tbuckley/cabot-search huggingface dataset:
QOLP-15. FEASIBILITY OF AN ELECTRONIC PATIENT REPORTED STEROID TOXICITY MONITORING PROGRAM IN PATIENTS WITH MALIGNANT GLIOMAS
Authors: Jared Macher, Andrea Wasilewski
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE To determine the feasibility of a longitudinal, electronic, patient-reported survey of steroid toxicity in patients with malignant glioma (MG). BACKGROUND Corticosteroids are frequently used for management of cerebral edema in MG, with side effects resulting from prolonged use or high dosage. Corticosteroid use is common and may negatively impact quality of life (QOL) and survival in MG. DESIGN/METHODS We prospectively enrolled patients with MG receiving neuro-oncologic care at the University of Rochester with or without their caregivers on an IRB-approved study. Subjects received 12 weekly electronic questionnaires through a secure health portal focused on symptoms of corticosteroid toxicities, dosing and functional status. Weekly toxicity scores were calculated based on the number of reported toxicities (0-17). Completed questionnaires were reviewed by a care team member to inform clinical management. Corticosteroid dosing adjustments were documented in the medical record. Feasibility was defined as an overall questionnaire completion rate of 70%. RESULTS 11 patient/caregiver pairs were enrolled (11 patients, including 9 with caregivers). Median patient age was 58. Patient tumors were glioblastoma (82%), anaplastic astrocytoma (9%) and anaplastic oligodendroglioma (9%). Phase of treatment was concurrent (55%), adjuvant (36%) and recurrence (9%). Median dexamethasone does at study start and conclusion were 4mg/day and 3mg/day. Median weekly toxicity score was 5/17 (range: 0-14). The most common toxicities were muscle weakness, sleep disturbance and weight gain and were reported by 82% of participants. Overall questionnaire completion rate was 81%. Ten percent of questionnaires resulted in clinically significant symptoms requiring follow-up from a provider. CONCLUSION Patients with MG experience frequent corticosteroid toxicities. Electronic corticosteroid toxicity monitoring is feasible in patients with MG and may lead to changes in management. Future studies are needed to assess utility of this tool and impact on QOL and survival.
DDRE-47. ASSESSMENT OF BRAIN PENETRANCE, BIODISTRIBUTION, AND EFFICACY OF PLATINUM (IV)-CONJUGATED FLUORINATED MACROCYCLIC CELL-PENETRATING PEPTIDES IN A MURINE GLIOBLASTOMA MODEL
Authors: Jorge Jimenez Macias, Yen-Chun Lee, Tomer Finkelberg, Mykola Zdioruk, Gilles Berger, Michal Nowicki, Choi-Fong Cho, Bogdan Fedeles, Andrei Loas, Bradley Pentelute, Sean Lawler
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma (GBM), an aggressive brain tumor with a poor prognosis, presents an average of 2% of patients surviving beyond 2 years after diagnosis. Therapies to effectively manage glioblastoma are hindered due to the presence of the blood-brain barrier (BBB). Previously, a cell-penetrating peptide, M13, was conjugated to a Pt(IV) cisplatin prodrug, via amide bond formation. The conjugated Pt(IV) releases active cisplatin upon intracellular reduction. Herein, we investigated the BBB-penetrance and biodistribution of M13 conjugated to Pt(IV), as well as its effectiveness against GBM in mouse models. METHODS M13 platinum-conjugate tumor cell killing capacity was assessed by luminescent cell viability assays in vitro. By using Inductively-Coupled Plasma Mass-Spectrometry for platinum detection, BBB penetration and bio-distribution studies were performed in a three-dimensional BBB spheroid in vitro model and in vivo in mouse brain, intracranial tumor, and peripheral organs. Dose-regime studies involved observations of symptomatology and weight variations after bi-weekly injections of platinum compounds at 2mg/kg and 5mg/kg. RESULTS The Pt(IV)-M13 conjugate possesses tumor cell killing effects similar to cisplatin when tested in GBM cell lines in vitro. Platinum increased by using Pt(IV)-M13 when compared to cisplatin in our in vitro BBB-spheroid model (20-fold, p-value=0.0033), in brain tissue (10-fold, p&amp;lt; 0.0001) and GBM tumor-bearing mice models (7.5-fold, p&amp;lt; 0.0001). Bio-distribution of platinum delivered by Pt(IV)-M13 in spleen, heart and blood was significantly different to cisplatin 5hrs. after intravenous injection (p&amp;lt; 0.001). Bi-weekly dose regimes of Pt(IV)-M13 are tolerable in nude mice without toxicity at a similar concentration to reported tolerable cisplatin doses at 5 mg/kg. Finally, Pt(IV)-M13 significantly increased survival in a murine glioblastoma xenograft model compared with controls (median 24 days vs. 29 days, p-value=0.0071). CONCLUSION Overall, our data support the further development of BBB-crossing peptide-drug conjugates for GBM treatment.
