tbuckley/cabot-search huggingface dataset:
IMMU-53. CHARACTERIZATION OF THE GENOMIC AND IMMUNOLOGICAL DIVERSITY OF MALIGNANT BRAIN TUMORS THROUGH MULTI-SECTOR ANALYSIS
Authors: Max Schaettler, Megan Richters, Malachi Griffith, Gavin Dunn
Journal: Neuro-Oncology (2020)

Abstract While the degree of spatial genomic heterogeneity within primary glioblastoma (GBM) has been previously investigated, the extent of this heterogeneity in other malignant brain tumors and its connection to the local immune microenvironment remains unknown. To address this, we performed whole-exome, RNA, and TCR sequencing on multiple spatially distinct sectors from a cohort of malignant brain tumors comprised of both brain metastases and primary and recurrent GBMs. Our results suggest a striking difference in which a majority of mutations and predicted neoantigens are shared between spatially distinct regions of metastatic brain tumors in contrast to the spatial heterogeneity observed within both primary and recurrent GBMs. Additionally, despite substantial differences in immunotherapy responsiveness between brain metastases and GBM, we can detect significantly expanded T-cell clonotypes within both tumor types with some clonal frequencies exceeding 10% of intratumoral T-cells. Similar to the observed distribution of variants and neoantigens, the expanded clonotypes are more shared among spatially distinct sectors in metastatic brain tumors than in primary or recurrent GBMs. Interestingly, the frequencies of most of these enriched T-cell clones are significantly diminished within expanded tumor infiltrating lymphocyte (TIL) cultures, advising caution in the use of expanded TIL for the detection of tumor-specific responses. These results provide novel insight into the immunogenomic landscape of malignant brain tumors with implications for our understanding of tumor-immune interactions and the development of immunotherapies.
QOL-13. NEUROCOGNITIVE OUTCOMES ACCORDING TO RISK-ADAPTED TREATMENT REGIMENS FOR CHILDREN OLDER THAN 4 WITH MEDULLOBLASTOMA AND POSTERIOR FOSSA EPENDYMOMA – RESULTS OF THE HIT2000 TRIAL
Authors: Martin Mynarek, Anne Neumann-Holbeck, Anika Resch, Holger Ottensmeier, Katja von Hoff, Thomas Traunwieser, Rolf-Dieter Kortmann, Denise Obrecht, Monika Warmuth-Metz, Brigitte Bison, Torsten Pietsch, Stefan M Pfister, Martin Sill, Marcel Kool, Dominik Sturm, David Jones, Andreas von Deimling, Felix Sahm, Tanja Tischler, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Reduced neuropsychological outcomes are a major concern in pediatric patients with malignant brain tumors. We aimed to estimate decline in cognitive function according to treatment regimens. METHODS Cross-sectional analysis of cognitive functions tested with the Neuropsychological Basic Diagnostic tool (NBD) in 279 patients &amp;gt;4 years at diagnosis (median: 8.66; range: 4.01–18.98) with medulloblastoma (n=110, 23.7–25.0Gy CSI; n=131, &amp;gt;30Gy CSI) or posterior fossa ependymoma (n=38 local radiotherapy) who participated in the HIT-2000 trial. Multivariable regression analysis was conducted to adjust for postoperative cerebellar mutism syndrome, preoperative hydrocephalus, postoperative shunt placement, the interval between diagnosis and assessment, sex and age. RESULTS Mean time from diagnosis to assessment was 5.1 years. Increasing CSI-dose was significantly associated with a deterioration in performance of most subtests, particularly in areas of fluid intelligence (mean z-values per test for no CSI/23.4Gy/&amp;gt;30Gy respectively: matrix reasoning:-0.40/-0.52/-0.98, p&amp;lt;.001), short-term memory (number recall: -0.07/-0.58/-0.64, p=.002), visuo-spatial skills (visual-motor integration:-0.49/-0.68/-1.12, p&amp;lt;.001) and fine motor skills (dominant-hand:-1.09/-1.80/-2.12, p=.008; non-dominant-hand:-1.47/-2.59/-2.82, p=.003; bimanual coordination:-1.33/-2.68/-2.76, p=.001). These differences were retained after adjustment for confounding variables. Within medulloblastoma patients treated with &amp;gt;30Gy CSI, selective attention, but no other function was reduced in patients treated with pre-radiotherapy chemotherapy including intraventricular MTX (selective attention (with chemotherapy/without chemotherapy mean z-values: -0.66/0.00, p=.006)). Patients with SHH-activated medulloblastoma did significantly better than WNT or Group3/Group4 medulloblastoma patients in fluid intelligence and fine motor skills. CONCLUSION CSI dose among other highly relevant factors had significant effects on neuropsychological outcome. Pre-radiotherapy intraventricular MTX had only minor effects. Patients with SHH-activated medulloblastomas showed a more favorable outcome when compared to patients in the other subgroups.
