tbuckley/cabot-search huggingface dataset:
CSIG-10. PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA ONCOGENE DEPENDENCY IN GLIOBLASTOMA
Authors: Artem Berezovsky, Indrani Datta, Ruicong She, Andrea Transou, Susan Irtenkauf, Laura Hasselbach, Laila Poisson, Ana deCarvalho
Journal: Neuro-Oncology (2021)

Abstract PDGFRA is the second most frequently amplified gene encoding receptor tyrosine kinase in adult glioblastoma (GBM), oftentimes as extrachromosomal elements (ecDNA). Our overall objective is to elucidate mechanisms underlying PDGFRα dependency in GBM tumor maintenance. We have isolated distinct subpopulations from a GBM model (HF3253), harboring two alterations in PDGFRA: constitutively active genomic rearrangement and extrachromosomal amplification, that differ in the frequency of PDGFRA ecDNA. HF3253 tumor growth rate correlates with the initial proportion of ecDNA+ population implanted. Furthermore, slower tumor growth is due to selection for initially low-frequency PDGFRA ecDNA amplified clones based on histology and TaqMan Copy Number assay. Further exploiting intra-tumoral heterogeneity, we have isolated single cell clones from bulk cells. Compared to bulk cells, single cell clones do not express PDGFRα, PDGFRA mRNA and exhibit diploid PDGFRA copy number. Tumor growth was reduced in 4 ecDNA(-) clones compared to parental ecDNA(+) (log-rank test p= 0.00772, 0.00379, 0.00076, 0.00379). In contrast to parental HF3253, ecDNA(-) tumors demonstrated diffuse tumor morphology and weak PDGFRα activation. HF3253 ecDNA(-) PDX tumors lack detectable PDGFRα. Correspondingly, HF3253 ecDNA(-) cell populations do not exhibit de novo PDGFRA copy number gains post-implant. We conducted paired, whole RNA-sequencing on 20 HF3253 populations (ecDNA+/-: 6 clones from 3 biological replicates PDXs and 4 clones from 4 in vitro technical replicates). Employing a false discovery rate of 0.05, we identified 785 differentially expressed genes. Platelet-derived growth factor binding (GO:0048407) and central carbon metabolism were down-regulated in ecDNA(-) while genes significantly associated with astrocytic processes were upregulated. We demonstrated the dependency on PDGFRα signaling in a patient-derived GBM model carrying ecDNA PDGFRA amplification. Our data validates PDGFRɑ as a therapeutic target in a subset of GBM patients and demonstrates that detection of ecDNA-amplified PDGFRA has the potential to be a predictive biomarker of future PDGFRɑ targeted therapies.
Abstract 12946: Identification of a LMNA Synonymous Variant Associated With Severe Dilated Cardiomyopathy
Authors: Shanshan Gao, Abigail Mumme-monheit, Suet Nee Chen, Dobromir Slavov, Elaine B Spector, Francisco Baralle, Michael Bristow, Luisa Mestroni, Matthew Taylor
Journal: Circulation (2021)

Dilated cardiomyopathy (DCM) is one of the most common cardiac phenotypes caused by mutations of lamin A/C (LMNA) gene in humans. Almost 50% of LMNA variants reported in ClinVar as pathogenic or likely pathogenic are due to frameshift, nonsense, or splicing variants, predictive of haploinsufficiency for LMNA protein. In contrast, synonymous variants that do not immediately suggest a haploinsufficiency mechanism are much harder to interpret. We evaluated a cohort of 57 patients who underwent heart transplant for dilated cardiomyopathy for LMNA variants and identified a novel synonymous variant c.936G&gt;A in the last nucleotide of exon 5 of LMNA in a DCM family. Clinically, LMNA c.936G&gt;A carriers presented with severe DCM, conduction disease and high creatine-kinase levels. Sanger sequencing showed the presence of LMNA c.936G&gt;A in the genomic DNA but not in the cDNA derived from one family member’s heart tissue. RT-PCR using RNA from the patient’s heart tissue was performed with primers that amplified LMNA exons 4-6. DNA fragments amplified by RT-PCR were then cloned into pcDNAII vector and 40 clones were picked and sequenced. An aberrantly spliced mRNA containing the variant and a premature stop codon was identified in 1 of the 40 clones. Real-time quantitative PCR showed significantly lower LMNA mRNA levels in the patient’s heart compared to the controls. Our findings suggest that the c.936G&gt;A LMNA variant resulted in aberrant RNA splicing, which possibly triggers nonsense-mediated RNA decay, leading to reduced mRNA and likely protein expression. These results expand the understanding on the association between synonymous LMNA variants and the molecular pathogenesis of LMNA-DCM.
IMMU-17. SYSTEMIC IMMUNOSUPPRESSION OF CD4+ T HELPER CELLS IN GLIOMA
Authors: Malte Mohme, Cecile Maire, Alessandra Rünger, Laura Glau, Eva Tolosa, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2021)

