Progesterone receptors in development and metatstais of endometrial cancer

Many women may acquire endometrial cancer during their life. The vast majority of these women will be cured because of early detection of the disease. As in most types of cancer however, the main cause of death lies in metastasis of the primary tumor to other sites in the body. In approximately 25% of endometrial cancer patients, the tumor has spread beyond the uterus at the time of initial surgical treatment. During endometrial carcinogenesis, the balance between estrogen and progesterone is of great importance. This is indicated by the fact that virtually all risk factors for endometrial cancer are linked to a surplus of estrogenic effects that are not balanced by appropriate progestagenic effects. Also during further development and progression of endometrial cancer, steroid receptor signaling has many important effects. The major research question of this thesis is summarized as follows: what is the effect of loss of progesterone regulation due to loss of PR expression during development of endometrial cancer? More specifically, the questions that this thesis addresses are: 1) Is loss of PR expression in endometrial cancer linked to development of endometrial cancer to a more advanced stage? 2) What are the effects of changes in expression of PRA and PRB on invasion and metastasis of endometrial cancer? 3) What is the effect of progesterone on invasion and metastasis of endometrial cancer cells that express different PR isotypes? 4) Does any crosstalk exist between PR signaling and Wnt signaling

Progestogenic effects of tibolone on human endometrial cancer cells

Tibolone, a synthetic steroid acting in a tissue-specific manner and used in hormone replacement therapy, is converted into three active metabolites: a Delta(4) isomer (exerting progestogenic and androgenic effects) and two hydroxy metabolites, 3 alpha-hydroxytibolone (3 alpha-OH-tibolone) and 3beta-OH-tibolone (exerting estrogenic effects). In the present study an endometrial carcinoma cell line (Ishikawa PRAB-36) was used to investigate the progestogenic properties of tibolone and its metabolites. This cell line contains progesterone receptors A and B, but lacks estrogen and androgen receptors. When tibolone was added to the cells, complete conversion into the progestogenic/androgenic Delta(4) isomer was observed within 6 d. Furthermore, when cells were cultured with tibolone or when the Delta(4) isomer or the established progestagen medroxyprogesterone acetate was added to the medium, marked inhibition of growth was observed. Interestingly, 3 beta-OH-tibolone also induces some inhibition of growth. These growth inhibitions were not observed in progesterone receptor-negative parental Ishikawa cells, and progestagen-induced growth inhibition of PRAB-36 cells could readily be reversed using the antiprogestagen Org-31489. Upon measuring the expression of two progesterone-regulated genes (fibronectin and IGF-binding protein-3), tibolone, the Delta(4) isomer and medroxyprogesterone acetate showed similar gene expression regulation. These results indicate that tibolone, the Delta(4) metabolite, and to some extent 3 beta-OH-tibolone exert progestogenic effects. Tibolone and most likely 3 beta-OH-tibolone are converted into the Delta(4) metabolite

Consequences of loss of progesterone receptor expression in development of invasive endometrial cancer

PURPOSE: In endometrial cancer, loss of progesterone receptors (PR) is associated with more advanced disease. This study aimed to investigate the mechanism of action of progesterone and the loss of its receptors (PRA and PRB) in development of endometrial cancer. EXPERIMENTAL DESIGN: A 9600-cDNA microarray analysis was performed to study regulation of gene expression in the human endometrial cancer subcell line Ishikawa PRAB-36 by the progestagen medroxy progesterone acetate (MPA). Five MPA-regulated genes were selected for additional investigation. Expression of these genes was studied by Northern blot and by immunohistochemistry in Ishikawa subcell lines expressing different PR isoforms. Additionally, endometrial cancer tissue samples were immunohistochemically stained to study the in vivo protein expression of the selected genes. RESULTS: In the PRAB-36 cell line, MPA was found to regulate the expression of a number of invasion- and metastasis-related genes. On additional investigation of five of these genes (CD44, CSPG/Versican, Tenascin-C, Fibronectin-1, and Integrin-beta 1), it was observed that expression and progesterone regulation of expression of these genes varied in subcell lines expressing different PR isoforms. Furthermore, in advanced endometrial cancer, it was shown that loss of expression of both PR and E-cadherin was associated with increased expression CD44 and CSPG/Versican. CONCLUSION: The present study shows that progestagens exert a modulatory effect on the expression of genes involved in tumor cell invasion. As a consequence, loss of PR expression in human endometrial cancer may lead to development of a more invasive phenotype of the respective tumor