Abstract 10068: Guideline Directed Medical Therapy in Newly Diagnosed Heart Failure with Reduced Ejection Fraction in the Community: Impact of Heart Failure Clinic
Authors: Shannon M Dunlay, Jill Killian, Veronique L Roger, Philip Schulte, Samuel Savitz, Saul Blecker, Margaret M Redfield
Journal: Circulation (2021)

Introduction: Guideline-directed medical therapy (GDMT) dramatically improves outcomes in heart failure with reduced ejection fraction (HFrEF). Our goal was to examine GDMT use in community patients with newly diagnosed HFrEF. Methods: We performed a population-based, retrospective cohort study of all Olmsted County, Minnesota residents with newly diagnosed HFrEF (EF≤40%) 2007-2017. We excluded patients with contraindications to medication initiation (allergy, intolerance, heart rate&lt;50 for beta blockers, SBP &lt;80mm Hg for beta blockers, ACEi/ARB/ARNI; high creatinine (&gt;3 mg/dL ACEi/ARB/ARNI, &gt;2.5 men or &gt;2.0 mg/dL women for mineralocorticoid receptor antagonists, MRAs) or hyperkalemia (potassium &gt;5 meQ/L for ACEi/ARB/ARNI, MRA). We examined use and peak dose achieved for beta blockers, HF beta blockers (metoprolol succinate, carvedilol, bisoprolol), ACEi/ARB/ARNI, and MRA in the first year after HFrEF diagnosis. We used logistic regression to evaluate predictors of GDMT use. Results: From 2007-2017, 1160 patients were diagnosed with HFrEF (mean age 69.7 years, 65.6% men). Most eligible patients received beta blockers (92.1%) and ACEi/ARB/ARNI (86.5%) in the first year after HFrEF. However, only 63.6% of patients were treated with a HF beta blocker, and most did not receive MRAs (82.6%). The percentage of treated patients reaching medication target doses was 20.5% for HF beta blockers, 25.3% for ACEi/ARB/ARNI, and 11.2% for MRA. Compared to patients not seen in an HF clinic, patients seen in an HF clinic (n=380, 32.8%) were at greater odds of receiving beta blockers (OR 3.85, 95% CI 1.79-8.33); HF beta blockers (OR 3.85, 95% CI 2.63-5.26); ACEi/ARB/ARNIs (OR 3.85, 95% CI 2.17-6.67); and MRAs (OR 3.03, 95% CI 2.08-4.35). Other independent predictors of GDMT use included younger age (beta blockers, ACEi/ARB/ARNI), male gender (MRAs), higher SBP (beta blockers, ACEi/ARB/ARNI), lower EF (HF beta blockers), higher BMI (MRAs), and diabetes (ACEi/ARB/ARNI, p&lt;0.05 for each). Conclusions: In this population-based study, most patients with newly diagnosed HFrEF received beta blockers and ACEi/ARB/ARNIs, but goal doses were usually not achieved. GDMT use was much higher in patients referred to an HF clinic.
