tbuckley/cabot-search huggingface dataset:
INNV-41. MY STORI – A SYMPTOM TRACKING AND REPORTING INSTRUMENT MOBILE APPLICATION FOR BRAIN TUMOR PATIENTS
Authors: Orieta Celiku, Kristin Odom, Mahendar Ramidi, Terri Armstrong
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Managing symptom burden is an integral part of brain tumor patient care, but tools to facilitate tracking symptoms and self-management for this population are lacking. Reporting is often limited to self-report as part of clinical follow-up care, or episodic between visits if symptoms are severe. While general-purpose and cancer-specific mobile applications that track medical symptoms are becoming more prevalent, they may not cover the entire range of symptoms experienced by patients with brain tumors or allow tracking of self-management strategies. METHODS We developed an iOS operating system mobile application using Apple’s UIKit, Foundation, WebKit, and Core Graphics frameworks. Core Data and iCloud were used to implement local and cloud-based data storage for personal use. Findings from our Outcomes Surveys informed selection of core symptoms to track. A multidisciplinary team of neuro-oncology scientists, providers, and communication specialists developed self-care content from evidence-based sources. RESULTS We developed My STORI, a free mobile application to capture the experiences of brain tumor patients. Patients and their family members can track daily symptoms and their impact on function and record any actions that were taken to mitigate them. Evidence-based self-care information on how to recognize, manage, and report symptoms is provided. Graphical summaries of how these symptoms evolve over time, and how they are impacted by clinical appointments, treatment, and self-care activities can be displayed and compiled into reports that can be shared with their care team, family, or health care record. CONCLUSIONS Mobile applications have the potential to promote self-care, facilitate symptom management, and enable intuitive, frequent, and convenient reporting of clinically relevant data to the health-care team. The My STORI application is an innovation in patient care guided by evidence-based research and can be used to track symptom management, promote self-care, and enhance communication to improve clinical care and research.
Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer
Authors: Eunhee Yi, Amit D. Gujar, Molly Guthrie, Hoon Kim, Dacheng Zhao, Kevin C. Johnson, Samirkumar B. Amin, Megan L. Costa, Qianru Yu, Sunit Das, Nathaniel Jillette, Patricia A. Clow, Albert W. Cheng, Roel G.W. Verhaak
Journal: Cancer Discovery (2021)

Oncogenic extrachromosomal DNA elements (ecDNA) play an important role in tumor evolution, but our understanding of ecDNA biology is limited. We determined the distribution of single-cell ecDNA copy number across patient tissues and cell line models and observed how cell-to-cell ecDNA frequency varies greatly. The exceptional intratumoral heterogeneity of ecDNA suggested ecDNA-specific replication and propagation mechanisms. To evaluate the transfer of ecDNA genetic material from parental to offspring cells during mitosis, we established the CRISPR-based ecTag method. ecTag leverages ecDNA-specific breakpoint sequences to tag ecDNA with fluorescent markers in living cells. Applying ecTag during mitosis revealed disjointed ecDNA inheritance patterns, enabling rapid ecDNA accumulation in individual cells. After mitosis, ecDNAs clustered into ecDNA hubs, and ecDNA hubs colocalized with RNA polymerase II, promoting transcription of cargo oncogenes. Our observations provide direct evidence for uneven segregation of ecDNA and shed new light on mechanisms through which ecDNAs contribute to oncogenesis. SIGNIFICANCE: ecDNAs are vehicles for oncogene amplification. The circular nature of ecDNA affords unique properties, such as mobility and ecDNA-specific replication and segregation behavior. We uncovered fundamental ecDNA properties by tracking ecDNAs in live cells, highlighting uneven and random segregation and ecDNA hubs that drive cargo gene transcription.See related commentary by Henssen, p. 293.This article is highlighted in the In This Issue feature, p. 275.
