tbuckley/cabot-search huggingface dataset:
Abstract 17228: Gender Differences in Treatment and Outcomes of Patients With COVID-19 Respiratory Failure
Authors: Rafey A Feroze, Tariq Azam, Husam Shadid, Michael Pan, Hanna Berlin, Chelsea Meloche, Jeff Leya, Patrick O'Hayer, Elizabeth Anderson, Rayan Kaakati, abbas bitar, Kishan Padalia, Daniel Perry, Pennelope Blakely, Peiyao Zhao, Lili Zhao, Salim Hayek
Journal: Circulation (2020)

Introduction: The COVID-19 pandemic has spread across the globe and claimed many lives. Initial studies suggest that there are gender-based differences in severity of disease and mortality, with male patients having worse outcomes. We sought to further characterize gender differences to COVID-19 infection. Hypothesis: Male patients have a higher severity of illness from COVID-19. Methods: The Michigan Medicine COVID-19 Cohort (M2C2) is an ongoing prospective observational study in which detailed clinical, laboratory and outcomes data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without symptoms of COVID-19 were not included in this cohort. The M2C2registry consists of 553 patients with 491 included in this analysis. There were 282 male patients and 208 female patients. Baseline characteristics, comorbidities, and characteristics of in-patient management were compared among male and female patients. The primary outcomes analyzed were in-hospital death of any cause including dismissal to hospice, need for renal replacement therapy (RRT), need for mechanical ventilation, and hospital length of stay. Results: Significant differences were observed among various patient characteristics and outcomes across gender. While no mortality difference was present between males and females, 43.8% of male patients were diagnosed with ARDS compared to 35.1% of female patients. The average days on mechanical ventilation were greater for male ICU patients (4.1 ± 5.91 vs. 3.4 ± 5.75) and the length of stay (days) was also longer for males (13.6 ± 11.94 vs. 12.2 ± 12.29). Admission creatinine was higher in males compared to females (2.95 ± 12.97 vs. 1.31 ± 1.33) and more male patients required RRT during their ICU admission (19.5% vs. 10.6%). Conclusions: While no difference in in hospital mortality was observed across gender, the severity of disease was greater among male patients in regards to ARDS, the need for ventilatory support, and kidney injury with requirement for RRT.
<i>MET</i> Exon 14–altered Lung Cancers and MET Inhibitor Resistance
Authors: Robin Guo, Michael Offin, A. Rose Brannon, Jason Chang, Andrew Chow, Lukas Delasos, Jeffrey Girshman, Olivia Wilkins, Caroline G. McCarthy, Alex Makhnin, Christina Falcon, Kerry Scott, Yuan Tian, Fabiola Cecchi, Todd Hembrough, Deepu Alex, Ronglai Shen, Ryma Benayed, Bob T. Li, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Natasha Rekhtman, Paul Paik, Ahmet Zehir, Alexander Drilon
Journal: Clinical Cancer Research (2020)

MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed.We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of MET exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.Seventy-five of 168 MET exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (P > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (N = 15) or immunochemistry (N = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; P = 0.02).In MET exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation
Authors: Aurélien Justet, Dymph Klay, Raphaël Porcher, Vincent Cottin, Kais Ahmad, Maria Molina Molina, Hilario Nunes, Martine Reynaud-Gaubert, Jean Marc Naccache, Effrosyni Manali, Antoine Froidure, Stéphane Jouneau, Lidwine Wemeau, Claire Andrejak, Anne Gondouin, Sandrine Hirschi, Elodie Blanchard, Benjamin Bondue, Philippe Bonniaud, Cécile Tromeur, Grégoire Prévot, Sylvain Marchand-Adam, Manuela Funke-Chambour, Anne Sophie Gamez, Ibrahima Ba, Spyridon Papiris, Jan Grutters, Bruno Crestani, Coline van Moorsel, Caroline Kannengiesser, Raphaël Borie
Journal: European Respiratory Journal (2020)

