tbuckley/cabot-search huggingface dataset:
Abstract 13813: Prior β-Blocker Treatment Dampens Immune Cell Responses Following Myocardial Infarction
Authors: Laurel A Grisanti, Erhe Gao, Walter J Koch, Douglas G Tilley
Journal: Circulation (2016)

Following myocardial infarction (MI), immune cell infiltration initiates and regulates cardiac remodeling and repair. Our previous work has shown the importance of β2-adrenergic receptors (β2AR) in modulating immune cell infiltration to the heart following injury through the regulation of chemokine receptor expression and splenic retention of bone marrow (BM)-derived leukocyte populations. Pharmacological inhibition of βAR is a common strategy for the treatment of many cardiovascular etiologies, however the impact of β-blocker therapy on immune cell responses following acute cardiac injury is unknown. We hypothesized that prior treatment with β-blockers with distinct isoform selectivity would differentially decrease leukocyte infiltration to the heart following MI. Mice were administered either vehicle, a β1AR-selective (Metoprolol; Met), a β2AR-selective (ICI 118,551; ICI) or a βAR non-selective (Carvedilol; Carv) antagonist for two weeks via minipump. Analysis of mice treated with ICI or Carv showed decreased BM expression of CCR2 and CXCR4, as well as elevated levels of leukocyte populations within the spleen. While these effects were not observed in mice infused with a β1AR-selective dose of Met, a higher concentration of Met (equivalent to moderate doses used in humans) also decreased CCR2 and CXCR4 expression in BM and increased splenic leukocyte retention. To determine the impact of β2AR-selective versus non-selective blockade on immune cell responses following acute cardiac injury, mice from each treatment group underwent sham or MI surgery. In addition to decreased CCR2 and CXCR4 expression in the BM, mice administered ICI, Carv and the non-selective dose of Met had impaired recruitment of leukocyte populations to the heart following MI. Toward clinically relevant ends, we assessed CCR2 and CXCR4 expression in leukocytes isolated from blood samples of healthy and heart failure patients and found that levels of each were decreased in patients having taken β-blockers. In all, these results demonstrate that prior β-blocker treatment negatively regulates immune cell responsiveness to acute cardiac injury.
Deleting Malignant B Cells With Second-Generation Anti-CD20 Antibodies
Authors: Josh Sopp, Mark S. Cragg
Journal: Journal of Clinical Oncology (2018)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study. March 27, 2018 ARTICLE CITATION DOI: 10.1200/JCO.2018.78.7390 Journal of Clinical Oncology - published online before print June 12, 2018 PMID: 29894272 Deleting Malignant B Cells With Second-Generation Anti-CD20 Antibodies Josh SoppxJosh SoppSearch for articles by this author and Mark S. CraggxMark S. CraggSearch for articles by this author Show More Josh Sopp and Mark S. Cragg, University of Southampton, Southampton, United Kingdom https://doi.org/10.1200/JCO.2018.78.7390 First Page Full Text PDF Figures and Tables © 2018 by American Society of Clinical Oncology Original Article Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study
First-in-human study of the safety and viability of intraocular robotic surgery
Authors: T. L. Edwards, K. Xue, H. C. M. Meenink, M. J. Beelen, G. J. L. Naus, M. P. Simunovic, M. Latasiewicz, A. D. Farmery, M. D. de Smet, R. E. MacLaren
Journal: Nature Biomedical Engineering (2018)
AB1266 Autoimmune diseases induced by biological agents used in patients with advanced cancer: a nationwide multicenter registry of cases diagnosed in daily practice (CBIOGEAS-SEMI)
Authors: S. Retamozo, R. Pérez-Álvarez, I. Gutiérrez-Gosálvez, M.T. Herranz, S. Prieto-González, A. Robles-Marhuenda, P. Brito-Zerón, E.M. Aguilar Romo, C. Yllera Gutiérrez, A.C. Antolí-Royo, A. Flores-Chavez, C. Morcillo, L. Caminal, M. Pérez-de-Lis, M. Ramos-Casals