Abstract 9861: Establishing Normal Pediatric Aortic Valve Cusp Effective Height Utilizing the Pediatric Heart Network Normal Echo Z Score Project Echocardiograms
Authors: Ben H Goot, Michael Kim, Evelyn Kuhn, Karen Altmann, joseph Camarda, Shahryar M Chowdhury, Steven D Colan, Andreea Dragulescu, David Goldberg, Leo Lopez, David Parra, Jyoti K Patel, Ricardo H Pignatelli, Ashwin Prakash, Ritu Sachdeva, Brian Soriano, Christopher Spurney, Mario Stylianou, Thor Thorsson, Justin Tretter, Dongngan Truong, Peter C Frommelt
Journal: Circulation (2021)

Introduction: Standard echocardiographic dimensions provide little geometric insight into aortic valve (AV) function. The height difference between cusp insertion and free edge, known as AV cusp effective height (eH), can be assessed from the parasternal long axis view and is a surrogate measure of leaflet geometry. This is useful data when planning valve repair although normal values and methods of indexing eH have not been established in pediatric patients. Images from the Pediatric Heart Network (PHN) Normal Echocardiogram Database were analyzed to establish normal pediatric eH ranges and to assess relationship to typical AV and aortic root measures, age, and body size. Methods: AV eH and annulus diameter were retrospectively measured from 600 PHN echocardiograms divided into equal sized groups based on categories of age, sex, and race proportions in the primary study. Subset size was determined utilizing similar methods and presumed margin of error to primary study. Normal ranges were calculated and eH was compared to PHN AV annulus and aortic root dimensions, age groups, and BSA using Pearson correlation. Interobserver and intraobserver reliability was assessed. Regression equations were created using BSA and/or annulus diameter as the independent variables. Results: AV eH increases predictably with age in children (Fig 1). It correlates strongly with aortic dimensions (all r&gt;0.82) and indexes incorporating BSA 0.5 (r=0.85). It is reproducible, with good interobserver (ICC=0.66, 0.11-0.85) and excellent intraobserver (ICC=0.82, 0.74-0.88) reliability. Regression equation created is eH=0.7+5.74* BSA 0.5 . Conclusions: Normal eH correlates well with age, standard aortic dimensions, and BSA 0.5 in healthy children and regression equations can be used to predict mean eH values in this population. Understanding these relationships will help in evaluating patient-specific valvular morphology when developing a surgical repair strategy.
Abstract 12854: Long Term Outcomes of Pulmonary Vein Isolation With Additional Linear Ablation: Insights From the UC San Diego Atrial Fibrillation Registry
Authors: Edward Wang, Anjali Kumar, Omar M Aldaas, Muhammad Munir, Gordon Ho, Kurt S Hoffmayer, Frederick Han, David Krummen, farshad raissi, Gregory K Feld, Jonathan C Hsu, Douglas J Darden
Journal: Circulation (2021)

Introduction: Pulmonary vein isolation (PVI) alone or in combination with empiric linear ablations (PVI + lines) at the left atrial roof or mitral isthmus (MI) is often performed in patients undergoing first-time atrial fibrillation (AF) ablation despite lack of evidence of benefit from clinical trials and pro-arrhythmic potential, however real-world long-term follow-up is limited. Hypothesis: Patients undergoing PVI + lines will be more likely to experience long-term adverse outcomes as compared to PVI alone. Methods: Patients undergoing AF ablation with either PVI or PVI + lines were included with follow-up data from a single institution between 2005 and 2009. Long-term outcomes included late recurrence of atrial tachyarrhythmias (LRAT), defined as AF, atrial