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Background: The G protein-coupled oestrogen receptor, GPER, has been suggested as an alternative oestrogen receptor. Our purpose was to investigate the potential of GPER as a prognostic and predictive marker in endometrial carcinoma and to search for new drug candidates to improve treatment of aggressive disease.Materials and Method: A total of 767 primary endometrial carcinomas derived from three patient series, including an external dataset, were studied for protein and mRNA expression levels to investigate and validate if GPER loss identifies poor prognosis and new targets for therapy in endometrial carcinoma. Gene expression levels, according to ERα/GPER status, were used to search the connectivity map database for small molecular inhibitors with potential for treatment of metastatic disease for receptor status subgroups.Results: Loss of GPER protein is significantly correlated with low GPER mRNA, high FIGO stage, non-endometrioid histology, high grade, aneuploidy and ERα loss (all P-values ≤0.05). Loss of GPER among ERα-positive patients identifies a subgroup with poor prognosis that until now has been unrecognised, with reduced 5-year survival from 93% to 76% (P=0.003). Additional loss of GPER from primary to metastatic lesion counterparts further supports that loss of GPER is associated with disease progression.Conclusion: These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The transcription factor GATA3 has recently been found to be involved in the carcinogenesis for numerous cancers. We investigated this marker in relation to clinicopathologic characteristics, hormone receptors, other biomarkers, and survival in endometrial carcinoma. STUDY DESIGN: A population-based study of 316 endometrial carcinomas with complete follow-up was studied for GATA3, estrogen receptor (ER)-alpha, ERbeta2, and progesterone receptor (PR) expression. RESULTS: Positive GATA3 expression in hysterectomy specimens significantly correlated to high International Federation of Gynecology and Obstetrics stage, serous papillary/clear cell subtypes, high histologic grade, loss of PR expression, aneuploidy, high proliferation, pathologic p53 and p16 expression, and poor prognosis (P = .003). Loss of hormone receptors significantly correlated with aggressive phenotype and poor prognosis. Pathologic expression of GATA3/ERalpha in combination added independent prognostic information. CONCLUSION: GATA3 expression is associated with an aggressive phenotype and adds independent prognostic information in addition to receptor status. Further studies of its value in tailored treatment protocols seem justified. [ABSTRACT FROM AUTHOR]

Background: Abnormal uterine bleeding needs surgical treatment if medical therapy fails. After introduction of non-hysteroscopic endometrial ablation as alternative to hysteroscopic endometrial resection, we aimed to compare short and long-term outcomes for women treated with these two minimally-invasive procedures. A secondary goal was comparing the present cohort to a previous cohort of women treated with hysteroscopic resection only., Materials and Methods: Historical cohort study of women treated for abnormal uterine bleeding with hysteroscopic resection or endometrial ablation at Haukeland University Hospital during 2006-2014. Similar patient file and patient-reported outcome data were collected from 386 hysteroscopic resections in a previous cohort (1992-1998). Categorical variables were compared by Chi-square or Fisher´s Exact-test, linear variables by Mann-Whitney U-test and time to hysterectomy by the Kaplan-Meier method., Results: During 2006-2014, 772 women were treated with endometrial resection or ablation, 468 women (61%) consented to study-inclusion; 333 women (71%) were treated with hysteroscopic resection and 135 (29%) with endometrial ablation. Preoperative characteristics were significantly different for women treated with hysteroscopic resection compared to endometrial ablation in the 2006-2014-cohort and between the two time-cohorts regarding menopausal, sterilization and myoma status (p≤0.036). The endometrial ablation group had significantly shorter operation time, median 13 minutes (95% Confidence Interval (CI) 12-14) and a lower complication rate (2%) versus operation time, median 25 minutes (95% CI 23-26) and complication rate (13%) in the hysteroscopy group, all p ≤0.001. The patient-reported rate of satisfaction with treatment was equivalent in both groups (85%, p = 0.955). The endometrial ablation group had lower hysterectomy rate (8% vs 16%, p = 0.024). Patient-reported satisfaction rate was higher (85%) in the 2006-2014-cohort compared with the 1992-1998-cohort (73%), p<0.001., Conclusions: Endometrial ablation has similar patient satisfaction rate, but shorter operation time and lower complication rate and may be a good alternative to hysteroscopic resection for treatment of abnormal uterine bleeding., Competing Interests: The authors have declared that no competing interest exist.

