tbuckley/cabot-search huggingface dataset:
Changes in circulating tumor DNA levels are associated with treatment response and progression-free survival in relapse/refractory DLBCL subjects.
Authors: Alexander F. Lovejoy, Hai Lin, Ehsan Tabari, Seng Lor Saelee, David Matthew Kurtz, Patrik Vitazka, Franck Morschhauser, Yu-Waye Chu, Edith Szafer-Glusman, Jeffrey Michael Venstrom, Khai Luong, Daniel M. Klass
Journal: Journal of Clinical Oncology (2019)

7546 Background: Detection of an initial molecular response to therapy in DLBCL could help differentiate patients who will relapse (30-40% of frontline subjects) from those who will not. Recent studies in DLBCL showed ability to detect residual disease and molecular response to therapy from analysis of circulating tumor DNA (ctDNA). Here we performed targeted next generation sequencing (NGS) of baseline ctDNA vs. tumor tissue, and on-treatment ctDNA samples in 32 relapse/refractory DLBCL subjects from the ROMULUS study to assess correlation of outcome with molecular response. Methods: We sequenced plasma, plasma depleted whole blood (PDWB), and tumor DNA from 32 subjects (range 2-6 samples / subject). Library preparation and NGS were performed using hybrid capture-based workflows, with a panel of ~300 kb targeting regions relevant for disease detection in DLBCL. Variants were called from tissue and plasma data, and PDWB data were used to filter out non-tumor specific variants. Results: 83% of variants detected in tissue (1441/1745) were found in the corresponding plasma samples, and 78% of variants detected in plasma (1441/1846) were found in corresponding tissue samples, in line with previous reports. To follow ctDNA changes with treatment, tumor-specific variants were determined from tissue or cycle 1 day 1 (C1D1) plasma samples. These variants were then monitored in C1D1 and later timepoints, with similar ctDNA levels based on variants determined from C1D1 plasma or tissue (R 2 =0.99). Change in ctDNA levels from C1D1 to C2D1 separated subjects that responded from subjects that progressed (Wilcoxon p-value: 9.39×10 -4 ). Subjects that showed a 10-fold or higher drop in ctDNA levels between C1D1 and C2D1 had significantly longer PFS than those with a smaller ctDNA fold change (HR: 8.06; p=0.0008). Conclusions: This study showed that tumor-specific variants can be identified in baseline plasma with similar performance as from tumor tissue, and that monitoring molecular response as an early change in ctDNA levels after one cycle of treatment correlated with outcomes in this DLBCL study. Clinical trial information: NCT01691898.
ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Authors: Peter Hillmen, Jennifer R. Brown, John C. Byrd, Barbara Eichhorst, Nicole Lamanna, Susan Mary O'Brien, Lugui Qiu, Jason C. Paik, James D. Hilger, Jane Huang, Constantine S. Tam
Journal: Journal of Clinical Oncology (2019)

TPS7572 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (&lt; 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.
Patient-reported outcomes (PROs) with ibrutinib-rituximab in Waldenström macroglobulinemia (WM): Results from iNNOVATE.
Authors: Alessandra Tedeschi, Meletios A. Dimopoulos, Judith Trotman, Ramón Garcia-Sanz, David MacDonald, Beatrice Mahe, Charles Herbaux, Leonard T. Heffner, Constantine Si Lun Tam, Marzia Varettoni, Maria Lia Palomba, Jeffrey Matous, Chaim Shustik, Efstathios Kastritis, Steven P. Treon, Jianling Li, Erik Poulsen, Bernhard Hauns, Christian Buske, Veronique Leblond
Journal: Journal of Clinical Oncology (2019)