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To characterise the development of autoimmune diseases triggered by the new biological therapies used as immunotherapy in patients with advanced cancer in a real-life clinical setting. <h3>Methods</h3> In 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use and safety of biological agents in adult patients. In December 2016, the cBIOGEAS-SEMI multicenter registry was formed with the aim of collecting patients with cancer treated with biological immunotherapies who developed autoimmune diseases. <h3>Results</h3> By January 2018, the cBIOGEAS-SEMI Registry includes 40 patients (26 men and 14 women, mean age of 59.7 years) who developed 54 triggered autoimmune diseases, including interstitial lung disease (n=11), enterocolitis (n=8), hypophysitis (n=6), polyarthritis (n=4), thyroiditis (n=3), vasculitis (n=3), severe cutaneous involvement (n=3), adrenalitis (n=2), Sjögren syndrome (n=2), cardiomyopathy (n=2), pancreatitis (n=2), Guillain-Barre syndrome (n=2), hepatitis (n=2) and CNS involvement, sclerosing cholangitis, glomerulonephritis and sarcoidosis (one case each). Underlying neoplasia consisted mainly in pulmonary neoplasia (n=16), melanoma (n=11) and breast cancer (n=3). The main pharmacological groups of cancer immunotherapies included PD1 inhibitors (n=26), CTL4 inhibitors (n=7), growth factor/adhesion molecules inhibitors (n=4), combined PD1/CTL4 blockade (n=2) and TK inhibitors (n=1); biologics included nivolumab (n=20), ipilimumab (n=9), pembrolizumab (n=8), trastuzumab (n=3), catumaxomab (n=1) and vemurafenib/combimetinib (n=1). Glucocorticoids were used in all cases but 4, and 9 patients required intravenous methylprednisolone pulses); 5 patients required additional immunosuppressive therapies (intravenous immunoglobulins in 4, methotrexate in one). All cases responded to treatment with glucocorticoids except 4 patients who died (3 due to ILD and one due to neurological disease). <h3>Conclusions</h3> A wide variety of systemic and organ-specific autoimmune diseases triggered by the new cancer immunotherapies is emerging. In this nationwide real-life Registry, immune checkpoint inhibitors are the biologics involved in nearly 90% of cases. We found an excellent response to glucocorticoids, with a poor prognosis in those patients who developed pulmonary and neurological autoimmune diseases. <h3>Disclosure of Interest</h3> None declared
Abstract 18210: Acetylated Proline-Glycine-Proline Couples Extracellular Matrix Fragmentation to Increased Vascular Endothelin-1 Production in Heart Transplant Patients
Authors: Gregory A Payne, Jindong Li, Xin Xu, Patricia Jackson, J. Michael Wells, Suzanne Oparil, Massoud Leesar, Palaniappan Sethu, Rakesh P Patel, J. Edwin Blalock, Amit Gaggar
Journal: Circulation (2016)

Introduction:  The endothelium is a critical regulator of vascular function, and alterations in the production of nitric oxide (NO) and endothelin-1 (ET1) are known to correlate with cardiovascular disease. Acetylated Proline-Glycine-Proline (AcPGP), a pro-inflammatory matrix-derived cytokine (matrikine), has recently been demonstrated to couple extracellular matrix (ECM) fragmentation to increased endothelial permeability. However, the impact of ECM damage and fragmentation in regulating endothelial function remains unknown. Herein, we report AcPGP to be a potent stimulator of ET1 both  in vitro  and in a cohort of heart transplant (HTx) patients.   Methods:  Coronary serum from HTx patients was collected during angiographic screening for transplant vasculopathy (N=7). Serum AcPGP was measured by mass spectroscopy.  In vitro  experiments employed human aortic endothelial cells cultured in a microfluidic cell culture model with both laminar and disturbed flow. Cells were treated with either AcPGP or control peptide Proline-Glycine-Glycine (PGG) for 48hours (250μg/mL). Static endothelial cell culture experiments were also conducted. An ET1 ELISA kit (R&D Systems) was used to measure ET1 concentrations. NO concentrations were measured by a chemiluminescence assay. Protein expression of Endothelin Converting Enzyme 1 (ECE1) was determined by western blot analysis.   Results:  Compared to PGG, AcPGP in the endothelial flow model induced a 2.7 fold increase in ET1 production (14.7 ± 2.8 versus 40 ± 8.5 pg/mL,  P  ). AcPGP in static endothelial cell culture also increased ET1 production in a dose-dependent manner within 24hours (0.1 – 1.0mg/mL,  P  ). No differences in endothelial cell NO production or ECE1 expression were observed. Clinically, ET1 linearly correlated with serum AcPGP concentrations from coronary samples (R 2  = 0.8,  P  = 0.01).   Conclusions:  The results identify AcPGP as a novel matrikine capable of increasing vascular ET1, and highlight its potential role as a paracrine regulator of vascular function and inflammation. Importantly, these results are the first to link ECM fragmentation with an established mediator of cardiovascular disease in HTx patients.
