tbuckley/cabot-search huggingface dataset:
The risk of death from prostate cancer in men with Gleason Score 3+4 prostate cancer treated using brachytherapy with or without a short course of androgen deprivation therapy.
Authors: David Dewei Yang, Ming-Hui Chen, Michelle H. Braccioforte, Brian Joseph Moran, Anthony Victor D'Amico
Journal: Journal of Clinical Oncology (2020)

330 Background: We evaluated whether the intermediate-risk factors of percentage of positive biopsies (PPB), clinical tumor category, and prostate-specific antigen (PSA) level, in addition to age, were associated with the risk of prostate cancer-specific mortality (PCSM) among men with Gleason 3+4 prostate cancer treated with brachytherapy (BT) alone or BT and a short course of androgen deprivation therapy (ADT). Methods: We conducted a prospective cohort study of 1920 consecutively treated men with Gleason 3+4 adenocarcinoma of the prostate who received BT or BT and a median of 4 months of ADT between 10/14/1997 and 5/28/2013. Separate multivariable Fine and Gray competing risks regression models among men treated with BT or BT and ADT were used to assess whether PPB, cT2b-T2c, and PSA of 10.1-20.0 ng/ml, in addition to age greater than the median of 70 years, were associated with the risk of PCSM after adjustment for comorbidity. Results: After a median follow-up of 7.8 years (interquartile range 5.2-10.4 years), 284 men (14.8%) had died, including 31 (10.9% of deaths) from PC of which 18 (58.1%) and 13 (41.9%) occurred in men treated with BT or BT and ADT, respectively. For men treated with BT alone, increasing PPB, PSA of 10.1-20.0 vs 4.0-10.0 ng/mL, and age &gt;70 vs ≤70 years were significantly associated with an increased risk of PCSM (adjusted hazard ratio [AHR] 1.015 95% confidence interval [CI] 1.000-1.031, P=0.048; AHR 5.55, 95% CI 2.01-15.29, P&lt;0.001; and AHR 3.66, 95% CI 1.16-11.56, P=0.03, respectively). The respective results for men treated with BT and ADT were AHR 1.009, 95% CI 0.987-1.031, P=0.44; AHR 4.17, 95% CI 1.29-13.50, P=0.02; and AHR 3.74, 95% CI 0.87-16.05, P=0.08. The clinical tumor category was not significantly associated with the risk of PCSM. Conclusions: Among men with biopsy Gleason score 3+4 PC, both age &gt;70 years and PSA of 10.1-20.0 ng/ml were significantly associated with an increased risk of PCSM following BT, and adding 4 months of ADT may not be sufficient to mitigate this risk. Advanced imaging and targeted biopsy of suspicious areas should be considered to personalize treatment in order to minimize the risk of PCSM in these men.
Endotyping of chronic rhinosinusitis with nasal polyp based on eosinophil, mast cell and basophil microparticles in nasal lavage fluid
Authors: Toru Takahashi, Atsushi Kato, Lydia Suh, Roderick Carter, Kathleen Harris, Caroline Price, Kathryn Hulse, Leslie Grammer, Anju Peters, Bruce Tan, David Conley, Robert Kern, Robert Schleimer
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 14250: Fis1 Knockdown Rescues Vascular Monolayer Integrity and Reduces Vascular Inflammation Under Dysglycemic Conditions
Authors: Mamatha Kakarla, David Trykall, Jingli Wang, Sudhi Tyagi, Rong Ying, Megan Harwig, John Egner, Blake Hill, Michael Widlansky
Journal: Circulation (2018)

Introduction: Abnormal glucose levels as seen in diabetes (DM) result in endothelial dysfunction characterized in part by increased vascular endothelial inflammation and increased permeability betw...
Blood natural killer cell deficiency reveals an immunotherapy strategy for atopic dermatitis
Authors: Madison R. Mack, Jonathan R. Brestoff, Melissa M. Berrien-Elliott, Anna M. Trier, Ting-Lin B. Yang, Matthew McCullen, Patrick L. Collins, Haixia Niu, Nancy D. Bodet, Julia A. Wagner, Eugene Park, Amy Z. Xu, Fang Wang, Rebecca Chibnall, M. Laurin Council, Carrie Heffington, Friederike Kreisel, David J. Margolis, David Sheinbein, Paola Lovato, Eric Vivier, Marina Cella, Marco Colonna, Wayne M. Yokoyama, Eugene M. Oltz, Todd A. Fehniger, Brian S. Kim
Journal: Science Translational Medicine (2020)

