tbuckley/cabot-search huggingface dataset:
NIMG-72. QUANTIFYING INTRA-TUMOR MULTI-GENE HETEROGENEITY OF GBM FROM MRI USING A DATA-INCLUSIVE MACHINE LEARNING ALGORITHM
Authors: Lujia Wang, Leland Hu, Andrea Hawkins-Daarud, Kyle Singleton, Christopher Sereduk, Nhan Tran, Kristin Swanson, Jing Li
Journal: Neuro-Oncology (2021)

Abstract Intra-tumor genetic heterogeneity is an important cause of treatment failure of GBM. Using MRI and image-localized biopsies, it is possible to train machine learning (ML) models to predict regional genetic status. However, biopsy samples are limited, making it difficult to train a robust ML model. We proposed a data-inclusive model called Weakly Supervised Ordinal Support Vector Machines (WSO-SVM) which leverages the vast amount of MRI data outside the sparsely sampled biopsy regions to augment the biopsy samples to improve ML accuracy. Our study included a unique dataset of 104 image-localized biopsies with spatially matched multiparametric MRI from 30 untreated Glioblastoma (GBM) patients. Each biopsy sample went through genetic sequencing analysis and our study focused on two GBM hallmark genes, EGFR and PDGFRA. For each gene, a biopsy sample was labeled as “altered” if the copy number of this gene was amplified or a mutation was found, and “non-altered” otherwise. From the localized region of six MRI contrasts from T1gd, T2w, diffusion and perfusion imaging, over 300 texture features were extracted. To account for biopsy sample location uncertainty, six neighboring regions of the biopsy sample including four neighbors two pixels away from the biopsy location and two neighbors on adjacent slices were also included in model training. WSO-SVM achieved 0.83 accuracy, 0.77 sensitivity, and 0.86 specificity for classifying EGFR; 0.77 accuracy, 0.74 sensitivity, and 0.79 specificity for classifying PDGFRA, based on 10-fold cross validation. Furthermore, using the trained models, we generated regional EGFR and PDGFRA alteration maps for each patient within the enhancing and non-enhancing tumoral areas. On average we found a greater proportion of enhancing tumor with co-alteration than non-enhancing tumor, while this trend was reversed when considering only one altered gene. The ratio of EGFR vs PDGFRA alterations was higher in non-enhancing tumor than enhancing tumor.
Abstract 10822: Lower EPA/AA Ratio is Associated with a Higher Prevalence of Vulnerable Characteristics in Non-Culprit Coronary Plaques in Statin-Treated Patients with Coronary Artery Disease
Authors: Kiyoshi Asakura, Yoshiyasu Minami, Daisuke Kinoshita, Takako Nagata, Masahiro Katamine, Aritomo Katsura, Takuya Hashimoto, RYO KAMEDA, Kentaro Meguro, Takao Shimohama, Junya Ako
Journal: Circulation (2021)

Introduction: Low eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is associated with an increased risk of cardiovascular events in patients with coronary artery disease (CAD). However, the association between EPA/AA ratio and the characteristics of non-culprit coronary plaque in statin-treated patients with CAD remains to be elucidated. Hypothesis: Lower EPA/AA ratio is associated with a higher prevalence of vulnerable characteristics in non-culprit coronary plaque in statin-treated patients with CAD. Methods: A total of 367 consecutive stain-treated patients with stable coronary disease, who underwent percutaneous coronary intervention for the culprit lesion and optical coherence tomography (OCT) imaging of a non-culprit plaque in a culprit vessel were included. The characteristics of non-culprit plaque assessed by OCT were compared between the lower EPA/AA group (EPA/AA &lt;0.4, n=255) and the higher EPA/AA group (EPA/AA ≥0.4, n=112). Results: The prevalence of lipid-rich plaque (58.8 vs. 42.0%, p=0.004) and plaque with macrophage (56.1 vs. 32.1%, p&lt;0.001) was significantly higher in the lower EPA/AA group than in the higher EPA/AA group (Panel A). The lower EPA/AA was independently associated with the presence of lipid-rich plaque (Odds ratio [OR], 1.837; 95% confidence interval [CI]: 1.130-3.004, p=0.015) and plaque with macrophage (OR, 2.764; 95% CI: 1.672-4.639, p&lt;0.001) (Panel B). Conclusions: Lower EPA/AA ratio was associated with a higher prevalence of vulnerable characteristics in non-culprit plaque. The present results may partly explain the impact of low EPA/AA ratio on the increased incidence of recurrent events in patients with CAD.
Abstract 10398: Clot or Not? A Meta-Analysis of Autopsy Findings in Spontaneous Coronary Artery Dissection
Authors: Vita Jaspan, Amy Rapkiewicz, Harmony Reynolds
Journal: Circulation (2021)