Objective: To assess whether gynecologists have impaired laparoscopic skills and/or reduced cognitive function after long on-call hours., Design: Prospective cohort study., Setting: Department of Gynecology and Obstetrics, Norway., Population: 28 gynecologists working long shifts in a single department., Methods: Pre-training of laparoscopic skills on a virtual reality simulator. Simulator- and cognitive testing on two different occasions; one in the morning after a normal nights' sleep at home and one in the morning directly after 17.5 h on call. The virtual reality simulator test consisted of three repetitive salpingectomies in an ectopic pregnancy module. The cognitive test consisted of a standardized cognitive test battery (Cambridge neuropsychological test automated battery)., Main Outcome Measures: Simulated laparoscopic performance was assessed by time to perform the procedure, total length of instrument movement (tip trajectory) and blood loss. Cognitive function was assessed by reaction time, errors and total score., Results: No significant impairment in laparoscopic skills was found after 17.5 h on call. Cognitive testing revealed a statistically significant increase in reaction time post-call. Construct validity for the metrics "time to perform procedure" and "tip trajectory" in the ectopic pregnancy module was established in a validation study prior to our main study., Conclusions: We were not able to detect impaired laparoscopic skills among gynecologists tested by a virtual reality procedural module after 17.5 h on call. We found a small increase in reaction time but no other signs of reduced cognitive function. The study adds information on surgical performance of sleep-deprived gynecologists., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: The objective of the study was to investigate the prognostic impact of deoxyribonucleic acid (DNA) ploidy in endometrial carcinoma in a routine diagnostic series as compared with a research series., Study Design: We studied a population-based series of 363 endometrial carcinomas prospectively collected, with long and complete follow-up. The prognostic value of DNA ploidy was investigated in a routine diagnostic series (n=262) and compared with the results from a previous research series (n=101)., Results: The proportion of DNA aneuploid tumors was 21% in the research series and 25% in the routine diagnostic series (P=NS). In both series, DNA aneuploidy was significantly correlated to higher age at diagnosis, nonendometrioid subtype, and high histologic grade. Patients with DNA aneuploid tumors had significantly poorer survival, adjusted for established clinicopathologic prognostic factors., Conclusion: DNA ploidy estimation in endometrial carcinoma adds independent prognostic information in a routine diagnostic setting.

With a lifetime risk among women of 2-3%, endometrial cancer is the most common pelvic gynecologic malignancy in industrialized countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis, accounts for the majority of cases and is associated with a low-stage, low-grade and endometrioid histology. In contrast, type II, associated with a poor prognosis, is characterized by a high-stage, high-grade and non-endometrioid histology. However, the prognostic value of this distinction is limited, as up to 20% of type I endometrial cancers recur, while half of type II cancers do not. We review the current literature on epidemiology, etiology, pathology, molecular alterations, staging, treatment and prognostic factors in endometrial cancer. Ongoing molecular-based clinical trials and newly reported molecular alterations with a potential for development of new targeted therapy are discussed.

Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.

We studied the expression of polycomb group (PcG) protein BMI-1 in a large population-based patient series of endometrial carcinomas in relation to clinical and molecular phenotype. Also, 57 fresh frozen endometrial carcinomas were studied for the relationship between BMI-1 protein expression, BMI-1 mRNA level, and activation of an 11-gene signature reported to represent a BMI-1-driven pathway. BMI-1 protein expression was significantly weaker in tumours with vascular invasion (P<0.0001), deep myometrial infiltration (P=0.004), and loss of oestrogen receptor (ER) (P<0.0001) and progesterone receptors (PR) (P=0.03). Low BMI-1 protein expression was highly associated with low BMI-1 mRNA expression (P=0.002), and similarly low BMI-1 mRNA expression correlated significantly with vascular invasion, ER and PR loss, and histologic grade 3. In contrast, activation of the reported 11-gene signature, supposed to represent a BMI-1-driven pathway, correlated with low mRNA expression of BMI-1 (P<0.001), hormone receptor loss, presence of vascular invasion, and poor prognosis. We conclude that BMI-1 protein and mRNA expression are significantly correlated and that BMI-1 expression is inversely associated with activation of the 11-gene signature. Loss of BMI-1 seems to be associated with an aggressive phenotype in endometrial carcinomas.