<b>This study suggests that pirfenidone and nintedanib can be used safely in IPF patients with a telomerase related gene mutation and that both drugs reduce FVC decline. These results should be confirmed in a larger prospective study.</b>https://bit.ly/3k7b4Zx
Health system interventions for adults with type 2 diabetes in low- and middle-income countries: A systematic review and meta-analysis
Authors: David Flood, Jessica Hane, Matthew Dunn, Sarah Jane Brown, Bradley H. Wagenaar, Elizabeth A. Rogers, Michele Heisler, Peter Rohloff, Vineet Chopra
Journal: PLoS Medicine (2020)

Effective health system interventions may help address the disproportionate burden of diabetes in low- and middle-income countries (LMICs). We assessed the impact of health system interventions to improve outcomes for adults with type 2 diabetes in LMICs.
OP0125 Overexpression of vascular endothelial growth factor (vegf) and its receptors in systemic sclerosis (ssc): evidence for protective effects of vegf against the development of fingertip ulcers
Authors: O Distler, A Del Rosso, A Scheid, J Rethage, M Neidhart, A Carossino, RE Gay, U Müller-Ladner, BA Michel, M Gassmann, M Matucii-Cerinic, S Gay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Vascular changes are consistent early findings in SSc and often proceed the development of fibrosis. Despite a severe reduction in the capillary density, signs of neoangiogenesis cannot be detected. <h3>Objectives</h3> To examine the role of VEGF and its receptors in the impaired angiogenesis of SSc. <h3>Methods</h3> Skin pO2 was measured intradermally using the pO2 histograph in 13 patients with SSc and in 5 healthy controls. Cultured SSc and normal skin fibroblasts were exposed to hypoxia and analysed for VEGF mRNA by real-time PCR (TaqMan). Immunohistochemistry with anti-VEGF-Receptor-1 and anti-VEGF-Receptor-2 antibodies was performed on skin biopsies of SSc patients and healthy controls. Serum samples of 47 patients with SSc and 21 healthy controls were analysed for VEGF by ELISA and correlated with clinical parameters. <h3>Results</h3> PO2 values from involved skin of SSc patients (23,7 ± 2,1 mmHg) were significantly lower compared to healthy controls (33,6 ± 4,1 mmHg) and non-involved skin areas (37,8 ± 8,6 mmHg, p &lt; 0.05). After hypoxic exposure of cultured fibroblasts, VEGF mRNA was found to be upregulated compared to normoxic controls in SSc (3,7 ± 1,7 fold) and normal skin fibroblasts (3,0 ± 1,8 fold). The bioavailability of VEGF was not reduced, since the expression of VEGF-Receptor-1 and VEGF-Receptor-2 was found on endothelial cells of 4/5 patients with SSc, whereas no signal could be detected in healthy controls. In addition to the overexpression of VEGF mRNA in skin samples, serum levels of VEGF protein were significantly higher in SSc patients compared to healthy controls (mean 461 pg/ml, range 93–1153 pg/ml vs. 106 pg/ml, range 0–500 pg/ml, p &lt; 0.001). Interestingly, levels of VEGF were upregulated in patients with pre-SSc (clinical evidence for SSc without fulfilling ACR criteria, mean 451 pg/ml, range 230–601 pg/ml, p &lt; 0.05) and in patients with early disease stages (disease duration &lt; 2 years, mean 569 pg/ml, range 135–1013 pg/ml, p &lt; 0.01). Patients with diffuse disease and the presence of fingertip ulcers had higher levels of VEGF (mean 339 pg/ml, range 93–714 pg/ml) than healthy controls, but highly significant lower levels than patients without fingertip ulcers (mean 655 pg/ml, range 281–1151 pg/ml, p &lt; 0.001). <h3>Conclusion</h3> Our results suggest a hypoxia mediated activation of the VEGF/VEGF-receptor axis in SSc. The correlation with clinical parameters indicate that elevated levels of VEGF are a feature of early disease stages and might be protective against the development of fingertip ulcers. Since the feasibility of a treatment with VEGF has just been approved in other ischaemic diseases, the application of VEGF may be a therapeutic option for the vascular insufficiency in SSc.
Abstract 14244: Circulating Vascular Cell Adhesion Molecule-1 and Incident Heart Failure: The Multi- Ethnic Study of Atherosclerosis
Authors: Ravi B Patel, Laura A Colangelo, Suzette J Bielinski, Nicholas B Larson, Jingzhong Ding, Norrina B Allen, Erin D Michos, Sanjiv J Shah, Donald M Lloyd-jones
Journal: Circulation (2020)

