Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON) : a randomised controlled phase III trial

Acknowledgments This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).Peer reviewedPublisher PD

Gene expression profiling of mid to late secretory phase endometrial biopsies from women with menstrual complaint

Objective The purpose of this study was to test whether a quantitative high-throughput molecular screen can be used to probe human endometrium and initiate the development of molecular diagnostic tools with potential for identification of therapeutic targets in women with menstrual complaints. Study design Endometrium was collected from 10 patients with complaint of heavy bleeding, classified into mid or late secretory phase of the menstrual cycle by histologic dating and serum progesterone concentration. Total RNA was extracted and gene activity assessed using high-density oligonucleotide arrays. Results Statistical testing identified 83 ‘signature’ genes whose expression levels differentiated the mid and late secretory phases of the menstrual cycle. Conclusion The results show that the endometrium, a complex heterogeneous tissue, is amenable to high-throughput molecular analyses and this work provides further support for the future application of molecular profiling to clinical diagnosi

Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients.

Purpose: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)–positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. Experimental Design: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. Results: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, χ2 for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. Conclusions: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response

Interleukin-11 in Endometrial Adenocarcinoma Is Regulated by Prostaglandin F2α-F-Prostanoid Receptor Interaction via the Calcium-Calcineurin-Nuclear Factor of Activated T Cells Pathway and Negatively Regulated by the Regulator of Calcineurin-1

Interleukin-11 (IL-11) up-regulates the proliferative and invasive capacity of many cancers. Coexpression of glycoprotein 130 (GP130) and IL-11 receptor α (IL-11Rα) is necessary for high-affinity binding of IL-11 to IL-11Rα. This study investigated the expression of IL-11 and role of prostaglandin F2α-F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11Rα, and GP130 expression was performed by immunohistochemistry. IL-11 and regulator of calcineurin 1 isoform 4 (RCAN1-4) mRNA and protein expression were determined by real-time RT-PCR and/or enzyme-linked immunosorbent assay/Western blot analysis using Ishikawa endometrial adenocarcinoma cells stably expressing the FP receptor (FPS cells) and endometrial adenocarcinoma explants. IL-11 mRNA expression was significantly elevated in endometrial adenocarcinoma samples compared with normal endometrium and increased with tumor grade. IL-11 protein expression localized with FP receptor, IL-11Rα, and GP130 in the neoplastic glandular epithelium of endometrial adenocarcinomas. Prostaglandin F2α-FP receptor signaling significantly elevated the expression of IL-11 mRNA and protein in a Gq-protein kinase C-calcium-calcineurin-nuclear factor of activated T cells-dependent manner in FPS cells. The calcineurin signaling pathway is known to be controlled by the RCAN (RCAN1-4). Indeed, RCAN1-4 expression was significantly elevated in well-differentiated endometrial adenocarcinoma compared with normal endometrium and was found to decrease with tumor grade and negatively regulate IL-11 expression in vitro. This study has highlighted a new mechanism regulating IL-11 expression in endometrial adenocarcinoma cells by the FP receptor via the calcium-calcineurin-nuclear factor of activated T cells pathway

Prostaglandin F2α-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium–calcineurin–NFAT pathway

Pro-inflammatory mediators, like prostaglandin (PG) and chemokines, promote tumourigenesis by enhancing cell proliferation, migration of immune cells and recruitment of blood vessels. Recently we showed elevated expression of the chemokine (C-X-C motif) receptor 2 (CXCR2) in endometrial adenocarcinomas localized to neutrophils and neoplastic epithelial and vascular cells. Furthermore we found that PGF2α-F-prostanoid (FP) receptor regulates the expression of the CXCR2 ligand CXCL1, to promote neutrophil chemotaxis in endometrial adenocarcinomas. In the present study we identified another CXCR2 ligand, CXCL8 as a target for PGF2α-FP receptor signalling which enhances epithelial cell proliferation in endometrial adenocarcinoma cells in vitro and in nude mice in vivo. We found that PGF2α-FP receptor interaction induces CXCL8 expression in endometrial adenocarcinoma cells via the protein kinase C–calcium–calcineurin–NFAT signaling pathway. Promoter analysis revealed that CXCL8 transcriptional activation by PGF2α signaling is mediated by cooperative interactions between the AP1 and NFAT binding sites. Furthermore, PGF2α via the FP receptor induced the expression of the regulator of calcineurin 1 isoform 4 (RCAN1-4) via the calcineurin/NFAT pathway in a reciprocal manner to CXCL8. Using an adenovirus to overexpress RCAN1-4, we found that RCAN1-4 is a negative regulator of CXCL8 expression in endometrial adenocarcinoma cells. Taken together our data have elucidated the molecular and cellular mechanism whereby PGF2α regulates CXCL8 expression via the FP receptor in endometrial adenocarcinomas and have highlighted RCAN1-4 as a negative regulator of CXCL8 expression which may be exploited therapeutically to inhibit CXCL8-mediated tumour development