Gene alterations and overexpression of various oncogenes and cell-cycle regulators are important in tumor development. In a population based series of 316 endometrial carcinomas with long and complete follow-up we investigated the distribution of HER-2/neu and EGFR expression and copy number alteration in endometrial cancers. HER-2/ neu, EGFR and Ki-67 expression in curettage and hysterectomy specimens were studied immunohistochemically for expression in relation to molecular markers and clinical phenotype. Fresh tumor samples (n=76) were studied by global characterization of genetic alterations by single nucleotide polymorphism (SNP) array for detection of high level amplification for HER-2/neu and EGFR. Pathological expression of HER-2/neu in curettage was detected in 23% which significantly correlated to high FIGO stage, non-endometrioid subtype, high grade and aneuploidy. In hysterectomy specimens, pathological HER-2/neu staining was seen in 13% which correlated significantly with high FIGO stage, non-endometrioid subtype, high proliferation and poor survival (p=0.009). Expression of EGFR was examined with three different antibodies, but none showed significant correlation with molecular markers or clinical phenotype. High level amplification of HER-2/neu or EGFR was seen in only one out of 76 samples, respectively. High proliferation estimated in tumors from hysterectomy specimens showed independent prognostic impact and was superior to estimation in curettage specimens as a prognostic marker. In conclusion, high level amplification of HER-2/neu or EGFR is infrequent in endometrial cancer. Pathological HER-2/neu staining identifies endometrial carcinomas with an aggressive phenotype, high proliferation and patients with poor survival in a population based setting. These results motivate further clinical trials with trastuzumab based on HER-2/neu status in endometrial carcinomas.

Objective: The purpose of this study was to investigate the prognostic impact of p53 and p16 expression in curettage material from patients with endometrial carcinoma., Study Design: Preoperative curettage material from a population-based series of 236 endometrial carcinomas from Norway with long and complete follow-up was studied immunohistochemically for p53 and p16 expression., Results: Pathologic expression of p53 and p16 was seen in 24% and 25%, respectively, and was significantly correlated with high International Federation of Gynecology and Obstetrics (FIGO) stage and serous/clear cell histologic subtypes. Pathologic p53 expression showed significant correlation with postmenopausal status, high grade, high tumor cell proliferation, and aneuploidy. Patients with normal expression had 85% 5-year survival compared with 51% and 50% when pathologic expression of p53 and p16, respectively. Five-year survival for patients with 2 pathologic markers was 13%, compared with 67% and 91% for 1 or no pathologic markers, respectively., Conclusion: Pathologic expression of p53 and p16 in curettage material identifies high-risk endometrial carcinoma patients with poor prognosis.

Background: The aim of the study was to find the incidence and clinical implications of peripartum hysterectomy in our department and to identify women at risk to improve treatment before resorting to hysterectomy., Material and Methods: In the period 1981-1996, cases with peripartum hysterectomy among a total of 70,546 deliveries in our department were identified from three different sources. The clinical variables were obtained by review of the maternal records., Results: In the study period, 11 cases, representing an incidence of 0.2 peripartum hysterectomies per 1000 deliveries was found. Eight women had a cesarean section and three women had a spontaneous vaginal delivery. Six of the patients had previous operation on the uterus. The indication for hysterectomy was atony in seven, suspected rupture in two, placenta accreta in one and DIC in one woman. The maternal morbidity was substantial as the mean number of transfusions given was 15 units (range 7-24), and the mean hospitalization time was 15 days (range 11-29). There was no maternal mortality, but one infant died due to asphyxia caused by placental abruption., Conclusions: The incidence of peripartum hysterectomy was low, but the condition is serious with significant maternal morbidity.