8018 Background: Anemia and fatigue can impair quality of life in patients (pts) with WM. Ibrutinib (ibr) as single agent or in combination with RTX is FDA-approved for WM. In pts with RTX-refractory WM, single-agent ibr induced meaningful improvements in PROs (Trotman, EHA 2017). In iNNOVATE, ibr-RTX (IR) produced higher rates of sustained hemoglobin improvement and meaningful improvements in PROs versus placebo-RTX (R; Dimopoulos NEJM 2018). Here, we report detailed PRO analyses from iNNOVATE. Methods: Pts with symptomatic WM requiring therapy were randomized to daily 420 mg oral ibr or placebo, both with RTX (375 mg/m 2 /week IV at weeks 1–4 and 17–20). PRO measures included FACIT-Fatigue (FACIT-F), FACT-An total score (TS) and anemia subscale score (AS), and EQ-5D-5L (EuroQol Research Foundation. EQ-5D is a trade mark of the EuroQol Research Foundation) visual analog scale (VAS), and utility score (US). Results: For 150 randomized pts (n=75/arm), most common reasons for initiating therapy were fatigue (61%), constitutional symptoms (32%), and anemia (32%). Baseline PRO scores were comparable in both arms. At a median follow-up of 26.5 mo, numerically more pts showed clinically meaningful improvement in FACIT-F, TS, and AS with IR than R (Table). Median time to PRO improvement was short (1-2 mo) in both arms. At week 25, the Pearson correlation coefficients were 0.28, 0.29, and 0.26 for changes in hemoglobin levels vs changes in FACIT-F, TS and AS, respectively, in the IR arm; no meaningful correlations were observed on R. The correlation coefficients were -0.32, -0.33, -0.35 and -0.26 for changes in IgM levels vs changes in FACIT-F, TS, AS, and EQ-VAS, respectively, for IR and 0.29 and 0.35 vs FACIT-F and TS for R. Conclusions: Clinical response and improvements in anemia with IR are consistent with more pts showing clinically meaningful improvement in PROs versus R. Changes in IgM correlate with improvements in PROs. Clinical trial information: NCT02165397. [Table: see text]
Abstract 10402: Early Reduction of Myocardial Reactive Oxygen Species Production by Postconditioning in a Porcine Model of Cardiac Arrest and Resuscitation
Authors: Anna E Dikalova, Sergey I Dikalov, Michele M Salzman, Qunli Cheng, Timothy R Matsuura, Jason A Bartos, Demetris Yannopoulos, Matthias L Riess
Journal: Circulation (2015)

Introduction: Ischemic (IPoC) and anesthetic postconditioning (APoC) during cardiopulmonary resuscitation (CPR) are effective interventions to improve hemodynamic outcome and survival in a porcine model of prolonged cardiac arrest. We hypothesized that both strategies decrease the myocardial production of reactive oxygen species (ROS) early during reperfusion. Methods: After 15 min of untreated ventricular fibrillation (VF), 22 pigs were randomized to receive mechanical CPR for 4 min without (control) or with IPoC (three 20-sec CPR interruptions) or APoC with low- (2 Vol%) or high-dose (4 Vol%) sevoflurane for 3 min before euthanasia and organ harvest. Left ventricular myocardial tissue was immediately frozen in liquid nitrogen and stored at -80°C until electroparamagnetic resonance (EPR) measurements were performed to quantify ROS. Data are mean±SEM. Statistics: ANOVA with SNK-post hoc testing, alpha = 0.05. Results: EPR spectral changes showed that high-dose APoC (10±1 arbitrary units) and IPoC (15±4) reduced reactive oxygen species normalized to dry tissue weight compared to untreated control animals (33±2); low-dose APoC (34±4) did not. Conclusions: Our data show that the cardio- and neuroprotective strategies of IPoC and APoC result in decreased myocardial ROS production that can be detected as early as 4 min after reintroduction of blood flow by mechanical CPR; the effective concentration of sevoflurane, however, has to be high enough to achieve APoC. Our findings underline the importance of early organ-protective strategies and contribute to our understanding of the mechanisms of these important clinical interventions to improve outcome and survival after cardiac arrest.
Abstract 2764A: Elucidating the pharmacological effects of covalent microtubule stabilizing taccalonolides through functional tagging
Authors: Samantha S. Yee, Lin Du, April L. Risinger
Journal: Cancer Research (2019)