Safety of a 1-hour Rule-out High-sensitive Troponin T Protocol in Patients With Chest Pain at the Emergency Department

Background: The 1-hour rule-out high-sensitive cardiac troponin T protocol (hs-cTnT), in which a serial troponin measurement is performed 1 hour after the first to assess the possibility of acute coronary syndrome (ACS), has been implemented in the European guidelines in 2015. Our aim was to assess the safety of this protocol in low-risk patients in the Emergency Department (ED) when implemented in daily practice. Methods: Patients with acute chest pain presenting to the ED of our hospital and younger than 75 years were included (May 2013 to October 2014, The Netherlands). Hs-cTnT was measured at presentation (T0) and 1-1.5 hours after T0 (T1). Patients with a first troponin (T0) ≥ 0.012 ug/l were excluded. Primary endpoint was the 6-week occurrence of major adverse cardiac events (MACEs), defined as unstable angina, acute myocardial infarction (AMI), percutaneous coronary intervention, significant stenosis managed conservatively, coronary artery bypass grafting, and death. Results: Of the 374 analyzed patients, 16 patients (4.3%) developed 35 MACE. Of these 16 patients with endpoints, 3 were primarily discharged with noncardiac chest pain but returned within 6 weeks with unstable angina. Importantly, no patients experienced an AMI or died during follow-up. Conclusion: No AMIs or deaths occurred after introducing the 1-hour hscTnT protocol to rule-out ACS in chest pain patients, but other MACE such as unstable angina occurred. Our results suggest the protocol is safe to implement in the ED in The Netherlands

Randomized study to compare balloon angioplasty and elective stent implantation in venous bypass grafts: the Venestent study

The aim of the study was to compare acute and long-term angiographic and clinical outcome of balloon angioplasty and elective stenting in de novo lesions in the body of a saphenous vein graft (SVG). A total of 150 patients, with de novo lesions in SVG, were randomly assigned to balloon angioplasty or elective Wiktor I stent implantation. The angiographic restenosis rate at 6-month follow-up was 32.8% in the balloon group and 19.1% in the stent group (P = 0.069). At 1-year follow-up, target vessel revascularization rate was 31. 4% vs. 14.5% (P < 0.05), and event-free survival was 60.0% vs. 76.3% (P < 0.05) for the balloon and stent group, respectively. Elective stent implantation in de novo SVG lesions is associated with a significant lower target vessel revascularization rate and a significant higher event-free survival at 1-year follow-up as compared to balloon angioplasty

Effect of using the HEART score in patients with chest pain in the emergency department: A Stepped-wedge, cluster randomized trial

Background: The HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score is an easy-to-apply instrument to stratify patients with chest pain according to their short-term risk for major adverse cardiac events (MACEs), but its effect on daily practice is unknown. Objective: To measure the effect of use of the HEART score on patient outcomes and use of health care resources. Design: Stepped-wedge, cluster randomized trial. (Clinical Trials.gov: NCT01756846) Setting: Emergency departments in 9 Dutch hospitals. Patients: Unselected patients with chest pain presenting at emergency departments in 2013 and 2014. Intervention: All hospitals started with usual care. Every 6 weeks, 1 hospital was randomly assigned to switch to "HEART care," during which physicians calculated the HEART score to guide patient management. Measurements: For safety, a noninferiority margin of a 3.0% absolute increase in MACEs within 6 weeks was set. Other outcomes included use of health care resources, quality of life, and cost-effectiveness. Results: A total of 3648 patients were included (1827 receiving usual care and 1821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed. Limitation: Physicians were hesitant to refrain from admission and diagnostic tests in patients classified as low risk by the HEART score. Conclusion: Using the HEART score during initial assessment of patients with chest pain is safe, but the effect on health care resources is limited, possibly due to nonadherence to management recommendations