RADT-35. CHANGE IN HIPPOCAMPAL VOLUME AS A FUNCTION OF RADIATION DOSE: RESULTS FROM A PROSPECTIVE TRIAL WITH STANDARDIZED IMAGING AND MORPHOMETRIC EVALUATION
Authors: Matthew Hall, Yazmin Odia, Toba Niazi, Reshma Naidoo, Golnar Alamdari, Rupesh Kotecha, Martin Tom, Alexander Mohler, Andrew Wroe, Jen Yu, Katherine Von Werne, Laura Gallardo, Rameen Walters, Kevin Abrams, Nolan Altman, Santiago Medina, Michael Chuong, Minesh Mehta
Journal: Neuro-Oncology (2021)

Abstract PURPOSE/OBJECTIVES MRIs in pediatric and adult brain tumor patients (Age&amp;lt; 35) were prospectively collected at baseline and during follow-up to measure volumetric changes in multiple brain substructures with neurocognitive, laboratory, and quality-of-life assessments. In this planned interim analysis, we model early outcomes for change in hippocampal volume at 6 months following radiotherapy. MATERIALS AND METHODS As of 5/15/2021, 50 patients enrolled on this prospective study and 41 completed 6-month post-treatment assessments after fractionated intensity-modulated proton therapy. Left and right hippocampus volumes were independently measured on T1 sagittal precontrast MRI at baseline and 6-months after radiotherapy using both automated software and physician-delineated contours. The relationship between mean hippocampus dose and change in volume was assessed by Pearson’s correlation coefficient. A linear mixed-effects model was applied to evaluate other predictors associated with change in hippocampal volume, assuming random effects of subjects. RESULTS Mean hippocampus dose was strongly correlated with change in hippocampal volume at 6 months following radiotherapy (r=−0.727, 95% CI [-0.820,-0.596], p&amp;lt; 0.001). Changes in hippocampal volumes over time were similar between software and physician contours. Hippocampal volume was significantly reduced for mean doses ≥10 Gy (mean Δ -10.8% ± 5.5%, p&amp;lt; 0.001), while no significant volume change was observed with mean doses &amp;lt; 10 Gy (mean Δ +0.7% ± 3.9%). In the mixed-effects model, only mean hippocampus dose was significantly associated with hippocampal volume change (p&amp;lt; 0.001). The final model predicted a -3.4% change in hippocampal volume for every 10 Gy increase in mean dose. CONCLUSIONS Change in hippocampal volume was correlated with hippocampus mean dose at 6 months following radiotherapy. Future analyses will assess volume change in the hippocampus and other brain substructures over time as a function of radiation dose and correlate with measured neurocognitive and other effects.
Abstract 11992: Rat Engineered Heart Tissue is a Novel in vitro Model to Evaluate Cardiomyocyte Proliferation and Fibroblast Activation After Injury
Authors: Giulio Ciucci, Dario Collia, Giovanni Cimmino, Paolo Golino, Gianni Pedrizzetti, Gianfranco Sinagra, Francesco Loffredo
Journal: Circulation (2021)

Introduction: Adult mammals, including humans, fail to regenerate the majority of the lost cardiomyocytes (CMs) that are replaced with scar tissue after injury. This lack of regenerative response is due to the loss of proliferative capacity of adult CMs which in mice occurs 7 days after birth. An in vitro model that recapitulates these changes has not been developed yet. Hypothesis: Using rat engineered heart tissues (rEHT) we have developed a custom-made cryoinjury system to test the hypothesis that maturation of CMs in EHTs regulates the proliferative response of CMs after injury. Methods: rEHT were generated using neonatal rat heart cells. A discrete lesion was produced on the mid-section of mature (day 18) and immature (day 6) EHTs using a custom-made system based on liquid nitrogen and a 23G needle and medium was supplemented with EdU for 48h. Results: Cryoinjury in mature EHTs produces a localized injury, preserving their residual contractile activity that does not recover over time. We observed a significant increase of EdU + CMs post injury (6.3 ± 1.9% vs. 10.1 ± 1.6 %) without significant changes in Ki67 + and pH3 + CMs suggesting that cryoinjury in mature rEHTs induces DNA synthesis but not CM proliferation. Injury in mature EHTs induced also significant proliferation and activation of fibroblasts with collagen deposition. Interestingly, cryoinjury performed in immature EHTs stimulated a significant proliferative response in CMs. Discussion: Similar to adult rodents, we show that cryoinjury induces DNA synthesis in CMs without proliferative response and contractile recovery. On the other hand, cryoinjury in immature EHTs leads to CMs proliferation. Moreover, mature EHT fibroblast response to injury retraces the activation progression of cardiac fibroblast after infarction characterized by proliferation, increase of activation markers, increase of collagen deposition suggesting EHTs as a novel model to investigate the biology of cardiac regeneration upon injury.
