tbuckley/cabot-search huggingface dataset:
Abstract 11774: Coronary Artery Calcium and All-Cause Mortality
Authors: Bibinaz Eghtedari, April Kinninger, Sion Roy, Matthew Budoff
Journal: Circulation (2021)

Objectives: Coronary artery calcium (CAC) has been demonstrated as a non-invasive, low-cost means of assessing atherosclerotic burden and risk of major cardiovascular events in asymptomatic individuals. While it has been previously shown that CAC progression predicts all-cause mortality, we sought to further quantify this association by examining a large cohort of individuals over a follow-up period of between 1 to 22 years. Methods: We studied 3,260 persons aged 30 to 89 years who were referred by their primary care physician for CAC measurement, and had a follow-up scan at least 12 months from initial scan. CAC change was evaluated by absolute change between baseline and follow-up scan. Multivariate analyses using Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between CAC progression and death after adjusting for age, gender, race and other risk factors. Participants were considered at risk from the date of exam 1 to the first occurrence of an event of death or lost to follow-up. The occurrence of death across the follow-up period was verified with the National Death Index. Results: The average time between scans was 4.7±3.2 years with an additional average of 9.1±4.0 years of follow-up time. The average age of the cohort was 58.1 ±10.5 years, 70% being male. A total of 164 deaths occurred. A clinical cut point of CAC progression of 100 units was significantly associated with mortality, hazard ratio 1.51 (95% CI 1.10 -2.13) P=0.017, while adjusting for age, gender, race, diabetes mellitus, hypertension, hyperlipidemia, smoking, baseline CAC and family history. Figure 1. Conclusions: CAC progression of greater than 100 units predicts all-cause mortality. This may add clinical value in encouraging close surveillance and aggressive treatment of individuals within this range.
INNV-36. NON-INTRUSIVE, NON-INVASIVE AND PATIENT FRIENDLY FOCUSED ULTRASOUND DEVICE AS A DELIVERY VEHICLE FOR CNS TUMORS
Authors: Bhaskar Ramamurthy, Mallika Keralapura, John Marshall, Daniel Need, Ryan Dittamore, Santosh Kesari, Ekokobe Fonkem
Journal: Neuro-Oncology (2021)

Abstract A major impediment to treatment of brain cancers is the inability to transport drugs across the blood-brain barrier (BBB). The development of an effective, targeted, and non-invasive method to penetrate the BBB to deliver cancer therapeutics is an unmet need in the treatment of brain cancers. Large molecular weight chemo- and immuno-therapies such as doxorubicin and others may be potentially effective against brain cancers if such drugs are sufficiently bioavailable in the brain. Focused ultrasound techniques can safely and transiently open the BBB but current techniques require invasive/intrusive or expensive and high-touch procedures and are not optimal for wide adoption. To address this unmet need, we are developing an innovative technique to non-intrusively, non-invasively and transiently open the BBB in a specified location within the brain using guided ultrasound (US). Our device consists of a proprietary US generator that is controlled by a highly portable system that has a small physical footprint, enabling the US generator and system to be placed in confined spaces such as chemotherapy infusion centers. The US generator is cap-shaped device that is placed on a patient’s head that includes multiple sets of ultrasound transducers that are distributed within the cap according to the anatomy of the skull. With our proprietary technique, we calculate the position of the cap in relation to the internal anatomy in a real-time manner and in a non-intrusive and a non-invasive manner. We have recently concluded an extensive study that resulted in algorithms that can accurately guide the US to various targets within the brain across a spectrum of patients. We also have completed a pilot preclinical study on a large animal demonstrating our ability to open the BBB non-invasively and deposit a drug proxy (gadolinium and Evans Blue).
Abstract 12467: Maternal Vaping Effects on Cerebrovascular Function in Offspring
Authors: Amber Mills, Rachel Plants, Sydney Nassabeh, Alex Bruce, Madison Robinson, Paul D Chantler, I. Mark Olfert
Journal: Circulation (2021)