Patients with atopic dermatitis harbor deficiencies in subsets of NK cells that can be therapeutically reversed to improve disease in mice.
Association of Black Race With Early Recurrence After Minor Ischemic Stroke or Transient Ischemic Attack
Authors: Hooman Kamel, Cenai Zhang, Dawn O. Kleindorfer, Emily B. Levitan, Virginia J. Howard, George Howard, Elsayed Z. Soliman, S. Claiborne Johnston
Journal: JAMA Neurology (2020)

<h3>Importance</h3> Stroke incidence is higher among black than white individuals in the United States. It is unclear whether black individuals have a higher risk of stroke recurrence after a minor ischemic stroke or transient ischemic attack (TIA), a high-risk setting in which focused preventive efforts can be effective. <h3>Objective</h3> To examine the association between black race and early ischemic stroke recurrence. <h3>Design, Setting, and Participants</h3> This cohort study analyzed data from the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial conducted at 269 sites from May 28, 2010, to December 19, 2017. The trial enrolled 4881 adults within 12 hours of onset of a minor ischemic stroke (National Institutes of Health Stroke Scale score, 0-3) or high-risk TIA (ABCD<sup>2</sup>score, ≥4). For this analysis, we excluded 598 patients enrolled outside the United States and 239 US patients with missing race/ethnicity data. <h3>Main Outcomes and Measures</h3> The primary outcome for this analysis was ischemic stroke within 90 days after randomization. Covariates included age, sex, Hispanic ethnicity, study assignment to take clopidogrel vs placebo, index stroke vs TIA, vascular risk factors, statin use, study drug adherence, and index event etiological subtype. <h3>Results</h3> Among 4044 patients included in the analysis, 918 (22.7%) were black. In an adjusted Cox model, black race was associated with a higher risk of recurrence compared with white race (hazard ratio, 1.6; 95% CI, 1.1-2.3). Findings were similar in subgroup analyses and in analyses limited to sites that enrolled black patients. <h3>Conclusions and Relevance</h3> Among US participants in the POINT trial, black individuals faced a higher risk of early stroke recurrence after a minor ischemic stroke or TIA. Our findings support research into black-white racial differences in the underlying mechanisms of recurrent stroke. In the meantime, extra effort should be made to ensure that black patients have access to proven secondary prevention measures. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00991029
Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): Update from the CHHiP Trial.
Authors: David P. Dearnaley, Clare Griffin, Isabel Syndikus, Vincent Khoo, Alison Jane Birtle, Ananya Choudhury, Catherine Ferguson, John Graham, Joe O'Sullivan, Miguel Panades, Yvonne L. Rimmer, Christopher D. Scrase, John Staffurth, Clare Cruickshank, Shama Hassan, Julia Pugh, Emma Hall
Journal: Journal of Clinical Oncology (2020)

325 Background: CHHiP is a non-inferiority trial to determine efficacy and safety of hypofractionated radiotherapy for localised prostate cancer (PCa). Five year results indicated that moderate hypofractionation of 60 Gray (Gy)/20 fractions (f) was non-inferior to 74Gy/37f (Lancet Oncology, 2016). Moderate hypofractionation is now an international standard of care but with patients remaining at risk of recurrence for many years, information on long-term outcomes is important. Here we report pre-planned analysis of 8 year outcomes. Methods: Between October 2002 and June 2011, 3216 men with node negative T1b-T3a localised PCa with risk of seminal vesical involvement ≤30% were randomised (1:1:1 ratio) to 74Gy/37f (control), 60Gy/20f or 57Gy/19f. Androgen deprivation began at least 3 months prior to radiotherapy (RT) and continued until end of RT. The primary endpoint was time to biochemical failure (Phoenix consensus guidelines) or clinical failure (BCF). The non-inferiority design specified a critical hazard ratio (HR) of 1.208 for each hypofractionated schedule compared to 74Gy/37f. Late toxicity was assessed at 5 years by RTOG and LENT-SOM scales. Analysis was by intention-to-treat. Results: With a median follow up of 9.2 years, 8 year BCF-free rates (95% CI) were 74Gy: 80.6% (77.9%, 83.0%); 60Gy: 83.7% (81.2%, 85.9%) and 57Gy: 78.5% (75.8%, 81.0%). For 60Gy/20f, non-inferiority was confirmed: HR 60 =0.84 (90% CI 0.71, 0.99). For 57Gy/19f, non-inferiority could not be declared: HR 57 =1.17 (90% CI 1.00, 1.37). Clinician assessments of late toxicity were similar across groups. At 5 years, RTOG grade≥2 (G2+) bowel toxicity was observed in 14/879 (1.6%), 18/908 (2.0%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. RTOG G2+ bladder toxicity was observed in 17/879 (1.9%), 14/908 (1.5%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. Conclusions: With BCF rates over 80%, long-term follow-up confirms that 60Gy/20f is non-inferior to 74Gy/37f. Late side effects were very low across all groups. These results support the continued use of 60Gy/20f as standard of care for men with localised PCa. Clinical trial information: 97182923.
Comparison of Aortitis Versus Noninflammatory Aortic Aneurysms Among Patients Who Undergo Open Aortic Aneurysm Repair
Authors: Laarni Quimson, Adam Mayer, Sarah Capponi, Bryan Rea, Rennie L. Rhee
Journal: Arthritis & Rheumatology (2020)

