tbuckley/cabot-search huggingface dataset:
A phase II study of pemetrexed and doxorubicin in patients with advanced or metastatic breast cancer (MBC)
Authors: M. Blasinska-Morawiec, M. Martin, F. Salas, S. Falcon, J. Rolski, B. L. Ferrari, N. Guedez, L. Simms, S. Gulyas, A. Melemed
Journal: Journal of Clinical Oncology (2007)

1047 Background: Pemetrexed has a single-agent activity in MBC while doxorubicin is an established agent in breast cancer chemotherapy. This phase II study investigated the combination in patients with advanced or MBC who had not been previously treated with anthracyclines. Primary objective was to evaluate the overall response rate. Methods: Patients received pemetrexed 500 mg/m 2 (10-min intravenous infusion) followed by doxorubicin 50 mg/m 2 on day 1 of six 21-day cycles. Additional cycles were permitted based upon: absence of progressive disease, adequate cardiac function, and a maximum cumulative limit of doxorubicin 450 mg/m 2 . Routine folic acid and vitamin B 12 supplementation was given to all patients. Results: A total of 79 women with advanced or MBC were enrolled at 15 centers in 7 countries. Major racial groups were Caucasians (50.6%) and Hispanics (24.1%). Median age was 55 years (range, 26–79) and most (91.1%) had performance status of 0 or 1. Patients had either metastatic (72.2 %) or locally advanced disease (27.9%). Sixteen (20.3%) patients had received prior adjuvant chemotherapy. A median of 6 cycles (range, 1–9) was delivered. During the 438 cycles, no doses were omitted, and 7 doses were reduced (3 for pemetrexed, 4 for doxorubicin). A total of 129 doses (29.5%) were delayed, primarily due to scheduling conflicts (84 doses) and neutropenia (19 doses). The relative dose intensity for both drugs was 93%. Overall response rate was 60.8% (95% CI, 49.1–71.6) with complete response in 8 patients (10.1%), partial response in 40 patients (50.6%), and stable disease in 20 patients (25.3%). Maximum CTC grade 3 and 4 toxicities observed in &gt;5% patients were neutropenia (19 patients, 24.1%), leukopenia (8 patients, 10.1%), and vomiting (5 patients, 6.3%). Five deaths occurred during study treatment, 2 of which had causes (diarrhea, pneumonia) possibly related to the study drugs. One patient had resting left ventricular ejection fraction decreased to &lt;50% after 6 cycles and did not receive further treatment. Conclusions: The combination of pemetrexed and doxorubicin was well tolerated and had promising response in patients with advanced or MBC. Survival and time-to-event results are forthcoming. No significant financial relationships to disclose.
Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery
Authors: C. David Mazer, Richard P. Whitlock, Dean A. Fergusson, Emilie Belley-Cote, Katherine Connolly, Boris Khanykin, Alexander J. Gregory, Étienne de Médicis, François M. Carrier, Shay McGuinness, Paul J. Young, Kelly Byrne, Juan C. Villar, Alistair Royse, Hilary P. Grocott, Manfred D. Seeberger, Chirag Mehta, François Lellouche, Gregory M.T. Hare, Thomas W. Painter, Stephen Fremes, Summer Syed, Sean M. Bagshaw, Nian-Chih Hwang, Colin Royse, Judith Hall, David Dai, Nikhil Mistry, Kevin Thorpe, Subodh Verma, Peter Jüni, Nadine Shehata
Journal: New England Journal of Medicine (2018)

We reported previously that, in patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive transfusion strategy was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or 28 days after surgery, whichever came first. We now report the clinical outcomes at 6 months after surgery.
Abstract 18648: Suspected Acute Coronary Syndrome With Normal Coronary Arteries: The Value of Cardiac Magnetic Resonance in Changes of Treatment
Authors: Alexandre M Soeiro, Débora Y Nakamura, Tatiana C Leal, Aline S Bossa, Maria C Soeiro, Carlos V Serrano Jr, Múcio T Oliveira Jr
Journal: Circulation (2015)

