tbuckley/cabot-search huggingface dataset:
Abstract 10451: A Potential Therapeutic Antibody to Induce Collateral Formation in Cardiovascular Diseases
Authors: Jason Amartey, Mussarat Wahid, Sohni R Bhalla, David O Bates
Journal: Circulation (2021)

Introduction: Lack of efficient collateralisation during vascular occlusion leads to tissue ischemia in coronary, peripheral and cerebrovascular disease. Patients with peripheral, coronary, and cerebrovascular disease have elevated levels of the anti-angiogenic isoform of VEGF (VEGF-A 165 b), which correlate with poorer outcomes. In experimental animals, VEGF-A 165 b neutralisation improves blood flow and collateralisation after femoral or coronary artery ligation. Hypothesis: We tested the hypothesis that a potent, high affinity, humanised neutralising antibody to VEGF-A 165 b could have therapeutic potential in models of cardiovascular disease. Methods: A mouse monoclonal antibody to VEGF-A 165 b was humanised by cloning and site directed mutagenesis. Multiple clones were screened, and one with high affinity (measured by biolayer interferometry) was amplified. The efficacy in vitro was tested using endothelial cell migration assays and in vivo using the hindlimb ischemia (HLI) model in C57Bl6 mice fed a high fat high sucrose (HFHS) diet, and in Zucker Diabetic Fatty rats. Results: One clone (HC4LC2) had a VEGF-A 165 b affinity of 600pM. 0.3μg/ml of this clone reversed the inhibitory effect of recombinant human VEGF-A 165 b (31±4%, N=6 of VEGF-A 165 a alone) on migration of endothelial cells to 40ng/ml rhVEGF-A 165 a (89±9% N=3). Human monocyte dependent inhibition of VEGF-A 165 a mediated migration was dose dependently reversed by HC4LC2 (EC50, 55ng/ml, N=9 per concentration). HLI in HFHS mice impaired blood flow after 28 days in IgG treated mice (70±7.7% of pre-ischemic blood flow, N=6), which was restored to normal (93.3±5.5, p&lt;0.05, N=8) by intraperitoneal injection of 1mg/kg HC4LC2. Blood flow recovery after HLI was also seen in ZDF rats treated with HC4LC2 (106±16% of pre-ischemic flow, N=5) compared with IgG treated animals (76±.9%, N=5, p&lt;0.05, two-way ANOVA, all values mean ±SEM). Conclusions: These results indicate that HC4LC2 is a humanised, high affinity neutralising antibody to VEGF-A 165 b that could have therapeutic potential for patients with cardiovascular disease, by enhancing collateral formation.
Abstract 10315: Cost-Effectiveness of Bempedoic Acid in Patients with Established Atherosclerotic Cardiovascular Disease
Authors: Neel M Butala, Salim S Virani, Nicolas Isaza, Grace A Lin, Steven Pearson, Brandon Bellows, Chia Liang Liu, Rahul Aggarwal, Yiyi Zhang, Dhruv S Kazi
Journal: Circulation (2021)

Introduction: Non-statin therapies may improve long-term outcomes in patients with atherosclerotic cardiovascular disease (ASCVD) who experience statin-associated side effects (SASE). Objective: To examine the cost-effectiveness of a newly approved combination of bempedoic acid and ezetimibe (BAEze) in patients with ASCVD from a U.S. healthcare sector perspective. Methods: State-transition Markov model of US adults with ASCVD and low-density lipoprotein cholesterol (LDL-C) ≥70mg/dL on maximally tolerated statin and ezetimibe. The study cohort was stratified by concurrent statin use: high-intensity (group1), moderate-/low-intensity (group 2), or no statin due to severe SASE (group 3). The intervention group received BAEze (annual cost $2,447) instead of ezetimibe. We estimated baseline LDL-C from NHANES; relative LDL-C lowering and rate of adverse events from randomized trials; and the relationship between LDL-C lowering and cardiovascular events from meta-analyses of statin trials. The main outcome was lifetime incremental cost-effectiveness ratio (ICER), with a threshold of $100,000 per quality-adjusted-life-year (QALY) gained. Results: BAEze had an ICER of $188,000/QALY in group 1 (95% UI: 141,500-284,600; cost-effective in 0% of 10,000 probabilistic simulations) and $175,600/QALY (132,700-264,700; cost-effective in 0% simulations) in group 2. In group 3, BAEze produced 0.28 incremental QALYs at a lifetime cost of $25,600, yielding an ICER of $92,600/QALY (66,000-152,100; cost-effective in 59% simulations). Conclusions: Among US adults with ASCVD, cost-effectiveness of BAEze varies substantially by concurrent statin use, and only meets conventional cost-effectiveness thresholds among patients unable to take a statin due to severe SASE. Our findings argue for the selective use of BAEze among patients with ASCVD and severe SASE but should be updated when more data on long-term effectiveness and safety become available.
