The role of regulatory T-cells in the development of endometriosis.

Endometriosis is a benign disease of the female reproductive tract, characterized by the process of chronic inflammation and alterations in immune response. It is estimated to affect 2-19% of women in the general population and is commonly associated with symptoms of chronic pelvic pain and infertility. Regulatory T cells (Treg) are a subpopulation of T lymphocytes that are potent suppressors of inflammatory immune response, essential in preventing destructive immunity in all tissues. In endometriosis, several studies have investigated the possible role of Treg cells in the development of the disease. Most studies to date are heterogeneous in methodology and are based on a small number of cases, which means that it is impossible to define their exact role at present. Based on current knowledge, it seems that disturbed Treg homeostasis, leading to increased systemic and local inflammation within ectopic and eutopic endometrium, is present in women who eventually develop endometriosis. It is also evident that different subsets of human Treg cells have different roles in suppressing the immune response. Recent studies in patients with endometriosis have investigated naive/resting FOXP3lowCD45RA+ Treg cells, which upon T cell receptor stimulation, differentiate into activated/effector FOXP3highCD45RA- Treg cells, characterized by a strong immunosuppressive activity. In addition, critical factors controlling expression of Treg/effector genes, including reactive oxygen species and heme-responsive master transcription factor BACH2, were found to be upregulated in endometriotic lesions. As shown recently for cancer microenvironments, microbial inflammation may also contribute to the local composition of FOXP3+ subpopulations in endometriotic lesions. Furthermore, cytokines, such as IL-7, which control the homeostasis of Treg subsets through the tyrosine phosphorylation STAT5 signalling pathway, have also been shown to be dysregulated. To better understand the role of Treg in the development of endometriosis, future studies should use clear definitions of Tregs along with specific characterization of the non-Treg (FOXP3lowCD45RA-) fraction, which itself is a mixture of follicular Tregs and cells producing inflammatory cytokines.

Improving Endometrial cancer assessment by combining the new techniqUe of GENomic profiling with surgical Extra uterIne disEase assessment (EUGENIE).

BACKGROUND: The molecular classification of endometrial cancer revolutionized our knowledge of its biology but so far has not affected our surgical approach. The exact risk of extra-uterine metastasis and hence the type of surgical staging for each of the four molecular subgroups are currently unknown. PRIMARY OBJECTIVE: To determine the association between molecular classification and disease stage. STUDY HYPOTHESIS: Each endometrial cancer molecular subgroup has a specific pattern of spread and this pattern of spread could guide the extent of surgical staging. TRIAL DESIGN: Prospective, multicenter study MAJOR INCLUSION/EXCLUSION CRITERIA: Participants eligible for inclusion in this study must meet all the following criteria: women ≥18 years with primary endometrial cancer, any histology and stage. PRIMARY ENDPOINT: Number and site of metastasis in each endometrial cancer molecular subgroup. SAMPLE SIZE: 1000 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The trial will last 6 years: 4 years of accrual, and 2 years of follow-up of all patients. Results on staging and oncological outcomes are expected in 2027 and 2029, respectively. TRIAL REGISTRATION: The study has been accepted by UZ Leuven Ethical Committee. Belg. Reg. nr: B3222022000997.

Natural progression of deep pelvic endometriosis in women who opt for expectant management.