EPID-07. EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OF PATIENTS WITH DIFFUSE GLIOMA IN BRAZIL: PRELIMINARY RESULTS OF A MULTICENTRIC RETROSPECTIVE STUDY - LACOG 0619
Authors: Camilla Yamada, Carolina Vasques, Rodrigo Coutinho, Marcos Maldaun, Clarissa Baldotto, Fabiana Viola, Fernando Maluf, Vanessa Santos, Carolina Pessoa, Patrícia Pacheco, Danielli Matias, Daniela Oliveira, Fernanda Peria, Rafaela de Jesus, Taiane Rebelatto, Suzana Malheiros
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION In Brazil, most of the 9,196 deaths due to brain cancers in 2017 were gliomas. There is a dearth of epidemiological data on diffuse glioma in Brazil. METHODS LACOG 0619 is a multicentric retrospective cohort study, which included patients from nine tertiary oncology centers. Patients aged ≥18 years with histologically proven astrocytoma, oligodendroglioma, oligoastrocytoma or glioblastoma diagnosed from June 2010 to June 2019 were included. The study protocol was approved by each Institutional Review Board. RESULTS 642 patients were included in the analysis. Median age was 51.0 (19-91) years. Most patients were male (n=364, 56.8%), 175 (27.3%) had ECOG 0-1, and 480 (74.8%) had private healthcare insurance. Neurological symptoms were present in 568 (88.5%) patients at diagnosis, and 263 (41.0%) had a history of seizure before surgery. Regarding histology, 361 (56.2%) had glioblastoma, 162 (25.2%) had astrocytoma, 90 (14.0%) had oligodendroglioma, and 23 (3.6%) had glioma NOS. Gross total resection was performed in 168 (26.2%), subtotal resection in 292 (45.5%), biopsy in 108 (16.8%), conventional radiotherapy in 380 (59.2%), and hypofractionation in 44 (6.9%) patients. Concomitant chemoradiotherapy was administered to 370 (57.6%) patients, mostly with temozolamide (n=362, 97.8%). Furthermore, 434 (67.7%) patients received maintenance chemotherapy, 398 with temozolamide (&amp;lt; 6 cycles in 112 [28.4%], 6 cycles in 75 [18.8%], and &amp;gt;6 cycles in 214 [3.8%]). Median follow-up was 29 months (26-33). Median OS according to histology was: 35 months (95%CI 26-46) for glioblastoma, 91 months (95%CI 35-NR) for glioma NOS, and not reached for astrocytoma and oligodendroglioma. Median OS by number of temozolamide maintenance cycles was 18 months (95%CI 15-24) for &amp;lt; 6 cycles and not reached for 6 cycles or more. CONCLUSIONS This is the first multicentric cohort evaluating Brazilian patients with diffuse glioma, providing important data on epidemiology, treatment patterns, and survival in the country.
Abstract 10129: Long-Term Prescription of Beta-Blockers After Myocardial Infarction with Preserved Left Ventricular Function is Associated with Reduction in Recurrent ACS but Not Repeat Revascularization or All-Cause Mortality
Authors: Michael H Chiu, Yuan Dong, Danielle Southern, Nowell Fine, McAlister Finlay, Tolulope Sajobi, Michelle Graham, Sean Van Diepen, Matthew James, Stephen Wilton
Journal: Circulation (2021)

Background: Beta-blockers (BB) are cornerstones of medical therapy for acute coronary syndromes (ACS). However, benefits of long-term treatment with preserved left ventricular ejection fraction (LVEF) are not well established. We examined whether long-term BB prescription is associated with risks of recurrent ischemic events or all-cause mortality in patients with LVEF&gt;50% after ACS. Methods: We conducted a retrospective observational study in Alberta, Canada by linking data from provincial databases (APPROACH, echo, discharge and pharmacy). We included patients with NSTEMI or STEMI between 2008-2017, in-hospital LVEF≥50%, who survived ≥180 days after index discharge and had a new prescription for a BB post ACS. We used adjusted Cox proportional hazards models to determine the association between duration of BB therapy (dichotomized at 180 days) and the primary composite outcome of recurrent ACS, repeat revascularization or all-cause mortality ≥180 days after index ACS. Secondary outcomes were the components of the composite. Results: Of 4,768 included patients (mean age 62.0y, 28.1% female), 1155 (24.2%) discontinued BB before 180 days. During a median follow up time of 56.6 months, 964 patients (20.2%) had a primary outcome event. In the overall population, early BB discontinuation was not associated with an increased risk of the primary outcome (adjusted HR 1.13, 95% CI:0.99-1.29 p=0.07) but was associated with the secondary outcome of recurrent ACS (HR 1.43; 95% CI: 1.164-1.756, p&lt;0.001). In the subgroup with STEMI (n=2,428) early BB discontinuation was associated with increased risk of the primary outcome (HR 1.27; 95% CI: 1.054-1.524, p=0.01), again driven by recurrent ACS. Early BB discontinuation was not associated with secondary outcomes of receipt of repeat revascularization or all-cause mortality. Conclusion: In patients discharged after ACS with preserved LVEF, continuation of BB beyond 180 days was not associated with a reduced risk of the composite primary outcome overall, though subgroup analysis suggested a benefit in the subgroup with STEMI, and in the secondary outcome of recurrent ACS. Large-scale randomized trials are required to clarify the appropriate duration of BB therapy after ACS in patients with preserved LVEF.