flutter, or atrial tachycardia lasting &gt; 30 seconds after the 3-month blanking period, repeat ablation, and cardioversion. Multivariable adjusted Cox regression was used to evaluate long-term outcomes. Results: Among 516 patients (64 ± 10 years, 68% male, 31% persistent AF) included, 376 (73%) underwent PVI only and 140 (27%) underwent PVI + lines. Of those with lines, 74 (53%) had both roof and MI line, 61 (43%) had a roof line, and 5 (4%) had a MI line. Predictors of PVI + lines included persistent AF, coronary artery disease, and male sex. Over a median follow-up of 1016 (IQR: 385 - 1752) days, approximately 63% of those with PVI only and 53% of those with PVI + lines experienced LRAT. After multivariable adjustment, there was a trend toward higher risk of LRAT in those with PVI + lines as compared to PVI only (HR 1.35, 95% CI 0.99 - 1.85, p = 0.06). There was no difference in the risk of repeat ablation (HR 0.96, 95% CI 0.63 - 1.45), while those with PVI + lines had a significantly higher risk of cardioversion as compared to PVI only (HR 2.50, CI 1.67-3.73, p&lt;0.001). Conclusions: Those receiving linear ablations to complement PVI experienced a trend in higher risk of LRAT as compared with PVI only. While there was no significant difference in the risk of repeat ablations, there was a two-fold higher risk of cardioversion associated with PVI + lines. In line with clinical trial data, these findings suggest that empiric linear ablations are not beneficial, but may also be associated with adverse outcomes in long-term follow-up.
Deep learning enables genetic analysis of the human thoracic aorta
Authors: James P. Pirruccello, Mark D. Chaffin, Elizabeth L. Chou, Stephen J. Fleming, Honghuang Lin, Mahan Nekoui, Shaan Khurshid, Samuel F. Friedman, Alexander G. Bick, Alessandro Arduini, Lu-Chen Weng, Seung Hoan Choi, Amer-Denis Akkad, Puneet Batra, Nathan R. Tucker, Amelia W. Hall, Carolina Roselli, Emelia J. Benjamin, Shamsudheen K. Vellarikkal, Rajat M. Gupta, Christian M. Stegmann, Dejan Juric, James R. Stone, Ramachandran S. Vasan, Jennifer E. Ho, Udo Hoffmann, Steven A. Lubitz, Anthony A. Philippakis, Mark E. Lindsay, Patrick T. Ellinor
Journal: Nature Genetics (2021)
Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma
Authors: Arun Kanakkanthara, Xiaonan Hou, Thomas L. Ekstrom, Valentina Zanfagnin, Amelia M. Huehls, Rebecca L. Kelly, Husheng Ding, Melissa C. Larson, George Vasmatzis, Ann L. Oberg, Scott H. Kaufmann, Aaron S. Mansfield, S. John Weroha, Larry M. Karnitz
Journal: Cancer Research (2021)

Abstract PARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects. Significance: The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer.
Abstract 11118: Cardiac Ferroptosis Induced Through Novel Signaling Pathways
Authors: Nadezhda Fefelova, Natthaphat Siri-angkul, Judith K Gwathmey, Lai-hua Xie
Journal: Circulation (2021)

Background: Ferroptosis is a newly described form of non-apoptotic cell death caused by iron (Fe)-dependent lipid peroxidation. It remains unclear how different signaling pathways/molecules are involved in ferroptosis induction and prevention in cardiac myocytes. In the present study, we aimed to determine the presence of ferroptosis induction via different pathways and the effects of potential anti-ferroptotic strategies in mouse ventricular myocytes. Methods: Ferroptosis was analyzed using the Live/Dead cell viability assay in isolated mouse ventricular myocytes after primary culture and drug treatment. Lipid peroxidation was evaluated by using Liperfluo. Cardiac-specific mitochondrial calcium uniporter (mCU) knockout (KO) mice were used to determine the involvement