Radical Cystectomy Against Intravesical BCG for High-Risk High-Grade Nonmuscle Invasive Bladder Cancer: Results From the Randomized Controlled BRAVO-Feasibility Study
Authors: James W. F. Catto, Kathryn Gordon, Michelle Collinson, Heather Poad, Maureen Twiddy, Mark Johnson, Sunjay Jain, Rohit Chahal, Matt Simms, Mohantha Dooldeniya, Richard Bell, Phillip Koenig, Samantha Conroy, Louise Goodwin, Aidan P. Noon, Julie Croft, Julia M. Brown
Journal: Journal of Clinical Oncology (2020)

PURPOSE High-grade nonmuscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease. Treatments include intravesical maintenance Bacillus Calmette-Guerin (mBCG) and radical cystectomy (RC). We wanted to understand whether a randomized trial comparing these options was possible. MATERIALS AND METHODS We conducted a two-arm, prospective multicenter randomized study to determine the feasibility in Bacillus Calmette-Guerin-naive patients. Participants had new high-risk HRNMIBC suitable for both treatments. Random assignment was stratified by age, sex, center, stage, presence of carcinoma in situ, and prior low-risk bladder cancer. Qualitative work investigated how to maintain equipoise. The primary outcome was the number of patients screened, eligible, recruited, and randomly assigned. RESULTS We screened 407 patients, approached 185, and obtained consent from 51 (27.6%) patients. Of these, one did not proceed and therefore 50 were randomly assigned (1:1). In the mBCG arm, 23/25 (92.0%) patients received mBCG, four had nonmuscle invasive bladder cancer (NMIBC) after induction, three had NMIBC at 4 months, and four received RC. At closure, two patients had metastatic BC. In the RC arm, 20 (80.0%) participants received cystectomy, including five (25.0%) with no tumor, 13 (65.0%) with HRNMIBC, and two (10.0%) with muscle invasion in their specimen. At follow-up, all patients in the RC arm were free of disease. Adverse events were mostly mild and equally distributed (15/23 [65.2%] patients with mBCG and 13/20 [65.0%] patients with RC). The quality of life (QOL) of both arms was broadly similar at 12 months. CONCLUSION A randomized controlled trial comparing mBCG and RC will be challenging to recruit into. Around 10% of patients with high-risk HRNMIBC have a lethal disease and may be better treated by primary radical treatment. Conversely, many are suitable for bladder preservation and may maintain their prediagnosis QOL.