Distinguishing aortitis-induced aneurysms from noninflammatory aortic aneurysms is difficult and often incidentally diagnosed on histologic examination after surgical repair. This study was undertaken to examine surgically diagnosed aortitis and identify patient characteristics and imaging findings associated with the disease.In this case-control study, cases had newly diagnosed, biopsy-proven noninfectious aortitis after open thoracic aortic aneurysm surgical repair. Five controls were matched with cases for year of surgery and lacked significant inflammation on surgical pathology analysis. Data on comorbidities, demographic characteristics, and laboratory and imaging abnormalities prior to surgery were collected. Associations between exposures and outcomes were evaluated using conditional logistic regression. Backward stepwise logistic regression was used to determine factors independently associated with aortitis. Odds ratios (ORs) with 95%confidence intervals (95%CIs) were calculated.The study included 262 patients (43 patients with aortitis and 219 controls). Patients with aortitis were older at the time of surgery, predominantly female, and less likely to have a history of coronary artery disease (CAD). Multivariable analysis revealed that aortitis was independently associated with an older age at the time of surgery (OR 1.08 [95%CI 1.03-1.13], P < 0.01), female sex (OR 2.36 [95%CI 1.01-5.51], P = 0.04), absence of CAD (OR 6.92 [95%CI 2.14-22.34], P = 0.04), a larger aneurysm diameter (OR 1.74 [95%CI 1.02-2.98], P = 0.04), and arterial wall thickening on imaging (OR 56.93 [95%CI 4.31-752.33], P < 0.01).Among patients who undergo open surgical repair of an aortic aneurysm, elderly women with no history of CAD who have evidence of other aortic or arterial wall thickening on imaging are more likely to have histologic evidence of aortitis. Patients with these characteristics may benefit from further rheumatologic evaluation.
Comprehensive immune profiling of patients (pts) with metastatic urothelial cancer (mUC) or renal cell cancer (mRCC) receiving immune checkpoint inhibitors (CPIs).
Authors: Jean-Michel Lavoie, Michael Nissen, Priya Baichoo, Lucia Nappi, Daniel Joseph Khalaf, Christian K. Kollmannsberger, Kim N. Chi, Andrew Weng, Bernhard J. Eigl
Journal: Journal of Clinical Oncology (2020)

532 Background: CPIs have had a major impact on pts with mUC and mRCC. Only a small subset of pts benefit from CPI, and predictive biomarkers are needed. The role of circulating immune cells is poorly understood, but early changes after CPI exposure may predict response. We aimed to study the changes in circulating immune cell populations of pts receiving CPIs. Methods: Whole blood was collected prior to, and 3 wks after initiation of CPI in CPI-naïve pts with mUC or mRCC. PBMCs were isolated and profiled using mass cytometry (CyTOF) to provide a comprehensive overview of immune cell populations, expression of immune checkpoints, proliferation, and viability. Expression of chemokine receptors and cytokines was measured by flow cytometry. Treatment-emergent changes were correlated with response. Effects of treatment were determined by Wilcoxon signed-rank test; interactions of treatment and other variables like cluster size were determined by repeated measures two-way ANOVA. Any effects described had a significance of p&lt;0.05. Results: Ten pts enrolled in this pilot study (mRCC = 4, mUC = 6) received anti-PDL1 (n=5), anti-PDL1/anti-CTLA4 (n=3), and anti-PDL1/chemotherapy (n=2). Best response was: 1 CR, 3 PR, 2 SD, 4 PD. Treatment induced an increase in dendritic cells (DC) and a decrease in PD1+ CD4+ and CD8+ T-cells. Elevated Ki-67, CTLA-4, LAMP-1, granzyme B and perforin expression in PD1+ cells post CPI suggested re-invigoration of exhausted T-cells. PD1+ T-cells had increased expression of the chemokine receptors CCR4 and CCR5, and decreased expression of CCR7 and CXCR4, irrespective of treatment. Response was associated with fewer CCR4+ CD4+ T cells and fewer PD1+ CD8+ T cells. Conclusions: Deep profiling by CyTOF provides a means of immune monitoring, with potential applications in clinical trials involving CPIs. Immune responses to CPIs are heterogeneous, with pt subgroups segregated by shifts in both T cell and DCs, and patterns of chemokine receptors and cytokines. Therapy reinvigorates exhausted T cells, and may cause these cells to infiltrate tumors or tumor-draining lymph nodes via chemokine receptors.
MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide.
Authors: Johann S. De Bono, Mark T. Fleming, Judy Sing-Zan Wang, Richard Cathomas, Marna Williams, John G. Bothos, Kemal Balic, Song Hye Cho, Pablo Martinez, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2020)