Abstract Microtubule stabilizing taxanes are highly effective in the treatment of solid tumors and continue to be used as single agents and in combination with targeted therapies and immunotherapies. However, limitations of taxane therapy include acquired and inherent drug resistance. The taccalonolides are a novel class of microtubule stabilizers that circumvent clinically relevant forms of drug resistance to the taxanes in vitro and in vivo. The taccalonolides are efficacious in taxane-resistant models due to their distinct mechanism of microtubule stabilization that involves covalent binding to β-tubulin. Pharmacological studies of the taccalonolides have been complicated by their irreversible binding to tubulin. A functional tagged taccalonolide would facilitate a greater understanding of the pharmacological, cellular, and physiological effects of this novel drug class. We have generated and characterized a series of fluorescently tagged taccalonolides that retain microtubule binding and stabilizing activities to serve as functional pharmacological taccalonolide probes. Biochemical tubulin polymerization, live cell fluorescence, immunofluorescence imaging, and the sulforhodamine B cytotoxicity assay were conducted to evaluate the microtubule binding and stabilizing effects of these taccalonolide probes. We identified stable taccalonolide probes that retain the biological activities of untagged taccalonolides and facilitate their detection in live cells and in cell lysates. The rates of taccalonolide uptake and tubulin binding in cells, tumors, and normal tissues were determined. These studies have also allowed for an evaluation of the anatomical distribution of the taccalonolides in vivo, which can inform on their potential for antitumor efficacy in distinct tumor sites. Furthermore, we have generated a cellular model to evaluate the kinetics of taccalonolide binding to β-tubulin mutants that are predicted to influence drug binding based on the crystal structure. These studies have confirmed the covalent interaction between the taccalonolides and D224 on β-tubulin and informed on other residues critical for drug binding. The generation of a functional tagged taccalonolide will continue to be a valuable tool in evaluating the pharmacokinetics of these agents and inform on drug targeting strategies that will facilitate their clinical development. Citation Format: Samantha S. Yee, Lin Du, April L. Risinger. Elucidating the pharmacological effects of covalent microtubule stabilizing taccalonolides through functional tagging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2764A.
Abstract 5155: Increased longevity of continuous bone marrow cultures and radioresistance of bone marrow stromal cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) mice
Authors: Andrew Henderson, Michael W. Epperly, Renee Fisher, Donna Shields, Lora Rigatti, Christopher Donnelly, Simon Watkins, Joel S. Greenberger
Journal: Cancer Research (2019)

Abstract Introduction: The SOD1G93A mouse model of ALS, demonstrates hind limb paralysis beginning at 90 - 100 days of age with stage 4 paralysis at 125 days of age and progressive neuromuscular loss. Materials and Methods: To determine whether deficiency of functional SOD1 influenced parameters of hematopoiesis, long-term bone marrow cultures were established from ALS and control mice. Bone marrow stromal cell lines derived from LTBMCs were tested for clonogenic radiation survival. We tested the effect of bone marrow transplant after total body irradiation on delay of paralysis. Results: SOD1G93A marrow cultures demonstrated significant increase in production of hematopoietic progenitor cells (p &amp;lt; 0.0001) and overall longevity of production of hematopoietic cells (p = 0.0354), and bone marrow stromal cell lines were significantly radioresistant (D0 = 1.33 ± 0.09, and ñ = 8.57 ± 1.8) compared to control C57BL/6J mice (D0 = 1.59 ± 0.11, p = 0.117; and ñ = 3.4 ± 0.4, p= 0.0466). Total body irradiation and bone marrow transplantation with GFP+ donor marrow demonstrated a significant increase in paralysis free interval from 129.2 ± 3.0 to 240.7 ± 21.1 days (p = 0.0010), normalization of blood/brain barrier permeability, and increase in M2 marrow origin microglial cells in proximity to degenerating anterior horn cell/motor neurons. Isolated brain and spinal cord irradiation did not prolong the paralysis free interval (129.0 ± 2.7 days, p = 0.7748). Conclusions: The results of hematopoiesis in LTBMCs in the absence of functional SOD1 showed improved LTBMC longevity and radioresistance of marrow stromal cells both unexpected pleiotropic effects of the SOD1G93A genotype. Marrow transplant after TBI prolonged the paralysis free interval in ALS mice. Citation Format: Andrew Henderson, Michael W. Epperly, Renee Fisher, Donna Shields, Lora Rigatti, Christopher Donnelly, Simon Watkins, Joel S. Greenberger. Increased longevity of continuous bone marrow cultures and radioresistance of bone marrow stromal cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5155.
Association Between Warfarin Control Metrics and Atrial Fibrillation Outcomes in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation
Authors: Sean D. Pokorney, DaJuanicia N. Holmes, Laine Thomas, Gregg C. Fonarow, Peter R. Kowey, James A. Reiffel, Daniel E. Singer, James V. Freeman, Bernard J. Gersh, Kenneth W. Mahaffey, Elaine M. Hylek, Gerald V. Naccarelli, Michael D. Ezekowitz, Jonathan P. Piccini, Eric D. Peterson
Journal: JAMA Cardiology (2019)

