tbuckley/cabot-search huggingface dataset:
Predictors of prostate cancer-specific anxiety following stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer.
Authors: Kamran Salari, Nima Aghdam, Luara Gersony, Malika Danner, Marilyn Ayoob, Thomas M. Yung, Shaan Kataria, Siyuan Lei, Brian Timothy Collins, Deepak Kumar, Jonathan W. Lischalk, Anatoly Dritschilo, Simeng Suy, John J. Lynch, Sean P. Collins
Journal: Journal of Clinical Oncology (2019)

64 Background: Prostate Cancer (PCa) related anxiety varies widely based on management option. SBRT offers a safe and effective treatment for localized PCa. However, there is a paucity of data regarding PCa specific anxiety following SBRT and its relationship with PSA kinetics. In this report we present the results of a mail-in survey conducted amongst the participants of our prospective institutional quality of life (QOL) trial and identify sociodemographic and disease specific predictors of anxiety. Methods: Patients with localized PCa treated with SBRT at a single institution from 2007-2018 were eligible for inclusion in this study. The Memorial Anxiety Scale for PCa (MAX-PC) survey, was mailed to 450 patients on July of 2018. Patient’s total MAX-PC score (scale 0-54) was recorded. A score of ≥ 27 was defined as significant anxiety. Disease specific as well as demographic features were analyzed for possible correlation with self-reported anxiety. Results: By August 31, 2018, 227 patients had responded to the survey . The median score at all time points was 5 (1-41). Stratified by risk grouping; Low, Intermediate, and High Risk patients’ median scores were 7, 4.5 and 6. Six patients had a MAX-PC score≥27. Patients who were at least 2 years out from SBRT treatment had lower mean MAX-PC scores than those who were still within 2 years (6.3 versus 8.1, p = 0.045). Stratified by age, patients &gt; 80 years old had a median score of 2 versus those &lt; 70 with a median score of 6. Caucasian patients had lower mean MAX-PC scores than non-Caucasian patients (6.6 versus 9.1, p = 0.021). Patients who had at least a 0.5 ng/mL increase in PSA in their last 3 measurements had higher mean MAX-PC scores than those who did not (13.0 versus 7.0, p = 0.040). Conclusions: Patients with clinically localized PCa treated with SBRT experience minimal PCa specific anxiety. Anxiety surrounding PCa decreases with time. Non-Caucasian patients tended to have more anxiety than Caucasian patients. Patients who had recent PSA bounces tend to have higher levels of anxiety about their disease. Further follow-up of these patients over time would aid in assessing the progression of PCa specific anxiety as their lives progress.
Effect of immunotherapy (IO) on primary renal tumor in metastatic renal cell cancer (mRCC).
Authors: Antoine Jamet, Caroline Caramella, Annalisa Guida, Julia Arfi-Rouche, Zahira Merabet, Emeline Colomba, Bernard Escudier, Laurence Albiges
Journal: Journal of Clinical Oncology (2019)