of mCU. Results: Ferroptosis was induced and the level of lipid peroxidation was increased by the treatment with: 1) iron (Fe; ferric ammonium citrate, 0.1-10 mM), 2) RSL-3 (0.4 μM), a direct inhibitor of the glutathione peroxidase 4 (GPX4), 3) erastin (50 μM), an inhibitor of cystine/glutamate antiporter xCT, 4) the ferroptosis suppressor protein 1 inhibitor (iFSP1, 3 μM). Furthermore, the relationship between the induction of ferroptosis and the cardiotoxicity of doxorubicin (an anthracycline anti-cancer drug) was also evaluated. Ferroptosis induced by above-mentioned inducers was prevented by ferrostatin-1 (a lipid radical scavenger) alone or in combination with Fe chelators (deferoxamine or 2, 2’-bipyridyl) or antioxidants (Trolox or mitoTEMPO) consistent with the dependency of ferroptosis on Fe, oxidative stress and lipid oxidation. Importantly, Fe- and iFSP1- induced ferroptosis was abrogated by mCU KO suggesting mCU-mediated mitochondrial Fe uptake plays an essential role in the occurrence of ferroptosis. However, mCU KO did not prevent the occurrence of ferroptosis induced by RSL-3 or erastin. Conclusions: Ferroptosis induced via different signaling pathways exhibited differential sensitivities to the currently known anti-ferroptosis approaches reported in other cell types. Combination of various suppressers of ferroptotic pathways to alleviate the progression of ferroptosis may provide a promising therapeutic strategy for heart disease.
Abstract 11551: Using the UK Biobank to Identify Novel Genetic Risk Factors Associated with Renal Artery Atherosclerosis
Authors: Fahad Alkhalfan, Alex Gyftopoulos, Yi-Ju Chen, Charles H Williams, James A Perry, Charles C Hong
Journal: Circulation (2021)

Introduction: Atherosclerotic renal artery stenosis (ARAS) is one of the most common pathologies affecting the renal vessels and accounts for 90% of all renovascular lesions. ARAS is associated with renovascular hypertension and nephropathy. ARAS tends to be a progressive disease that has a significant impact on a patient’s overall prognosis. ARAS is likely to occur because of a complex interaction between environmental and genetic factors. We aim to utilize the UK Biobank to identify novel genetic markers associated with renal artery atherosclerosis. Methods: The UK Biobank is a prospective cohort containing clinical and genetic data gathered from over 500,000 individuals. We used Plink’s GLM options for analyzing associations between genotypes and phenotypic manifestations of the disease. We defined renal artery atherosclerosis by selecting ICD-10 code I70.1 and compared cases to age- and gender-matched controls with a case-to-control ratio of 20:1. Related individuals and those with confounding diagnoses such as coronary artery disease, ischemic cerebrovascular disease, and peripheral artery disease were excluded from the controls. Results: There are 80 and 131 instances of I70.1 as a primary or secondary diagnosis, respectively. We identified 32 variants in 22 different genes with p ≤ 1 x 10 -6 . Identified genes have a minor allele frequency ≥ 0.5%. Variants achieving genome-wide significance (p &lt; 5 x 10 -8 ) tightly linked, representing a single haplotype on chromosome 22 near the L3MBTL2 (L3MBTL histone methyl-lysine binding protein 2; p = 3.2 x 10 -8 , OR = 8.0) and EP300-AS1 (EP300 antisense RNA 1; p = 3.5 x 10 -8 , OR = 7.9) genes. Conclusions: Genome wide analysis using ICD-10 codes as a phenotype has the potential to identify previously unknown gene loci that may contribute to an increased risk of ARAS. Future studies are warranted to confirm the association of the chromosome 22 loci to ARAS.