Bleeding and thrombotic events (eg, stroke and systemic embolism) are common in patients with atrial fibrillation (AF) taking warfarin sodium despite a well-established therapeutic range.To evaluate whether history of therapeutic warfarin control in patients with AF is independently associated with subsequent bleeding or thrombotic events.In this multicenter cohort study of 176 primary care, cardiology, and electrophysiology clinics in the United States, data were obtained during 51 830 visits among 10 137 patients with AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry; 5545 patients treated with warfarin were included in the bleeding analysis, and 5635 patients were included in the thrombotic event analysis. Patient follow-up was performed from June 29, 2010, to November 30, 2014. Data analysis was performed from August 4, 2016, to February 15, 2019.Multiple measures of warfarin control within the preceding 6 months were analyzed: time in therapeutic range of 2.0 to 3.0, most recent international normalized ratio (INR), percentage of time that a patient had interpolated INR values less than 2.0 or greater than 3.0, INR variance, INR range, and percentage of INR values in therapeutic range.Association of INR measures, alone or in combination, with clinical factors and risk for thrombotic events and bleeding during the subsequent 6 months was assessed post hoc using logistic regression models.A total of 5545 patients (mean [SD] age, 74.5 [9.8] years; 3184 [57.4%] male) with AF were included in the major bleeding analysis and 5635 patients (mean [SD] age, 74.5 [9.8] years; 3236 [57.4%] male) in the thrombotic event analysis. During a median follow-up of 1.5 years (interquartile range, 1.0-2.5 years), there were 339 major bleeds (6.1%) and 51 strokes (0.9%). Multiple metrics of warfarin control were individually associated with subsequent bleeding. After adjustment for clinical bleeding risk, 3 measures-time in therapeutic range (per 1-SD increase ≤55: adjusted odds ratio [aOR], 1.16; 95% CI, 1.02-1.32), variation in INR values (aOR, 1.32; 95% CI, 1.19-1.47), and maximum INR (aOR, 1.20; 95% CI, 1.10-1.31)-remained associated with bleeding risk. Adding INR variance to a clinical risk model slightly increased the C statistic from 0.68 to 0.69 and had a net reclassification improvement index of 0.028 (95% CI, -0.029 to 0.067). No INR measures were associated with subsequent stroke risk.Three metrics of prior warfarin control were associated with bleeding risk but only marginally more so than traditional clinical factors. This study did not identify any measures of INR control that were significantly associated with stroke risk.
A rule-based method for predicting the electrical activation of the heart with cardiac resynchronization therapy from non-invasive clinical data
Authors: A.W.C. Lee, U.C. Nguyen, O. Razeghi, J. Gould, B.S. Sidhu, B. Sieniewicz, J. Behar, M. Mafi-Rad, G. Plank, F.W. Prinzen, C.A. Rinaldi, K. Vernooy, S. Niederer
Journal: Medical Image Analysis (2019)