Abstract P251: Monitoring the Success of Smoking Cessation Using Dna Methylation Status at Cg05575921: Implications for Incentive Based Strategies for Quantitative Reduction of Harm
Authors: Robert Philibert, Meesha Dogan, Eric Hoffman
Journal: Circulation (2020)

Cigarette smoking accounts for about 1/5 of all deaths from heart disease in the United States. Despite this grim fact, getting patients to quit smoking is extremely difficult. Encouragingly, several studies have shown that incentive based smoking cessation interventions may be more effective than traditional strategies. However, their implementation has been stymied by the lack of clinically implementable objective mechanisms to determine smoking cessation in those using nicotine replacement. Over the past several years, we and others have shown that DNA methylation status at a CpG site in the AHRR gene referred to as cg05575921 accurately classifies smoking status and predicts smoking intensity. In addition, we have developed a rapid clinically implementable digital PCR assay for assessing methylation at this locus using DNA prepared from blood or saliva. However, whether changes in DNA methylation at this locus occur quickly enough to allow the monitoring and possible incentivization of smoking cessation is unknown. To examine these possibilities, we followed 70 regular adult smokers as they underwent smoking cessation using a financial incentive based, pharmacologically assisted paradigm that stipulated no use of nicotine replacement. Consistent with prior reports, we found that as quantified by nondetectable serum cotinine levels at 1 month, 2 months and 3 months, 30% of all subjects who attempted to quit smoking in order to receive a $400 reward succeeded in quitting smoking. Over the course of their cessation trajectory, cg05575921 methylation demonstrated a stepwise increase commiserate with initial smoking intensity. Overall, the heaviest smokers, manifested a stepwise 14% increase in cg05575921 methylation while the lightest smokers manifested a 5% increase in cg05575921 methylation over the three month follow up period. Taken together with prior data, these new data demonstrate a robust reversion of cg05575921 in response to smoking cessation whose values can be used as objective evidence of smoking cessation even in those using nicotine replacement. In addition, because this method can detect and quantify partial cessation, these findings further suggest that the use of this technology together with incentive based approaches may also be useful in encouraging quantitative reduction of harm for cancer and smoking related cardiovascular risk in those who can reduce, but cannot fully quit smoking.
BIOM-60. BIOMARKER EVALUATION FOR IMIPRIDONE ONC206 REVEALS ClpP, ATF4, MYC, EGFR and HIF1 AS KEY PREDICTORS OF ANTI-CANCER EFFICACY
Authors: Sara Morrow, Mathew Garnett, Ultan McDermott, Cyril Benes, Joshua Allen, Varun Prabhu
Journal: Neuro-Oncology (2020)

Abstract ONC206 is a DRD2 antagonist and ClpP agonist that is a chemical derivative of ONC201, which is in Phase II clinical trials for H3 K27M-mutant glioma. We have previously reported that dopamine receptor expression correlates with ONC201 and ONC206 efficacy. Here, we evaluated additional predictive biomarkers for both agents in the GDSC panel using RNA-seq expression data. ClpP emerged as a strong predictor of efficacy for ONC206 (IC50: p = 1.83E-4, AUC: 9.92E-13). ClpP activation enhances degradation of its substrates, including electron transport chain members responsible for oxidative phosphorylation (OXPHOS). Imipridones activate the integrated stress response involving ATF4 and cause proteasomal degradation of c-myc, which also reduces OXPHOS. Accordingly, high ATF4 (IC50: p = 4.92E-5, AUC: p=2.84E-9) and elevated c-myc correlated with ONC206 efficacy (IC50: p = 6.42E-6, AUC: 3.31E-12). EGFR expression is inversely correlate with DRD2 expression in glioma and its activation is associated with glycolysis. Low EGFR expression correlated with increased ONC206 efficacy (IC50: p = 4.32E-7, AUC: p = 6.44E-20). Loss of HIF1 shunts cellular metabolism toward OXPHOS. Low HIF1 expression correlated with increased anticancer efficacy for ONC206 (IC50: p = 1.96E-3, AUC: p = 1.56E-11). Expression of each of the five markers was significantly different in cell lines that achieved an IC90 with ONC206 (~10%) versus those that did not. A similar analysis for ONC201 revealed that ClpP, MYC and EGFR are more predictive of efficacy relative to ATF4 and HIF1. Combinatorial biomarker analyses revealed MYC/EGFR as the most significant predictor of IC50 for both agents. ClpP/MYC and ClpP/HIF1 were the most significant predictors of AUC for ONC201 and ONC206, respectively. Ongoing studies are further investigating tumor type enrichment of biomarkers. Prediction of innate imipridone sensitivity using biomarkers identified in this study may guide patient and tumor type selection in clinical trials.
