tbuckley/cabot-search huggingface dataset:
Posaconazole at Standard Dose Is Safe and More Effective Than Echinocandins As IFD Prophylaxis in Patients with FLT3 Mutated AML Treated with Midostaurin
Authors: Chiara Cattaneo, Francesco Marchesi, Valentina Bonuomo, Nicola S Fracchiolla, Anna Candoni, Marianna Criscuolo, Lucia Prezioso, Crescenza Pasciolla, Maria Ilaria Del Principe, Michelina Dargenio, Giuseppe Tarantini, Maria Enza Mitra, Francesca Farina, Federica Colnaghi, Mariarita Sciumè, Gianpaolo Nadali, Alessandro Busca, Giuseppe Rossi, Livio Pagano
Journal: Blood (2021)
STEM-17. THE GLIOMA STEM CELL PLATELET INTERACTION DRIVES GBM ONCOGENESIS IDENTIFYING A NOVEL THERAPEUTIC APPROACH
Authors: Anthony Sloan, Harry Hoffman, Peggy Harris, Christine Lee-Poturalski, Theresa Elder, Amber Kerstetter-Fogle, Gino Cioffi, Ansh Desai, Jeremy N Rich, Jill Barnholtz-Sloan, Anirban Sen Gupta, Eckhard Jankowsky, Andrew Sloan
Journal: Neuro-Oncology (2021)

Abstract The effect of platelets on oncogenesis has been studied extensively in cancer metastasis, but not in glioblastoma (GBM), where metastasis is rare. Here we identify the unique crosstalk between glioma stem cells (GSCs) and platelets within GBM solid tumors that enhance disease progression. Targeting GSCs is considered a promising therapeutic approach; however, no clear method has been identified. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian and endometrial cancer. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Immunofluorescence, qPCR, and western blot were used to evaluate the presence of GSCs and platelets and their colocalization in GBM patient tissue at University Hospitals-Seidman Cancer Center. Functional assays followed by RNA sequencing were conducted to determine the functional effect of healthy and GBM platelets on growth of patient derived, autologous GSCs. Our clinical studies suggest elevated platelet counts positively correlate with GSC proliferation and negatively correlate with overall survival in patients with GBM. Patients with high platelet counts ( &amp;gt;350k/µl) had a median survival time of 9 months compared to 16 months median survival for patients with normal platelet count (150-350/µl) (p&amp;lt;0.05). We demonstrate platelet and GSC co-localization in GBM solid tissue and platelet exposure to patient derived GSCs cell lines results in a ≥ 3-fold increase in GSC proliferation compared to GSCs not exposed to platelets (p&amp;lt;0.0005). Similarly we found that platelets increased the self-renewing capacity by enhancing the average sphere size (p &amp;lt; 0.005), and increasing the GSC “Stem-like” transcriptional pattern (P&amp;lt; 0.05). Conversely, pharmacologic inhibition of platelet activation reversed the effect of platelets on GSC proliferation (p ranging from 0.05-0.005). These studies suggests the platelet-GSC interactions appear to stimulate GBM oncogenesis, identifying a potential therapeutic target for the treatment of GBM.
Abstract 12424: A Non-Invasive Proteomic Model Predicts Pulmonary Arterial Hypertension Survival
Authors: Megan Griffiths, Catherine Simpson, Jun Yang, Guillermo Torres, Dhananjay Vaidya, Melanie Nies, Stephanie Brandal, Rachel L Damico, Dunbar D Ivy, Eric D Austin, Michael Pauciulo, Katie Lutz, Raymond L Benza, Russel Hirsch, Delphine Yung, Erika S Berman Rosenzweig, Bill Nichols, Cedric Manlhiot, Allen D Everett
Journal: Circulation (2021)