Introduction: Acute chest pain, ST-changes on EKG and elevation of cardiac troponin in patients without obstructive coronary artery disease represent a clinical challenge. Cardiovascular magnetic resonance (CMR) can be used to diagnose causes other than obstructive coronary artery disease. Hypothesis: The aim of this study was to evaluate the usefulness of CMR to diagnose conditions in the emergency room that otherwise would be considered as acute coronary syndrome (ACS) in patients with normal coronary arteries. Methods: Fifty-nine patients with chest pain and/or electrocardiographic changes and elevated troponin concentration occurring in the absence of significant coronary artery stenosis (normal or stenosis &lt; 50% of the vessel diameter on angiography, computed tomography or both) were selected and prospectively submitted to CMR exam in a 1.5T Philips scanner between May 2013 and December 2014. Ventricular function by cine MR with SSFP technique, and myocardial tissue characterization using late gadolinium enhancement (LGE) were evaluated in patients referred to the Emergency room. LGE patterns were analyzed visually by 2 observers and classified as ischemic (involving subendocardial layer) and nonischemic (multifocal, not involving subendocardial layer, non coronary distribution). Results: Among 59 patients, all with interpretable CMR exams, diagnosis of acute myocarditis was found in 39% of patients, acute myocardial infarction in 17% and Takotsubo cardiomyopathy in 12%. Other final diagnoses were hypertrophic cardiomyopathy (5%), coronary embolism (10%), cardiomyopathy (3%), sepsis (4%), aortic stenosis (3%) and non-compaction myocardium (2%). In 38 patients (66%), CMR changed the initial ACS diagnosis to another final diagnosis. Additionally,3 patients primarily considered as having myocarditis received a final diagnosis of myocardial infarction. Conclusions: In the study, 66% of patients had their primary diagnosis and treatment changed after CMR study. The presence, distribution and pattern of late gadolinium enhancement by CMR were crucial in establishing a precise final diagnosis and appropriately changing patient management.
Abstract 18654: Expert Adjudication of Device Electrograms: Is an Atrial Channel More Important than Gray Hair?
Authors: Michael V Orlov, Haley Houde-Walter, Steven Swiryn, Fujian Qu, Albert Waldo, Brian Olshansky
Journal: Circulation (2015)