649 Background: Recent data showed that cytoreductive nephrectomy (CN) should not be performed prior to systemic therapy in intermediate and poor risk groups. Immune checkpoint inhibitors (ICI) are now approved in first and second line in mRCC, but ICI effect on the primary tumor is unknown. Methods: All patients (pts) treated with ICI for mRCC without prior CN were retrospectively collected and sequential computed tomography (CT) scan evaluated for response. Primary objective was Objective Response Rate (ORR) in the primary renal tumor in the primary RECIST 1.1. Secondary objective included systemic ORR and nephrometry score changes. Results: A total of 20 pts were treated with ICI with primary tumor in situ between 12/2012 and 10/2018. Among these, CT scans were available for evaluation of response for 19 primary tumors in 18 pts. Median age was 59.5 years. Pathology was 16 clear cell RCC, 2 translocation RCC, 1 Collecting duct carcinoma. Baseline median primary renal tumor size was 7.3 cm. ICI was used in first line setting in 7 pts, in second line or beyond in 13 pts. IMDC risk group at ICI start was favourable in 2 pts, intermediate in 9 pts and poor in 9 pts. ICI used was NIVOLUMAB(N) single agent in 13 pts or in combination in 7 pts (6 N-IPILIMUMAB and 1 N-VEGFRTKI). After a median follow up of 6.5 month from ICI start and a median duration of immunotherapy of 3.0 month, ORR on the primary tumor, was 3/19 (16%) (1 CR and 2 PR), 14 tumors (74%) were stable, and 2 had PD as best response. Median change in primary renal tumor was -1%. ICI use did not change nephrometry score. At extra renal assessment, ORR (systemic) was 5/18 (28%), (2 CR, 3 PR), 5 (28%) SD, and 8 (44%) PD (including 1 with new lesion and 1 with non-target lesion PD). Interestingly, 4 pts/18 (22%) had mixed response with opposite response between primary and systemic response. Furthermore, 11/18 (61%) would not classified in same RECIST group (CR, PR, SD, PD) between primary and metastatic sites assessment. Conclusions: To our knowledge, we report the first cohort of patients treated with ICI investigating the response on the primary tumor. ICI can induce a significant reduction in primary renal tumor, especially complete response and therefore raise the question of delayed CN in responders under ICI.
Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway
Authors: Xiaoying Yan, Ran Zhao, Xiaorong Feng, Jingzhou Mu, Ying Li, Yue Chen, Chunmei Li, Qiying Yao, Lijie Cai, Lingling Jin, Chuanchun Han, Dongmei Zhang
Journal: Cardiovascular Research (2019)

Sialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy.Siat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt -1285 to -1274 bp) in the cardiomyocytes following ANG II stimulus.Siat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.
Immune response from STRIDE, a randomized, phase 2, open label study of sipuleucel-T (sip-T) with concurrent vs sequential enzalutamide (enz) administration in metastatic castration-resistant prostate cancer (mCRPC).
Authors: David I. Quinn, Charles G. Drake, Robert Dreicer, Emmanuel S. Antonarakis, Neal D. Shore, John M. Corman, Raoul S. Concepcion, Christopher Michael Pieczonka, Nancy N. Chang, Todd DeVries, Nadeem A. Sheikh, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2015)

5040 Background: In mCRPC, data are limited regarding optimal combinatorial or sequential use of available treatments. P12-2 (STRIDE; NCT01981122) is an ongoing, randomized, open-label, phase 2 study evaluating concurrent vs sequential administration of the androgen receptor inhibitor, enz, with the autologous cellular immunotherapy, sip-T. Methods: Fifty-twopatients (pts) with asymptomatic or minimally symptomatic mCRPC were randomized 1:1 to receive 3 sip-T infusions with enz starting 2 wks before (n = 25, concurrent arm A) or 10 wks after (n = 27, sequential arm B) sip-T initiation. The primary endpoint is peripheral T cell proliferation response to PA2024, the sip-T immunizing antigen. Secondary endpoints include interferon (IFN)-γ ELISPOT and humoral immune responses to PA2024 and prostatic acid phosphatase (PAP), product release parameters (total nucleated cell count, CD54+ cell counts, and antigen presenting cell activation [as measured by CD54 upregulation]), cytokine production, and adverse events (AEs). Results through wk 26 are described. Results: PA2024-specific T cell proliferative response was significantly elevated at all post-baseline time points (p < 0.001) and was sustained through wk 26, including a > 10-fold increase at wk 20 in both arms. This PA2024-specific response was observed in nearly all pts, 95.8% in arm A vs 92.6% in arm B. Both arms showed a significant and sustained increase in humoral responses to PA2024 and PAP as well as IFN-γ ELISPOT response to PA2024. Sip-T product parameters were similar between arms. Cytokines indicative of immune activation (such as IFN-γ, interleukin-2, and tumor necrosis factor-α) were also elevated in both arms. AEs were observed in 88% (arm A) and 100% (arm B) of pts. The incidence of grade ≥ 3 AEs was similar between arms. Conclusions: Most mCRPC pts receivingenz concurrently with or subsequent to sip-T demonstrated significant and sustained peripheral T cell and humoral immune responses through wk 26. These interim data suggest that both schedules were safe, and enz did not impair sip-T production or subsequent immune responses. Clinical trial information: NCT01981122.
Multiple Cutaneous Squamous Cell Carcinoma in Immunosuppressed vs Immunocompetent Patients
Authors: Jessica L. Gonzalez, Nithin D. Reddy, Kiera Cunningham, Rebecca Silverman, Elena Madan, Bichchau Michelle Nguyen
Journal: JAMA Dermatology (2019)