Expert Curation of Somatic <i>FLT3</i> Variants By the Clingen Somatic Hematologic Cancer Taskforce (ClinGen HCT)
Authors: Xiangqiang Shao, Shruti Rao, Coumarane Mani, Jason Saliba, Rong He, Chimene Kesserwan, Arpad Danos, Lana Sheta, Panieh Terraf, Gordana Raca, Heather Williams, Piers Blombery, David S Viswanatha, Celeste Eno, Nan Jiang, Kevin C Vavra, Liying Zhang, Zonggao Shi, Peng Li, Yuwen Li, Madhu Michael Ouseph, Ella R Thompson, Yiming Zhong, Kilannin Krysiak, Alex Wagner, Matthew McCoy, Mariam T Matthew, Kristin Deeb, Fengli Zhang, Jie Liu, Xiaonan Zhao, Alejandro Ferrer, Nathan Kopp, Wenying Zhang, Santhi Pondugula, Yasmina Jaufeerally Fakim, David Wu, Sheeja T Pullarkat, Shashikant Kulkarni, Subha Madhavan, Obi L. Griffith, Malachi Griffith, Rashmi Kanagal-Shamanna, Xinjie Xu
Journal: Blood (2021)
EPCO-13. MULTIOMIC SINGLE NUCLEUS RNA- AND ATACseq PROFILING REVEALS REGULATORS OF GLIOMA CELL STATE DIVERSITY
Authors: Kevin Anderson, Kevin Johnson, Frederick Varn, Shannon Bessonett, Amit Gujar, Bill Flynn, Elise Courtois, Ann-Christin Hau, Anna Golebiewska, Sun Ha Paek, Simone Niclou, Michael Samuels, Paul Robson, Roel Verhaak
Journal: Neuro-Oncology (2021)

Abstract Multiomic single nucleus RNA- and ATACseq profiling reveals regulators of glioma cell state diversity. The extensive intra- and intertumoral heterogeneity observed in glioma reflects the resistance to therapy and poor prognosis observed clinically. Single-cell sequencing studies have highlighted that glioma heterogeneity reflects the co-existence of cell subpopulations with distinct cell states. Prior studies have also shown that EGFR-amplifying extrachromosomal DNA (ecDNA) elements in IDH-wild-type gliomas can contribute to heterogeneity by driving oncogene amplification through long range chromatin contacts. However, single cell studies have largely focused on analyses of transcriptional profiles, and the epigenetic mechanisms underlying the contribution of ecDNA elements to tumor cell state diversity remain poorly understood. To further our understanding of the regulatory programs that contribute to transcriptional diversity and mediate the distribution of tumor cell states, we profiled primary-recurrent tumor pairs from 18 patient samples with multiomic single-nucleus RNA- and ATACseq, resulting in 86,135 cells identified with linked chromatin accessibility and gene expression profiles. Integrative clustering of the tumor cells identified tumor cell states ranging from a stem-like to differentiated- phenotype that were also associated with differences in chromatin accessibility and inferred transcription factor binding activity. Analyses of chromatin accessibility resulted in the identification of ecDNA, and integrative clustering of ecDNA+ cells highlighted distinct cell states with increased copy number burden, oncogene amplification, and differential chromatin accessibility. These results suggest that a better understanding of extrachromosomal contributions to tumor diversity would aid in development of more efficient therapies.