Abstract Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. CD4+ T helper (TH) cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how far cerebral glioma impacts the systemic CD4+ immune repertoire. We therefore analyzed the peripheral blood CD4+ TH cell phenotype and cytokine production in 100 patients with IDHwt, 30 IDHmut and 16 IDHmut 1p19q co-deleted gliomas in comparison with age-matched healthy donors (HD). We found a significant skewing of the peripheral phenotype in IDHwt glioma patients, showing a TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells, while TH2 and TH17 percentages remained stable compared to IDHmut and HD. Interestingly, although TH1 cells were dominant in IDHwt patients, intracellular cytokine staining showed a distinct reduction of IFNg and TNFa production after in vitro stimulation, while IL-4 was significantly increased compared to HD. No alterations between all groups were observed in IL-2, IL-10 or IL-17 production. Profiling of metabolic surface markers further revealed three distinct groups of CD4+ T cells which are altered in IDHwt patients, indicating a metabolic shift in the CD4+ repertoire compared to HD. Taken together, our results show a CD4+ TH cell type specific skewing of the peripheral immune repertoire in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a systemic disease that fundamentally alters the immune repertoire in affected patients.
Abstract 11435: A New Paradigm in Therapy: A Vaccine Against the Progression of Heart Failure
Authors: Keith A Youker, Haifa Shen, Arvind Bhimaraj, Guillermo Torre-Amione
Journal: Circulation (2021)