Discussion | Patients with HS have malignant lymphomas more frequently than the general population.Rates of NHL, HL, and CTCL in the general population are low.However, patients with HS appear to have 2 to 4 times the overall risk of developing lymphomas.Overall and subgroup associations between HS and lymphoma subtypes have not been evaluated previously in a population.A single-center retrospective series identified 1776 patients with HS in whom frequency of unspecified lymphoma was 1.8%. 5In a Swedish retrospective analysis including 2119 patients hospitalized for HS, 6 cases of any hematopoietic cancer, which may include lymphomas, were identified. 6Neither study observed greater risk of malignant lymphoproliferative disease among patients with HS.A limitation of our study was that we could not assess the disease duration or severity in this claims analysis.The uncommonness of the event did not permit us to evaluate systemic treatment or other exposures and the association between HS and lymphoma.To our knowledge, this is the first investigation to systematically evaluate this association in a US population of patients with HS.Size and diversity of our cohort may overcome selection biases and limitations inherent to smaller cohorts recruited with specialty centers.
TNF-α Driven Inflammation and Mitochondrial Dysfunction Characterize the Platelet Hyperreactivity of Aging and Myeloproliferative Neoplasms (MPN)
Authors: Pavel Davizon-Castillo, Brandon McMahon, Sonia Aguila, Kenneth L. Jones, George D Trahan, Katrina J. Ashworth, David Bark, Robert A. Campbell, Kelly Higa, Lauren Christine Shih, Natalie Saunders, James DeGregori, Matthew T. Rondina, Jorge Di Paola
Journal: Blood (2018)
Mass migration to Europe: an opportunity for elimination of hepatitis B virus?
Authors: Marijn Thijssen, Philippe Lemey, Samad Amini-Bavil-Olyaee, Simon Dellicour, Seyed Moayed Alavian, Frank Tacke, Chris Verslype, Frederik Nevens, Mahmoud Reza Pourkarim
Journal: The Lancet. Gastroenterology & hepatology (2019)
Abstract P345: Change in Cardiovascular Health Metrics Over Time, CVD Events and Total and Cause-Specific Mortality
Authors: Bamba Gaye, Gabriel S Tajeu, Lucile Offredo, Maxime Vignac, Norrina B Allen, Xavier Jouven
Journal: Circulation (2019)

Background: The impact of changes in cardiovascular health (CVH) on cardiovascular disease (CVD) and total and all-cause mortality has yet to be described. Methods: CVH was computed according to smoking, body mass index, total cholesterol, blood glucose and blood pressure, physical activity and diet. Change in CVH was defined as a point-to-point difference in each metric or the score. We used time-dependent Cox Proportional Hazard models to calculate hazard ratios for all-cause mortality and CVD events among 10,656 adult participants from the ARIC study, aged 44 to 66 years at baseline (1987-1989) and followed up until 2014. Hazard ratios for all-cause mortality and CVD event according to CVH change at the component metrics and an aggregate score level were calculated with Cox Proportional Hazard models with consistently low CVH considered as the reference group. Results: Overall, 17% of the sample improved their overall CVH, while the percentage which maintained a low CVH or decreased CVH was 29% and 21%, respectively. Higher levels of overall CVH over time were associated with a graded decrease in risk in CVD events and all-cause mortality. The hazard ratios for all-cause mortality among participant that decreased their overall CVH from favorable to low or moderate, that increased their CVH from low to moderate or favorable, and had consistently favorable CVH, as compared with the constantly low CVH group, were: 0.47 (95% confidence interval [CI], 0.39 to 0.57), 0.80 (95 CI%, 0.72 to 0.89), and 0.37 (95% CI, 0.30 to 0.46). The risk reductions were of a same magnitude for CVD events. In the adjusted Cox time dependent model, compared with low overall CVH, having moderate or favorable CVH was associated with a decreased risk in mortality: 24% (HR=0.76, 95% CI, 0.72 to 0.80) and 44% (HR=0.56, 95% CI, 0.51 to 0.62), respectively and a decreased risk in CVD 37% (HR=0.63, 95% CI, 0.59 to 0.66) and 56% (HR=0.44, 95% CI, 0.39 to 0.49), respectively. Conclusion: Earlier life stage favorable CVH was associated with lower CVD events and total and cause-specific mortality regardless of CVH change patterns over time. Furthermore, improving CVH is associated with lower CVD event risk and lower total and all-cause mortality. However, we observed an alarming low percentage of overall CVH improvement and a high percentage of maintaining low overall CVH. Understanding the mechanisms underlying CVH change patterns may help to tackle the low prevalence of moderate or optimal CVH.
The Portal Inflammatory Infiltrate and Ductular Niche in Non-Alcoholic Fatty Liver Disease
Authors: Victoria L. Gadd, Richard Skoien, Kevin Fagan, Katharine Irvine, Elizabeth E. Powell, Andrew D. Clouston
Journal: Hepatology (2013)