Introduction: Spontaneous coronary artery dissection (SCAD) is an uncommon but likely underdiagnosed cause of acute coronary syndrome. Current treatment of SCAD commonly includes antiplatelet agents, though pathogenesis relates to intramural hematoma, rather than atherothrombosis as in typical myocardial infarction. Our goal was to determine whether thrombus in the true lumen is part of the pathophysiology of fatal cases of SCAD, which could help guide treatment decisions. Methods: A review of electronic databases including PubMed and EMBASE was conducted from inception through June 2021. Citations were included that provided pathology images of dissected coronary arteries acquired from autopsies of patients who died of SCAD. Images were independently reviewed by a pathologist who described the presence or absence of thrombus and inflammatory cells. Results: A total of 35 citations containing autopsy images were identified. These included 42 cases of which 88% were female, with an average age of 44 years. The most common vessel involved was the left anterior descending (74%), with 40% involving multiple vessels. Most decedents had no medical history, though 5% had systemic vasculitis and 17% were pregnant or peri-partum. On independent review of the pathology images, all had intramural hematoma, none had evidence of thrombus in the true lumen, and 16% had evidence of thrombus in the false lumen. There was eosinophilic inflammation of the affected artery in 64% of cases. Conclusions: There was no evidence of thrombus in the true lumen in any of 42 cases of fatal SCAD for whom autopsy images were available. This suggests that the use of antiplatelet agents in the treatment of SCAD should be re-evaluated. Clinical trials are necessary to determine whether antiplatelet agents are beneficial for patients with SCAD. Additionally, further research is necessary to better understand the role of eosinophils in the pathophysiology of SCAD.
Abstract 11915: Less Aspirin, Less Bleeding for Patients on Chronic Warfarin Anticoagulation for Atrial Fibrillation and/or Venous Thromboembolic Disease
Authors: Jordan K Schaefer, Josh Errickson, Xiaokui Gu, Constantina Alexandris-Souphis, Mona A Ali, Brian Haymart, Scott Kaatz, Eva M Kline-rogers, Jay H Kozlowski, Gregory D Krol, Vinay Shah, Suman L Sood, James B Froehlich, Geoffrey D Barnes
Journal: Circulation (2021)