Introduction: Many therapies have been used to treat the underlying causes of heart failure (HF) and alleviate the symptoms but often the heart failure continues to progress until death or transplant. We have identified a new target which may be a key element in the continued progression and have used a vaccine approach to limit its downstream effects. Methods: We used a non-ischemic mouse model of heart failure which included NaCl and L-NAME in the drinking water with implantation of an osmotic pump filled with Angiotensin II to create a hypertensive model of heart failure. The vaccine group (HA Vaccine) was vaccinated with recombinant HSP60 protein along with a potent form of ALUM adjuvant prior to initiation of heart failure. Results: The vaccinated mice demonstrated an increase in antibodies to HSP60 and a decrease in the apoptosis rate (Tunnel positive cells/10X field Control=2.0, HF=10.8, HA Vaccine=2.5). There was also a decrease in interstitial fibrotic area in the left ventricle (Control=0.8%, HF=4.3%, HA Vaccine=2.6%); as well as a decrease in heart weight and myocyte size in the vaccinated group. These changes resulted in preservation of cardiac ejection fraction (Control=62%, HF=40%, HA Vaccine=58%) as measured by MRI. Conclusions: As far as we know, this is the first time a vaccination approach has been used to address heart failure. It is also the first time the endogenous protein HSP60 has been a target for therapy in heart failure. Our data demonstrates a dramatic reduction in heart failure in mice in response to a vaccine against HSP60.
INNV-22. FACTORS GUIDING THE INITIATION OF TUMOR TREATING FIELDS (TTFIELDS; 200 KHZ) THERAPY FOR GLIOBLASTOMA: SELF-REPORTED PATIENT AND ONCOLOGIST PERSPECTIVES
Authors: Peggy Frongillo, P Gage Gwyn, Connie Wagenknecht, Nichelle Renae Adams
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The standard-of-care for newly-diagnosed glioblastoma (ndGBM) has been the standard Stupp protocol. In ndGBM, approved TTFields (200 KHz) concomitant with maintenance temozolomide significantly improved progression-free survival and overall survival. TTFields-therapy selectively disrupts cancer cell division, requiring array-application to the shaved-scalp to non-invasively deliver TTFields to tumor location and confer clinical benefit. This survey-study assessed factors impacting decision of oncologist/patient/caregiver to initiate TTFields-therapy. METHODS A clinical-market research group administered double-blinded, online-questionnaires (30-min) to oncologists/ndGBM-patients/caregivers. Survey questions, an amalgamate of closed-/open-ended questions, were designed to track awareness, perceptions, and acceptance of ndGBM treatments in a representative United States (US) oncologist and adult patient/caregiver population (semi-annually; 2018-2020). The present survey-analysis focuses on results related to initiation of TTFields-therapy for ndGBM. RESULTS Four separate patient/caregiver surveys (Q1/2018-Q3/2020; (n=50-51/wave) and 4 separate oncologist surveys (Q2/2019-Q4/2020; n=130/wave) were conducted. Results suggest majority of patients with ndGBM research treatment options, including TTFields-therapy, immediately after surgery and before radiation/initial temozolomide; and initiate TTFields-therapy after radiation/initial temozolomide (ie, before maintenance temozolomide). Patients-reported initially learning about TTFields post-surgery via oncologists, nurses, support groups, social-media, and TTFields web-based resources. Among 97% of current/previous TTFields-users, the key patient-driver for selecting TTFields, mirroring oncologist-driver to recommend, was efficacy/survival benefit. Other highly-rated selection-drivers were anti-mitotic mechanism (93%), improved long-term 5-year survival (87%), sustained quality-of-life (87%), and no travel requirement to start (87%). In latest study wave, reported patient usage-barrier was the inability to subsequently enroll in clinical trials (64%), while the top-reported oncologist prescribing-barrier was concern with patient treatment usage (60%). Also, survey suggests oncologists discuss TTFields with most patients with ndGBM, citing efficacy and National Comprehensive Cancer Network® inclusion as key treatment-initiation drivers. CONCLUSIONS Overall, survey data suggests awareness (100%, aided; 61%-68%, unaided) by US oncologists/patients/caregivers of TTFields (200 kHz) as a viable treatment option for adults with ndGBM.
NIMG-07. BEYOND RANDOM AND NUMERIC LESIONS: DIFFERENT IMAGING PATTERNS OF CENTRAL NERVOUS SYSTEM METASTASIS BASED ON PRIMARY TUMOR LOCATION AND MOLECULAR PROFILE
Authors: Júlia Magalhães, Raquel Moreno, Jorge Takahashi, Leandro Lucato, Carlos Silva
Journal: Neuro-Oncology (2021)

Abstract The purpose of this exhibit is to discuss different imaging patterns of central nervous system (CNS) metastasis based on their primary cancer site and to review the recent literature of the particularities of CNS metastasis distribution in the era of molecular advancement in oncology. Selected cases extracted from our institutions database will be presented. The cases will be didactically organized to illustrate the most common imaging characteristics and distribution of brain metastasis based on their organ of origin, such as lung, breast, renal, skin, testicle and gastrointestinal tract. (SCHROEDER T. et al., J Neurooncol. 2020). We will also discuss the correlation between tumor imaging findings and genetic profile. We intend to review well-known CNS metastasis imaging patterns, as preferential involvement of the posterior fossa and anatomic watershed areas in cases of lung cancer (TAKANO, K. et al. Neuro-Oncology, 2016) and the rarity of parenchyma metastasis from prostate cancer (HATZOGLOU V. et al, J Neuroimaging. 2014). We will also demonstrate newly described imaging findings in correlation with primary tumors genetic mutations, such as higher incidence of leptomeningeal involvement in triple negative breast cancer and increase in the number of brain lesions in cases of EGFR positive lung cancer. Familiarity with the most prevalent imaging characteristics of central nervous system metastasis helps oncologists and radiologists not to miss out a CNS progression in case of a known tumor, and also helps to direct systemic investigation of a primary tumor when brain metastasis is the initial presentation. The correlation between molecular profile and the most common sites of CNS involvement can help on treatment planning, including brain radiation (Yanagihara TK,et al., Tomography. 2017), and also bring to discussion the mechanisms of tumor dissemination, which can be targets for future treatments.
Abstract 12473: Seasonal Differences In Management And Outcomes Of Cardiac Arrest Complicating Acute Myocardial Infarction
Authors: Ardaas Kanwar, Saraschandra Vallabhajosyula, Sri Patlolla
Journal: Circulation (2021)

