Of fingers, toes and penises

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62765/1/390029a0.pd

Everolimus pharmacokinetics and its exposure-toxicity relationship in patients with thyroid cancer

Contains fulltext : 172498.pdf (publisher's version ) (Open Access)BACKGROUND: Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored. METHODS: Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure-toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK. RESULTS: Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0-24 (SD) 600 (274) vs. 395 (129) microg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure. CONCLUSION: The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer. CLINICALTRIAL. GOV NUMBER: NCT01118065

Discontinuation of anti-PD-1 monotherapy in advanced melanoma:Outcomes of daily clinical practice

There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti-PD-1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti-PD-1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24-month progression-free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti-PD-1 discontinuation was not due to adverse events. Having a PR at anti-PD-1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11-2.97) and HR = 1.10 (95% CI = 1.02-1.19; per month increase)]. In 17 of the 27 anti-PD-1 re-treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti-PD-1 discontinuation

Labor Productivity - The Use of Staffing Guides and Other Productivity Methods in U.S. Hotels: A Survey Study

This paper examines the issue of labor productivity in hotels. It elaborates on various measurement methods used by American hoteliers including staffing guides, with a special focus on productivity standards. Advantages of physical, financial and mixed methods such as percentage methods, revenue per employee, value-added, Data Envelope Analysis and Stochastic Frontier Analysis are discussed. While the use of percentages and staffing guides were found to be commonplace, results revealed that some fairly stable standards were already in place in the surveyed hotels. Results also revealed that at least in the surveyed companies, few hoteliers attempted to monitor or improve revenue per employee, focusing instead on physical labor inputs and outputs or simple labor percentages

Cardiovascular dynamics in ischemic cardiomyopathy during exercise

Cardiac Dysfunction and Arrhythmia

Stress imaging in patients with diabetes; routine practice?

Ventricular Dysfunction & Heart Failur

Sex differences in patients with out-of-hospital cardiac arrest without ST-segment elevation:A COACT trial substudy

Background: Whether sex is associated with outcomes of out-of-hospital cardiac arrest (OHCA) is unclear. Objectives: This study examined sex differences in survival in patients with OHCA without ST-segment elevation myocardial infarction (STEMI). Methods: Using data from the randomized controlled Coronary Angiography after Cardiac Arrest (COACT) trial, the primary point of interest was sex differences in OHCA-related one-year survival. Secondary points of interest included the benefit of immediate coronary angiography compared to delayed angiography until after neurologic recovery, angiographic and clinical outcomes. Results: In total, 522 patients (79.1% men) were included. Overall one-year survival was 59.6% in women and 63.4% in men (HR 1.18; 95% CI: 0.761.81;p = 0.47). No cardiovascular risk factors were found that modified survival. Women less often had significant coronary artery disease (CAD) (37.0% vs. 71.3%; p < 0.001), but when present, they had a worse prognosis than women without CAD (HR 3.06; 95% CI 1.31-7.19; p = 0.01). This was not the case for men (HR 1.05; 95% CI 0.67-1.65; p = 0.83). In both sexes, immediate coronary angiography did not improve one-year survival compared to delayed angiography (women, odds ratio (OR) 0.87; 95% CI 0.58-1.30;p = 0.49; vs. men, OR 0.97; 95% CI 0.45-2.09; p = 0.93). Conclusion: In OHCA patients without STEMI, we found no sex differences in overall one-year survival. Women less often had significant CAD, but when CAD was present they had worse survival than women without CAD. This was not the case for men. Both sexes did not benefit from a strategy of immediate coronary angiography as compared to delayed strategy with respect to one-year survival

Coronary Angiography After Cardiac Arrest Without ST Segment Elevation:One-Year Outcomes of the COACT Randomized Clinical Trial