Background: Pulmonary arterial hypertension (PH) is a progressive disease of the pulmonary vasculature. Risk assessment to guide treatment is fundamental to improved outcomes. Current risk models rely on invasive (cardiac cath) and subjective features, prompting need for a non-invasive risk assessment tool in PH. Hypothesis: A multi-marker protein model will accurately predict PH survival Methods: Using a custom multiplex ELISA (based on prior models), we measured proteins targeting pathobiologic pathways in PAH; NTproBNP (cardiac function), ST2 (cardiac fibrosis), IL-6 (inflammation), endostatin (angiogenesis), and HDGF (vascular growth). Subjects were enrolled from the PH Biobank (PAHB, N=2335, age&gt;15) and a validation cohort from Johns Hopkins and Vanderbilt Universities (N=250, age&gt;18). Unsupervised k-means clustering classified subjects by biomarkers. Transplant free survival by cluster were examined using Kaplan-Meier and Cox proportional hazard modeling. Risk by cluster was compared to current clinical models (REVEAL and ESC/ERS Risk) using Harrell’s C Index. Results: The algorithm generated 4 clusters with excellent risk discrimination in both cohorts (Figure 1). The HR for the severe group (vs lowest risk) in the PAHB was 10.1, (C Index 0.72), while in the validation the HR was 8.6 (C Index 0.74). Addition of genetic mutations, age, sex, and comorbidities did not improve model fit. When compared to the REVEAL and ERS/ESC scores (C Index 0.69 and 0.59 respectively), the proteomic model had better discrimination. Conclusions: This multimarker proteomic model non-invasively assessed PH severity and prognosis with improved accuracy compared to current clinical models. A simple blood test may enable frequent assessment of PH patients in a routine clinic setting to support therapeutic decision-making. In addition, this non-invasive model may provide a surrogate endpoint for future clinical trial designs (after prospective validation).
Abstract 13017: An Innovative Clinical Decision Support Alert to Increase Utilization of ARNIs Among HFrEF Patients
Authors: Tudor Sturzoiu, David Katzianer, Eitan Frankel, Ryan D'Angelo, Reid Stocker, Yair Lev
Journal: Circulation (2021)

Introduction: After PARADIGM-HF showed a significant reduction in cardiovascular death and heart failure hospitalizations in patients treated with sacubitril-valsartan, an angiotensin receptor blocker-neprilysin inhibitor, the ACC/AHA/HFSA guidelines for management of HFrEF included a class I recommendation for ARNI therapy in these patients and recommended replacement of ACE-Is/ARBs with ARNI in patients with NYHA class II or III chronic HFrEF. A 2021 update recommends initiation of ARNI over ACEi or ARB when possible. Intervention: At Thomas Jefferson University Hospital, 2,322 unique patients with a history of HFrEF were admitted between January 2019 and August 2020. Of these, 217 were discharged on sacubitril-valsartan - an individual utilization rate of only 9.3%. Working with the electronic medical record (EMR) team, we devised a set of clinical decision support (CDS) alerts to facilitate transition to ARNI in patients with HFrEF. The first alert fires if an ACE-I is ordered, to encourage switching to an ARB for washout. A second alert fires if an ARB is ordered, suggesting ARNI as a therapeutic alternative. Results: Between December 2020 and May 2021, the alert fired 569 times for 143 unique patients. 102 (71%) were discharged on RAAS blockade. Major reasons for no RAAS blockade included hypotension (51%) and AKI/CKD (20%). Of patients who were discharged on RAAS blockade, 17 (16.7%) were discharged on sacubitril-valsartan. During the intervention period, sacubitril-valsartan use on discharge increased from 9.3% to 16.7% for patients with a history of HFrEF. Conclusion: This project demonstrates how an innovative CDS tool within the EMR can increase adherence to guideline directed medical therapies in HFrEF. While not possible to directly implicate this alert with increased ARNI usage, chart review implies that it at least spurred discussion around the topic and triggered follow-up actions to further investigate the feasibility of prescribing them.
Abstract 10792: Immediate Reduction in Left Ventricular End-Diastolic Pressure During Alcohol Septal Ablation in Patients with Hypertrophic Obstructive Cardiomyopathy
Authors: Peyton Tharp, Katrina Bidwell, Daniel Cook, Noah Blaker, Eric Taylor, Andrew Dorsey, Courtney Kramer, VALERIAN Fernandes, Chris Nielsen
Journal: Circulation (2021)

Introduction: Alcohol septal ablation (ASA) is an elective nonsurgical procedure proven to be effective for patients with hypertrophic obstructive cardiomyopathy (HOCM). The intraprocedural change in left ventricular end-diastolic pressure (LVEDP) is unknown. In this study we assessed the hypothesis that LVEDP decreases immediately post ablation during ASA in patients with HOCM independently of the effects of sedation and heart rate. Methods: We retrospectively identified 133 elective ASA procedures for patients with HOCM between 2015 and 2021 at our institution using an internally maintained database. Pre- and post-ablation LVEDP measurements were taken using the pressure tracing corresponding with end-expiratory R wave of the ECG tracing. LVEDP was recorded for post-“a” wave points on the pressure tracing at three distinct points during the procedure: the immediate start of the procedure (Group A), prior to alcohol injection after sedation had taken effect (Group B), and post ablation (Group C). Heart rate (HR) and left ventricular outflow tract gradient (LVOTG) were obtained from the catheterization report. Paired t-tests, ANOVA, and regression analyses were performed using SPSS Statistics. Results: The average patient age was 64 years old; mean NYHA Class 2.7; and 67% were women. There was no difference between LVEDP of Groups A and B (32mmHg, 32mmHg, p=0.92). LVEDP between Groups A and C (32mmHg, 26mmHg, respectively; p&lt;0.001) and Groups B and C (32mmHg, 26mmHg, respectively; p&lt;0.001) were significantly different. There was no correlation between HR and LVEDP for the groups (R2A=0.002, R2B=0.000, R2C=0.054), and similarly, no correlation between the average change in LVEDP and the change in resting or provoked LVOTG (R2=0.033, R2=0.003, respectively). Conclusions: These results support that alcohol septal ablation causes an immediate reduction in LVEDP post-ablation independent of heart rate, reduction in LVOTG, and effects of sedation. In conclusion, this instantaneous change in LVEDP may account for the immediate resolution in symptoms reported by patients with HOCM undergoing ASA.
Abstract 11134: The Feasibility of a Mail-Out 12-Lead ECG in a Pediatric Cardiac Electrophysiology Telemedicine Environment
Authors: Henry Chubb, Kara Motonaga, William R Goodyer, Anthony Trela, Deb Hanisch, Nicole Boramanand, Erin Lencioni, Mithras Maurille, Anne M Dubin, Scott R Ceresnak
Journal: Circulation (2021)

