitors and immunotherapy targeting IDH-mutant tumor cells are developed, imaging to diagnose and follow IDH-mutant tumors can be invaluable. *equal contribution
Interaction between intakes of B vitamins and NSAID use on risk of colorectal adenoma
Authors: Elizabeth Poole, John Whitton, John Potter, Cornelia Ulrich
Journal: Cancer Research (2007)

857  Introduction: Inflammation plays a major role in colorectal cancer. Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to reduce risk of colorectal cancer. Inflammation has also been linked to one-carbon metabolism; deficiencies of vitamins B6 and B12 are associated with inflammatory conditions, such as rheumatoid arthritis. Similarly, ulcerative colitis, an inflammatory condition that predisposes to colorectal cancer, can be ameliorated through folate supplementation. We hypothesized that the risk reduction associated with regular NSAID use may be stronger among those with lower folate, vitamin B6, and vitamin B12 compared to those with higher intakes.  Methods: In a Minnesota-based case-control study of adenomas (n=517) vs. polyp-free controls (n=618), we investigated the role of intakes of folate, vitamin B6, and vitamin B12 (in tertiles of daily intake) in conjunction with regular aspirin or other NSAID use (at least once per week for one year) on risk of colorectal polyps. Multiple logistic regression was used, adjusting for age, sex, BMI, caloric intake, alcohol intake, fiber intake, hormone use, smoking, and intakes of the respective other one-carbon metabolism nutrients.  Results: When stratified by regular, current use of aspirin or other NSAIDs, increasing intakes of vitamin B6 and vitamin B12 were found to be inversely associated with adenoma risk only among non-users. Among regular NSAID users, no differences in adenoma risk with increasing intakes of vitamin B6 or B12 were observed (Table). For folate, the risk reduction associated with regular NSAID use was attenuated as intake increased; among NSAID non-users, there was no risk reduction as folate intake increased. The interaction was statistically significant for vitamin B12 (p=0.01) and suggestive for folate (p=0.09).  Conclusion: These findings suggest that the suppression of inflammatory processes by NSAIDs may reduce the requirement for nutrients relevant to DNA synthesis.
CBMT-34. TARGETING THE RNA-PROCESSING GENE MAGOH AS A NOVEL THERAPY FOR MEDULLOBLASTOMA
Authors: Jennifer Ocasio, Hedi Liu, Timothy Gershon
Journal: Neuro-Oncology (2018)

We have proposed that microcephaly-producing mutations identify genes required for growth in the nervous system that may be new targets for brain tumor treatment. We tested this hypothesis by deleting the RNA-processing gene Magoh during cerebellar development and medulloblastoma pathogenesis. Magoh mutation has been shown to induce DNA damage and apoptosis in forebrain progenitors, resulting in microcephaly. We conditionally deleted Magoh during postnatal cerebellar neurogenesis by crossing MagohloxP/loxP mice with CAG-CreER transgenic mice (MagohCre-ER). Magoh-deleted cerebellar granule neuron progenitors (CGNPs) of the cerebellum of MagohCre-ER mice showed DNA damage, cell cycle arrest and apoptosis, which depleted the progenitor-rich external granule layer within 72 hrs. Moreover, deleting Magoh in SHH-driven medulloblastomas in SmoA1 mice similarly induced DNA damage, apoptosis and tumor shrinkage. These data show that MAGOH is required for SHH-driven proliferation in both normal cerebellar progenitors and in SHH-driven medulloblastoma. These findings are the first to show that medulloblastoma growth can be disrupted by targeting the RNA processing machinery.
HOUT-21. REAL-WORD EVALUATION OF THE IMPACT OF RADIOTHERAPY AND CHEMOTHERAPY IN ELDERLY PATIENTS WITH GLIOBLASTOMA BASED ON AGE AND PERFORMANCE STATUS: A NATIONAL CANCER DATABASE ANALYSIS
Authors: Karine Al Feghali, Samantha M Buszek, Hesham ElHalawani, Neil Chevli, Pamela K Allen, Caroline Chung
Journal: Neuro-Oncology (2018)