Electronic cigarettes (E-cigs) are traditionally marketed as a safer alternative to smoking even during pregnancy. Previous studies have shown cerebrovascular dysfunction from direct chronic E-cig exposures, but little is known about the effect of indirect exposure to offspring while in utero. We hypothesize maternal vaping would induce cerebrovascular impairment in offspring, and that vaping at 30 watts would have greater effect compared to 5 watts. Female Sprague Dawley rats (N=8) were time mated, and once pregnant, the dams were randomly assigned to the following groups 1) 5 watts (N=3), 2) 30 watts (N=3), 3) and ambient air (control, N=2). Exposure (consisting of 20 puffs, 1hr/day, 5 days/week) began on gestational day 2-3 using whole-body chambers. E-liquid was 50% vegetable glycerin (VG), 50% propylene glycol (PG) and contained no nicotine or flavor. One male and female offspring per dam were studied 30-days after birth, where the middle cerebral artery (MCA) was isolated and reactivity assessed using dose response (10 -9 M to 10 -4 M) to acetylcholine (ACh), Serotonin (5-HT), L-arginine methyl ester (L-NAME), and sodium nitroprusside (SNP) via pressure myography. Maximal MCA dilation to ACh (10 -4 M) was impaired in both 5 and 30 watts compared to air (33±3% and 56±6%, respectively, p&lt;0.05), and 30-watt group was greater than 5 watt (p&lt;0.05). MCA vasoconstrictory response to 5-HT in both 5 and 30 watts were impaired compared to control (39±3% vs 52±8%, respectively, p&lt;0.05), but 5 and 30 watts were not different from each other (p=0.08). SNP was only different for 30 watts compared to control (19±7%, p&lt;0.05), and not for 5 watts (9±9%, p=0.07). Changes observed with 5 and 30 watts using L-NAME were not statistically different compared to control (7±11% vs 27±16%, respectively, p=0.15). These data show maternal vaping during pregnancy results in cerebrovascular impairment involving endothelial–dependent and –independent pathways in 1-month old offspring, and suggests that the magnitude of impairment is greater with increasing vaping wattage.
Genome-Wide Association Study of Susceptibility Loci for <i>TCF3-PBX1</i> Acute Lymphoblastic Leukemia in Children
Authors: Shawn H. R Lee, Maoxiang Qian, Wentao Yang, Jonathan D Diedrich, Elizabeth Raetz, Wenjian Yang, Qian Dong, Meenakshi Devidas, Deqing Pei, Allen Yeoh, Cheng Cheng, Ching-Hon Pui, William E Evans, Charles G Mullighan, Stephen P Hunger, Daniel Savic, Mary V Relling, Mignon L Loh, Jun J Yang
Journal: JNCI Journal of the National Cancer Institute (2020)

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.
CarboCell provides new opportunities for image-guided high-precision intratumoral combinatorial immunotherapy
Authors: Sophie B. Jensen, Elizabeth S. Chavez, Holmfridur R. Haldorsdottir, Fredrik Melander, Marouschka J. Scheeper, Linda M. Bruun, Jonas R. Henriksen, Anders Elias Hansen, Thomas L. Andresen
Journal: Cancer Research (2021)
Abstract 13587: Long-Term Outcomes of CT-Derived Fractional Flow Reserve in the Emergency Department
Authors: Thomas F O'Connell, Andres Palomo, Rehan Tariq, Robert D Safian, Michael Gallagher, Kavitha M Chinnaiyan
Journal: Circulation (2021)