Introduction: For some patients on chronic warfarin anticoagulation for atrial fibrillation and/or venous thromboembolic disease, the addition of aspirin (ASA) may increase bleeding with uncertain therapeutic benefit. Between 2017 and 2018, the six-center Michigan Anticoagulation Quality Improvement Initiative implemented a multi-center quality improvement project to reduce excess aspirin use. Hypothesis: We anticipated reductions in overall ASA use and bleeding. Methods: Warfarin treated patients taking ASA without a clear indication (eg. coronary artery disease) were identified. Their primary care provider was contacted to advise if ongoing ASA+warfarin was recommended. ASA was discontinued if suggested by their doctor. Data was abstracted by trained abstractors using predefined forms. In December 2019, we evaluated monthly rates of excess ASA use, bleeding, and thrombotic outcomes. Data were analyzed using piecewise linear regression. Results: We followed 6,738 patients for a median (interquartile range) of 6.7 months (3.2-19.3 months). Aspirin use declined significantly over the 24 months before our intervention (P&lt;0.001) with an accelerated decline post intervention (p=0.001, Figure 1). Our intervention was associated with a non-significant decline in bleeding (p=0.12), emergency room (ER) visits for bleeding (p=0.35), admissions for bleeding (p=0.97), a significant decline in major bleeding (p=0.029), and no significant change in thrombotic outcomes (p=0.34). Including the decline in ASA use starting 24 months pre-intervention, reducing ASA use resulted in significant declines in any bleeding, major bleeding, and ER visits for bleeding (p=0.021, p=0.001, p=0.038 respectively). There remained no change in thrombotic outcomes (p=0.36). Conclusions: Our quality improvement intervention reduced aspirin use. Reductions in aspirin use were associated with reduced bleeding outcomes without increased thrombotic outcomes.
CTNI-48. A PHASE 0 ‘TRIGGER’ TRIAL OF CDK4/6 PLUS ERK1/2 INHIBITORS IN RECURRENT GLIOBLASTOMA
Authors: Nader Sanai, Yu-Wei Chang, Tigran Margaryan, Anita DeSantis, Mackenna Elliott, Chelsea Pennington-Krygier, Garry Hook, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. METHODS Adult recurrent GBM patients (n=10) with intact RB expression, &amp;gt; 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration &amp;gt; 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. RESULTS No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. CONCLUSION Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.
Abstract 9728: A Novel Emergency Department Syncope Protocol Reduces Unnecessary Hospital Admissions
Authors: Brian Wood, Michael Craig, Meredith Williamson, Anil K Gehi
Journal: Circulation (2021)

Background: More than 1.2 million emergency department (ED) visits for syncope occur each year in the US. Many associated admissions and diagnostic studies may be unnecessary. Objective: To determine the effectiveness of a novel protocol for syncope care in the ED in reducing unnecessary admissions and diagnostic testing. Methods: A multi-disciplinary team developed a decision aid for ED syncope management guided by focused history, physical, and diagnostic testing. Clear indications for diagnostic testing were laid out in the protocol and incorporated into the ED workflow through education and medical record system integration. Patients considered safe for discharge were provided an expedited appointment in a specialty clinic. Rates of admission, utilization of diagnostic studies (head CT, carotid ultrasound, echocardiogram), and rates of return presentation to the ED within 30 days were compared before and after implementation. Results: Between September 2019 and December 2019, 308 syncope patients presented to the ED. Between January 2020 and June 2020 (following implementation), 321 syncope patients presented to the ED. The proportion admitted decreased (44.6% to 30.0%, p&lt;0.001. Figure), while the proportion undergoing diagnostic studies was unchanged (19.5% to 16.0%, p=0.303). The proportion returning to the ED within thirty days was unchanged (11.2% to 10.2%, p=0.769). The proportion referred for expedited follow up to a syncope specialty clinic increased (1.5% to 8.8%, p&lt;0.001). Conclusion: Implementation of an ED syncope care pathway with utilization of a syncope specialty clinic was associated with significantly reduced hospital admissions. Utilization of diagnostic testing and rates of return ED presentation within thirty days were unchanged. Additional studies to evaluate the scalability and cost benefits of this program are warranted.
Patients with primary brain tumors and COVID-19: A report from the Dutch Oncology COVID-19 Consortium
Authors: Karlijn de Joode, Walter Taal, Tom J Snijders, Monique Hanse, Johan A F Koekkoek, Esther Oomen - de Hoop, Jan Willem B de Groot, Mathilde C M Kouwenhoven, Laurens V Beerepoot, Anne-Marie C Dingemans, Martin J van den Bent, Astrid A M van der Veldt
Journal: Neuro-Oncology (2021)
Abstract 9117: Heart Failure E-learning Training for Low Income Countries is Effective and Feasible: A Pilot Study
Authors: Faraz Alizadeh, Gedeon Ngoga, Sheila L Klassen, Adrien Habineza, Nadine Karema, Innocent Karera, Mwihaki L Ng'ang'a, Symaque DUSABEYEZU, Kalisa Viateur, Dushimimana Emmanuel, Paul Park, Egide Mpanumusingo, Gene Bukhman, Vincent Cubaka, Gene F Kwan
Journal: Circulation (2021)