The Role of Lipoprotein(a) in Cardiovascular Diseases
Authors: Margaret Nachtigall, Richard H. Nachtigall
Journal: JAMA (2021)

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A Novel Isoflavone, ME-344, Enhances Venetoclax Antileukemic Activity Against AML Via Suppression of Oxidative Phosphorylation and Purine Biosynthesis
Authors: Katie Hege Hurrish, Yongwei Su, Sandra Wiley, Zhanjun Hou, Jenna Carter, Hasini Kalpage, Maik Hüttemann, Holly Edwards, Lisa Polin, Jing Li, Jay Yang, Larry Matherly, Jeffrey W. Taub, Yubin Ge
Journal: Blood (2021)
Abstract 13290: Childhood-Onset Arrhythmogenic Cardiomyopathy Associated With Genetic Variants in Desmoplakin
Authors: Robyn J Hylind, Thomas M Roston, Karyn M Austin, Vassilios J Bezzerides, Elizabeth S DeWitt, Dominic J Abrams
Journal: Circulation (2021)

Introduction: Arrhythmogenic cardiomyopathy (ACM) resulting from variants in the desmosomal gene desmoplakin (DSP) is typically an adult onset disorder. Here, we describe penetrance, expression and outcomes of DSP-associated ACM in children. Methods: Patients aged ≤21 years with pathogenic/likely pathogenic variants in DSP were included. Penetrance was defined by:(i) ECG: T-wave inversion V4-V6; mean QRS amplitude &lt;0.5mV in limb leads.(ii) Arrhythmia: &gt;500 VPBs/24 hours, non-sustained or sustained ventricular arrhythmia (VA)(iii) LV dysfunction (EF&lt;50%)(iv) Sub-epicardial late gadolinium enhancement (LGE). The cardiac phenotype was defined as primarily RV, isolated LV (left dominant) or biventricular. Myocardial inflammation was defined as chest pain with elevated troponin ± ST segment changes. A composite primary outcome was sustained VA, death or transplant. Results: We identified 24 patients (67% female) inclusive of 8 probands and 16 family members. Variants were truncating in 22 and missense in 2; a second variant occurred in 4. Presenting symptoms were cardiac arrest (1); myocardial inflammation (3) with cardiac arrest (1), sustained VA (1), dyspnea (2), syncope (1), palpitations (1). ACM was penetrant in 17 (71%), with expression first evident at 15.2±3.3 years. The cardiac phenotype was left dominant (12) and biventricular (5). Isolated RV disease was not seen. Penetrant features were:(i) ECG: transient T-wave inversion in 1 (6%) and QRS amplitude &lt;0.5mV in 6 (35%). (ii) Arrhythmia in 14 (82%) evident at presentation in 13 (92%) and an isolated finding in 2. (iii) LV dysfunction in 10 (59%; EF 35 ± 12%) evident at presentation in 9. (iv) Sub-epicardial LGE in 13 (76%) evident at presentation in 12 (92%) and an isolated finding in 2. Over 3.4±3.2 years, 6 (35%; 4 probands and 2 family members) reached the primary outcome; sustained VA at presentation (3), sustained VA (2), transplant (1). Myocardial inflammation occurred in 5 (21%), 2 of whom reached the primary outcome but this was not significant (p=0.79). Conclusions: DSP-mediated ACM may be fully penetrant in children affecting both probands and family members. VA and subepicardial LGE are prominent early features of disease and pediatric surveillance should reflect these findings.
Abstract 13755: A Systematic Review and Meta-Analysis of Interventions to Support Caregivers of Patients With Heart Disease
Authors: Kellen Knowles, Helen Xun, Sun Y Jang, Sharon Pang, Charles Ng, Apurva Sharma, Erin Spaulding, Rohanit Singh, Alaa Diab, Ngozi Osuji, Joshua Materi, Danielle Amundsen, Shannon Wongvibulsin, Daniel Weng, Pauline Huynh, Julie Nanavati, Jennifer Wolff, Francoise A Marvel, Seth S Martin
Journal: Circulation (2021)

Background: Family caregivers play an important role in the support of patients with heart disease, yet little is known about how the clinical team can best support them. We recently published the CARE model (Caregiver-centered, Active engagement, Reflection &amp; reinforcement, Education) as a guide for the clinical team to better engage caregivers. In this current study, we aimed to determine if psychoeducational interventions designed to support caregivers of patients with heart disease led to improvements in caregiver anxiety, depression, burden, and quality of life. Methods and Results: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) written in English that evaluated outcomes of interventions to support caregivers of patients with heart disease. In our review of six databases, we identified 20 unique RCTs, representing a total of 1,570 patients and 1,776 caregivers, with 17/20 RCTs using a psychoeducational approach. The meta-analysis suggested small increases in physical QoL (Hedges’ g = 0.178, 95% CI: -0.09 to 0.45) and mental QoL (Hedges’ g = 0.22, 95% CI: -0.04 to 0.48) and small reductions in anxiety (Hedges’ g = -0.48, 95% CI: -1.08 to 0.12), as well as moderate reductions in caregiver depression (Hedges’ g = -0.64, 95% CI: -1.34 to 0.06) and caregiver burden (Hedges’ g = -0.51, 95% CI: -2.71 to 1.70); however, none of these improvements were statistically significant. Study results were limited by use of various outcome measures, variable intervention designs, and may have been insufficiently powered. Conclusion: Our study highlights the need for greater understanding of the challenges faced by caregivers of heart disease patients. Future work should focus on consistent intervention design, use established outcome measures, and be conducted in larger populations.