A Comparison Study of Anti-CLL1 CART Cells Equipped with Different Co-Stimulatory Domains in the Treatment of Children with Refractory/Relapsed Acute Myeloid Leukemia
Authors: Kunlin PEI, Haoyu Xu, Peng-Fei Wang, Wenting Gan, Zhengbin HU, Yingyi He, Hui Zhang
Journal: Blood (2021)
Abstract 13557: Impact of Cardiac Resynchronization Therapy on Clinical Outcomes in Transthyretin Amyloid Cardiomyopathy
Authors: Pranav Chandrashekar, Lana Rashdan, Zack Dale, Scott Warner, Sajan Gill, Yunwoo Burton, Babak Nazer, Ahmad Masri
Journal: Circulation (2021)

Introduction: Due to conduction disease and dyssynchrony in transthyretin amyloid cardiomyopathy (ATTR-CM), cardiac resynchronization therapy (CRT) may be beneficial. We aimed to determine the impact of CRT on clinical outcomes in ATTR-CM. Methods: We studied 116 consecutive ATTR-CM patients, 23 of whom underwent CRT (70% CRT + defibrillator, median 10 months (IQR 4-20) from ATTR-CM diagnosis). Outcome was a composite of 1 st cardiovascular hospitalization or all-cause mortality. CRT was treated as a time dependent co-variate and entered into multivariate Cox proportional hazards model. Results: Both groups were similar at diagnosis except for a higher proportion with atrial fibrillation (AF) and lower ejection fraction among those who underwent CRT ( Table 1) . CRT indication in 80% was progressive LV dysfunction with wide QRS [mean 152 ± 36 msec] and the remaining at time of AV node ablation for AF. Half of CRT group were ≥ NYHA class III at device implantation. Older age, higher National Amyloidosis Cohort (NAC) ATTR stage, and not taking tafamidis were significantly associated with the outcome. On multivariate analysis, CRT was associated with a HR of 0.6 (95% CI: 0.32 - 1.16) for all-cause mortality or cardiovascular hospitalization after adjusting for age at diagnosis, NAC ATTR stage, and tafamidis use ( Figure 1). Conclusion: CRT implantation maybe associated with improved outcomes in ATTR-CM. Larger prospective randomized, sham-controlled trials are warranted to confirm these findings.
Abstract 12958: Prognostic Value of Body Composition for Predicting Venous Thromboembolism in Pediatric, Adolescent, and Young Adult Patients With Lymphoma
Authors: Nguyen K Tram, Laila Ettefagh, Ting-heng Chou, Kyra Deep, Dariya Hardisky, Adam J Bobbey, Anthony N Audino, Mitchel R Stacy
Journal: Circulation (2021)

Introduction: Body composition (BC) influences chemotherapy toxicity, surgical complication rates, and overall survival in cancer patients. While recent studies have shown the connection between BC and clinical outcomes in adult oncology populations, BC measures are still often overlooked in the pediatric, adolescent, and young adult (AYA) oncology populations. The objective of this study was to determine the effect of BC on the occurrence of venous thromboembolism (VTE) in pediatric and AYA patients with lymphoma. Methods: Skeletal muscle (SkM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) volumes were manually segmented at vertebral level L3 from 5 consecutive axial CT images ( Fig. 1A ) acquired in a 5-year retrospective cohort of 78 patients with lymphoma (mean age = 13.3 ± 0.6 years). All CT images were acquired at initial staging of disease. Incidence of VTE, including deep vein thrombosis and pulmonary embolism, was evaluated for 12 months after diagnosis. Results and Conclusions: In the first 12 months after diagnosis, 26 of 88 patients (33%) had a VTE event. Patients with VTE had a significantly higher percent of SAT (p = 0.022) and lower percent of SkM (p = 0.036) compared to patients without VTE ( Fig. 1B ). Patients were stratified based on a SkM/SAT cut-off ratio of 0.963, determined using the Receiver-Operating-Characteristic Curve. Patients who were below this SkM/SAT cutoff ratio had a significantly higher probability for VTE in the first 12 months compared to patients who were above the cutoff (log-rank test, p &lt; 0.005) ( Fig. 1C ). This cutoff ratio remained significant after correcting for lymphoma subtype, body mass index, age, and sex using the Cox Proportional-Hazards model. Standard-of-care CT imaging may offer a technique for evaluating BC and predicting outcomes such as VTE in pediatric and AYA patients, thereby offering personalized approaches to cancer care by guiding chemotherapy dosing and nutritional recommendations.