99 Background: MEDI3726 is an ADC targeting PSMA. Once bound to PSMA and internalized, the released pyrrolobenzodiazepine dimer toxin crosslinks DNA and triggers cell death. This phase 1 study evaluated the safety and efficacy of MEDI3726 in mCRPC after failure of abiraterone and/or enzalutamide and a taxane-based therapy. Methods: The starting dose was 0.015 mg/kg MEDI3726 IV Q3W until disease progression or unacceptable toxicity. Dose escalation used a modified toxicity probability interval algorithm (mTPI). The primary objectives were safety, adverse events (AEs) and dose-limiting toxicities (DLTs) and to determine the maximum tolerated (MTD) or administered (MAD) dose. Secondary objectives included antitumor activity, pharmacokinetics and immunogenicity. The endpoint for activity was composite response: confirmed response by RECIST v1.1, and/or PSA decrease of ≥ 50% after ≥ 12 wks, and/or confirmed conversion in circulating tumor cell count, defined as a decrease from ≥ 5 to &lt; 5 cells/7.5 mL. Efficacy analyses were based on Prostate Working Group Criteria. Mutational profiles were evaluated in ctDNA. Results: As of Sept 27 2019, 33 pts received MEDI3726. Median age was 71.0 yr. Median number of prior regimens was 4. Median follow-up was 5.4 mo. Drug-related AEs occurred in 30 (90.9%), being grade 3/4 in 15 (45.5%), serious in 11 (33.3%) and causing discontinuation in 13 (39.4%). There were no drug-related deaths. One pt at 0.3 mg/kg had a DLT of Grade 3 thrombocytopenia. No MTD was identified per mTPI; the MAD was 0.3 mg/kg. MEDI3726 had nonlinear PK with a short t 1/2 (0.3–2 d). Three pts (15.8%) at baseline and 6 (33.3%) post-baseline had antidrug antibodies, with no correlation to PK exposure. Composite response rate across all doses was 2/33 (6.1%). Time to response was 0.3 mo; duration of response was 1.8–3.8 mo. Median progression-free survival was 3.9 mo and median overall survival was 10.6 mo. Conclusions: An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911.
Lifetime Benefits and Harms of Prostate-Specific Antigen–Based Risk-Stratified Screening for Prostate Cancer
Authors: Eveline A M Heijnsdijk, Roman Gulati, Alex Tsodikov, Jane M Lange, Angela B Mariotto, Andrew J Vickers, Sigrid V Carlsson, Ruth Etzioni
Journal: JNCI Journal of the National Cancer Institute (2020)

