tbuckley/cabot-search huggingface dataset:
RDNA-17. POWER DENSITY LOSS CAN BE USED TO DEFINED TUMOR TREATING FIELDS DOSE
Authors: Hadas Hershkovich, Noa Urman, Ariel Naveh, Shay Levi, Zeev Bomzon
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are alternating electric at 200 kHz approved for the treatment of Glioblastoma Multiforme. Historically, TTFields dose has been quantified using the magnitude of the electric field, indicative of the force that the field applies on charged objects. However, when considering TTFields dose, it is important to consider the amount of energy transferred from the electric fields to the tissue. This energy quantifies the extent to which the field alters the state of the objects on which it operates. Since power loss density quantifies the energy transferred by an electric field to tissue, we analyzed the power loss density distributions when TTFields is delivered to the brain. The analysis was performed by numerically simulating delivery of TTFields to computational models of glioblastoma patient. The simulations showed that TTFields magnitude tends to be higher in regions of low conductivity and tends to decrease in regions of high conductivity such as the ventricles and resection cavities. On the other hand, power loss density tends to increase in regions of higher conductivity. Within the highly conductive ventricles and resection cavity, it can take on values comparable to those observed in other tissue types. The total power loss of TTFields within the simulated cases was between 20–40 Watts, which is equivalent to 412–825 Kcalories per day, on-par with the resting metabolic rate of the brain (about 20% of the body’s resting metabolic rate). This analysis shows that power loss density is a viable measure for quantifying TTFields dose. The observation that the power delivered by TTFields to cells is comparable to the metabolic rate of the cells could lead to new insights into the mechanism of action of TTFields.
GENE-31. MULTIPLATFORM MOLECULAR PROFILING AND QUANTITATIVE IMAGING OF AN ANAPLASTIC EPENDYMOMA REVEALS INTRATUMORAL HETEROGENEITY
Authors: Stephen Magill, John Liu, Harish Vasudevan, Stephanie Hilz, Sean Ferris, Nancy Ann, Oberheim Bush, Javier Villanueva-Meyer, Andrew Bollen, Joseph Costello, Michael McDermott, David Raleigh
Journal: Neuro-Oncology (2018)

Ependymomas are associated with distinct anatomic, genomic and clinical characteristics, but the diversity of molecular features within individual ependymomas is incompletely understood. Here, we perform multiplatform molecular profiling from 6 spatially- and radiographically-distinct regions within a single anaplastic ependymoma to shed light on intratumoral heterogeneity. Immunohistochemistry, UCSF500 sequencing, whole exome sequencing, 850k DNA-methylation profiling and RNA-sequencing were performed to define the genomic, epigenomic and transcriptomic characteristics of stereotactically-collected samples that were separated by an average 19 mm (range 6–34 mm). Data were analyzed using hierarchical clustering, principal component analysis, molecular phylogenetic approaches, and multi-parametric radiologic techniques. Immunohistochemistry revealed diffuse L1CAM positivity, and UCSF500 detected chromosome 11 chromothripsis, suggestive of C11orf95-RELAfusion. All 6 regions expressed equivalent ependymoma markers such as L1CAMand CCND1 byRNA-sequencing, which also confirmed C11orf95-RELAfusion. Principal component analysis of transcriptomic data identified three transcriptionally distinct tumor regions that were delineated by stem/proliferative genes (HOXB3, OLIG2, PTPRN2), neuronal differentiation genes (DLK1, LBX1, HDAC9) or immune/stress response genes (CXCL8, HSPA1B, VEGFA). DNA methylation analysis was consistent with C11orf95-RELAfusion ependymoma, but also identified three epigenetic profiles with similar characteristics to those discovered by RNA-sequencing from different tumor regions. Whole exome sequencing identified shared SETD2and IL5RAmutations throughout the tumor, as well as private mutations specific to individual regions, including MUC4, ZNRF3 and TGFBR2. Stem/proliferative regions were additionally characterized by SETD2deletion and increased cerebral blood flow relative to other regions by magnetic resonance perfusion. Anaplastic ependymoma is associated with a previously unappreciated molecular heterogeneity that may influence tumorigenesis and design of molecular therapeutics.
RTHP-40. ENDOCRINE AND METABOLIC ABNORMALITIES IN INTRACRANIAL GERM CELL TUMOR PATIENTS TREATED WITH IRRADIATION
Authors: Xiang Boni, Ye Hongying, Wang Yang
Journal: Neuro-Oncology (2018)