SAT0273 PROGNOSTIC FACTORS FOR POOR OUTCOME IN BEHÇET’S SYNDROME WITH NEUROLOGICAL INVOLVEMENT: RESULTS FROM A CLINICAL LONG-TERM FOLLOW-UP OF A SINGLE CENTRE
Authors: D. Sahin Eroglu, M. Torgutalp, S. Sezer, A. Boyvat, C. Yucesan, A. Ates
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background:</h3> Behçet’s Syndrome (BS) is a vasculitis of unknown cause. Neurological disease is a type of its serious involvement and causes morbidity and mortality. <h3>Objectives:</h3> In this study, we aimed to describe the clinical characteristics of neuro-Behçet Syndrome (NBS) and to define prognostic factors that were associated with poor outcome. <h3>Methods:</h3> Among 2033 patients with BS, we performed a retrospective analysis of 94 patients (52.1% male; mean age 36.1 (11.9) years), who fulfilled the ISG-1990 for BS. We divided patients into two subgroups, either parenchymal (p-NBS) or non-parenchymal (np-NBS). Clinical, laboratory, and imaging characteristics of the patients were defined. We described the poor outcome as a modified Rankin score (mRS) &gt;= 3 at last follow-up and/or death, and assessed the predictor factors associated such kind of outcome. <h3>Results:</h3> In total, 52 (55.3%) patients presented with p-NBS, of whom 15 (28.8%) had progressive course, and 42 (44.7%) presented with np-NBS (Table.1). Ocular involvement was more common in p-NBS than np-NBS (59.6% vs. 39.1% respectively, p=0.04), whereas vascular involvement excluding sinus vein thrombosis was more frequent in patients with np-NBS (15.4% vs. 50.0%, respectively, p=0.001). Headache and papilledema were frequently observed in np-NBS (p&lt;0.001), whereas paresis, sensory symptoms, pyramidal and cerebellar signs were significantly common in p-NB (&lt;0.001). Twenty-five patients (26.6%) experienced at least one relapse. After a median of 54 (IQR 79.4) months, 11 patients (11.7%) had disabling sequela and a total of 5 (5.3%) deaths occurred. Characteristics of patients with and without poor outcome are presented in table 2. In multivariable logistic regression analysis, factors associated with poor outcome were initial mRS (OR 24.2 (95% CI 3.16 – 108.67)) and age &gt;= 40 at NBS diagnosis (OR 4.59 (95% CI 1.02 – 20.69)), meanwhile, headache at presentation was associated with a lower risk for poor outcome. (OR 0.22 (95% CI 0.05 – 0.91)). <h3>Conclusion:</h3> Neurologic involvement is a detrimental manifestation of BS and causes disability, even death. Patients who have an initial disabling presentation in advanced age are more likely to have poor prognosis. Treatment intensification in this subpopulation might be considered. <h3>References:</h3> None <h3>Disclosure of Interests:</h3> None declared
Infants Born to Mothers With COVID-19—Making Room for Rooming-in
Authors: David A. Kaufman, Karen M. Puopolo
Journal: JAMA Pediatrics (2020)

Andrea Ronchi, MD; Carlo Pietrasanta, MD; Maurizio Zavattoni, MD; Martina Saruggia, MD; Federico Schena, MD; Maria Teresa Sinelli, MD; Massimo Agosti, MD; Chryssoula Tzialla, MD; Felicia Filomena Varsalone, MD; Lea Testa, MD; Claudia Ballerini, MD; Stefania Ferrari, MD; Giovanna Mangili, MD; Maria Luisa Ventura, MD; Simona Perniciaro, MD; Elena Spada, PhD; Giovanna Lunghi, MD; Antonio Piralla, PhD; Fausto Baldanti, MD; Fabio Mosca, MD; Lorenza Pugni, MD
IL-17A from innate and adaptive lymphocytes contributes to inflammation and damage in cystic fibrosis lung disease
Authors: Matthias Hagner, Melanie Albrecht, Matteo Guerra, Peter Braubach, Olga Halle, Zhe Zhou-Suckow, Simone Butz, Danny Jonigk, Gesine Hansen, Carsten Schultz, Anna-Maria Dittrich, Marcus A. Mall
Journal: European Respiratory Journal (2020)