Introduction: The role of seasons in the outcomes and management of acute myocardial infarction (AMI) patients with cardiac arrest (CA) remains understudied. Methods: We used the National Inpatient Sample (2000-2017) to identify adults AMI admissions with concomitant CA. Admission month was used to classify them into- Spring (March-May), Summer (June-August), Fall (September-November) and Winter (December-February) admissions. We evaluated seasonal variation in the prevalence of CA among AMI admissions and associated in-hospital mortality. Use of cardiac and non-cardiac procedures, hospital length of stay, hospitalization costs and discharge disposition were also analyzed. Results: Between 2000-2017, of the 10,880,856 AMI admissions with information on admission month available, CA was identified in 546,334 (5.0%). Incidence of CA was 4.9% in spring, 5.0% in summer, 5.1% in fall, and 5.1% in winter AMI admissions. Adjusted trends identified a steady increase in STEMI-CA admissions with a relatively stable or declining trend for NSTEMI-CA admissions across all seasons. AMI-CA admissions admitted in summer were less often female, had lower comorbidity, more often presented with STEMI and had higher rates of cardiogenic shock and shockable rhythms compared to AMI-CA admissions in spring, fall and winter. Compared to AMI-CA admissions in other seasons, those admitted in winter had slightly lower rates of coronary angiography (61.4% vs. 63.3%-64.3%) and PCI (45.6% vs. 47.2-48.4%) (p&lt;0.001). Compared to those admitted in the spring, adjusted in-hospital mortality was higher for winter (OR 1.08 [95% CI 1.06-1.10]; p&lt;0.001), lower for summer (OR 0.96 [95% CI 0.94-0.98]; p&lt;0.001) and comparable for fall (OR 1.00 [95% CI 0.98-1.02]; p=0.91) AMI-CA admissions. Length of hospital stay, total hospitalization charges, and discharge dispositions for AMI-CA admissions were comparable across the seasons. Conclusions: Lower use of guideline directed therapies and higher in-hospital mortality was identified in winter AMI-CA hospitalizations. The role of pathobiology and/or impact of environmental conditions across seasons in AMI-CA remains to be evaluated.
Multi-Antigen Primed T Cells Promote Apoptosis of Acute Myeloid Leukemia (AML)
Authors: Ebtesam Nafie, Mathias Oelke, Melissa Valerio, Sojung Kim, Ivan Rodriguez, Benjamin Peton, Ketevan Gendzekhadze, Michiko Taniguchi, Guido Marcucci, Monzr M. Al Malki, Lucy Y Ghoda
Journal: Blood (2021)
Abstract 10612: Immune Cells in Calcific Aortic Valve Disease
Authors: Francesca Bartoli-leonard, Elena Aikawa
Journal: Circulation (2021)

Introduction: Calcific aortic valve disease is a multifaceted disease in which pathogenic mineralisation of the valvular tissue occurs in tandem with fibrocalcific remodelling of the aortic valve, resulting in a wide variety of clinical presentations. Immunity, both innate and adaptive have been shown to play important roles in chronic cardiovascular diseases. Noteably, 15% of cells within healthy aortic valves are up to hematopoietic origin and these populations are further increased within calcified valves however, the role of the immune system within CAVD remains to be elucidated. Objectives: Investigate the prevalence and distribution of immune cells within CAVD. Methods &amp; Results: Human calcified aortic heart valves were obtained from valve replacement surgeries. Immunohistological assessment of immune cells within the tissue was conducted, with the presence of T cells, B cells, macrophages and dendritic cells detected in the vicinity of calcific nodules. Flow cytometry analysis of cells isolated from the valve was conducted. 69% of cells isolated from the valve were CD45+, with 57% and 42% of CD45+ CD3+ presenting as CD8+ and CD4+ respectively. Within the CD8+ population, 56% of these were central memory CD8+ T cells, with 24% as activated CD8+ T cells. Likewise, within the CD4+ population 29.5% CD4+ cells were activated T cells and 55% central memory T cells. Small populations of naïve CD4+ and CD8+ T cells; 9% and 13% respectively, were present within the valve. CD45+, CD3+, CD4+/CD8+ cells were isolated via FACS and their global proteomic profile was analysed on the Thermo Scientific Lumos orbitrap mass spectrometer. IL-31RA was present within the T cell population, alongside MAPK pathway mediators were also present. Network analysis of T cell proteomics showed increased IL-4 and IL-13 pathways (p&lt;0.01) indicative of a Type II inflammatory pathway, correlating with the presence of basophils and eosinophils present within the valve. Conclusions: Prevalence of immune cells within the valve suggests an inflammatory role in the development of calcific aortic valve disease, with the prevalence of T cells within the valve suggesting an adaptive immune response may be central to the pathology of CAVD.
Validation of four cutaneous squamous cell carcinoma staging systems using nationwide data*
Authors: Zoe Claire Venables, Selin Tokez, Loes M. Hollestein, Antien L. Mooyaart, Renate Ruth van den Bos, Brian Rous, Irene M. Leigh, Tamar Nijsten, Marlies Wakkee
Journal: British Journal of Dermatology (2021)