To evaluate the endocrine and metabolic abnormalities in intracranial germ cell tumor (iGCT) patients treated with irradiation. PATIENTS AND METHOD: Seventy-seven iGCT patients who had received radiotherapy and endocrine follow-up in Huashan Hospital between January, 2010 and July, 2017 were retrospectively analyzed, consisting of forty-nine germinomas and twenty-eight NGGCTs. The median doses for the whole brain, spine and primary tumor site were 30.6Gy, 30.6Gy and 50.0Gy. The median follow-up period was 50.0 months. Fifty-one patients had radiologically proved suprasellar/sellar lesions. The 5-year overall and recurrence-free survival rates were both 98.7%. The prevalence of central adrenal insufficiency (CAI), central hypothyroidism (CHT), central hypogonadism (CHG), hyperprolactinemia (HPL) and central diabetes insipidus (CDI) in those with radiologically proved suprasellar/sellar lesions was 71.4%, 70.0%, 73.5%, 48.4% and 70.2%, while that in patients without suprasellar/sellar lesions was 30.8%, 28.0%, 25.9%, 15.0% and 16.7% separately. Compared to that before irradiation, CAI, CHT and CHG wasn`t significantly improved while the overall level of prolactin and prevalence of CDI declined significantly (P=0.03 and 0.001). The irradiation dosage wasn`t significantly associated with the prevalence of CAI, CHT and CHG. Based on BMI, 30.4% were overweight and 3.0% were obesed in patients below 18 years old. 72.1% patients had dyslipidemia, with the abnormality of triglyceride most commonly. One patient developed diabetes mellitus after irradiation. The prevalence of hyperuricemia was 50.0%. The irradiation dosage wasn`t associated with BMI, triglyceride, total cholesterol LDL-c, HDL-c, HOMA-IR or serum uric acid level. The prevalence of CAI, CHT, CHG, HPL and CDI was high in iGCTs patients, and those without suprasellar/sellar lesions may develop those endocrine abnormalities too. The post-irradiation level of prolactin and prevalence of CDI declined significantly. Metabolic abnormalities including overweight, dyslipidemia, and hyperuricemia were common in iGCTs patients. The irradiation dosage wasn`t associated with occurrence of hypopituitarism and those metabolic parameters.
Abstract 17819: Implications of the Post-myocardial Infarction Bimodal Edematous Reaction for Quantifying Area at Risk, Infarct Size And Salvaged Myocardium by Cardiac Magnetic Resonance Imaging
Authors: Rodrigo Fernández-Jiménez, Carlos Galán-Arriola, Jaume Agüero, Javier Sánchez-González, Jaime García-Prieto, Gonzalo J López-Martin, Inés García-Lunar, Gonzalo Pizarro, Valentin Fuster, Borja Ibanez
Journal: Circulation (2015)

Background: Contrary to the accepted view, it has been recently demonstrated that myocardial edema after ischemia/reperfusion (I/R) follows a bimodal pattern during the first week. Purpose: To study the implications of the bimodal edema phenomenon on the cardiac magnetic resonance (CMR)-measured area at risk (AAR), infarct size and salvaged myocardium. Methods: Closed-chest 40min I/R was performed in 20 pigs. True anatomical AAR was assessed by arterial enhanced multidetector computed tomography (CT) performed during coronary occlusion. CMR with CINE, T2-weighted short-tau inversion recovery and late gadolinium-enhanced (LGE) sequences were performed at every follow-up (120 min, 24 hours, day 4 and day 7 after reperfusion) for the quantification of left ventricular mass, edema (CMR-AAR), and necrosis (infarct size). Salvaged myocardium was calculated by correcting infarct size for CMR-AAR extent. Results: A sharp increase in left ventricular mass due to huge swelling of the ischemic tissue was detected in early reperfusion (Figure 1A and 1E) leading to overestimation of CMR-AAR as compared to true AAR by CT at this time-point (Figure 1B and 1E). Due to reabsorption of initial edema and presence of significant hemorrhage, CMR-AAR was barely detectable at 24 hours while due to the progression of the deferred wave of edema, CMR-AAR accurately delineated true AAR at day 4 and day 7 (Figure 1B and 1E). A progressive decrease in infarct size was shown in LGE sequences (Figure 1C and 1E). As a consequence, salvaged myocardium dynamically varied within the first week after I/R (Figure 1D). Conclusions: The bimodal edematous reaction after I/R greatly impacts on the non-invasive quantification of CMR-AAR, infarct size and salvaged myocardium by CMR. The most appropriate day to perform CMR after reperfused infarction seems to be around day 7 coinciding with the peak of the deferred wave of edema.
RARE-05. TUMOR PROFILING REVEALS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) AND ENHANCED IMMUNE SUPPRESSION IN GLIOSARCOMAS RELATIVE TO GLIOBLASTOMA
Authors: Christopher Dardis, Surasak Phuphanich, Nader Sanai, Joanne Xiu, Sandeep Mittal, Sharon Michelhaugh, Deepa Subramaniam, Majari Pandey, Santosh Kesari, Amy Heimberger, Zoran Gatalica, W Michael Korn, Ashley Sumrall
Journal: Neuro-Oncology (2018)

