Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer

Molecular Profiling; Endometrial CancerPerfil molecular; Càncer d'endometriPerfil molecular; Cáncer de endometrioImportance Patients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear. Objective To determine the association of molecular profiling with outcomes among patients with low-grade EC. Design, Setting, and Participants This retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon (POLE)-altered, microsatellite instable (MSI), tumor protein p53 (TP53)-altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022. Exposures Molecular testing of the 4 molecular subgroups. Main Outcomes and Measures The main outcome was disease-specific survival (DSS) within the molecular subgroups. Results A total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE-altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53-altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% (P < .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P < .001), TP53-altered (HR, 1.76; 95% CI, 1.04-2.95; P = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P < .001) disease were independently associated with reduced DSS. Conclusions and Relevance This cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness

High body mass index and pre-existing autoimmune disease are associated with an increased risk of immune-related adverse events in cancer patients treated with PD-(L)1 inhibitors across different solid tumors

BACKGROUND\nPATIENTS AND METHODS\nRESULTS\nCONCLUSION\nTreatment with anti-PD-(L)1 antibodies, approved for several oncology indications, can lead to immune-related adverse events (irAEs). We aimed to investigate risk factors associated with an increased reporting of irAEs in patients treated with PD-(L)1 inhibitors approved for solid tumor indications.\nA retrospective review was performed of individual data from patients in phase II/III registrational studies for PD-(L)1 inhibitors in solid tumors. Data on baseline characteristics and adverse events were extracted. Univariate and multivariable logistic regression models were used to identify risk factors.\nIn total, 5123 patients were included from 15 studies reporting on the use of four PD-(L)1 inhibitors for five solid tumor indications. Univariate analysis suggested that type of study drug (P 2 [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.2-1.8] in comparison to normal BMI, having an autoimmune disease at baseline (OR 1.8, 95% CI 1.1-2.7), and use of a PD-L1 inhibitor (OR 1.6, 95% CI 1.2-2.0). The latter finding is probably biased due to the selection of the studies in the dataset with complete information on baseline characteristics.\nThis study was conducted using a large dataset of individual patient data from clinical trials comprising multiple solid tumor indications. We demonstrated that patients with obesity and concurrent autoimmune disease were at increased risk of developing irAEs.FWN – Publicaties zonder aanstelling Universiteit Leide

Divination: Exemplifying and Configuring Archetypes in Ceramics

Abstract/Summary Dissertation Divination: Exemplifying and Configuring Archetypes in Ceramics is a study of my research practice. The cards of the tarot can be used as a conceptual framework and source of inspiration for making ceramic sculptures. The cards can be used to understand the creative process as an expression of archetypes. My dissertation discusses these archetypes from the tarot cards, both in their historical operation, their manifestation in my art practice, as well as, examining approaches taken to these archetypes by other artists such as Salvador Dali and Niki de Saint Phalle. The theoretical basis for the dissertation is informed by the writings of Carl G. Jung who has proposed concepts dealing with creativity, coincidence, a collective unconscious and archetypes. These ideas form a model for the understanding of my studio work. As background, the dissertation examines examples of artworks that could be seen to be drawn from a collective unconscious. Studio Work The studio work consists of a series of ceramic sculptures formulating the archetypes that I have derived from the tarot cards. The three dimensional clay, with found inclusions, examines the idea of specific archetypes. These archetypes are titled in the works including: The Fool, Strength, The Magician, Tarot Sun, The Empress II, The Lovers, Empress l, The Chariot I and II The Angel Temperance, The Tarot Devil and The World. The ceramic objects have been created in clay using handbuilding techniques. The clay was such that it could include found ceramic pieces and be refired. The pieces have been re-fired many times to achieve a variety of glaze effects. The works range in size from 30-60 cms approximately and include freestanding sculptures and complementing flat wall works

Can the PROPER intervention reduce psychotropic drug prescription in nursing home residents with dementia?:Results of a cluster-randomized controlled trial