Introduction: Progressive non-alcoholic fatty liver disease (NAFLD) is characterised by portal fibrosis, which is associated with a ductular reaction (DR). Growing evidence implicates portal inflammation as a key predictor of histological progression of NAFLD. We hypothesise that the manifestation of portal fibrosis and a pro-fibrogenic DR is driven by cross-talk between diverse infiltrating immune cells. Although numerous cytokines and multiple individual cell types have been implicated in NAFLD pathogenesis, the composition of the portal and peri-ductal inflammatory infiltrate has not been systematically investigated.Methods: Liver biopsy sections from 32 NAFLD patients were immunostained for keratin-7 to highlight the DR, and co-stained for markers of candidate cellular components of the portal inflammatory infiltrate, including CD3, CD8, CD20, CD68, neutrophil elastase (NE), IL-17 and MMP-9. Fresh-frozen liver biopsy samples were available from 23 NAFLD patients for analysis of Collagen-1A and inflammatory gene expression (TGFb, IL-1b, TNFa, IL-6, IFN-g, IL-4 and IL-10).Results: Inflammatory cells within the portal tracts were more numerous than centrilobular regions. The portal inflammatory compartment was comprised of a mix of inflammatory cells, including T cells, B cells, macrophages and neutrophils. Significant portal infiltration was not observed until the presence of progressive NASH (fibrosis stage 2n4) (all Ptlt0.05) with the exception of macrophage numbers, which increased with the appearance of simple steatosis (Ptlt0.01) as well as progressive NASH (Ptlt0.001) when compared with non-diseased control livers. Portal inflammatory cells were present in the peri-ductular inflammatory niche and cell numbers correlated with increasing grade of DR (all Ptlt0.05) and stage of fibrosis (all Ptlt0.001). Collagen-1A mRNA was elevated in patients with simple steatosis and highest in progressive NASH (Ptlt0.001). TNFa, IL-1b and IL-6 were highly expressed with progressive NASH (Ptlt0.05) whereas TGFb, IFN-g, IL-4 and IL-10 showed no association with disease state and progression. Elevated levels of pro-inflammatory cytokines TNFa and IL-1b occurred before significant portal inflammatory infiltration (Ptlt0.05). Functional markers highlighted IL-17 production by a subset of neutrophils and MMP-9 by a subset of portal and lobular macrophages.Conclusion: Cell phenotypes and subsequent signalling are greatly influenced by their microenvironments. A modified hepatic inflammatory environment likely influences resident inflammatory cell phenotypes, and may promote a profibrogenic DR and further infiltration of inflamed portal tracts.
Abstract MP12: The Risk of Adverse Outcomes Associated With Opioid Prescriptions in People With Chronic Kidney Disease
Authors: Tessa K Novick, Aditya Surapaneni, Shoshana Ballew, Jung-Im Shin, Caleb Alexander, Lesley A Inker, Alex R Chang, Morgan E Grams
Journal: Circulation (2019)