Elevated levels of interleukin (IL)-17A were detected in the airways of patients with cystic fibrosis (CF), but its cellular sources and role in the pathogenesis of CF lung disease remain poorly understood. The aim of this study was to determine the sources of IL-17A and its role in airway inflammation and lung damage in CF.We performed flow cytometry to identify IL-17A-producing cells in lungs and peripheral blood from CF patients and β-epithelial Na+ channel transgenic (Scnn1b-Tg) mice with CF-like lung disease, and determined the effects of genetic deletion of Il17a and Rag1 on the pulmonary phenotype of Scnn1b-Tg mice.T-helper 17 cells, CD3+CD8+ T-cells, γδ T-cells, invariant natural killer T-cells and innate lymphoid cells contribute to IL-17A secretion in lung tissue, lymph nodes and peripheral blood of patients with CF. Scnn1b-Tg mice displayed increased pulmonary expression of Il17a and elevated IL-17A-producing innate and adaptive lymphocytes with a major contribution by γδ T-cells. Lack of IL-17A, but not the recombination activating protein RAG1, reduced neutrophilic airway inflammation in Scnn1b-Tg mice. Genetic deletion of Il17a or Rag1 had no effect on mucus obstruction, but reduced structural lung damage and revealed an IL-17A-dependent macrophage activation in Scnn1b-Tg mice.We identify innate and adaptive sources of IL-17A in CF lung disease. Our data demonstrate that IL-17A contributes to airway neutrophilia, macrophage activation and structural lung damage in CF-like lung disease in mice. These results suggest IL-17A as a novel target for anti-inflammatory therapy of CF lung disease.
EXTH-15. INHIBITION OF 2-HG LEADS TO UPREGULATION OF A PRO-INFLAMMATORY GENE SIGNATURE IN A NOVEL HLA-A2/HLA-DR1 TRANSGENIC MOUSE MODEL OF IDH1R132H-EXPRESSING GLIOMA
Authors: Polly Chuntova, Brandon Nicolay, Christine Hudson, Rohini Narayanaswamy, Sebastien Ronseaux, Megan Montoya, Kira Downey, Hideho Okada
Journal: Neuro-Oncology (2020)

Abstract Recent studies have demonstrated the impacts of 2-HG on the anti-tumor immune response in isocitrate dehydrogenase (IDH)-mutant gliomas. Our laboratory has reported that mutant IDH1 (IDH1R132H) suppresses STAT1, the master regulator of IFN-responses and IFN-inducible chemokines, thereby contributing to the “cold” tumor environment. Our data also indicated that inhibition of 2-HG production, through the use of a small molecular inhibitor of mutant IDH, can restore anti-tumor immunity. As the IDH1R132H mutation has been shown to elicit a CD4+ T-cell response in human leukocyte antigen (HLA)-DR1 hosts, to establish a clinically relevant mouse model of IDH1R132H glioma, we generated a novel IDH1R132H glioma cell line syngeneic to the HLA-A2/HLA-DR1-transgenic mice. The cell line expresses the IDH1R132H protein, produces ~65 µg/ml 2-HG in vitro, and forms 2-HG producing orthotopic glioma in vivo. Furthermore, ex vivo sorted tumor-associated myeloid cells (TAMCs) demonstrate high levels of intracellular 2-HG (60–80ng/1M cells), suggesting 2-HG may be taken up by these TAMCs in vivo. Treatment of tumor-bearing mice with vorasidenib, a pan-mutant IDH inhibitor, resulted in a 10-fold reduction of 2-HG levels in the tumor cells, correlate reduction in intracellular 2-HG levels in TAMCs, and 2-fold smaller tumors at time of sacrifice. Analysis of tumor tissues using the NanoString platform revealed enhanced pro-inflammatory IFN-related responses as a result of IDH1R132H inhibition with vorasidenib. Furthermore, vorasidenib treatment increased CD4+ tumor-infiltrating T-cells coupled with upregulation of HLA-DR on tumor-infiltrating myeloid cells, suggesting the opportunity for enhanced antigen presentation. Currently ongoing studies are evaluating the benefit of combining this enhanced immune response with additional immunomodulatory treatments, such as vaccine therapy and immune checkpoint inhibition. These data represent highly translational findings as our major histocompatibility complex (MHC)-humanized model addresses current challenges in the study of IDH1R132H-specific immunity and utilizes a clinically relevant inhibitor in phase 3 clinical development.