Gliosarcoma (GS) accounts for approximately 2% of WHO grade 4 gliomas and have a worse prognosis relative to glioblastoma (GBM). Epithelial-to-mesenchymal transition (EMT) is well recognized in a variety of tumors of ectodermal lineage. MATERIALS AND Patients diagnosed with either a GS (n = 44) or GBM (n = 1449) underwent comprehensive molecular profiling including immunohistochemistry (IHC) and sequencing (DNA, RNA, pyrosequencing and fragment analysis). Statistical significance using Fisher’s exact test was set at p < 0.1 as this is exploratory work; no correction was made for multiple comparisons. The following were identified as enriched in GS based on the odds ratios (OR): CALR (copy number variation, CNV; OR= infinite; p = 0.032), LYL1 (CNV; OR=30; p=0.064); NTRK1 (fusion, RNAseq; OR= 30; p=0.063), IDH2 (mutation; OR=28; p=0.068), PTPN11 (mutation; OR=3; p=0.08), NF1 (mutation; OR=2.3; p=0.02; PD-L1 (IHC; OR=2.2; p=0.002); PD-1 (IHC; OR=1.6; p=0.0078). In contrast, the following were more common in GBM: EGFRvIII (fusion, RNAseq; OR=0.28; p=0.031); EGFRvIII (fragment analysis; OR=0.2; p=0.062); EGFR (CNV; OR=0.2; p=0.00083; IDH1 (mutation; OR=0; p=0.045) and EGFR (mutation; OS=0; p=0.012). Alterations with p>=0.1 are not reported here. CONCLUSIONS: Our study identified enriched markers in GS that have been associated with EMT in other tumor types. These findings are hypothesis generating and suggest that GS may be an example of EMT in GBM. The gene amplification in CALR and LYL1 has not been previously described. Higher levels of PD-1 and PD-L1 expression suggest that these may be targets of particular therapeutic importance in GS relative to GBM.
GENE-38. INTRON 1-MEDIATED REGULATION OF EGFR EXPRESSION IN EGFR-DEPENDENT MALIGNANCIES
Authors: Nathan Jameson, Justin Tang, Alison Parisian, Jorge Benitez, Frank Furnari
Journal: Neuro-Oncology (2018)

The epidermal growth factor receptor (EGFR) gene is frequently altered in a variety of cancer types, with mutation and/or amplification occurring in approximately 57% of glioblastoma (GBM), 47% of non-small-cell lung cancer (NSCLC) and 31% of cancers of the head and neck (HNSCC). In these cancers EGFR protein overexpression is detectable in as much as 45%, 89% and 84% of these tumors respectively. This data suggests that transcriptional control of EGFR expression contributes to high EGFR protein levels in NSCLC and HNSCC, and may be a novel target to control EGFR expression in other dependent malignancies. In GBM, in which there is a stronger correlation between EGFR copy number and expression, targeting EGFR transcription may also be a viable approach for targeting tumors with high EGFR irrespective of copy number. Epigenetic mechanisms are critical for transcriptional regulation, however studies investigating the mechanisms regulating EGFR transcription are limited. Here we identify two novel super enhancers present in the first intron of the EGFR gene that we have termed EGFR super enhancers 1 and 2 (SE1, SE2). SE1 and SE2 span 37kb and 33kb respectively, contain H3K27Ac enhancer histone marks in NSCLC, GBM and HNSCC cells that functionally enhance transcription in reporter assays, and negatively impact EGFR transcript levels when perturbed by CRISPR/Cas9 guided deletion. Using locally-generated ATAC-seq and transcription factor ChIP-seq from the ENCODE consortium we have identified putative binding sites for AP-1 transcription factor subunits in critical constituent enhancers within SE1 and SE2. Disrupting the binding of these transcription factors through site directed mutagenesis negatively impacts the enhancer function in reporter assays. Our results identify and characterize these novel enhancers, shedding light on the role that epigenetic mechanisms play in regulating EGFR transcription in EGFR-dependent cancer types and presents a novel angle by which these malignancies can be treated.
NIMG-01. A BLINDED IMAGE EVALUATION STUDY TO DETERMINE THE DIAGNOSTIC EFFICACY OF 18F-FLUCICLOVINE PET, AS AN ADJUNCT TO MRI IMAGING, IN ADULTS WITH GLIOMA
Authors: Matthew Miller, Karl-Josef Langen, Vikas Prasad, Igor Yakushev, Johannes Gerber, Marcus Bronzel, Tobias Meyer, Albert Chau, Dan Stevens, Diane Chisholm, Andreas Kluge
Journal: Neuro-Oncology (2018)