Introduction: In acute chest pain (ACP) patients, CT-derived fraction flow reserve (FFRCT) is feasible and adjudicates need for immediate coronary revascularization. There are no long-term outcome studies of FFRCT in ACP. Hypothesis: In ACP patients, FFRCT is safe and associated with favorable outcomes when negative. Methods: ACP patients with no known coronary artery disease or definitive acute coronary syndrome undergoing coronary CTA with FFRCT were compared to those having CTA alone for the composite major adverse cardiac event (MACE) endpoint of death, nonfatal myocardial infarction, unplanned percutaneous (PCI) or surgical (CABG) revascularization over 2 years. FFRCT ≤ 0.80 was considered positive for hemodynamically significant stenosis. Results: From September 2015 to July 2018, 2,568 ACP patients (mean age 55 years, 52% female) underwent CTA of which 236 (10%) had FFRCT (156 negative, 80 positive). Of the total, 1629 (63.2%) had normal coronaries, and 43 (1.7%) were uninterpretable. FFRCT patients were older (p&lt;0.001) with more diabetes mellitus (18.2% vs. 12.2%, p = 0.009), hypertension (50.8% vs. 38.2%, p&lt;0.001), hyperlipidemia (43.6% vs. 25.4%, p&lt;0.001), and &gt;25% stenosis on CTA (93% vs. 13.6%, p&lt;0.001). Positive FFRCT was associated with higher MACE (10% vs. 2.1%, p&lt;0.001). With comparable stenosis on CTA, positive FFRCT had higher MACE compared to negative FFRCT or CTA alone (Table 1). Conclusions: In ACP patients, negative FFRCT and CTA alone are comparable for MACE. Positive FFRCT portends higher MACE at 2 years within similar stenosis categories. FFRCT can provide incremental value to ACP evaluation with coronary CTA.
Abstract 10078: Facilitators and Barriers to Chronic Care Among Patients with Heart Failure in Rural Haiti: A Qualitative Study
Authors: Elizabeth Basow, Benito Isaac, Darius Fenelon, Evyrna Toussaint, Dawson Calixte, Michel Ibrahim, Lisa Hirschhorn, Mari-Lynn Drainoni, Alma Adler, Mary Clisbee, Gene Bukhman, Gene F Kwan
Journal: Circulation (2021)

Introduction: Heart failure (HF) is a leading cause of hospitalizations in rural Haiti. However, few patients hospitalized for HF return for outpatient care. The factors that contribute to chronic HF care access are poorly understood. Objective: To investigate the facilitators and barriers to accessing care for chronic HF from the patients’ perspectives. Methods: We conducted three group interviews and one individual interview with thirteen patients with HF. We recruited patients after discharge from a non-governmental organization-supported academic hospital in rural Haiti. We employed thematic analysis using emergent coding and categorized themes using the socioecological model. Results: Facilitators of chronic care included participants’ knowledge about the importance of HF treatment and engagement with health systems to manage symptoms. Strong social support networks helped participants access clinic visits. Participants reported low cost of care at this subsidized hospital, good medication accessibility, and trust in the healthcare system. Participants expressed the strong spiritual belief that the healthcare system is an extension of God’s influence. Barriers to chronic care included participants' misconceptions about adherence to medications and the need to take HF medications with food. Lack of social support prevented clinic access, and non-healthcare costs associated with clinic visits were prohibitive. Participants expressed low satisfaction regarding the clinic experience. Another barrier to healthcare was the belief that heart disease caused by supernatural spirits is incurable. Conclusions: We identified several facilitators and barriers to chronic HF care with implications for HF management in rural Haiti. Future interventions to improve chronic HF care should address misconceptions and foster patient support systems for visit and medication adherence. Leveraging local spiritual beliefs may promote care engagement.
Abstract 10367: An Unusual Vasodilator Response: Recognizing a Rare Subtype of Pulmonary Arterial Hypertension
Authors: Patrick M Hyland, Jamie Diamond, Miranda Theodore, Arthur Reshad Garan, Noah Schoenberg
Journal: Circulation (2021)

Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare subtype of pulmonary arterial hypertension (PAH) caused by intimal fibrosis of the pulmonary venules and septal veins. While the hemodynamic profile is suggestive of pre-capillary pulmonary hypertension, vascular obstruction distal to the pulmonary capillary beds distinguishes PVOD from other forms of PAH. Case: A 29-year-old woman presented with progressive dyspnea and fatigue. She was tachycardic, hypotensive, and volume overloaded on exam. ECG was notable for right-axis deviation. TTE showed a dilated, hypokinetic RV and small LV with mild global hypokinesis and septal flattening throughout the cardiac cycle. A CTA chest excluded pulmonary embolism but showed diffuse centrilobular ground-glass opacities and lymphadenopathy which raised suspicion for PVOD. She underwent right heart catheterization with the following measurements (mmHg): RA 14, PA 99/56 (mean 71), PCWP 12, and CI 1.1 L/min/m 2 with PVR 28.1 WU. Following initiation of an epoprostenol infusion, she became increasingly hypoxemic with repeat CT chest demonstrating dramatic worsening of ground-glass opacities and vascular congestion. This response to a vasodilator challenge led to a clinical diagnosis of PVOD. She was urgently listed for and underwent bilateral lung transplantation. Explanted lung tissue subsequently confirmed the diagnosis. Conclusion: In most forms of PAH, vasodilators mitigate arteriolar narrowing and improve pulmonary blood flow, while in PVOD they exacerbate pulmonary capillary congestion due to increased arteriolar blood flow relative to the venous outflow due to fixed narrowing of the pulmonary venule network. Because lung biopsy is contraindicated in severe pulmonary hypertension, the clinician must recognize that worsening pulmonary edema in response to vasodilator challenge with normal PCWP is a critical clue pointing towards PVOD. Timely diagnosis is essential given the poor prognosis for this condition for which lung transplantation is the definitive treatment.
PET-CT Quantitative Parameter Delta Suvmax As a Predictor of Early Relapse in Patients with Difuse Large B-Cell Lymphoma
Authors: Carolina Feres, Guilherme Fleury Perini, Carolina Leme de Moura Pereira, Larissa Lane Cardoso Teixeira, Mariana Nassif Kerbauy, Jackson Alex Barbosa, Denise Cunha Pasqualin, Leonardo Javier Arcuri, Nelson Hamerschlak
Journal: Blood (2021)
Abstract 14305: Diastolic Dysfunction and Activation of Ventricular and Atrial Unfolded Protein Response in a Novel Gottingen Miniswine Model of Heart Failure With Preserved Ejection Fraction
Authors: Thomas E Sharp, Erik A Blackwood, Amy L Scarborough, Chris C Glembotski, David J Lefer, Traci T Goodchild
Journal: Circulation (2021)

Introduction: During cardiac hypertrophy, the unfolded protein response (UPR) is activated which includes upregulation of chaperones to assist with protein folding and protein ubiquination for proteolytic degradation. We investigated the expression level of a key chaperone Hspa5 (heat shock protein A5) and ubiquinated protein levels in left ventricular (LV) and atrial (LA) tissue obtained from a preclinical porcine model heart failure with preserved ejection fraction (HFpEF) involving obesity and hypertension. Methods: Female Gottingen minipigs were fed standard or western diet (WD) for 20 weeks to induce obesity and metabolic syndrome and subsequent HFpEF. Those fed WD were also administered 11-deoxycorticosterone acetate (DOCA) (50 mg/kg, SQ) to induce hypertension. LV functional assessment was performed via transthoracic echocardiography and invasive hemodynamics at 20 weeks. In addition, UPR and proteasomal function were assayed following 20 weeks of HFpEF in ventricular and left atrial extracts via RT-qPCR and immunoblot. Results: Minipigs fed WD+DOCA demonstrated hypercholesterolemia, hypertension, LV hypertrophy and increased LVEDP. LVEF was &gt;50% in HFpEF and control groups. We observed significant LV diastolic dysfunction as measured by E/e’ and LA dysfunction as decreased LA fractional area of change (LAFAC) at 20 weeks. LV extracts from HFpEF swine demonstrated a marked increase in Hspa5 without measurable increases in standard fetal genes (e.g. Myh7 ). LA extracts from HFpEF swine exhibited robust accumulation of ubiquitylated proteins compared to control swine. There was a positive correlation between Hspa5 and E/e’ ratio, and the inverse for LA ubiquitylated proteins and LA function. Conclusions: Coordinate with myocardial stiffening, hypertrophy and functional decline, HFpEF robustly augments proteostasis in both LV myocardium and LA recapitulating the clinical presentation of HFpEF patients.
Abstract 10456: Direct Oral Anticoagulant is Associated with a Lower Prevalence of Thin-Cap Fibroatheroma in Patients with Coronary Artery Disease
Authors: Daisuke Kinoshita, Yoshiyasu Minami, Ryota Kakizaki, Kohki Ishida, Kazuhiro Fujiyoshi, Toshimitsu Sato, Ayami Kato, Takako Nagata, Kiyoshi Asakura, Masahiro Katamine, Aritomo Katsura, Junya Ako
Journal: Circulation (2021)