Prenatal Exposure to Perfluoroalkyl Substances and IQ Scores at Age 5; a Study in the Danish National Birth Cohort
Authors: Zeyan Liew, Beate Ritz, Cathrine Carlsen Bach, Robert F. Asarnow, Bodil Hammer Bech, Ellen A. Nohr, Rossana Bossi, Tine Brink Henriksen, Eva Cecilie Bonefeld-Jørgensen, Jørn Olsen
Journal: Environmental Health Perspectives (2018)

Perfluoroalkyl substances (PFASs) are widespread persistent organic compounds that have been suggested to affect neurodevelopment.We aimed to evaluate whether prenatal exposure to PFASs is associated with IQ in children.We studied 1,592 pregnancies enrolled in the Danish National Birth Cohort (DNBC) during 1996-2002. Sixteen PFASs were measured in maternal plasma collected in early gestation. Child IQ was assessed at 5 y of age using the Wechsler Primary and Preschool Scales of Intelligence-Revised (WPPSI-R) administered by trained psychologists. Using multivariable linear regression models, we estimated the differences in child IQ scores according to PFAS concentration [per natural-log (ng/mL) unit increase or values categorized in quartiles].Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples, and five additional PFASs were quantified in >80% of the samples. Overall, we found no strong associations between a natural-log unit increase in each of the seven PFASs we evaluated and child IQ scores. A few positive and negative associations were found in the sex-stratified PFAS quartile analyses, but the patterns were inconsistent.Overall, we did not find consistent evidence to suggest prenatal exposure to PFASs to be associated with child IQ scores at 5 y of age in the DNBC. Some of the sex-specific observations warrant further investigation. Additional studies should examine offspring IQ at older ages and assess other functional cognitive and neuropsychiatric measures in addition to intelligence. Postnatal exposures to PFASs and mixture effects for PFASs and PFASs with other environmental pollutants should also be considered in future research. https://doi.org/10.1289/EHP2754.
AB0700 Is it feasible to withdraw immunosuppressive treatment in real-life patients with anca-associated vasculitis?
Authors: S. Monti, B. Vitolo, S. Balduzzi, M. Felicetti, R. Padoan, A. Berti, M. Bond, L. Quartuccio, G. Paolazzi, F. Schiavon, C. Montecucco, R. Caporali
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The optimal duration of remission-maintenance treatment in ANCA-associated vasculitis (AAV) is still unknown,<sup>1</sup> with International recommendations suggesting to maintain it for at least 24 months. Data supporting the correct balance between relapse risk, treatment-related adverse events and damage are highly needed. <h3>Objectives</h3> To analyse the frequency and predictors of withdrawal of remission-maintenance immunosuppressive drugs (IS) in a large real-life cohort of AAV patients. <h3>Methods</h3> Clinical records of patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were retrospectively analysed from a multicentric cohort. We divided the cohort into group A (withdrawal) and group B (ongoing). <h3>Results</h3> We included 185 patients. Forty-one patients (22%) had withdrawn IS at the end of follow-up (median 73.5 months, IQR 54–115). Concomitant glucocorticoids were stopped in 33%. There were no significant differences in AAV subtype, ANCA pattern, age at diagnosis, diagnostic delay or comorbidities rates between group A and group B (table 1). Disease onset with pulmonary involvement was significantly more frequent in patients in whom IS was maintained (69.7% vs 45%; p=0.004). Figure 1. Disease activity at onset, but not during follow-up, was significantly higher in patients from group B (ongoing): median BVAS 18 (12–24) vs 