87P An augmented exome/transcriptome-based platform for precision cancer therapy selection, clinical trial matching, and oncology research applications, enabling next-generation composite biomarkers by combining tumour and immune features
Authors: R. Power, G. Bartha, J. Harris, S.M. Boyle, E. Levy, P. Milani, P. Tandon, P. McNitt, M. Morra, S. Desai, S. Saldivar, M. Clark, C. Haudenschild, J. West, R. Chen
Journal: Annals of Oncology (2020)
Effect of gender affirming hormones on athletic performance in transwomen and transmen: implications for sporting organisations and legislators
Authors: Timothy A Roberts, Joshua Smalley, Dale Ahrendt
Journal: British Journal of Sports Medicine (2020)

Objective To examine the effect of gender affirming hormones on athletic performance among transwomen and transmen. Methods We reviewed fitness test results and medical records of 29 transmen and 46 transwomen who started gender affirming hormones while in the United States Air Force. We compared pre- and post-hormone fitness test results of the transwomen and transmen with the average performance of all women and men under the age of 30 in the Air Force between 2004 and 2014. We also measured the rate of hormone associated changes in body composition and athletic performance. Results Participants were 26.2 years old (SD 5.5). Prior to gender affirming hormones, transwomen performed 31% more push-ups and 15% more sit-ups in 1 min and ran 1.5 miles 21% faster than their female counterparts. After 2 years of taking feminising hormones, the push-up and sit-up differences disappeared but transwomen were still 12% faster. Prior to gender affirming hormones, transmen performed 43% fewer push-ups and ran 1.5 miles 15% slower than their male counterparts. After 1 year of taking masculinising hormones, there was no longer a difference in push-ups or run times, and the number of sit-ups performed in 1 min by transmen exceeded the average performance of their male counterparts. Summary The 15–31% athletic advantage that transwomen displayed over their female counterparts prior to starting gender affirming hormones declined with feminising therapy. However, transwomen still had a 9% faster mean run speed after the 1 year period of testosterone suppression that is recommended by World Athletics for inclusion in women’s events.
SURG-16. SURGICAL TECHNIQUES TO AVOID COMPLICATIONS DURING REPEAT RESECTIONS FOR PEDIATRIC BRAIN TUMORS
Authors: Ichiyo Shibahara
Journal: Neuro-Oncology (2020)

Abstract Complications due to repeat resection for recurrent pediatric brain tumors remain unclear. The present study focused on surgical techniques to avoid surgical morbidities during repeat resections for pediatric brain tumors. This study included 57 consecutive repeat resections for 28 pediatric patients under the age of 15 with recurrent brain tumors. Resections were performed 2–14 times for each patient by the senior author (TK). Reviewed factors were wound-related complications, bleeding/ischemic complications, and Eastern Cooperative Oncology Group performance status (PS) before and after surgery. No patients presented any complications to decrease PS, postoperatively. No wound-related complications were worthy of special mention. Surgical techniques to prevent wound-related complications are as follows: 1) shaving the hair around the previous skin incision just before the surgery; 2) washing and disinfecting around the skin incision using chlorhexidine soap and an alcohol swab, followed by Povidone-Iodine solution; 3) after craniotomy, removing all granulation tissues, residual titanium plates, and screws; 4) brushing all surgical fields and a bone flap before opening the dura mater using Povidone-Iodine solution followed by normal saline; 5) maintaining a bone flap in normal saline with antibiotics; 6) changing all the surgical instrument and gloves; 8) closing the dura mater completely to prevent CSF leakage, and 8) using postoperative antibiotics for six days. Meticulous dissecting postsurgical adhesion of brain and dura mater, arteries and nerves; usage of neuronavigation system and neuromonitoring to understand the anatomy radiologically and functionally; applying papaverine hydrochloride for spastic arteries, are important to avoid complications during the intracranial procedure.