Cardiac Resynchronization Therapy (CRT) is one of the few effective treatments for heart failure patients with ventricular dyssynchrony. The pacing location of the left ventricle is indicated as a determinant of CRT outcome. Patient specific computational models allow the activation pattern following CRT implant to be predicted and this may be used to optimize CRT lead placement. In this study, the effects of heterogeneous cardiac substrate (scar, fast endocardial conduction, slow septal conduction, functional block) on accurately predicting the electrical activation of the LV epicardium were tested to determine the minimal detail required to create a rule based model of cardiac electrophysiology. Non-invasive clinical data (CT or CMR images and 12 lead ECG) from eighteen patients from two centers were used to investigate the models. Validation with invasive electro-anatomical mapping data identified that computer models with fast endocardial conduction were able to predict the electrical activation with a mean distance errors of 9.2 ± 0.5 mm (CMR data) or (CT data) 7.5 ± 0.7 mm. This study identified a simple rule-based fast endocardial conduction model, built using non-invasive clinical data that can be used to rapidly and robustly predict the electrical activation of the heart. Pre-procedural prediction of the latest electrically activating region to identify the optimal LV pacing site could potentially be a useful clinical planning tool for CRT procedures.
Abstract 1046: A breast cancer MET reporter cell line model for drug discovery and development
Authors: Metewo S. Enuameh, Weiguo Shu, Robert Newman, Sangeeta Kumari
Journal: Cancer Research (2019)

Abstract World-wide, cancer metastasis continues to be the leading cause of death in cancer (DIZON et al. 2016). Although epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) have been implicated in the incidence of cancer metastasis and drug resistance, their impact in cancer progression and patient survival is not fully understood (NIETO et al. 2016). This is partly due to the lack of suitable in vitro models. Thus, to facilitate the utility of the EMT concept in therapeutic development, we have utilized some of the basic biology of EMT/MET, to create a novel advanced in vitro model for use in both basic research and discovery of new anti-EMT drugs. In breast cancer, vimentin (VIM) intermediate filament (IF) proteins are generally upregulated during EMT and down-regulated during MET (GILLES et al. 1999; THIERY and SLEEMAN 2006; RICHARDSON et al. 2012; LAMOUILLE et al. 2014). Here we employed CRISPR/Cas9 gene editing to generate a VIM RFP (red fluorescent protein) reporter in the MDA-MB-231 breast adenocarcinoma cell line. The VIM RFP C-terminal fusion gene at the endogenous VIM locus, enables end-point or real-time tracking of the MET status as cells transition from epithelial to mesenchymal phenotype under distinct conditions. We have validated the cell line at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the MDA-MB-231 VIM RFP cell line shows sensitivity to metastatic breast cancer drugs axitinib (tyrosine kinase inhibitor) and U0126 (MEK1/2 inhibitor) via the inhibition of the inherent signaling pathways which impact EMT. These effects provide the basis for the use of this cell line in high throughput screening (HTS) applications including the discovery of new anti-EMT drugs for metastatic breast cancer. Furthermore, the MDA-MB-231 VIM RFP reporter cell line is also a convenient and sensitive model for studying the mechanisms of metastasis and for basic translational science research. Citation Format: Metewo S. Enuameh, Weiguo Shu, Robert Newman, Sangeeta Kumari. A breast cancer MET reporter cell line model for drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1046.
Abstract 17839: Sustained Mechanical Load Regulates Conduction Velocity, Connexin 43 Expression and Propensity to Arrhythmia in Rat Ultrathin Myocardial Slices
Authors: Samuel A Watson, James Duff, Filippo Perbellini, Sian E Harding, Cesare M Terracciano
Journal: Circulation (2017)

Introduction: Mechanical load is one of the main determinants of cardiac function. It increases substantially during heart failure and is reduced by the use of ventricular assist devices. Connexin ...