Abstract 13808: Impact of Complex Percutaneous Coronary Intervention Features Among Patients With or Without Chronic Kidney Disease
Authors: Johny Nicolas, Davide Cao, Zhongjie Zhang, Samantha Sartori, Carlo Andrea Pivato, Annerieke Tavenier, Frans Beerkens, Anton Camaj, Victor Razuk, Davis Jones, Mauro Chiarito, Usman Baber, Joseph Sweeny, Prakash Krishnan, Samin K Sharma, Annapoorna Kini, George Dangas, Roxana Mehran
Journal: Circulation (2021)

Introduction: Among patients undergoing percutaneous coronary intervention (PCI), those with chronic kidney disease (CKD) sustain poor clinical outcomes. However, there is a paucity of data on the impact of complex PCI (CPCI) on long-term prognosis, according to the presence of CKD. Objective: To determine the prognostic impact of complex procedural features in patients undergoing PCI with and without CKD. Methods: Patients undergoing PCI at a tertiary-care center between 2012 and 2019 were stratified according to the presence of CKD and procedural complexity. A CPCI was defined by the presence of ≥1 of the following: stent length &gt;60 mm, ≥3 stents, ≥3 lesions, ≥3 target vessels, bifurcation with ≥2 stents, or chronic total occlusion. The primary outcome of interest was major adverse cardiac events (MACE), a composite of death, myocardial infarction (MI) and target vessel revascularization (TVR) at 1 year. Results: Out of 15,071 patients, our study population consisted of 4,537 (30.1%) with CKD of whom 1,151 (25.4%) underwent CPCI, while 2,983 (28.3%) patients without CKD underwent a CPCI. The prevalence of traditional risk factors was similar among patients within the same group (CKD and no-CKD), irrespective of PCI complexity. Nonetheless, patients undergoing CPCI had more extensive coronary artery disease (i.e., higher syntax score, severe calcification, and longer lesion length). CPCI was associated with a higher risk of MACE at 1 year in both groups, though a greater risk was observed in those without concomitant CKD, mainly driven by a higher risk of MI and TVR (Figure 1). However, the risk of all-cause death was significantly higher among CKD patients undergoing a CPCI, and there was no significant difference between those with and without CPCI in non-CKD group. Conclusions: CPCI is associated with an increase in the risk of 1-year MACE among patients with or without CKD. The larger increase in the risk of MACE is observed in those without CKD, than those with CKD.
Abstract 11627: Effectiveness of Statin Therapy in an Urban Metropolitan Patient Population
Authors: Manoj Ambalavanan, Sanket Gokhale, Minji Seok, Noreen T Nazir
Journal: Circulation (2021)

Introduction: Severely elevated serum LDL (&gt;190 mg/dL) is an independent risk factor in the development of ASCVD complications. Despite current guidelines recommending the immediate initiation of high dose statin therapy in high-risk patients, limitations in care continue to exist, especially amongst different genders, races and populations with a higher burden of health disparities. Hypothesis: We assessed the hypothesis of whether or not race and gender affected the timeliness and appropriateness of initiating statin therapy in a patient population that has a higher burden of health disparities. Methods: We performed a single centered, retrospective observational study where 499 patients with an initial LDL level greater than 190 mg/dL were identified. These patients were then stratified according to race and gender and evaluated for intensity and timing of statin therapy for 12 months after their initial lipid profile. Institutional survey data was acquired to quantify health disparities of our patient population in comparison to US census and Chicago Public Health data. Results: All 499 patients were included in the study. The mean LDL was 224.72 mg/dL and the SEM was 1.775 mg/dL. When compared to state and national averages, respectively, patients from our geographic region were found to have a higher percentage of unemployment (11% vs 7% vs 7%), uninsured status (13% vs 9% vs 10%) and inadequate access to transportation (25% vs 11% vs 9%). There was no significant difference between race or gender regarding the timing of statin initiation or degree of statin intensity. Of all patients, 38.2% were not started on any statin while 29.8% were immediately started on statin therapy (p=0.04). Of those patients started on statin therapy, only 11.4% were started on a high intensity statin (p=0.039). Conclusions: In conclusion, we found that, regarding race or gender, there was no significant difference in initiation of statin or strength of statin started. However, the overall percentage of patients that were started on a timely and appropriate dosage was significantly lower, especially in comparison to national averages. This may be due to the high degree of health disparities that are prevalent amongst our patient population.