Background: Serum levels of vascular cell adhesion molecule-1 (VCAM-1) are reflective of endothelial activation, a pathologic process that is associated with subclinical cardiac dysfunction. While VCAM-1 has been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF), the prospective association of VCAM-1 with clinically overt HF is unclear. Methods: In the Multi-Ethnic Study of Atherosclerosis, we evaluated the association of VCAM-1 at Exam 2 (2002-2004) with incident HF across ejection fraction (EF) categories (HFpEF and HF with reduced EF [HFrEF]) after adjustment for cardiovascular risk factors. Incident HF was adjudicated as first hospitalization for symptomatic HF, requiring specific clinical and/or imaging criteria. Results: Of 2,298 participants (mean age: 63.0 years, female: 53%), those with higher VCAM-1 were more likely white race, had higher blood pressure, and lower renal function. Over a median of 16.0 years, there were 102 HF events (HFpEF = 65; HFrEF = 37) ( Figure ). After covariate adjustment, VCAM-1 was independently associated with incident HF ( Table ). Upon evaluation of HF subtypes, VCAM-1 was associated with incident HFpEF, and risk effect estimates were consistent for incident HFrEF. The association of VCAM-1 with incident HF was consistent across the spectrum of age, sex, and BMI. Conclusion: In a multiethnic cohort, VCAM-1 was independently associated with incident HF over long-term follow up. These findings suggest a potential role for endothelial activation in driving clinical HF. Lifestyle and pharmacologic therapies that decrease endothelial activation may prevent the progression to clinical HF.
Abstract 16839: Maternal Placental Vascular Malperfusion Lesions Associated With Increased Cardiometabolic Risk and Reduced Microvascular Density in Women a Decade After Delivery: Which Placental Features Matter?
Authors: Robin E Gandley, Judith Brands, Carl A Hubel, Alisse Hauspurg, William Tony Parks, Janet M Catov
Journal: Circulation (2020)

Introduction: Maternal vascular malperfusion (MVM) lesions in the placenta are commonly found in women with adverse pregnancy outcomes associated with increased CVD in later life. Minimal criteria for MVM include vasculopathy, accelerated villous maturation and increased syncytial knots, and villous infarction upon pathologic examination; expanded definitions have included presence of fibrin deposition (intervillous or perivillous) or low placental weight (&lt;10 th %). Hypothesis: Women with a history of MVM lesions would have evidence of cardiometabolic risk factors and peripheral microvascular changes a decade after delivery independent of pregnancy outcome. Methods: A total of 469 women with placental pathology data available were evaluated at 8-10 years postpartum. Placental specimens were reviewed by a perinatal pathologist. Cardiometabolic variables were measured at the time of the study visit. Sidestream dark field imaging was used to assess the sublingual microcirculation. We compared the median size (diameter) of microvessels, density (total length of perfused microvessels/mm 2 ) and penetration of red cells into the glycocalyx of vessels 5-25μm diameter (perfused boundary region, PBR) in women 8-10 years after pregnancy, using the minimal MVM criteria (compared to none). Expanded criteria were examined alone. Significance =*p&lt;0.05 vs no MVM lesions. Results: Women with minimally defined MVM lesions in their placentas had higher diastolic blood pressure (79mmHg MVM vs. 75 mmHg No MVM*), LDL (111mg/dL MVM vs. 101 mg/dL No MVM*), Cholesterol (185 mg/dL MVM vs. 175mg/dL No MVM*) and insulin (14mg/dL MVM vs. 12mg/dL No MVM*), along with smaller-sized microvessels (median 8.75±1.1 μM vs. 9.06±0.7 μM*), and a lower density of perfused microvessels compared to women without MVM lesions (3590±1260mm/mm 2 MVM vs. 3970±820 mm/mm 2 No MVM*) a decade after delivery. Glycocalyx PBR was smaller in women with prior MVM vs. women without lesions (2.01±0.23μm vs. 2.09±0.15μm, P=0.02). Similar results were not seen in subjects with either presence of fibrin or small placenta in the absence of other MVM criteria. Discussion: Using minimal criteria MVM was associated most strongly with maternal cardiometabolic and microvascular differences a decade later.
Association of Baseline Low-Density Lipoprotein Cholesterol and Percentage Low-Density Lipoprotein Cholesterol Reduction With Statins, Ezetimibe, and PCSK9 Inhibition
Authors: Daniel P. Marcusa, Robert P. Giugliano, Jeong-Gun Park, James A. de Lemos, Christopher P. Cannon, Marc S. Sabatine
Journal: JAMA Cardiology (2020)

Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels.
Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets
Authors: Shady Adnan-Awad, Daehong Kim, Helena Hohtari, Komal Kumar Javarappa, Tania Brandstoetter, Isabella Mayer, Swapnil Potdar, Caroline A. Heckman, Soili Kytölä, Kimmo Porkka, Eszter Doma, Veronika Sexl, Matti Kankainen, Satu Mustjoki
Journal: Leukemia (2020)

Abstract The oncogenic protein Bcr-Abl has two major isoforms, p190 Bcr-Abl and p210 Bcr-Abl . While p210 Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190 Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190 Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190 Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190 Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190 Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210 Bcr-Abl , p190 Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190 Bcr-Abl CML patients, p190 Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190 Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190 Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.
Abstract 14722: The Utility of Tei Index in Subclinical Cardiotoxicity After Chemotherapy
Authors: Yuki Hamamoto, Toshinori Yuasa, Akio Tokushige, Yoshihisa Horizoe, Hisayo Yasuda, Mitsuru Ohishi
Journal: Circulation (2020)

Introduction: It was reported left ventricular global longitudinal strain (LVGLS) was useful to diagnose subclinical cardiotoxicity (SC) after chemotherapy. Doppler Tei index has been known as a noninvasive and useful indicator of systolic and diastolic myocardial performance. Until now, it has not been reported about the utility of Tei index in SC after anthracycline-based chemotherapy. Methods: We retrospectively enrolled patients with malignant lymphoma or acute myeloid leukemia receiving anthracycline-based chemotherapy from 2010 to 2019. Thirty patients were performed echocardiographic examination before and after chemotherapy. We measured LV parameters (LVGLS, LV end-diastolic diameter, LV end-systolic diameter, LV ejection fraction, LV-Tei index), and RV parameters (RV fractional area change, RV-Tei index). Patients were divided into SC and non-SC groups according to a relative percentage reduction in LVGLS of greater than 15% to baselines. Then, we compared LV and RV parameters between groups, and explored which parameters were related to SC. Results: Five patients (16%) were divided into SC group with decreased %ΔGLS (22.5±6.7%). LV end-diastolic diameter, LV end-systolic diameter, and RV fractional area change were slightly higher in non-SC although still no significance. ΔLV-Tei index and ΔRV-Tei index were significantly greater In SC group compared to non-SC group (0.22±0.10 versus 0.15±0.03, p=0.032. 0.18±0.08 versus 0.14±0.02, p=0.014, respectively). ΔLV-Tei index and ΔRV-Tei index significantly correlated with ΔGLS (r=0.46, p=0.009. r=0.39, p=0.03). Receiver-operating characteristic curve analysis identified the optimal ΔLV-Tei index and ΔRV-Tei cutoff for predicting SC as 0.09 and 0.05 (area under the curve of 0.81, p=0.029. 0.86, p=0.028). Conclusions: LV and RV-Tei index was affected by chemotherapy. Our study suggests that Tei index can be a useful indicator for SC after anthracycline-based chemotherapy.
Abstract 14157: Racial Differences in Outcomes of Ischemic Stroke and Mortality With Left Atrial Appendage Closure With Watchman Device in Medicare Population
Authors: Rajesh Kabra, Saket Girotra, Mary S Vaughan Sarrazin
Journal: Circulation (2020)