OBJECTIVES: This retrospective study evaluates the impact of Karnofsky performance status (KPS) in addition to age on the management and outcomes of elderly patients with glioblastoma (GBM). The National Cancer Database (NCDB) was queried between 2004–2015 for GBM patients with age 60 and reported KPS. Four groups were created: Age 60/ KPS<70 (Gp1), Age 60–69/KPS 70 (Gp2), age 70–79/KPS 70 (Gp3), age 80/KPS 70 (Gp4). Univariate (UVA) and multivariable (MVA) modeling with Cox regression determined predictors of survival (OS), and propensity score-matched analysis was performed. A total of 30,530 patients were included. Median age at diagnosis was 69, and median follow-up was 7.3 months. Median survivals were 5.2, 11.3, 6.3 and 3.7 months in groups 1, 2, 3 and 4, respectively (p <0.001). Combined chemotherapy (CT) and radiotherapy (RT) was received in 65.5% of Gp2, 53.7% of Gp3, 48.2% of Gp1 and 33.1% of Gp4 (p<0.001). On both UVA and matched OS analysis, all patients benefited from combined CT and RT, except those in Gp1, who did better with CT alone (p<0.01). RT alone was associated with the worst OS in all groups (p<0.01). Predictors of worse OS on MVA were greater age, lower KPS, white ethnicity, higher comorbidity score, worse socioeconomic status, treatment in a community center, tumor multifocality, subtotal resection, non-IMRT use, and no adjuvant treatment (all p<0.01). Based on this NCDB review, patients with GBM aged 60 with poor KPS have better survival following CT alone, whereas elderly, even those 80 years old, with good KPS fared best with combined CT and RT. RT alone resulted in worse OS compared to CT or combined CT and RT. Functional status is an independent, key prognostic factor that should be incorporated with age for management decisions in the elderly GBM population.
RTHP-31. STEREOTACTIC RADIOSURGERY FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Susan Wu, Steve Braunstein, James Rubenstein, Penny Sneed
Journal: Neuro-Oncology (2018)

Primary central nervous system lymphoma (PCNSL) is rare, with a treatment backbone that typically includes high-dose methotrexate. Whole brain radiotherapy (WBRT) is often reserved for patients who cannot receive chemotherapy, or with residual/recurrent disease, and demonstrates favorable local control however with significant toxicity. We report outcomes of stereotactic radiosurgery (SRS) in patients with PCNSL. We performed a retrospective single-institution review to identify 21 patients with PCNSL treated with SRS between 1998 and 2017. The Kaplan-Meier method was used to describe overall survival (OS) and freedom-from distant brain progression (FFDBP). The median age at diagnosis was 66 years (IQR 55–73), and the median age at SRS was 67 years (IQR 56–75). The median KPS at SRS was 80 (IQR 50–80). Nineteen patients (90%) received methotrexate-based chemotherapy prior to SRS (median of 8 cycles). Eleven patients (52%) received SRS for recurrent disease, while 8 patients (38%) underwent SRS for persistent disease after chemotherapy. The median dose was 15 Gy in 1 fraction or 23 Gy (IQR 22.5–25 Gy) in 3–5 fractions. The median PTV was 3.3 cc (IQR 1.5–19.8cc). Local control at 3 and 6 months was 93% and 92% respectively, however 3 month FFDBP was 30%. OS at 3 and 6 months was 67% and 38%, respectively. Local control was higher in patients who received pomalidomide or lenalidomide after SRS (p = 0.035). Consolidative etoposide and cytarabine was associated with longer time to progression after SRS (p = 0.032) and improved OS at 6 months (p = 0.017). SRS offers effective local tumor control, however prognosis remains poor due to a high rate of distant progression after treatment. SRS may have a role in the salvage setting for patients with recurrence after WBRT, or allow deferral of WBRT, however systemic therapy may most strongly influence survival outcomes.
Abstract 18580: High Sensitivity Cardiac Troponin Sex Specific 99th Percentiles Derived From Universal Sample Bank
Authors: Yader Sandoval, Robert Christenson, Alan Wu, Anne Sexter, Sara Love, Karen Schulz, Fred S Apple
Journal: Circulation (2017)

Introduction: Defining the 99th percentile upper-reference limit (URL) of cardiac troponin (cTn), the concentration threshold used to support the Universal Definition of Myocardial Infarction is critically important; with challenges in defining normality for subjects used to derive this threshold. With increasing implementation of high sensitivity cTnI (hs-cTnI) and hs-cTnT assays in global clinical practice, our goal was to determine overall and sex-specific 99th percentiles in 6 hs-cTn assays using a universal sample bank. Methods: Apparently normal subjects were obtained from the American Association of Clinical Chemistry (AACC) Universal Sample Bank, comprised of 423 men and 415 women, screened using a health questionnaire. Hemoglobin A1c (URL 6.5%), NT-proBNP (URL 125 ng/L) and eGFR (60 mL/min), along with statin use, assisted in verifying subject normality, and used as surrogate biomarker exclusion criteria. 99th percentiles were determined by the non-parametric, Harrell-Davis Bootstrap, and Robust ...