Importance: Ischemic heart disease is a common cause of cardiac arrest. However, randomized data on long-term clinical outcomes of immediate coronary angiography and percutaneous coronary intervention (PCI) in patients successfully resuscitated from cardiac arrest in the absence of ST segment elevation myocardial infarction (STEMI) are lacking. Objective: To determine whether immediate coronary angiography improves clinical outcomes at 1 year in patients after cardiac arrest without signs of STEMI, compared with a delayed coronary angiography strategy. Design, Setting, and Participants: A prespecified analysis of a multicenter, open-label, randomized clinical trial evaluated 552 patients who were enrolled in 19 Dutch centers between January 8, 2015, and July 17, 2018. The study included patients who experienced out-of-hospital cardiac arrest with a shockable rhythm who were successfully resuscitated without signs of STEMI. Follow-up was performed at 1 year. Data were analyzed, using the intention-to-treat principle, between August 29 and October 10, 2019. Interventions: Immediate coronary angiography and PCI if indicated or coronary angiography and PCI if indicated, delayed until after neurologic recovery. Main Outcomes and Measures: Survival, myocardial infarction, revascularization, implantable cardiac defibrillator shock, quality of life, hospitalization for heart failure, and the composite of death or myocardial infarction or revascularization after 1 year. Results: At 1 year, data on 522 of 552 patients (94.6%) were available for analysis. Of these patients, 413 were men (79.1%); mean (SD) age was 65.4 (12.3) years. A total of 162 of 264 patients (61.4%) in the immediate angiography group and 165 of 258 patients (64.0%) in the delayed angiography group were alive (odds ratio, 0.90; 95% CI, 0.63-1.28). The composite end point of death, myocardial infarction, or repeated revascularization since the index hospitalization was met in 112 patients (42.9%) in the immediate group and 104 patients (40.6%) in the delayed group (odds ratio, 1.10; 95% CI, 0.77-1.56). No significant differences between the groups were observed for the other outcomes at 1-year follow-up. For example, the rate of ICD shocks was 20.4% in the immediate group and 16.2% in the delayed group (odds ratio, 1.32; 95% CI, 0.66-2.64). Conclusions and Relevance: In this trial of patients successfully resuscitated after out-of-hospital cardiac arrest and without signs of STEMI, a strategy of immediate angiography was not found to be superior to a strategy of delayed angiography with respect to clinical outcomes at 1 year. Coronary angiography in this patient group can therefore be delayed until after neurologic recovery without affecting outcomes

Cost Analysis From a Randomized Comparison of Immediate Versus Delayed Angiography After Cardiac Arrest

Background In patients with out‐of‐hospital cardiac arrest without ST‐segment elevation, immediate coronary angiography did not improve clinical outcomes when compared with delayed angiography in the COACT (Coronary Angiography After Cardiac Arrest) trial. Whether 1 of the 2 strategies has benefits in terms of health care resource use and costs is currently unknown. We assess the health care resource use and costs in patients with out‐of‐hospital cardiac arrest. Methods and Results A total of 538 patients were randomly assigned to a strategy of either immediate or delayed coronary angiography. Detailed health care resource use and cost‐prices were collected from the initial hospital episode. A generalized linear model and a gamma distribution were performed. Generic quality of life was measured with the RAND‐36 and collected at 12‐month follow‐up. Overall total mean costs were similar between both groups (EUR 33 575±19 612 versus EUR 33 880±21 044; P=0.86). Generalized linear model: (β, 0.991; 95% CI, 0.894–1.099; P=0.86). Mean procedural costs (coronary angiography and percutaneous coronary intervention, coronary artery bypass graft) were higher in the immediate angiography group (EUR 4384±3447 versus EUR 3028±4220; P<0.001). Costs concerning intensive care unit and ward stay did not show any significant difference. The RAND‐36 questionnaire did not differ between both groups. Conclusions The mean total costs between patients with out‐of‐hospital cardiac arrest randomly assigned to an immediate angiography or a delayed invasive strategy were similar during the initial hospital stay. With respect to the higher invasive procedure costs in the immediate group, a strategy awaiting neurological recovery followed by coronary angiography and planned revascularization may be considered. Registration URL: https://trialregister.nl; Unique identifier: NL4857