Introduction: Left atrial appendage closure by Watchman implantation is a novel non-pharmacological alternative for stroke prevention in non-valvular atrial fibrillation (AF) patients who are deemed unable to take long term anticoagulation. Blacks and Hispanics were under-represented in the clinical trials for Watchman device and therefore more outcome data is needed in these populations. Hypothesis: We sought to study racial differences in outcomes of mortality and ischemic stroke in Medicare beneficiaries who received a Watchman device Methods: Medicare claims were used to identify 13,598 patients with AF who underwent Watchman implantation during January 2015 to November 2017. Patient demographics including race and comorbid conditions were identified based on the hospital discharge record. Death and readmission rate for ischemic strokes and transient ischemic attacks (TIA’s) were assessed. Primary readmission diagnoses were classified using the AHRQ Clinical Classification Software. Results: The mean age of patients was 78±6.3 years and 40.3% were female. There were 11,955 whites (88%), 453 blacks (3.3%) and 523 Hispanic patients (3.8%). Mean CHAD 2 S 2 VASc score was 4.7 in blacks, 4.6 in Hispanics and 4.5 in whites. One year mortality after watchman implantation was 6.8% in blacks, 8% in Hispanics and 7.69% in whites. After risk adjustment, compared to whites, the Hazard Ratio for death was 0.82 in blacks (p=0.31) and 0.96 in Hispanics (p=0.82). The rate of ischemic stroke and TIA following Watchman implantation was highest at 4.75 per 100 patient years in blacks followed by 2.87 per 100 patient years in Hispanics and 2.37 per 100 patient years in whites. After risk adjustment, blacks continued to have higher risk for ischemic stroke (HR 1.87, p = 0.01) compared to whites, while Hispanics had a similar risk (HR 1.19, p=0.51). Conclusions: In the Medicare population undergoing Watchman implantation, after risk adjustment, one year mortality following the procedure was similar in whites, Hispanics and blacks. However, the rate of ischemic stroke was significantly higher in blacks compared to whites even after risk adjustment. Further studies are needed in the real world to monitor the outcomes associated with watchman device in minority population.
FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer
Authors: Sakar Wahby, Lola Fashoyin-Aje, Christy L. Osgood, Joyce Cheng, Mallorie H. Fiero, Lijun Zhang, Shenghui Tang, Salaheldin S. Hamed, Pengfei Song, Rosane Charlab, Sarah E. Dorff, Tiffany K. Ricks, Kimberly Barnett-Ringgold, Jeannette Dinin, Kirsten B. Goldberg, Marc R. Theoret, Richard Pazdur, Laleh Amiri-Kordestani, Julia A. Beaver
Journal: Clinical Cancer Research (2020)

Abstract On April 22, 2020, the FDA granted accelerated approval to sacituzumab govitecan-hziy (TRODELVY; Immunomedics, Inc.) for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. Approval was based on data from the IMMU-132-01 trial, a single-arm, multicohort, multicenter, phase I/II trial of sacituzumab govitecan. The assessment of efficacy was based on 108 patients with mTNBC who had previously received at least two prior lines of therapy in the metastatic setting and who received sacituzumab govitecan 10 mg/kg i.v. The assessment of safety was based on 408 patients with advanced solid tumors who had received sacituzumab govitecan at doses up to 10 mg/kg i.v. The primary efficacy endpoint was investigator-assessed objective response rate (ORR) and duration of response (DoR) was a key secondary endpoint. The ORR was 33.3% [36/108; 95% confidence interval (CI), 24.6–43.1], and median DoR among responders was 7.7 months (95% CI, 4.9–10.8). The most common adverse reactions occurring in ≥25% of patients were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. This article summarizes the FDA review process and data supporting the approval of sacituzumab govitecan.