The Response Assessment in Neuro-Oncology (RANO) working group have emphasized the clinical utility of Positron Emission Tomography (PET) imaging in brain tumour, highlighting the superiority of amino acid PET tracers over glucose PET tracers in diagnosis, treatment monitoring, and response assessment (Albert, 2016). The amino acid PET tracer 18F-fluciclovine is commercially available for prostate cancer imaging in the US and EU and has Orphan Drug designation for imaging glioma in both jurisdictions. This blinded image evaluation determined the diagnostic performance of 18F-fluciclovine PET (as an adjunct to contrast-enhanced T1-weighted (CE-T1W) magnetic resonance imaging (MRI)), when interpreted by experienced PET-CT readers naïve to 18F-fluciclovine. Thirty-five PET and MRI (CE-T1W and fluid-attenuated inversion recovery (FLAIR)) image datasets, with corresponding histological standard-of-truth, collected during a prospective clinical trial were evaluated. A neuroradiologist read the MRI images and three nuclear medicine physicians, blinded to any patient-specific medical information, independently read each 18F-fluciclovine image (alongside the CE-T1W MRI). Positive/negative predictive values, sensitivity and specificity were determined for CE-T1W, FLAIR and for 18F-fluciclovine plus CE-T1W. Inter- and intra-reader reproducibility was assessed by determining agreement in diagnostic performance parameters and reader-defined Volumes of Interest using intersections and similarity metrics. Date of completion of planned analysis: 22nd June 2018. References: Albert N et al. Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-Oncology 18(9), 1199–1208, 2016
Left Atrial Electromechanical Remodeling Following 2 Years of High-Intensity Exercise Training in Sedentary Middle-Aged Adults
Authors: David A. McNamara, Norman Aiad, Erin Howden, Michinari Hieda, Mark S. Link, Dean Palmer, Mitchel Samels, Braden Everding, Jason Ng, Beverley Adams-Huet, Mildred Opondo, Satyam Sarma, Benjamin D. Levine
Journal: Circulation (2019)

Background: Moderate intensity exercise is associated with a decreased incidence of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk. We evaluated the effects of 24 months of high intensity exercise training on left atrial (LA) mechanical and electric remodeling in sedentary, healthy middle-aged adults. Methods: Sixty-one participants (53±5 years) were randomized to 10 months of exercise training followed by 14 months of maintenance exercise or stretching/balance control. Fourteen Masters athletes were added for comparison. Left ventricular (LV) and LA volumes underwent 3D echocardiographic assessment, and signal-averaged electrocardiographs for filtered P-wave duration and atrial late potentials were completed at 0, 10, and 24 months. Extended ambulatory monitoring was performed at 0 and 24 months. Within and between group differences from baseline were compared using mixed-effects model repeated-measures analysis. Results: Fifty-three participants completed the study (25 control, 28 exercise) with 88±11% adherence to assigned exercise sessions. In the exercise group, both LA and LV end diastolic volumes increased proportionately (19% and 17%, respectively) after 10 months of training (peak training load). However, only LA volumes continued to increase with an additional 14 months of exercise training (LA volumes 55%; LV end diastolic volumes 15% at 24 months versus baseline; P &lt;0.0001 for all). The LA:LV end diastolic volumes ratio did not change from baseline to 10 months, but increased 31% from baseline in the Ex group ( P &lt;0.0001) at 24 months, without a change in controls. There were no between group differences in the LA ejection fraction, filtered P-wave duration, atrial late potentials, and premature atrial contraction burden at 24 months and no atrial fibrillation was detected. Compared with Masters athletes, the exercise group demonstrated lower absolute LA and LV volumes, but had a similar LA:LV ratio after 24 months of training. Conclusions: Twenty-four months of high intensity exercise training resulted in LA greater than LV mechanical remodeling with no observed electric remodeling. Together, these data suggest different thresholds for electrophysiological and mechanical changes may exist in response to exercise training, and provide evidence supporting a potential mechanism by which high intensity exercise training leads to atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02039154.
Association Between Cannabis Use and Risk for Diabetic Ketoacidosis in Adults With Type 1 Diabetes
Authors: Halis K. Akturk, Daniel D. Taylor, Ulas M. Camsari, Amanda Rewers, Gregory L. Kinney, Viral N. Shah
Journal: JAMA Internal Medicine (2018)