15; (8–20) p=0.02. The type of IS used for remission induction did not differ between the two groups. Maintenance treatment with Rituximab (RTX) was associated with higher probability of discontinuing IS by the end of follow-up (21% vs 7.6%; p=0.02). There was no difference in the number of major relapses between the two groups. Safety profile was equally good in both groups, except for a higher number of infections over the course of disease in patients who withdrew IS (5% vs 0). Vasculitis damage index (VDI) was comparable between the two groups. <h3>Conclusions</h3> IS withdrawal was observed in a minority of real-life patients with AAV. Drug-free remission was negatively associated with pulmonary involvement and higher BVAS at disease onset. Remission maintenance with RTX was associated with a higher frequency of drug withdrawal at the end of follow-up. <h3>Reference</h3> [1] Karras, et al. Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis. Ann Rheum Dis2017;76:1662–68 <h3>Disclosure of Interest</h3> None declared
Peer-Delivered Linkage Case Management and Same-Day ART Initiation for Men and Young Persons with HIV Infection — Eswatini, 2015–2017
Authors: Duncan MacKellar, Daniel Williams, Bonsile Bhembe, Makhosazana Dlamini, Johnita Byrd, Lenhle Dube, Sikhathele Mazibuko, Trong Ao, Ishani Pathmanathan, Andrew F. Auld, Pamela Faura, Nomthandazo Lukhele, Caroline Ryan
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

To achieve epidemic control of human immunodeficiency virus (HIV) infection, sub-Saharan African countries are striving to diagnose 90% of HIV infections, initiate and retain 90% of HIV-diagnosed persons on antiretroviral therapy (ART), and achieve viral load suppression* for 90% of ART recipients (90-90-90) (1). In Eswatini (formerly Swaziland), the country with the world's highest estimated HIV prevalence (27.2%), achieving 90-90-90 depends upon improving access to early ART for men and young adults with HIV infection, two groups with low ART coverage (1-3). Although community-based strategies test many men and young adults with HIV infection in Eswatini, fewer than one third of all persons who test positive in community settings enroll in HIV care within 6 months of diagnosis after receiving standard referral services (4,5). To evaluate the effectiveness of peer-delivered linkage case management† in improving early ART initiation for persons with HIV infection diagnosed in community settings in Eswatini, CDC analyzed data on 651 participants in CommLink, a community-based, mobile HIV-testing, point-of-diagnosis HIV care, and peer-delivered linkage case management demonstration project, and found that after diagnosis, 635 (98%) enrolled in care within a median of 5 days (interquartile range [IQR] = 2-8 days), and 541 (83%) initiated ART within a median of 6 days (IQR = 2-14 days), including 402 (74%) on the day of their first clinic visit (same-day ART). After expanding ART eligibility to all persons with HIV infection on October 1, 2016, 96% of 225 CommLink clients initiated ART, including 87% at their first clinic visit. Compared with women and adult clients aged ≥30 years, similar high proportions of men and persons aged 15-29 years enrolled in HIV care and received same-day ART. To help achieve 90-90-90 by 2020, the United States President's Emergency Plan for AIDS Relief (PEPFAR) is supporting the national scale-up of CommLink in Eswatini and recommending peer-delivered linkage case management as a potential strategy for countries to achieve >90% early enrollment in care and ART initiation after diagnosis of HIV infection (6).
Impact of immune checkpoint inhibitor dose on toxicity, response rate, and survival: A pooled analysis of dose escalation phase 1 trials.