Introduction: Heart failure (HF) is a burden in low income countries (LICs). However, HF care is complex and skilled providers in LICs are limited. E-learning (EL) could offer access to specialized HF training, but little is known about its feasibility in rural LICs. We describe the design and pilot study of an EL HF module. Methods: An interdisciplinary team from Partners In Health adapted an existing classroom based HF curriculum for an online, self-guided, asynchronous EL format. We emphasized design features promoting user engagement (clinical cases, animations, interactions) and functionality (download for offline viewing). Due to paucity of EL data in LICs, an introduction to Heart Failure pilot module was used to evaluate implementation.In phase 1, we evaluated usability among 7 experienced HF providers in Rwanda, Malawi, and Liberia. In phase 2, we assessed the ability of 19 novice providers in Rwanda to learn concepts using EL ( Figure 1) . Pre and posttests, post-course surveys, and semi-structured group interviews were used for evaluation. Results from phase 1 informed changes piloted in phase 2. Results: Providers from both phases improved test scores with a significant change among novices ( Figure 1 ). Figure 2 summarizes key findings identified in surveys and focus group analyses. Discussion: An EL module teaching basic HF concepts is feasible and shows early signs of effectiveness in rural LICs. EL training modules may benefit from interactive content, reliable internet, and a simple interface. EL may facilitate HF training for both novice and experienced providers through decentralized programs like the Package of Essential Noncommunicable Disease Plus (PEN-Plus).
Abstract 13838: Life-Years Lost After Incident Atrial Fibrillation in Heart Failure
Authors: Nicklas Vinter, Pia Cordsen, Gregory Lip, Emelia J Benjamin, Søren P Johnsen, Lars Frost, Ludovic Trinquart
Journal: Circulation (2021)

Aims: To estimate the life-years lost after newly-diagnosed atrial fibrillation (AF) in heart failure (HF) patients. Methods and Results: Among patients diagnosed with HF in 2008-2018 in the nationwide Danish Heart Failure Registry, we compared patients with incident AF (n=4,463, mean age 73.7 years, 29% women) to AF-free referents matched on age, sex, and time since HF (n=17,792). By using G-computation, we estimated the marginal hazard ratio for death (HR) and difference in restricted mean survival times (RMST) at 10 years after AF diagnosis accounting for sex, age at AF diagnosis, lifestyle factors, clinical characteristics, comorbidities, and medications. The marginal HR was 1.41 (95%CI 1.38 to 1.44). The difference in marginal RMST between HF patients with and without AF was -18.2 months (95%CI -16.8 to -19.6) at 10 years after AF diagnosis. Subgroup analyses showed differences between patients diagnosed with AF &gt;1 year and ≤1 year after HF (marginal difference in RMST at 10 years, -25.7 months, 95%CI -23.7 to -27.7, vs. -10.4 months, 95%CI -8.2 to -12.5), women and men (-20.3 months, 95%CI -17.7 to -21.9, vs. -17.2 months, 95%CI -15.5 to -19.0, p&lt;0.001), patients ≥75 and &lt;75 years old at AF diagnosis (-20.1 months, 95%CI -17.9 to -22.2, vs. -17.8 months, 95%CI -15.6 to -20.0, p&lt;0.001). Conclusion: There is evidence of loss in life expectancy associated with AF in HF, with 1.5 life-years lost over 10 years after AF diagnosis. Life-years lost were significantly larger among patients diagnosed with AF &gt;1 year after HF, women, and older patients.
Abstract 9571: Major Adverse Cardiac Events in Hypertrophic Cardiomyopathy Among Index Patients and Their Affected Relatives
Authors: Soren K Nielsen, Frederikke G Hansen, Thomas A Fischer, Trine Madsen, Ib C Klausen, Dothe S Møller, Morten Jensen, Jens F Lassen, Torsten Bloch B Rasmussen, Jens Mogensen
Journal: Circulation (2021)