Objectives:To evaluate the effect of the PROPER intervention in nursing home residents with dementia on the prevalence of psychotropic drug use and neuropsychiatric symptoms.Design:A cluster-randomized controlled design with two parallel groups (intervention versus usual care) and assessments at 0, 6, 12, and 18 months.Setting:Thirty-one dementia special care units within 13 long-term care organizations in the Netherlands.Participants:Three hundred eighty nursing home residents with dementiaIntervention:The PROPER intervention consisted of a structured and repeated multidisciplinary medication review, supported by education and continuous evaluation.Measurements:Prescriptions of antipsychotics, antidepressants, anxiolytics, and hypnotics, and occurrence of neuropsychiatric symptoms.Results:The prescription of any type of psychotropic drugs increased in the intervention group, and decreased in the control group, with an estimated difference of 3.9 percentage points per 6 months (p = 0.01). Effects for the individual drug groups were minor (differences of 1.6 percentage points and below per 6 months) and not statistically significant. The occurrence of neuropsychiatric symptoms remained stable in both the intervention and control groups during the follow-up of 18 months.Conclusions:The PROPER intervention failed to demonstrate effectiveness in reducing the prevalence of psychotropic drugs. It may be interesting to enrich the intervention with components that address personal attitudes and communication between nursing home professionals, not only with respect to the prescription of psychotropic drugs, but also to neuropsychiatric symptoms

Sample Size Considerations for GEE Analyses of Three-Level Cluster Randomized Trials

Cluster randomized trials in health care may involve three instead of two levels, for instance, in trials where different interventions to improve quality of care are compared. In such trials, the intervention is implemented in health care units (“clusters”) and aims at changing the behavior of health care professionals working in this unit (“subjects”), while the effects are measured at the patient level (“evaluations”). Within the generalized estimating equations (GEE) approach, we derive a sample size formula that accounts for two levels of clustering: that of subjects within clusters and that of evaluations within subjects. The formula reveals that sample size is inflated, relative to a design with completely independent evaluations, by a multiplicative term that can be expressed as a product of two variance inflation factors, one that quantifies the impact of within-subject correlation of evaluations on the variance of subject-level means and the other that quantifies the impact of the correlation between subject level means on the variance of the cluster means. Power levels as predicted by the sample size formula agreed well with the simulated power for more than 10 clusters in total, when data was analyzed using bias-corrected estimating equations for the correlation parameters in combination with the model-based covariance estimator or the sandwich estimator with a finite sample correction

Increased adherence to perioperative safety guidelines associated with improved patient safety outcomes:a stepped-wedge, cluster-randomised multicentre trial

Background: National Dutch guidelines have been introduced to improve suboptimal perioperative care. A multifaceted implementation programme (IMPlementatie Richtlijnen Operatieve VEiligheid [IMPROVE]) has been developed to support hospitals in applying these guidelines. This study evaluated the effectiveness of IMPROVE on guideline adherence and the association between guideline adherence and patient safety. Methods: Nine hospitals participated in this unblinded, superiority, stepped-wedge, cluster RCT in patients with major noncardiac surgery (mortality risk >= 1%). IMPROVE consisted of educational activities, audit and feedback, reminders, organisational, team-directed, and patient-mediated activities. The primary outcome of the study was guideline adherence measured by nine patient safety indicators on the process (stop moments from the composite STOP bundle, and timely administration of antibiotics) and on the structure of perioperative care. Secondary safety outcomes included in-hospital complications, postoperative wound infections, mortality, length of hospital stay, and unplanned care. Results: Data were analysed for 1934 patients. The IMPROVE programme improved one stop moment: 'discharge from recovery room' (+16%; 95% confidence interval [CI], 9-23%). This stop moment was related to decreased mortality (-3%; 95% CI, -4% to -1%), fewer complications (-8%; 95% CI, -13% to -3%), and fewer unscheduled transfers to the ICU (-6%; 95% CI, -9% to -3%). IMPROVE negatively affected one other stop moment - 'discharge from the hospital' - possibly because of the limited resources of hospitals to improve all stop moments together. Conclusions: Mixed implementation effects of IMPROVE were found. We found some positive associations between guideline adherence and patient safety (i.e. mortality, complications, and unscheduled transfers to the ICU) except for the timely administration of antibiotics

Study protocol for an international, multicentre stepped-wedge cluster randomised trial to evaluate the impact of a digital antimicrobial stewardship smartphone application

Introduction With the widespread use of electronic health records and handheld electronic devices in hospitals, informatics-based antimicrobial stewardship interventions hold great promise as tools to promote appropriate antimicrobial drug prescribing. However, more research is needed to evaluate their optimal design and impact on quantity and quality of antimicrobial prescribing. Methods and analysis Use of smartphone-based digital stewardship applications (apps) with local guideline directed empirical antimicrobial use by physicians will be compared with antimicrobial prescription as per usual as primary outcome in three hospitals in the Netherlands, Sweden and Switzerland. Secondary outcomes will incl

The Impact of Age on Outcome of Embryonal and Alveolar Rhabdomyosarcoma Patients.:A Multicenter Study

Background: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS. Patients and Methods: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed. Results: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome. Conclusion: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS