tbuckley/cabot-search huggingface dataset:
Randomized Phase III Study of Alisertib or Investigator’s Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma
Authors: Owen A. O’Connor, Muhit Özcan, Eric D. Jacobsen, Josep M. Roncero, Judith Trotman, Judit Demeter, Tamás Masszi, Juliana Pereira, Radhakrishnan Ramchandren, Anne Beaven, Dolores Caballero, Steven M. Horwitz, Anne Lennard, Mehmet Turgut, Nelson Hamerschlak, Francesco A. d’Amore, Francine Foss, Won-Seog Kim, John P. Leonard, Pier Luigi Zinzani, Carlos S. Chiattone, Eric D. Hsi, Lorenz Trümper, Hua Liu, Emily Sheldon-Waniga, Claudio Dansky Ullmann, Karthik Venkatakrishnan, E. Jane Leonard, Andrei R. Shustov
Journal: Journal of Clinical Oncology (2019)

The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).Adult patients with relapsed/refractory PTCL-one or more prior therapy-were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m2 (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m2 or intravenous romidepsin 14 mg/m2 (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned.Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm.In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.
Management of Urinary Retention in Patients with Benign Prostatic Obstruction: A Systematic Review and Meta-analysis
Authors: Markos Karavitakis, Iason Kyriazis, Muhammad Imran Omar, Stavros Gravas, Jean-Nicolas Cornu, Marcus J. Drake, Mauro Gacci, Christian Gratzke, Thomas R.W. Herrmann, Stephan Madersbacher, Malte Rieken, Mark J. Speakman, Kari A.O. Tikkinen, Yuhong Yuan, Charalampos Mamoulakis
Journal: European Urology (2019)
The impact of socioeconomic factors on outcomes of patients with locally advanced rectal cancer (LARC).
Authors: Joanna Gotfrit, Tharshika Thangarasa, Horia Marginean, Shaan Dudani, Rachel Anne Goodwin, Patricia A. Tang, Jose Gerard Monzon, Kristopher Dennis, Winson Y. Cheung, Michael M. Vickers
Journal: Journal of Clinical Oncology (2019)

612 Background: Patients with rectal cancer may experience disparities in outcomes due to various socioeconomic (SES) factors. We assessed the impact of SES factors on outcomes in patients with LARC who received neoadjuvant chemoradiation (nCRT) and surgery (Sx) in three Canadian provinces. Methods: Associations between clinical variables, demographics, community characteristics (2015 Canadian Census data), distance and time to the nearest cancer center (mapping software), and outcomes were evaluated. Results: 1,098 patients were included (Table 1). Median follow-up time was 67.8 months. The 5-year survival rate was 0.80 (95% CI 0.77-0.82). Factors predictive of disease-free survival in univariate analysis (UVA) included age, worse performance status (PS), driving time &gt; 1 hour, median community income, and driving distance &gt; 100 km. Factors that remained significant in multivariate analysis (MVA) included age (HR 1.01; 95% CI 1.00-1.02; p = 0.01), worse PS (HR 1.30; 95% CI 1.01-1.68; p = 0.04) and driving time &gt; 1 hour (HR 1.31; 95% CI 1.01-1.71; p = 0.04). Factors predictive of overall survival in UVA included age, worse PS, driving time to the cancer centre &gt; 1 hour, median community income, and community proportion with post-secondary education. Factors that remained significant in MVA included age (HR 1.03; 95% CI 1.02-1.04; p &lt; 0.001), worse PS (HR 1.41; 95% CI 1.03-1.94; p = 0.03), and median community income (HR 1.00; 95% CI 1.00-1.00; p = 0.05). Conclusions: Outcomes of patients with LARC undergoing nCRT are significantly associated with driving time to the nearest cancer centre and community household income. Further efforts to understand and reduce these socioeconomic disparities are warranted. [Table: see text]
Abstract 15804: Hyperinsulinemia Disrupts Vascular Homeostasis, Enhances Oxidative Stress and Impairs Flow Induced Dilation of Human Skeletal Muscle Arterioles
Authors: Abeer M Mahmoud, Mary R Szczurek, Austin T Robinson, Jacob T Mey, Brian K Blackburn, Jing-Tan Bian, Michael D Brown, Phillips A Shane, Jacob M Haus
Journal: Circulation (2014)

Insulin resistance promotes vascular endothelial dysfunction (VED) and subsequent development of cardiovascular disease. At physiological levels, insulin maintains balance between vasodilators, mai...
Philippines measles outbreak is deadliest yet as vaccine scepticism spurs disease comeback
Authors: Owen Dyer
Journal: BMJ (2019)

Seventy people, most of them children, have died of measles in the Philippines since the start of 2019,1 the country’s health ministry has said, as many as were killed by the virus in the entire World Health Organization European region in all of 2018.2

There were over 18 000 cases of measles in the Philippines in 2018, compared with about 2400 in 2017. Measles vaccination rates fell from a 2014 high of 88% to 73% in 2017, then plummeted to about 55% last year.

The sharp drop came in the wake of a political battle over Sanofi’s dengue vaccine Dengvaxia, which was discontinued in the Philippines last year over safety concerns despite the company’s protests, as politicians traded blame.3

Lotta Sylwander, Unicef representative in the Philippines, said the agency was “deeply concerned” about the outbreak, adding that about 2.5 million children under five are not vaccinated against measles. “There has been a notable unwillingness on the part of parents to vaccinate their children on time,” she said.

The country’s Epidemiology Bureau said that 79% of those killed by measles …
Enhancement of Antitumor Immunity Using Dendritic Cells Combined with Lenalidomide and Programmed Death Ligand-1 Blockade in Multiple Myeloma Mouse Model
Authors: Je-Jung Lee, Manh-Cuong Vo, Sung-Hoon Jung, Tan-Huy Chu, Hyun-Ju Lee, Thangaraj Jaya Lakshmi, Hyeoung-Joon Kim
Journal: Blood (2018)
Comment on “Oral diabetes medications other than dipeptidyl peptidase-4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study” and a case report of glucagon-like peptide-1 receptor agonist–induced bullous pemphigoid
Authors: Zachary Schwager, Anar Mikailov, Adam D. Lipworth
Journal: Journal of the American Academy of Dermatology (2019)
RNA-Seq profiling of circular RNAs in human colorectal Cancer liver metastasis and the potential biomarkers
Authors: Hanchen Xu, Chunyan Wang, Haiyan Song, Yangxian Xu, Guang Ji
Journal: Molecular Cancer (2019)

In this study, the secondary sequencing was used to profile circRNA expression in the tissue samples from three CRC patients with liver metastasis and three matched CRC patients. After verified some candidates in another 40 CRC and CRC-m samples by qRT-PCR, we further demonstrated that circRNA_0001178 and circRNA_0000826 were significantly upregulated in CRC-m tissues, and both of them had the potential for diagnosing liver metastases from colorectal cancer. Finally, the networks of circRNA-miRNA-mRNA base on these two circRNAs were constructed respectively. This study showed that differentially expressed circRNAs were existed between the tissue samples from colorectal cancer patients with and without liver metastasis. And also suggested that circRNA_0001178 and circRNA_0000826 may serve as a potential diagnostic biomarker for liver metastases from colorectal cancer.
Combination therapy with TACE + ablation versus TACE + SBRT for hepatocellular carcinoma (HCC): Comparative analysis with propensity score-weighted cohorts.
Authors: Nima Nabavizadeh, Younes Jahangiri, Ramtin Rahmani, Catherine Degnin, Yiyi Chen, Yindee Geeratikun, Arthur Hung, Charles R. Thomas, Kenneth Kolbeck, Ryan Schenning, John Kaufman, Khashayar Farsad
Journal: Journal of Clinical Oncology (2019)

443 Background: To assess the relative efficacy and toxicity associated with TACE+Ablation (Ablation) or TACE+SBRT (SBRT) in a large cohort of patients with unresectable HCC. Methods: Patients with HCC undergoing Ablation or SBRT from 2006-2016 with available follow up were included. Treatment groups were different at baseline regarding tumor stage (BCLC A, B and C: 96%, 4%, 0% (Ablation) vs. 73%, 14% and 13% (SBRT), P &lt; 0.001) and severity of liver disease (CTP A, B, and C: 55%, 45% and 0% (Ablation) vs. 50%, 41%, and 9% (SBRT), P = 0.007). Propensity scores were calculated with age, sex, BCLC stage, CTP class, etiology of liver disease, tumor number, and diameter to balance the cohorts. Average treatment effects on survival with multivariable propensity score-weighted competing risk Cox regression models were evaluated, with BCLC stage, number of treated tumors and liver transplant as additionally controlled variables. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), local tumor control and hepatotoxicity. Treatment-related hepatotoxicity was defined as a two point change in CTP within six months after treatment. Results: 192 subjects were included (101 Ablation, 91 SBRT; median age=60 years, 75% men). Liver disease included HCV (78%), alcohol (35%) and NASH (8%). Liver transplant-adjusted 1- and 2-year OS rates were significantly greater for Ablation vs SBRT (88% vs. 75% and 77% vs. 50%, P&lt;0.001). 1-and 2-year PFS rates were significantly greater for Ablation vs. SBRT (84% vs. 65% and 75% vs. 51%, P &lt; 0.001). 1- and 2- year local tumor control rates were similar with both strategies (99% vs. 91% and 94% vs. 87%, P=0.298). Propensity score-weighted multivariable analysis showed significantly higher OS (sHR: 2.31, P = 0.006) and PFS rates (sHR:1.75, P = 0.008) with Ablation compared to SBRT. Ablation was also associated with lower post-treatment hepatotoxicity compared with SBRT (5% vs. 12%, P = 0.001). Conclusions: TACE+Ablation demonstrated higher OS/PFS and lower post-treatment hepatotoxicity compared with TACE+SBRT. Local disease control up to two years was equivocal, potentially suggesting equipoise for bridge to transplant.
Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia
Authors: Jeff D. Williamson, Nicholas M. Pajewski, Alexander P. Auchus, R. Nick Bryan, Gordon Chelune, Alfred K. Cheung, Maryjo L. Cleveland, Laura H. Coker, Michael G. Crowe, William C. Cushman, Jeffrey A. Cutler, Christos Davatzikos, Lisa Desiderio, Guray Erus, Larry J. Fine, Sarah A. Gaussoin, Darrin Harris, Meng-Kang Hsieh, Karen C. Johnson, Paul L. Kimmel, Manjula Kurella Tamura, Lenore J. Launer, Alan J. Lerner, Cora E. Lewis, Jennifer Martindale-Adams, Claudia S. Moy, Ilya M. Nasrallah, Linda O. Nichols, Suzanne Oparil, Paula K. Ogrocki, Mahboob Rahman, Stephen R. Rapp, David M. Reboussin, Michael V. Rocco, Bonnie C. Sachs, Kaycee M. Sink, Carolyn H. Still, Mark A. Supiano, Joni K. Snyder, Virginia G. Wadley, Jennifer Walker, Daniel E. Weiner, Paul K. Whelton, Valerie M. Wilson, Nancy Woolard, Jackson T. Wright, Clinton B. Wright
Journal: JAMA (2019)

There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia.To evaluate the effect of intensive blood pressure control on risk of dementia.Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018.Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683).The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia.Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97).Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point.ClinicalTrials.gov Identifier: NCT01206062.
Methodology Flaws and Implications of a Complementary Medicine Study
Authors: Lars Soraas, Espen Gaarder Haug, Lars Jørgensen
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 107: RNA Seq Transcriptome Analysis Reveals Genes and Pathways Involved in the Cardiac Protection of VCP Against Pressure Overload
Authors: Christiana Leimena, Xin Chen, Ning Zhou, Shaunrick Stoll, Charles Wang, Hongyu Qiu
Journal: Circulation Research (2017)

Aims: We previously showed that the valosin containing protein (VCP), a member of ATPases associated protein, protects the heart against pressure overload induced cardiac hypertrophy and dysfunction in transgenic (TG) mice. The mechanisms remain unknown. We hypothesize that VCP regulated alteration in transcriptome contributes to its cardio-protection by targeting cardiac cell growth and survival. Methods and results: Cardiac-specific VCPTG mice and their litter-matched wild type (WT) mice were subjected to transverse aortic constriction (TAC) for 2 and 5 weeks and compared to the sham mice. By using echocardiography and hemodynamic analysis, cardiac hypertrophy and dysfunction were confirmed in 2 weeks- and 5 weeks- TAC models respectively in WT but not in VCPTG mice. Total RNA was extracted from left ventricular tissues and gene expression was determined by RNA-Seq transcriptome analysis. Upon 2 weeks TAC, 690 differentially expressed genes were identified between VCPTG and WT (Fold Change ≥ 1.5, P value ≤ 0.05). Among these genes, VCPTG TAC mice, compared to WT TAC mice, showed significant activation of the genes linked to transcriptional factors, Protein Kinase CGMP-Dependent Type I ( Prkg1 ) and Kruppel Like factor 15 ( Klf15 ), the known repressors of cardiac hypertrophy under stress. On the contrary, there is significant increase in cardiac hypertrophy associated genes in WT TAC mice, such as myosin light chain 7 ( Myl7 ), periostin ( Postn ) and tropomyosin beta chain ( Tpm2) , and in fetal gene natriuretic peptide A ( Nppa) , but these alterations were not observed in VCPTG TAC mice, which may contribute to repression of cardiac hypertrophy in VCPTG mice. In addition, pro-apoptosis genes, such as platelet factor 4 ( Pf4), Pleckstrin homology like domain A1 ( Phlda1 ) and Radical S-Adenosyl Methionine Domain Containing 2 ( Rsad2 ), are significantly downregulated continually in 2 weeks through 5 weeks TAC in VCPTG mice, but not in WT TAC, which may contribute to the protection of cell survival in VCPTG mice. Conclusion: Significant difference of gene regulation exists between VCPTG and WT in the heart under the pressure overload which may be the mechanism of VCP mediated cardiac protection.
Genetically Determined Levels of Circulating Cytokines and Risk of Stroke
Authors: Marios K. Georgakis, Dipender Gill, Kristiina Rannikmäe, Matthew Traylor, Christopher D. Anderson, Jin-Moo Lee, Yoichiro Kamatani, Jemma C. Hopewell, Bradford B. Worrall, Jürgen Bernhagen, Cathie L. M. Sudlow, Rainer Malik, Martin Dichgans
Journal: Circulation (2019)

Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study. Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance–weighted meta-analysis, weighted-median analysis, Mendelian randomization–Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data. Results: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02–1.09; P =0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02–1.10; P =0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09–1.30; P =0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06–1.23; P =0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99–1.17; P =0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97–1.18; P =0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00–1.08; P =0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01–1.09; P =0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls. Conclusions: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.
Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective
Authors: Y. Bi, J. Liu, B. Furmanski, H. Zhao, J. Yu, C. Osgood, A. Ward, P. Keegan, B.P. Booth, A. Rahman, Y. Wang
Journal: Annals of Oncology (2019)

BackgroundA nivolumab dosage regimen of 480 mg intravenously (i.v.) every 4 weeks (Q4W) was approved by FDA for the majority of the approved indications for nivolumab.MethodsThe proposed new dosage regimen was supported by pharmacokinetic modeling and simulation, dose/exposure–response relationships for efficacy and safety in the indicated patient populations, and the clinical safety data with the 480 mg Q4W dosage regimen. Pharmacokinetic exposures achieved with 480 mg Q4W were predicted for 4166 patients in 21 clinical studies with various types of solid and hematological tumors. Exposure–response analyses were conducted to predict 480 mg Q4W safety and efficacy across all FDA-approved indications for nivolumab.ResultsFor the overall population, the geometric mean exposure achieved with 480 mg i.v. Q4W was 5.2% higher for steady state Cavg and 15.6% lower for Ctrough than those with 3 mg/kg i.v. Q2W, the approved dosage regimen. The simulated concentration–time course achieved with 480 mg Q4W regimen was below the median concentration achieved with 10 mg/kg i.v. Q2W that was also studied in clinical trials. The predicted probability of adverse events was similar between 480 mg Q4W and that observed with the 3 mg/kg Q2W regimen. Efficacy results were found to be similar between Q2W and Q3W dosage regimens in patients with renal cell carcinoma. The predicted efficacy for each indication suggested that the efficacy with 480 mg Q4W is unlikely to be compromised compared with that observed with 3 mg/kg Q2W.ConclusionsThe model-informed analyses of predicted exposure, efficacy and safety based on data from extensive clinical experience with nivolumab suggest that the benefit–risk profile of 480 mg Q4W regimen is comparable to the approved 3 mg/kg Q2W regimen, thus providing the regulatory basis for the approval of 480 mg Q4W regimen in the absence of clinical efficacy data with this new dosage regimen.