Introduction: The incidence of major adverse cardiac events (MACE) is well established among index patients with hypertrophic cardiomyopathy (HCM) carrying pathogenic sequence variants in recognized HCM genes. However, MACE among their affected relatives is unknown. It was the aim to compare the incidence of MACE among index patients with HCM and their affected relatives. Methods: Clinical and genetic investigations were performed in consecutive index patients with HCM. Genetic investigations by next-generation sequencing were made in 116 recognized and likely HCM genes, and variants were classified by American College of Medical Genetics and Genomics criteria. Relatives at risk of having HCM were invited for clinical investigations (echocardiography, ECG-recording, and genetic testing when relevant). MACE was defined as a composite endpoint of sudden cardiac death, death due to end-stage heart failure or stroke, and heart transplant. Results: A total of 453 HCM families underwent clinical and genetic investigations, of whom 40% (183/453) carried pathogenic variants. Among relatives, 383 carried the same variant as the index-patient, and the penetrance of HCM in those was 42% (160/383). The median age of diagnosis was 47 years (p=0.13) in relatives and index patients. MACE occurred in 18% (33/183) of index patients, 18% (28/160) of relatives with HCM, and 0% (0/223) of healthy variant carriers. The median age of MACE was 43 years for index patients and relatives (p=0.48). During eight years of follow-up, incidence rates of MACE were not significantly different between index patients and relatives (1.2%/year vs. 1.5%/year p=0.2). Conclusions: Affected Relatives in HCM families who carried pathogenic sequence variants in recognized HCM genes had the same risk of MACE as index patients. This finding emphasized the importance of family screening, follow-up, and continuous risk stratification to possibly avoid adverse disease complications and sudden death.
CTIM-05. A PHASE 1/2 STUDY OF THE COMBINATION OF INDOXIMOD AND TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY HIGH-GRADE GLIOMAS
Authors: Rimas Lukas, Surasak Phuphanich, Jeremy Rudnick, Howard Colman, Adam Cohen, Varun Monga, Mohammed Milham, Solmaz Sahebajam, Eugene Kennedy, Christopher Smith, Olivier Rixe
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG. METHODS A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity. RESULTS 33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation. CONCLUSIONS The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.
EXTH-53. ANTI-ROBO1 CAR T CELLS EFFECTIVELY TARGET MALIGNANT BRAIN CANCER
Authors: Chirayu R Chokshi, Benjamin Brakel, Martin A Rossotti, Chitra Venugopal, Sabra Salim, Darin Bloemberg, Parvez Vora, Kevin A Henry, Sheila K Singh
Journal: Neuro-Oncology (2021)

Abstract No standardized treatment exists for patients with recurrent glioblastoma (GBM). Given the aggressive nature of the disease and difficulty in modeling tumor recurrence, minimal efforts have been made to design rational therapies against it. The roundabout guidance receptor 1 (ROBO1) protein is involved in axonal guidance during neurodevelopment and is aberrantly upregulated in glioma where it mediates glioma cell migration. Here, we present that ROBO1 is highly expressed on the surface of malignant and treatment-refractory brain tumor initiating cells (BTICs), prompting the development of an anti-ROBO1 CAR-T cell therapy. Using the binding region of a single-domain antibody targeting ROBO1, we developed second-generation anti-ROBO1 CAR-T cells specific and effective against ROBO1-expressing BTICs. Upon antigen exposure, anti-ROBO1 CAR-T cells upregulated markers of activation and degranulation. Additionally, treatment of orthotopic and patient-derived brain tumor xenograft models with anti-ROBO1 CAR-T cells resulted in reduced tumor burden and prolonged survival, demonstrating the therapy’s therapeutic potential for treating neoplastic brain malignancies.