Introduction: The COVID pandemic has driven an expansion of telemedicine. Telemedicine may be well-suited for pediatric electrophysiology (EP) outpatient consultations. However, an ECG forms part of the standard of care and there is no established strategy for performing a remote 12-lead ECG. Hypothesis: The use of mail-out 12 lead ECG in a pediatric cardiology telemedicine environment is feasible. Methods: Between Nov 2020 and June 2021, select patients with telemedicine EP consultation were offered a mail-out 12 lead ECG (QT Medical, Diamond Bar, CA). The equipment was sent to the patient’s home with technical support from both company and the cardiac clinic. ECGs were read and reported on the electronic health record. ECG quality was independently rated by 2 reviewers. Patient experience was recorded via survey (Qualtrics, Seattle, WA). Results: A total of 146 ECG recordings were transmitted in 31 patients [age 13 ± 5 years, 11 female (35%)]. Indications were prior arrhythmia [24 (77%)] or new cardiac symptoms [7 (23%)]. Prior arrhythmia diagnoses included WPW, paced rhythm, Brugada syndrome, ventricular tachycardia, complete heart block, long QT and monitoring of introduction of anti-arrhythmic medication. A median 3 (IQR 3-6) ECGs were recorded per patient. All patients had recordings suitable for clinical decision-making [21 had an ‘excellent’ recording (68%), 10 ‘good’ (32%), Figure 1]. Total time to perform the ECG (including app set up, application of device and recording transmission) was 46 ± 18 min. 77% found it ‘easy’ or ‘extremely easy’ to perform, and 80% were ‘confident’ or ‘moderately confident’ in the recording. Median travel time to clinic saved was 62 min (IQR 30-151 min). However, only 33% would prefer to perform the ECG at home rather than in clinic Conclusions: Clinically acceptable pediatric 12-lead ECGs may be performed at home by the patient and family. This technology may be considered for adjunctive use with telemedicine consultation in pediatric EP.
Smartphone application improves fertility treatment-related literacy in a large-scale virtual randomized controlled trial in Japan
Authors: Ryo Yokomizo, Akari Nakamura, Makoto Sato, Risa Nasu, Maaya Hine, Kevin Y. Urayama, Hiroshi Kishi, Haruhiko Sago, Aikou Okamoto, Akihiro Umezawa
Journal: npj Digital Medicine (2021)

People of reproductive age have unmet needs related to deficiencies in fertility literacy. Here, we aimed to investigate whether providing fertility-related information via a smartphone application could improve fertility treatment-related literacy in participants. We performed a randomized control-group pretest posttest study and recruited participants between June 18 and 25, 2020. Participants' fertility treatment-related literacy was assessed with a pretest that comprised of 28 questions and participants were allocated with stratified randomization to either intervention group or control group. The intervention comprised a one-week smartphone application-based provision of information on fertility-related information and the control group received general information about women's healthcare. Effectiveness of intervention was assessed using a posttest. A total of 4137 participants were administered the questionnaire and pretest, among which 3765 participants (91.0 %) responded and were randomly allocated into either the intervention group (N = 1883) or the control group (N = 1882). A significantly higher posttest mean score was observed for the intervention group compared to the control group (P = 0.0017). We also observed that posttest scores were significantly improved compared to pretest scores in both the intervention and control group (P < 0.001). When examining by specific test question, the proportion answering correctly increased at posttest compared to pretest for both intervention and control groups (P < 0.001). Furthermore, the intervention group showed a greater mean difference between posttest and pretest scores than the control group (P < 0.001). In conclusion, educational intervention using a smartphone application contributed to enhancing fertility treatment-related literacy.
Abstract 13109: Epigenetic Regulation and Function of Pleiotropic GWAS Locus LRP1 in Human Induced Pluripotent Stem Cells Derived Contractile Smooth Muscle Cells
Authors: Lu Liu, Fatima Zahra Haimoud, Joséphine Henry, Takiy Berrandou, Adrien Georges, Nabila Bouatia-Naji
Journal: Circulation (2021)

Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction in young and middle-aged women. A common genetic variant, rs11172113, locate...
Abstract 10187: Renin-Angiotensin-Aldosterone System Inhibitors and Overall Survival in Cancer Patients Treated with Immune Checkpoint Inhibitors
Authors: Zsofia D Drobni, Olivier Michielin, Thiago Quinaglia, Daniel Zlotoff, Leyre Zubiri, Béla Merkely, Ryan Sullivan, Kerry Reynolds, Mikael Pittet, Rakesh Jain, Tomas Neilan
Journal: Circulation (2021)

Introduction: Preclinical studies indicate that the concurrent use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between inhibitors of RAAS and outcomes among patients treated with immune checkpoint inhibitors (ICI). Hypothesis: RAAS inhibitors improve overall survival in patients treated with ICI. Methods: We performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients; 5,910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3,426 were prescribed any RAAS inhibitor during ICI treatment and 2,484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by type of cancer. Results: Thoracic cancer (34%) and melanoma (16%) were the most common types of cancer and programmed cell death protein 1 inhibitor therapy was the most prescribed (76%). Those prescribed a RAAS inhibitor were older, more likely male and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (Figure). Among the different cancer types, there was a trend toward better overall survival among patients with gastrointestinal (Hazard Ratio (HR):0.82, [95% Confidence Interval (CI): 0.67-1.01], P=0.057) and genitourinary cancer (HR:0.81, [95% CI: 0.64-1.01], P=0.067). Conclusions: In this large retrospective study, patients who were concomitantly prescribed a RAAS inhibitor during ICI therapy had a better overall survival. The benefit of RAAS inhibitors was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in cancer patients who receive ICI therapy.
A Prospective Observational Multicenter Study on Deferiprone &amp; Deferasirox in Clinical Practice of Pediatric Patients with Transfusion-Dependent B-Thalassemia
Authors: Mohsen Saleh Elalfy, Amira Adly, Tamer Hassan, Mohamed Maebid, Rasha el Ashry, Khaled Sayeh, S Regab, Amal Elbeshlawy, Mona Hamdy, M Elshanshoury, Omar Elalfy, S Shehata, M EL Hawy, S Abd el Helim, Eman El Askary, N Shahein
Journal: Blood (2021)
Abstract 9741: Pharmacokinetics, Pharmacodynamics and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese and White Subjects
Authors: Benny M Amore, Rujun Teng, Jeffrey C Hanselman
Journal: Circulation (2021)

This study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of bempedoic acid (BA), an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US. This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180 mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70–190 mg/dL; not receiving a statin) after daily BA 180-mg dosing for 14 days. Enrolled subjects (28% female) ranged 23-59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180 mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (V z /F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and V z /F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was –29% (14) for Japanese subjects, –39% (8) for Chinese subjects, and –17% (28) for White subjects compared with +17% (21) for subjects receiving placebo. Results from this study suggest that administration of BA 180 mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and V z /F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA.
Efficacy and Safety of Chimeric Antigen Receptor T Cell Therapy in Chronic Lymphocytic Leukemia: A Systematic Review
Authors: Rooma Habib, Wajeeha Aiman, Ishan Garg, Rabiya Niaz, Sigmone Khalid Butt, Memoona Saeed, Hina Zubair, Tooba Kashif, Huda Khan, Mahwish Farrukh, Madiha Naveed, Nayha Tahir, Aqsa Fatima, Muhammad Ashar Ali
Journal: Blood (2021)
EXTH-04. ELUCIDATING THE PLEIOTROPIC EFFECTS OF VERTEPORFIN PHOTODYNAMIC THERAPY IN PRECLINICAL GLIOBLASTOMA MODELS
Authors: Gabrielle Price, Sweta Sudhir, Concetta Brusco, Alexandros Bouras, Nadejda Tsankova, Constantinos Hadjipanayis
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) has the highest mortality rate, incidence, and therapy resistance of all primary brain tumors. Deregulation of the epidermal growth factor receptor (EGFR) has been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), is an FDA-approved drug for photodynamic therapy (PDT) of macular degeneration. VP has been shown to have antitumor effects both in vitro and in vivo in GBM preclinical models. As a porphyrin derivative, VP can also exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate for the first time that VP-PDT reduces GBM cell viability to a greater extent than VP treatment alone (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.