Background: The diagnosis of a tachycardia from ICD recordings ultimately depends upon analysis of captured electrograms (EGMs). While atrial EGM may improve tachycardia discrimination, the degree of benefit has not been evaluated in medical professionals with different level of expertise. Methods: Expert-adjudicated supraventricular tachycardia (SVT) and ventricular tachycardia (VT) EGMs from the RATE Registry were given to EP Specialists (EPS), EP Fellows (EPF), and Nurse Practitioners or Physician Assistants (NPPA). Each participant diagnosed 112 EGMs (61 VTs, 51 SVTs) as SVT, VT, or Uncertain in two stages. First, participants made diagnosis based on ventricular EGM (VEGM) alone (Atrial Channel covered). Then the EGMs were re-randomized with atrial EGM exposed and diagnosis was made again. The accuracy of diagnosis by EPS, EPF, and NPPA in the use of VEGM alone vs dual-chamber EGM was assessed. Results: Fifteen participants (5 in each group) completed diagnosis. All 3 groups significantly improved diagnosis accuracy (&gt;20% for VTs, &gt;15% for SVTs, all p values &lt; 0.02) when dual-chamber EGM was provided. EPS diagnosed VTs more accurately than NPPA (VEGM: 73.1±7.6% vs 56.1±14.1%, p = 0.03; dual-chamber EGM: 98.0±2.7% vs 80.3±7.4%, p = 0.001). EPF diagnosed VTs better than NPPA but worse than EPS (not statistically significant). There was no significant intergroup difference in SVT diagnosis. Conclusion: These results suggest that atrial EGMs help rhythm discrimination at all levels of expertise. However, experience seems to improve diagnosis accuracy with and w/o atrial EGM.
Association of Body Mass Index With Blood Pressure Among 1.7 Million Chinese Adults
Authors: George C. Linderman, Jiapeng Lu, Yuan Lu, Xin Sun, Wei Xu, Khurram Nasir, Wade Schulz, Lixin Jiang, Harlan M. Krumholz
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Body mass index (BMI) is positively associated with blood pressure (BP); this association has critical implications for countries like China, where hypertension is highly prevalent and obesity is increasing. A greater understanding of the association between BMI and BP is required to determine its effect and develop strategies to mitigate it. <h3>Objective</h3> To assess the heterogeneity in the association between BMI and BP across a wide variety of subgroups of the Chinese population. <h3>Design, Setting, and Participants</h3> In this cross-sectional study, data were collected at 1 time point from 1.7 million adults (aged 35-80 years) from 141 primary health care sites (53 urban districts and 88 rural counties) from all 31 provinces in mainland China who were enrolled in the China PEACE (Patient-Centered Evaluative Assessment of Cardiac Events) Million Persons Project, conducted between September 15, 2014, and June 20, 2017. A comprehensive subgroup analysis was performed by defining more than 22 000 subgroups of individuals based on covariates, and within each subgroup, linearly regressing BMI to BP. <h3>Main Outcomes and Measures</h3> Systolic BP was measured twice with the participant in a seated position, using an electronic BP monitor. <h3>Results</h3> The study included 1 727 411 participants (1 027 711 women and 699 700 men; mean [SD] age, 55.7 [9.8] years). Among the study sample, the mean (SD) BMI was 24.7 (3.5), the mean (SD) systolic BP was 136.5 (20.4) mm Hg, and the mean (SD) diastolic BP was 81.1 (11.2) mm Hg. The increase of BP per unit BMI ranged from 0.8 to 1.7 mm Hg/(kg/m<sup>2</sup>) for 95% of the subgroups not taking antihypertensive medication. The association between BMI and BP was substantially weaker in subgroups of patients taking antihypertensive medication compared with those who were untreated. In untreated subgroups, 95% of the coefficients varied by less than 1 mm Hg/(kg/m<sup>2</sup>). <h3>Conclusions and Relevance</h3> The association between BMI and BP is positive across tens of thousands of individuals in population subgroups, and, if causal, given its magnitude, would have significant implications for public health.
Smokers with Normal Spirometry: Impact of Computed Tomography–detected Emphysema, Functional Mechanisms of Dyspnea, and Clinical Significance of Symptoms
Authors: Manuela Tobón-Trujillo, Pablo Gil-Torres, July Torres-González, Alejandra Cañas Arboleda, Carlos Celis-Preciado
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Simple deep sequencing-based post-remission MRD surveillance predicts clinical relapse in B-ALL
Authors: Shuhua Cheng, Giorgio Inghirami, Shuo Cheng, Wayne Tam
Journal: Journal of Hematology & Oncology (2018)

Next-generation sequencing (NGS) of the rearranged immunoglobulin heavy-chain gene has emerged as a highly sensitive method to detect minimal residual disease (MRD) in B acute lymphoblastic leukemia/lymphoma (B-ALL). However, a sensitive and easily implemented NGS methodology for routine clinical laboratories is lacking and clinical utility of NGS-MRD surveillance in a post-remission setting to predict clinical relapse has not been determined.Here we described a simple and quantitative NGS platform and assessed its performance characteristics, quantified NGS-MRD levels in 122 B-ALL samples from 30 B-ALL patients, and explored the clinical merit of NGS-based MRD surveillance.The current NGS platform has an analytic sensitivity of 0.0001% with excellent specificity and reproducibility. Overall, it performs better than routine multi-color flow cytometry (MCF) in detecting MRD. Utilizing this assay in MRD surveillance in a post-remission setting showed that it detected conversion to positive MRD (CPMRD) in patients with NGS-based molecular remission much earlier than MCF, and that positive MRD conversion could be detected as early as 25.6 weeks prior to clinical relapse in closely surveilled patients. Post-remission CPMRD, but not NGS-based MRD positivity at end of induction, can accurately predict clinical relapse in our limited cohort of B-ALL patients.This pilot proof-of-concept study illustrates the clinical utility of a simple, sensitive, and clinically feasible MRD detection platform in post-remission NGS-based MRD surveillance and early relapse detection in B-ALL patients.
Abstract 19593: Cardiac Rehabilitation in Premature Coronary Artery Disease
Authors: Michael Khoury, James Stone, Danielle Southern, Steven B Wilton, Diane Galbraith, Sandeep Aggarwal, Ross Arena, Billie-Jean Martin
Journal: Circulation (2017)