Abstract 10701: Suspension Differentiation of Cardiomyocyte Spheroids Improves Quality and Yields
Authors: Asher Kahn-krell, Danielle Pretorius, Jianfa Ou, Silvio Litovsky, Margaret Liu, Jianyi Zhang
Journal: Circulation (2021)

Introduction: Improvements in stem cell viability, differentiation efficiency, and functional activity opened the door for advanced research applications in cardiac regeneration. However, the use of cell-based cardiac therapies, including implantable patches and cell products as well as in-vitro models for mechanistic studies and drug development requires large numbers of high-quality cardiomyocytes (CMs). Typically, differentiation is conducted in 6-well culture plates via the GiWi method, which uses small-molecule inhibitors of glycogen synthase kinase (GSK) and tankyrase to first activate and then suppress Wnt signaling. This monolayer method requires significant manual labor and cannot be easily scaled. Suspension culture and differentiation of free-floating hiPSC aggregates following similar biochemical cues offers advantages for commercial biomanufacturing purposes and provides a more physiological environment for cell development. Hypothesis: We assessed the hypothesis that when hiPSCs are cultured and differentiated in suspension they will produce CMs with improved yield, purity, and quality. Methods: hiPSCs were expanded as aggregates in culture flask using a fed-batch approach then differentiated over a 12 day period with Wnt activation on day 0 and inhibition on day 3. Optimization studies examined purity on day 9 and complete characterization via morphological assessments and CM-specific genes expression was done on day 12 following metabolic purification. All studies were conducted with a minimum of 4 replicates. Results: Optimal conditions for both purity and yield based on cardiac troponin T staining were achieved with an initial cell density of 1.6x10 6 cells/mL, 6 μM CHIR99021, and 55 rpm shaking. After scaling to 30mL culture volume the purity of hiPSC-CMs differentiated via our novel protocol was 98.2±0.8% with yields of 1.47±0.18 million cells/mL and less between-batch purity variability than hiPSC-CMs produced in 2D cultures. Conclusions: Suspension differentiation of hiPSCs into CMs in a widely available format results in improved biomanufacturing endpoints. Therefore, this method functions as a groundwork for future bioreactor systems to produce the large number of cells needed for clinical applications.
Abstract 8858: Reduced Left Ventricular Ejection Fraction is Associated with Higher Long-Term Mortality in Patients with Electrical Storm
Authors: Cameron Incognito, Joshua Parker, Jeffrey Hedley, Venu Menon, Oussama M Wazni, John Rickard, Wai Hong Tang
Journal: Circulation (2021)

Introduction: Little is known about the relationship between LV ejection fraction (EF) and mortality in contemporary patients with electrical storm (ES). Objective: EF at the time of admission for ES was organized into subgroups: EF ≤ 22% (A), 23-32% (B), 33-42% (C), 43-52% (D), and &gt;52% (E). EF subgroups were compared to determine differences in 1-year all-cause mortality. Secondary outcomes included cardiogenic shock (CS), multiorgan system failure, acute tubular necrosis (ATN), and cardiac arrest. We hypothesize that patients with reduced EF will have poorer short-term prognosis and more in-hospital complications. Methods: Single center, retrospective study including consecutive patients admitted to the coronary ICU with ES between April 2014 - 2020. ES was defined as ≥ 3 isolated sustained ventricular arrhythmias or ICD therapies within 24 hours. Results: Of 214 patients admitted with ES, 203 had an echocardiogram on admission. 70 (34.5%) were group A, 58 (28.6%) group B, 36 (17.7%) group C, 23 (11.3%) group D, and 16 (7.9%) group E. The mean EF was 30 +/- 13% (Figure 1). The mean age was 64 +/- 13 years, 83.3% male. 1-year all-cause mortality between subgroups was significant by Kaplan-Meier survival estimate and Mantel-Cox log rank (χ 2 11.2; p 0.023; Figure 2). By Cox Regression using Group E as a reference, only Group A had a statistically significant difference in 1-year all-cause mortality (HR A/E 3.71 [95% CI 1.14 - 12.07]; p 0.029). Analysis of in-hospital complications showed a difference only in cardiogenic shock (p &lt; 0.0001) with higher incidence in those with lower EF (Figure 3). Conclusions: In patients with ES, LVEF is significantly associated with all-cause 1-year mortality. Those with significantly impaired LVEF (≤ 22%) had higher 1-year all-cause mortality compared to those with preserved EF (&gt; 52%).