Authors: Shiraj Sen, Kenneth R. Hess, David S. Hong, Aung Naing, Le Huang, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2018)

3077 Background: PK and PD studies demonstrate drug exposure and target saturation of immune checkpoint inhibitors (ICI) at doses below MTD. MTD remains a primary endpoint in ICI phase 1 trials and the optimal dosing to minimize toxicity and optimize response remains unclear. Methods: We analyzed clinical data from pts treated in phase 1 ICI dose escalation trials at MD Anderson Center for Targeted Therapy. Patients were stratified into a low-dose [LDG] ( < 33% MTD), medium dose [MDG] (34-66% MTD), high dose [HDG] (67-100% MTD), or very high dose [VHDG] ( > 100% MTD) group. Groups were compared for irAE, PFS, OS, ORR (CR + PR), and DCR (CR + PR + SD > 6 months). Results: Among 90 pts treated with escalating doses of ICI (57 CTLA4- and 33 PD1-based) between April 2013 and December 2015, median age was 59 years (range: 20-86 years) and 37 (41%) were females. The most common tumor types treated included renal cell carcinoma (n = 23; 25%), melanoma (n = 16; 18%), sarcoma (n = 10; 11%), and GIST (n = 10; 11%). PFS in the LDG (n = 16) was 2.76 months (mo) (95% CI 1.48-NA), MDG (n = 21) was 2.76 mo (95% CI 1.48-NA), HDG (n = 36) was 2.46 mo (95% CI 1.84-3.29), and VHDG (n = 17) was 3.68 mo (95% CI 2.76-NA). Log rank p = 0.22. OS in LDG was 6.18 mo (95% CI 3.45-NA), MDG was 17.05 mo (95% CI 3.94-NA), HDG was 5.16 mo (95% CI 4.24-7.62), and VHDG was 7.49 mo (95% CI 5.59-NA). Log rank p = 0.0070. In all evaluable patients, ORR in LDG, MDG, HDG, and VHDG was 0%, 6%, 6%, and 12% (p = 0.47) and DCR was 62%, 71%, 41%, and 81% (p = .027), respectively. irAE rates in LDG, MDG, HDG, and VHDG were 6%, 10%, 17%, and 29% (p = .045). Conclusions: Despite a dose-dependent increase in irAE, we identify no improvement in PFS, OS, or DCR with escalating doses of ICI administered in phase I trials but do detect an improvement in ORR. Prospective dose-/exposure-response relationships and biomarker-driven RP2D are warranted on all ICI dose-escalation phase 1 trials. Lower doses may reduce toxicity and cost without compromising disease control or survival. Dosing PFS, months (95% CI) OS, months (95% CI) ORR (%) DCR (%) irAE (%) LDG 2.76 (1.48-NA) 6.18 (3.45-NR) 0 62 6 MDG 2.76 (1.84-NA) 17.05 (3.94-NR) 6 71 10 HDG 2.46 (1.84-3.29) 5.16 (4.24-7.62) 6 41 17 VHDG 3.68 (2.76-NA) 7.49 (5.59-NR) 12 81 29
Stereotactic body radiotherapy for low and intermediate risk prostate cancer: Four-year outcomes.
Authors: Mahadev Potharaju, Ravishankar LS, Neetu Sasikumar, Sadiq ALI
Journal: Journal of Clinical Oncology (2018)

e17082 Background: Stereotactic body radiotherapy (SBRT) is an attractive treatment option for organ confined prostate cancer. We present the biochemical recurrence-free survival rates in low and intermediate risk prostate cancer with a median follow-up of 4 years after SBRT. Methods: Between April 2009 and December 2014, 58 and 14 patients diagnosed with organ confined, low and intermediate prostate cancer respectively were treated with SBRT using Cyberknife. All patients received 36.25 Gy in five fractions on consecutive days. No patient received hormonal therapy. Median follow-up was 48 months. Biochemical progression-free survival as per Phoenix guidelines was analyzed using Kaplan-Meir method. Bowel and bladder toxicity outcomes were also assessed per RTOG criteria. Results: The biochemical progression-free survival and overall survival was 94% and 98% respectively at a median follow-up of 48 months. Eighteen percent patients complained of urinary frequency and urgency which resolved completely within three months of completing radiotherapy. Two patients developed late grade 3 urinary toxicity in the form of urethral stricture which was managed with urethral dilatation. No patient had early or late bowel toxicity. Three patients (4%) developed mild to moderate erectile dysfunction graded per International index of erectile function. Conclusions: Hypofractionated SBRT for organ confined low and intermediate risk prostate cancer is well tolerated and achieves impressive biochemical recurrence free survival rates. Longer follow-up is required to validate these results.
Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer
Authors: Anishka D’Souza, Darcy Spicer, Janice Lu
Journal: Journal of Hematology & Oncology (2018)

Endocrine therapy has historically formed the basis of treatment of metastatic hormone receptor-positive breast cancer. The development of endocrine resistance has led to the development of newer endocrine drug combinations. Use of the CDK4/6 inhibitors has significantly improved progression-free survival in this group of patients. There are multiple studies of the use of P13K inhibitors and mTOR inhibitors for use as subsequent lines of therapy, particularly for endocrine resistance. The optimal sequencing of therapy should be based on medical comorbidities, prior adjuvant therapies, quality of life, side-effect profile, and disease-free interval.