Introduction: The reduced incidence of cardiovascular events in patients with direct oral anticoagulant (DOAC) has been demonstrated. However, the association between taking DOAC and the characteristic of coronary plaque remains to be elucidated. Hypothesis: Taking DOAC is associated with a lower prevalence of vulnerable plaque in patients with coronary artery disease (CAD). Methods: A total of 2168 coronary plaques in consecutive 1439 patients who underwent optical coherence tomography imaging of the culprit or non-culprit lesion were analyzed. The prevalence of thin-cap fibroatheroma (TCFA) were compared between patients with DOAC (149 plaques in 105 patients) and those without (2019 plaques in 1334 patients). Results: The prevalence of TCFA was significantly lower in patients with DOAC than those without in both culprit lesion (27.3% vs. 15.4%, p=0.002) and non-culprit lesion (22.1% vs. 5.2%, p&lt;0.001) (Panel A). In addition to P2Y12 inhibitor intake (odds ratio: 0.941 [95% confidence interval: 0.890-0.995], p=0.034), taking DOAC was independently associated with a lower prevalence of TCFA at any lesion (odds ratio: 0.891 [95% confidence interval: 0.837-0.949], p&lt;0.001) after adjustment of confounders. The prevalence of TCFA at any lesion was significantly lower in patients with a combination of DOAC and P2Y12 inhibitor than those on either DOAC or P2Y12 inhibitor and those without (Panel B). Conclusions: Taking DOAC was associated with a lower prevalence of TCFA in patients with CAD. The present results may partly explain the efficacy of DOAC on the reduced incidence of cardiovascular events in patients with CAD.
Current treatment and future directions in the management of anal cancer
Authors: Leila T. Tchelebi, Cathy Eng, Craig A. Messick, Theodore S. Hong, Ethan B. Ludmir, Lisa A. Kachnic, Nicholas G. Zaorsky
Journal: CA A Cancer Journal for Clinicians (2021)

Abstract Although rare, the rate of squamous cell carcinoma of the anus (SCCA) is rising globally. Most patients present with nonmetastatic disease and are curable with appropriate treatment, which has evolved significantly over the last several decades. Before the 1970s, SCCA was managed with radical surgery, resulting in a permanent colostomy. Researchers found that preoperative treatment with chemotherapy and concurrent radiation could achieve a pathologic complete response. After this observation, definitive therapy shifted from radical surgery to sphincter‐preserving chemoradiation. Investigations into the necessity of chemotherapy and the optimal regimen found that chemotherapy with mitomycin‐C and 5‐fluorouracil is required for cure. Further studies evaluating the addition of induction or maintenance chemotherapy, monoclonal antibody therapy, or higher radiation doses have demonstrated no significant benefit to disease control. Advanced radiation delivery with intensity‐modulated radiotherapy techniques is now considered the standard of care because of its prospectively determined, favorable acute toxicity profile compared with 3‐dimensional conformal radiation. It is important to note that chemoradiation treatment response may be slow (up to 26 weeks) and should be assessed through serial clinical examinations. Today, surgical management of SCCA is reserved only for the lowest risk, early stage tumors or for recurrent/persistent disease. Current studies are evaluating radiation dose de‐escalation in early stage disease and radiation dose escalation and the addition of immune checkpoint inhibitors in locally advanced cancers. In reviewing how and why modern‐day treatment of SCCA was established, the objective of this report is to reenforce adherence to current treatment paradigms to assure the best possible outcomes for patients.
EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM
Authors: Erica Power, Juhee Oh, Jonghoon Choi, William Elmquist, David Daniels
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.