ket.A biosimilar of Sanofi's popular insulin Lantus was approved for use in the European Union in 2014 but was initially delayed for 2 more years by a lawsuit in the United States. 6Now that the biosimilar product, Basaglar, has finally hit the market, its price is only minimally lower than the original brand. 7 The same insulin pen that retails for $140 in the United States costs less than $15 in Germany and Canada. 8 The US insurance system-private and public-does not cut people with chronic disease a break but instead tends to penalize them.People with type 1 diabetes are people who drew a short straw in the disease lottery.Most other developed countries have concluded that their citizens should therefore not be subject to copays or high deductibles."If you have a chronic disease, you shouldn't be burdened by the cost," York F. Zöllner, a professor of health economics at Hamburg University of Applied Sciences, told me in an interview for the New York Times before explaining the German approach, in which out-of-pocket contributions for insulin are less than $100 per year. 9Until very recently, the disease foundations (JDRF and the American Diabetes Association among them), as well as many diabetes patient groups, did not protest much as the prices rose, in part likely because so many receive funding from pharmaceutical companies.Extreme prices can lead to extreme solutions.A 29-year-old student in Missouri with diabetes whom I interviewed for my book 10 told me that she would only consider doctoral programs outside of the United States."My one goal in life has been to move to Europe so I don't have to pay these staggering prices just to survive," she said.But others-that 25%-will quietly skimp on their insulin, taking less than they need but more, perhaps, than they can really afford.Some of them will die.
ACTR-16. PERIPHERAL BLOOD CD4+ MONONUCLEAR CELL FRACTIONS ARE ASSOCIATED WITH OVERALL SURVIVAL AT FIRST RECURRENCE OF IDH-WILDTYPE GLIOBLASTOMA AFTER STANDARD CHEMORADIOTHERAPY: SECONDARY ANALYSES OF THE PHASE II DIRECTOR TRIAL
Authors: Hans-Georg Wirsching, Ekaterina Terksikh, Manuela Silginer, Carsten Krieg, Ghazaleh Tabatabai, Wolfgang Wick, Guido Reifenberger, Patrick Roth, Burkhard Becher, Michael Weller
Journal: Neuro-Oncology (2018)

The alkylating agent temozolomide prolongs survival of glioblastoma patients through induction of futile DNA mismatch repair in cancer cells. Whether systemic temozolomide effects on the immune system affect outcome has not been studied in detail. To address this question, we analyzed peripheral blood mononuclear cells (PBMC) of N=52 clinically well-annotated patients with recurrent, isocitrate dehydrogenase (IDH)-wildtype glioblastoma and of N=21 healthy donors by 11-color flow cytometry. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of two dose-intensified temozolomide regimens at first recurrence of glioblastoma after standard chemoradiotherapy with first-line temozolomide. There were no efficacy differences between both dose-intensified temozolomide schedules in this trial. Unsupervised clustering of flow cytometry annotations identified two patient clusters, which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by age, gender, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karnofsky performance score (KPS), number of first-line temozolomide cycles or steroid use. Progression-free survival was similar (CD4highvsCD4low2.1 vs 2.4 months, p=0.19), whereas overall survival was longer in the CD4high cluster of patients (12.7 vs8.7 months, p= 0.004). In a multivariate Cox model of overall survival that controlled for established prognostic factors, we found associations with overall survival for KPS (p=0.019), high CD4+ fractions (p=0.052) with relevant interactions with cluster assignment (p=0.058), residual tumor at study entry (p=0.068) and MGMT promoter methylation (p=0.072), but not age (p=0.96) or steroid use at study entry (p=0.32). There were no interactions of cluster assignment or CD4+ fractions with steroid use in this model. We conclude that temozolomide-associated CD4+ T-cell depletion may have unfavorable effects on the survival of glioblastoma patients, a finding that warrants further exploration.