Background: Patients with chronic kidney disease have limited therapeutic options for pain control and commonly are prescribed opioids. However, many opioids and/or their metabolites are renally excreted, which may increase risk for adverse drug effects. The objective of this study was to assess the safety of prescription opioid use across the range of kidney function. Methods: We used electronic health data from adult primary care patients followed from 2011 to 2016 in the Geisinger Health System, a fully integrated tertiary care center in Pennsylvania. In a propensity-matched cohort, we used Cox proportional hazards regression to estimate the association between opioid prescription (defined as at least two opioid prescriptions between January 1, 2011 and December 31, 2012) and death, first hospitalization and non-pathologic fracture. Results: Among 105,328 patients in the study population (mean [SD] age 55.4 [15] years; 66.4% female; 0.1% black race), 20,600 individuals received at least two opioid prescriptions between 2011 and 2013. In the propensity-matched cohort, over a median follow-up of 4.1 years, at least two opioid prescriptions was not significantly associated with mortality (HR 1.19, 95% CI: 0.98 to 1.43), but was significantly associated with higher risk of hospitalization (HR 1.38, 95% CI: 1.26 to 1.50), and non-pathological fracture (HR 1.71, 95% CI: 1.50 to 1.94) ( Figure ). The risk of adverse outcomes associated with opiate prescription did not differ by level of estimated glomerular filtration rate. Conclusions: Opioid prescriptions were associated with increased risk for adverse events at all levels of kidney function.
Durable clinical benefit from combination ipilimumab (IPI) and nivolumab (NIVO) in anti-PD-1 therapy resistant, platinum resistant metastatic urothelial carcinoma (mUC).
Authors: Niamh M. Keegan, Samuel Aaron Funt, Brooke Elizabeth Kania, Gopa Iyer, Jessica Mary Clement, Asia S. McCoy, Grace Hettich, Etay Ziv, Colleen Anne Maher, Suresh Nair, Katherine Panageas, Mark J. Bluth, Phillip Wong, Jedd D. Wolchok, Jonathan E. Rosenberg, Dean F. Bajorin, Margaret K. Callahan
Journal: Journal of Clinical Oncology (2019)

481 Background: Overcoming resistance to anti-PD-1 therapy in UC patients (pts) is of major interest given the modest single agent response rates for pts with mUC. Herein we report the outcome of combined NIVO and IPI in pts who progressed on single agent NIVO. Methods: This prospective, open label, adaptive study treated platinum resistant mUC pts with NIVO monotherapy with the designated intent to add IPI at disease progression. RECIST 1.1 assessments were performed every 6 wks for 24 wks then every 12 wks. Primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS) and possible associations between clinical endpoints and tumor genomic characteristics. Next generation sequencing (NGS) was performed to assess DNA Damage Response (DDR) gene mutations and Tumor Mutation Burden (TMB). Results: To date, 21 pts who progressed after NIVO monotherapy have received IPI plus NIVO. ORRs to prior NIVO monotherapy were variable; partial response (PR = 4/21, 19%), stable disease (SD = 6/21, 29%) and progressive disease (PD = 11/21,52%). 57% (12/21) had visceral metastases. For IPI + NIVO the ORR was 19% (PR: n=4, CR: n=0) and duration of response &gt;12 mo in a subset; 2 pts with PR remain on treatment (3+, 5+ mo), 1 pt has an ongoing PR (13+ months) after stopping treatment due to toxicity. Responding disease sites include node, liver and lung. Immune-related toxicity ≥ G3 seen in 9 pts (43%), of whom 4 (44%) had disease control (PR+SD≥3mo). No correlation detected between clinical outcome and TMB or DDR mutations. Conclusions: IPI plus NIVO responses can be seen in pts with NIVO resistance and the benefit from combined checkpoint blockade can be prolonged. Immune related toxicity frequently accompanied disease control. TMB and DDR were not associated with benefit in this small cohort; immune correlative analyses are ongoing. Clinical trial information: NCT02553642. [Table: see text]
Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity
Authors: Fabrizia Bonacina, Annalisa Moregola, Rémi Porte, Andrea Baragetti, Eduardo Bonavita, Alice Salatin, Liliana Grigore, Fabio Pellegatta, Martina Molgora, Marina Sironi, Elisa Barbati, Alberto Mantovani, Barbara Bottazzi, Alberico Luigi Catapano, Cecilia Garlanda, Giuseppe Danilo Norata
Journal: Cardiovascular Research (2019)

Abstract Aims Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity. Methods and results PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers. Conclusion Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.