Introduction: The role of cardiac rehabilitation (CR) in the premature coronary artery disease (premCAD) population has not been well evaluated. We sought to evaluate predictors of CR referral and ...
Association of Transsynaptic Degeneration of the Papez Circuit With Anterior Thalamic Encephalomalacia
Authors: Zarina Abdul Assis, Robert Sevick
Journal: JAMA Neurology (2018)

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The age-calibrated measured glomerular filtration rate improves living kidney donation selection process
Authors: François Gaillard, Marie Courbebaisse, Nassim Kamar, Lionel Rostaing, Arnaud Del Bello, Sophie Girerd, Michèle Kessler, Martin Flamant, Emmanuelle Vidal-Petiot, Marie-Noelle Peraldi, Lionel Couzi, Pierre Merville, Paolo Malvezzi, Benedicte Janbon, Bruno Moulin, Sophie Caillard, Philippe Gatault, Matthias Büchler, Nicolas Maillard, Laurence Dubourg, Olga Roquet, Cyril Garrouste, Christophe Legendre, Pierre Delanaye, Christophe Mariat
Journal: Kidney International (2018)
Abstract 17313: Multiparametric Cardiac MRI Documents Reduced LV Remodeling and Improved Contractile Function in Regions Adjacent to the Infarct After Pharmacologic Immunomodulation via Adenosine 2a Receptor Stimulation
Authors: Ya-Jian Cheng, Elie R Chemaly, Yikui Tian, Frederick H Epstein, Brent A French
Journal: Circulation (2015)

Introduction: Agonists of the Adenosine 2a Receptor (A2aR) are used clinically as pharm-stress agents for perfusion imaging, but they are also potent immunomodulators that reduce the size of acute MI when administered at reperfusion in both large and small animal models of MI. Hypothesis: Sustained administration of an A2aR agonist can reduce post-MI LV remodeling and improve cardiac strain even when treatment is withheld until after infarct size has stabilized. Methods: Two groups of mice were studied: C57BL/6 mice treated with Vehicle or a highly selective A2aR agonist (ATL313). All mice received 1h coronary occlusion and 28d of reperfusion. ATL313 was administered for 28 days by subcutaneous micro-osmotic pumps implanted after MI. All mice underwent 7T CMR imaging at baseline and 2, 7 &amp; 28 days post-MI. CMR included short-axis black-blood cines covering the entire heart, with mid-ventricular cine DENSE for circumferential strain (Ecc). Late Gd-enhanced (LGE) inversion recovery imaging was performed on Days 2&amp;7 and molecular imaging with a collagen-targeted Gd contrast agent (EP3533) on Days 14&amp;28. Mice with Day 2 LGE infarct sizes less than 22% or &gt;42% LV mass were excluded from analysis. Results: Examples of LGE and DENSE analysis are shown in Panels A&amp;B. Day 2 infarct size was similar between groups (ATL313 (n=9): 35±2 vs Vehicle (n=8): 34±2, mean±SEM, p=NS). In panel C, ATL313 significantly improved LV end-systolic volume as early as 2 days post-MI (mean±SEM, *p&lt;0.05 vs Vehicle). In panel D, ATL313 improved Day 2 Ecc in adjacent zones vs. Vehicle (-10±2 vs -6±2%, *p&lt;0.05). In panel E, ATL313 reduced LV mass at Day 28 vs Vehicle (121±7 vs 143±7mg, *p&lt;0.05). Conclusions: Pharmacologic immunomodulation with an A2aR agonist inhibits LV remodeling, improves contractile function in infarct-adjacent regions at Day 2 post-MI and reduces LV mass at Day 28. Combined with previous work, these results suggest that A2aR stimulation may prove beneficial in both acute and sub-acute MI.
Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted
Authors: Jeremy S. Tilstra, Lyndsay Avery, Ashley V. Menk, Rachael A. Gordon, Shuchi Smita, Lawrence P. Kane, Maria Chikina, Greg M. Delgoffe, Mark J. Shlomchik
Journal: Journal of Clinical Investigation (2018)