Studies conducted in Swedish populations have shown that men with lowest prostate-specific antigen (PSA) levels at ages 44-50 years and 60 years have very low risk of future distant metastasis or death from prostate cancer. This study investigates benefits and harms of screening strategies stratified by PSA levels.PSA levels and diagnosis patterns from two microsimulation models of prostate cancer progression, detection, and mortality were compared against results of the Malmö Preventive Project, which stored serum and tracked subsequent prostate cancer diagnoses for 25 years. The models predicted the harms (tests and overdiagnoses) and benefits (lives saved and life-years gained) of PSA-stratified screening strategies compared with biennial screening from age 45 years to age 69 years.Compared with biennial screening for ages 45-69 years, lengthening screening intervals for men with PSA less than 1.0 ng/mL at age 45 years led to 46.8-47.0% fewer tests (range between models), 0.9-2.1% fewer overdiagnoses, and 3.1-3.8% fewer lives saved. Stopping screening when PSA was less than 1.0 ng/mL at age 60 years and older led to 12.8-16.0% fewer tests, 5.0-24.0% fewer overdiagnoses, and 5.0-13.1% fewer lives saved. Differences in model results can be partially explained by differences in assumptions about the link between PSA growth and the risk of disease progression.Relative to a biennial screening strategy, PSA-stratified screening strategies investigated in this study substantially reduced the testing burden and modestly reduced overdiagnosis while preserving most lives saved. Further research is needed to clarify the link between PSA growth and disease progression.
Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis
Authors: Maxime G. Zermatten, Montserrat Fraga, Darius Moradpour, Debora Bertaggia Calderara, Alessandro Aliotta, Guido Stirnimann, Andrea De Gottardi, Lorenzo Alberio
Journal: Hepatology (2020)

In the setting of liver cirrhosis (LC), profound hemostatic changes occur, which affect primary hemostasis, coagulation, and fibrinolysis. They involve prohemorrhagic and prothrombotic alterations at each of these steps. Patients with cirrhosis exhibit multifactorial thrombocytopenia and in vitro thrombocytopathy, counterbalanced by increased von Willebrand factor. The resultant shift is difficult to assess, but overall these changes probably result in a rebalanced primary hemostasis. Concerning coagulation, the reduced activity of coagulation factors is counterbalanced by an increase in factor VIII (produced by liver sinusoidal endothelial cells), a decrease of the natural anticoagulants, and complex changes, including changes in circulating microparticles, cell‐free DNA, and neutrophil extracellular traps. Overall, these alterations result in a procoagulant state. As for fibrinolysis, increased tissue‐type and urokinase‐type plasminogen activators, a relatively decreased plasminogen activator inhibitor 1, and decreased levels of thrombin‐activatable fibrinolysis inhibitor and α2‐antiplasmin are counterbalanced by decreased plasminogen and a decreased fibrin clot permeability. Whether and how these changes shift fibrinolysis remains to be determined. Overall, the current consensus is that in patients with cirrhosis, the hemostasis is shifted toward a procoagulant state. We review the published evidence for the concept of LC as a prothrombotic state, discuss discordant data, and highlight the impact of the underlying cause of LC on the resultant imbalance.
Intraoperative application of platelet-rich plasma to the neurovascular bundles during radical prostatectomy: A prospective clinical trial.
Authors: Vidhu B. Joshi, Tristan Juvet, Paige E. Nichols, Stephen A. Boorjian, Jeffrey Karnes, Matthew K. Tollefson, Matthew Gettman
Journal: Journal of Clinical Oncology (2020)

TPS380 Background: Radical prostatectomy (RP) is the most common surgical treatment for prostate cancer (PC). Yet even with nerve-sparing RP (NS-RP), a significant proportion of men experience transient or permanent erectile dysfunction (ED) partially due to intraoperative neurovascular bundle (NVB) damage from thermal or mechanical trauma. Studies have shown that platelet released growth factors counteract trauma and facilitate healing. We evaluate the use of platelet rich plasma (PRP) to facilitate early nerve healing and decrease ED after NS-RP. Methods: A prospective, open label, 20 subject human trial evaluating intraoperative topical NVB PRP application was approved by the IRB and FDA under an Investigational Device Exemption (IDE 16915) for the investigational use of an approved blood separation device. Men aged 50-60 with newly diagnosed, localized PC and normal preoperative sexual and urinary function, defined as a Sexual Health Inventory for Men (SHIM) score of &gt;19 and an answer of “none” on question 5 of the Expanded Prostate Cancer Index Composite (EPIC) are eligible. Intraoperatively, a 10ml PRP product is created from a 180 mL sample of the patient’s whole blood using the Angel Concentrated Platelet Rich Plasma System (Cytomedix, Inc., Gaithersburg, MD USA). PRP is applied via mechanical transfer to the NVB after completion of the vesicourethral anastomosis. The primary endpoint is the safety and tolerability of PRP on the NVB after NS-RP. Secondary endpoints include feasibility of intraoperative PRP application and longitudinal assessment of erectile function and urinary continence by questionnaire administration at 3, 6, 9, 12 and 18 months after NS-RP. Clinical trial information: NCT02957149.