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer worldwide with relatively low metastatic potential (2-5%). Developments in therapeutic options have highlighted the need to better identify high-risk patients who could benefit from closer surveillance, adjuvant therapies and baseline/follow-up imaging, while at the same time safely omitting low-risk patients from further follow-up. Controversy remains regarding the predictive performance of current cSCC staging systems and which methodology to adopt.To validate the performance of four cSCC staging systems [American Joint Committee on Cancer 8th edition (AJCC8), Brigham and Women's Hospital (BWH), Tübingen and Salamanca T3 refinement] in predicting metastasis using a nationwide cohort.A nested case-control study using data from the National Disease Registration Service, England, 2013-2015 was conducted. Metastatic cSCC cases were identified using an algorithm to identify all potential cases for manual review. These were 1 : 1 matched on follow-up time to nonmetastatic controls randomly selected from 2013. Staging systems were analysed for distinctiveness, homogeneity, monotonicity, specificity, positive predictive value (PPV), negative predictive value (NPV) and c-index.We included 887 metastatic cSCC cases and 887 nonmetastatic cSCC controls. The BWH system showed the highest specificity [92.8%, 95% confidence interval (CI) 90.8-94.3%, PPV (13.2%, 95% CI 10.6-16.2) and c-index (0.84, 95% CI 0.82-0.86). The AJCC8 showed superior NPV (99.2%, 95% CI 99.2-99.3), homogeneity and monotonicity compared with the BWH and Tübingen diameter and thickness classifications (P < 0.001). Salamanca refinement did not show any improvement in AJCC8 T3 cSCC staging.We validated four cSCC staging systems using the largest nationwide dataset of metastatic cSCC so far. Although the BWH system showed the highest overall discriminative ability, PPV was low for all staging systems, which shows the need for further improvement and refining of current cSCC staging systems.
Abstract 14452: Echocardiographic Evaluation of Donor Cardiac Structure and Function Following Reanimation Using Normothermic Regional Perfusion in Donation After Circulatory Death
Authors: Nicholas W Markin, M. M Chacon, Anthony Castleberry, Lance Fristoe, Brian D Lowes, John Um, Marian Urban
Journal: Circulation (2021)

Introduction: As heart transplantation from donation after circulatory death (DCD) continues to increase, preliminary results suggest outcomes comparable to donation after brain death. It is unknown if the obligatory period of warm ischemia experienced during DCD withdrawal process causes immediate changes in cardiac allograft function. Methods: We retrospectively reviewed and compared pre-donation with post reanimation echocardiographic findings in all DCD donors at our institution from Jan to March 2021. All DCD donor organs were reanimated with in-situ thoracoabdominal normothermic regional perfusion (NRP) after circulatory death. Echocardiographic assessment included: a) 2-dimensional and speckle-tracking measures of chamber size and function; b) ejection fraction (EF); c) fractional area change (FAC); and d) global longitudinal strain (GLS). Results: Altogether 3 DCD heart donations were performed during the study period. Basic demographics and withdrawal ischemic time periods are depicted in Table 1. There were no changes in LV EF and RV FAC when comparing the pre-donation and the post-reanimation echocardiogram. There was a minimal decrease in LV GLS and RV free-wall systolic strain in 2 of the 3 donors following reanimation (Table 2). Conclusions: DCD cardiac allografts reanimated with NRP demonstrated no change in echocardiographic parameters used for a standard donor heart evaluation and were successfully transplanted. Findings suggest donor cardiac function is not clinically different from the pre-donation in DCD hearts reanimated after a relatively short functional ischemic time and without need for inotropic support.