Abstract 10760: Prophylactic versus Therapeutic Anticoagulation for Survival of Patients with Covid-19 on Steroid and Remdesivir
Authors: Toshiki Kuno, Matsuo So, Mai Takahashi, Natalia Egorova
Journal: Circulation (2021)

Introduction: Previous observational and randomized studies suggested potential benefit of therapeutic anticoagulation during hospitalization, but this treatment remains controversial Objective: We aimed to investigate the association of prophylactic and therapeutic anticoagulation with mortality for patients with COVID-19 who were treated with steroids and Remdesivir, which is the current standard treatments. Methods: This retrospective study was conducted by review of the electronic medical records for 9,565 patients with laboratory confirmed COVID-19 hospitalized in the Mount Sinai Health system between March 1 st 2020 and March 30 th 2021. The primary outcome of interest was the in-hospital mortality. Acute kidney injury was defined as any increase of creatinine by more than 0.3mg/dL or to more than 1.5 times baseline. A propensity score analysis (matching and weighting by inverse probability treatment weights) and multiple imputation was performed. Results: Of the 1,443 patients, 420 (29.1%) had therapeutic anticoagulation therapy. The 1,023 (70.9%) patients with prophylactic anticoagulation were older and had more comorbidities. After matching by propensity score (N=334 in each group), in-hospital mortality was not significantly different between patients with therapeutic anticoagulation and those with prophylactic anticoagulation (26.9% vs. 22.8%, P=0.24). Furthermore, IPTW and multiple imputation for missing data did not change the result (therapeutic versus prophylactic; odds ratio [95% confidential interval]: 1.14 [0.83-1.59], P=0.40]; 1.20 [0.84-1.73], P=0.31, respectively). Interestingly, patients with therapeutic anticoagulation had higher rate of acute kidney injury as compared to patients with prophylactic anticoagulation (26.6% vs. 16.8%, P=0.003). Conclusions: In conclusion, prophylactic versus therapeutic anticoagulation showed similar in-hospital mortality of COVID-19 patients treated with steroids and remdesivir, but therapeutic anticoagulation increased the risk of acute kidney injury compared to prophylactic anticoagulation.
CTIM-17. INTRA-CRANIAL ADMINISTRATION OF CTLA-4 AND PD-1 IMMUNE CHECKPOINT-INHIBITING MONOCLONAL ANTIBODIES IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTI-COHORT ADAPTIVE PHASE I CLINICAL TRIAL
Authors: Johnny Duerinck, Wietse Geens, Julia Katharina Schwarze, Cleo Bertels, Jens Tijtgat, Gil Awada, Freya Vaeyens, Louise cras, Lynn Nijland, Anne-Marie Vanbinst, Hendrik Everaert, Alex Michotte, Toon Janssens, Ben Caljon, Tom Cauwenbergh, Michaël Bruneau, Ramses Forsyth, Sandra Tuyaerts, Bart Neyns
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND: Intracerebral (iCE) administration of nivolumab (NIVO) and ipilimumab (IPI) after resection of recurrent glioblastoma (rGB), followed by repeated intravenous(IV) NIVO was recently shown to be feasible, safe and associated with encouraging survival. Subsequent cohorts were defined to investigate the addition of biweekly intracavitary (iCA) or intrathecal (iTH) NIVO +/- IPI administrations. METHODS Four groups were defined according to rGB resectability and postoperative treatment schedule. Group A and D underwent biopsy, B and C maximal safe resection. All patients received iCE injections of 10 mg/1ml NIVO + 5 mg/1ml IPI at the end of surgery, after which an Ommaya catheter was implanted iCA (A, B and C) or iTH (D). Following surgery, all patients received biweekly IV low-dose NIVO(10mg) combined with iCA/iTH 10 mg NIVO (A and B) + 1, 5 or 10 mg IPI (C and D) for up to 24 weeks. NIVO/IPI concentrations were dosed in the cerebrospinal fluid (CSF). Gene sequencing and RNA gene expression profiling were performed on all tissue samples RESULTS 39pts(27 male; 16 in A, 16 in B, 4 in C, 3 in D; recruitment ongoing in C+D) were enrolled. All patients received the predefined dose of iCE IPI/NIVO. Most frequent AEs were fatigue (n=30), headache (n=19), confusion (n=14), dysphasia (n=13), and fever (n=10). Ommaya infection occurred in 5patients, subacute neurological deterioration requiring corticosteroids in 6patients. There were no G5 AEs. irAEs were infrequent and mild. Median PFS and OS were 5w(95% CI 1-8) and 23w(95% CI 0-53) in A and 13w(95% CI 7-19) and 42w(95% CI 30-54) in B, respectively. &amp;gt;90% of CSF samples had elevated protein levels and lymphocytic pleocytosis. There was no evidence for accumulation of NIVO/IPI in the CSF. CONCLUSION Repeated intracavitary or intrathecal administration of NIVO +/- IPI in rGB is feasible and safe. Favourable survival outcome is seen in patients amenable to surgical resection.