While T cells are important for the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis, little is known about how T cells function after infiltrating the kidney. The current paradigm suggests that kidney-infiltrating T cells (KITs) are activated effector cells contributing to tissue damage and ultimately organ failure. Herein, we demonstrate that the majority of CD4+ and CD8+ KITs in 3 murine lupus models are not effector cells, as hypothesized, but rather express multiple inhibitory receptors and are highly dysfunctional, with reduced cytokine production and proliferative capacity. In other systems, this hypofunctional profile is linked directly to metabolic and specifically mitochondrial dysfunction, which we also observed in KITs. The T cell phenotype was driven by the expression of an "exhausted" transcriptional signature. Our data thus reveal that the tissue parenchyma has the capability of suppressing T cell responses and limiting damage to self. These findings suggest avenues for the treatment of autoimmunity based on selectively exploiting the exhausted phenotype of tissue-infiltrating T cells.
Abstract 13792: Molecular Imaging of Activated Platelets using Positron Emission Tomography: A Novel, Highly Sensitive Detection Method for Cardiac Ischemia
Authors: Melanie Ziegler, Karen Alt, Christoph E Hagemeyer, Karlheinz Peter
Journal: Circulation (2015)

Introduction: Coronary artery disease (CAD) causing symptomatic ischemia is often missed in patients that present with angina pectoris but without ECG changes or rise in troponin. A sensitive diagnostic test that could diagnose an ischemic event, before cardiac damage is causing troponin release, would change the clinical path of emergency patients with angina and reduce the number of CAD patients to remain undiagnosed and thus have an increased risk of myocardial infarction. Methods: We developed a sensitive, non-invasive imaging approach using PET imaging of activated platelets for the detection of minimal cardiac ischemia and inflammation. Different extents of ischemia were induced in mice by temporary LAD ligation for 10, 20 or 60 min. Activated platelets were imaged in a PET/CT scanner with 64 Cu bound to the chelator MeCOSar that was conjugated to a single-chain antibody directed against activated GPIIb/IIIa. Results: A time course of platelet adhesion within the infarcted myocardium indicates an early inflammatory response of activated platelets to the ischemic insult peaking 2h post reperfusion. Sensitive biomarkers such as troponin I and heart-type fatty acid-binding protein (H-FABP) could not detect smaller degrees of cardiac ischemia (10 and 20 min of ischemia). In contrast, PET-based imaging of activated platelets detects even minor degree of ischemia. The significant adhesion of platelets in the ischemic heart even after minor degrees of ischemia was confirmed by flow cytometry and histology. Conclusions: Cardiac ischemia is associated with a significant adhesion of activated platelets within the ischemic heart. Even minimal extents of cardiac ischemia not associated with troponin rises are detectable by platelet-based PET imaging. This novel, highly sensitive non-invasive detection of minimal degrees of cardiac ischemia has the potential to detect otherwise undetected CAD. Figure: PET/CT imaging of activated platelets within ischemic hearts.
Aprepitant for the Treatment of Pruritus in Sézary Syndrome
Authors: John A. Zic, Brittany T. Straka, Laura Y. McGirt, Hui Nian, Chang Yu, Nancy J. Brown
Journal: JAMA Dermatology (2018)

This randomized clinical trial assesses whether treatment with the neurokinin 1 receptor antagonist aprepitant decreases pruritus vs placebo in patients with Sezary syndrome.
SLC46A3 as a Potential Predictive Biomarker for Antibody–Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads
Authors: Krista Kinneer, John Meekin, Arnaud C. Tiberghien, Yu-Tzu Tai, Sandrina Phipps, Christine Mione Kiefer, Marlon C. Rebelatto, Nazzareno Dimasi, Alyssa Moriarty, Kyriakos P. Papadopoulos, Sriram Sridhar, Stephen J. Gregson, Michael J. Wick, Luke Masterson, Kenneth C. Anderson, Ronald Herbst, Philip W. Howard, David A. Tice
Journal: Clinical Cancer Research (2018)

Antibody-drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance.The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, in vitro. The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft and in vitro models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR.Loss of SLC46A3 expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of SLC46A3, suggesting that expression of SLC46A3 may be more predictive of activity than target antigen levels alone. Interrogation of primary multiple myeloma samples indicated a range of SLC46A3 expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs.Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.