QOLP-14. LONG-TERM IMPACT OF ADULT GLIOMA ON HEALTH-RELATED QUALITY OF LIFE: A SYSTEMATIC REVIEW
Authors: Se Maria Frances, Martin Klein, Susan Short, Louise Murray, Galina Velikova, Judy Wright, Florien Boele
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioma diagnosis can be devastating, and results in a wide range of symptoms. Relatively little is known about the long-term challenges these symptoms pose on HRQOL. The aim of this review is to identify the long-term HRQOL issues reported at least two years following diagnosis of glioma. METHOD Systematic literature searches were carried out using Medline, EMBASE, CINAHL, PsycINFO, and Web of Science Core Collection. Searches were designed to identify a range of reported HRQOL aspects defined as physical, mental or social issues, in adult WHO grade II or III patients. To capture the full extent of patients’ experience, studies of any design reporting on primary data where patients had at least two years follow-up from diagnosis were included. WHO grade I and grade IV tumours were excluded due to their different prognoses and the expected nature of their disease trajectories. Narrative synthesis was used to collate findings. RESULTS The search returned 8438 articles. 477 titles remained after title and abstract screening, with seventeen full text articles included in the final analysis. The majority of studies used quantitative methods, with only two articles reporting qualitative or mixed methodology. Articles were predominantly cross-sectional studies (n = 9), along with cohort studies (n = 3), clinical trials (n = 3) and pilot studies (n = 2). Results indicated that patients reported a variety of issues influencing their HRQOL, with emotional/psychological/cognitive changes the most frequently reported. Physical complaints included problems with fatigue, seizures and maintaining daily activity. Social challenges included strained social relationships and issues managing finances. Patient coping strategies were found to significantly influence wellbeing and subsequent HRQOL. CONCLUSION Glioma patients’ long-term HRQOL and daily functioning can be impacted by their physical, mental and social wellbeing. Findings from this review lay the groundwork for efforts to improve patient long-term HRQOL.
TAMI-66. FUNCTIONAL ALTERATIONS IN CORTICAL PROCESSING OF SPEECH IN GLIOMA-INFILTRATED CORTEX
Authors: alexander Aabedi, Benjamin Lipkin, Jasleen Kaur, Sofia Kakaizada, Jacob Young, Anthony Lee, Saritha Krishna, Edward Chang, David Brang, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity, in a manner similar to normal-appearing cortex, but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. METHODS Here, we acquired invasive electrophysiologic recordings to sample both normal-appearing and glioma-infiltrated cortex during speech initiation in order to measure language task-related circuit dynamics of IDH-wild-type glioblastoma patients. We then applied an information theoretical framework to directly compare the encoding capacity and decodability of signals arising from these regions. RESULTS We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex, but recruits a diffuse spatial network. On a temporal scale, we show that glioma-infiltrated cortex has lower capacity for information encoding when performing nuanced tasks such as speech production of monosyllabic versus polysyllabic words. As a result, temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex, but not from glioma-infiltrated cortex. CONCLUSION These findings inform our understanding of cognitive processing in patients with malignant gliomas and have implications for patient survival, neuromodulation, and prosthetics in patients with malignant gliomas.