INTRODUCTION: The natural history of endometriosis is poorly understood, and despite numerous studies, the rate of the disease progression and optimal treatment planning in women who are asymptomatic or experience mild symptoms not requiring treatment are unknown. The aim of this study was to assess the behavior of deep endometriosis in women who are managed expectantly without any medical or surgical intervention. MATERIAL AND METHODS: A retrospective cohort study of women diagnosed with deep endometriosis on transvaginal ultrasound scan at the Department of Gynecology, University College London Hospitals and The Gynecology Ultrasound Centre, London, UK, from April 2007 to April 2022. All women attended for at least two ultrasound scans which were carried out by a single expert ultrasound examiner and at least 6 months apart. The number and position of endometriotic nodules were recorded, and the mean diameter of each nodule was calculated from measurements taken in three orthogonal planes. RESULTS: During the study period, 1922 women were found to have moderate or severe deep endometriosis on pelvic ultrasound examination. A total of 135 premenopausal women who were managed expectantly fitted the inclusion criteria. The median number of endometriotic nodules per woman at the initial visit was 2 (range: 0-7), and the median follow-up time was 666 days (181-2984). In the follow-up period, 50/135 women (37%, 95% CI: 29-46) developed additional nodules or experienced an increase in nodule size, and 17/135 women (13%, 95% CI: 8-19) had a regression in the number or size of the nodules. In the remaining 68/135 women (50%, 95% CI: 42-59) the disease remained static during the follow-up. The median change in mean diameter of nodules during the study period per woman was +0.13 mm (-11.67 - +5.83), with an annual growth rate of +0.09 mm/year (-6.65 - +6.45). CONCLUSIONS: In our study we found evidence of deep endometriosis progression in just over a third of women. In view of this, asymptomatic or mildly symptomatic women diagnosed with deep endometriosis could be reassured that their disease is unlikely to worsen with time.

Outcomes of Gestational Trophoblastic Disease Management: A Single Centre Review.

Background and Objectives: Gestational trophoblastic disease (GTD) is a group of pregnancy-related malignant and premalignant diseases. The aim of this study was to assess the prognostic value of clinical characteristics to predict treatment outcomes in women with GTD. Materials and Methods: In this retrospective study, 34 patients treated for GTD at the Division of Gynaecology and Perinatology, University Medical Centre Maribor, between 2008 and 2022 were identified. Clinical and pathological characteristics were obtained by analysing patient data records. Results: Within the cohort of 34 patients with GTD, 29 patients (85.3%) had a partial hydatidiform mole (HM) and five patients545 (14.7%) had a complete HM. Two patients with a complete HM developed a postmolar gestational trophoblastic neoplasia (GTN), which represents 5.8% of all cases. Conclusions: GTD is a rare disease that is frequently asymptomatic. The subsequent consequences of GTD, which can lead to malignant transformation, as well life-threatening disease complications, warrant training for early recognition of HMs and timely treatment and surveillance.

Transcriptomics of receptive endometrium in women with sonographic features of adenomyosis.

BACKGROUND: Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis. METHODS: We obtained endometrial biopsies LH-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps. RESULTS: Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group but only 4 enriched pathways (Bonferroni p value < 0.05). The analysis of 13 samples only dated to the receptive phase provided suggestive 382 DEGs (p<0.05; nonsignificant after adjusted p value) in the adenomyosis group, leading to 33 enriched pathways (Bonferroni p value < 0.05). These included pathways were already associated with endometrial biology, such as "Expression of interferon (IFN)-induced genes" and "Response to IFN-alpha". Data integration revealed pathways indicating a unique effect of adenomyosis on endometrial molecular organization (e.g., "Expression of IFN-induced genes") and its interference with endometrial receptivity establishment (e.g., "Extracellular matrix organization" and "Tumour necrosis factor production"). CONCLUSIONS: Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.

To collapse or not to collapse blastocysts before vitrification? A matched case-control study on single vitrified-warmed blastocyst transfers.

RESEARCH QUESTION: Does laser-induced artificial blastocoel collapse result in better blastocyst cryopreservation survival and a higher live birth rate (LBR) in comparison with intact counterparts? DESIGN: Half of the supernumerary blastocysts from IVF cycles were randomly selected before vitrification for laser-induced artificial collapsing or vitrification in intact form. A matched case-control study of first transfers of single blastocysts artificially collapsed (case) or intact (control) before vitrification was conducted. Controls were matched to cases on a 1:1 ratio by female age, parity, fresh and vitrified cycle protocol, blastocyst age and quality, resulting in 309 case-control pairs. RESULTS: The two groups were comparable in terms of their characteristics. Survival rates in the case and control groups (97.8% and 95.7%; P = 0.133) were comparable, but the optimal survival rate was higher in the case group (78.2% and 69.3%; P = 0.03). Clinical pregnancy rates (38.2% and 35.3%; P = 0.518), miscarriage rates (15.2% and 22%; P = 0.190), LBR per transfer (32.4% and 27.5%; P = 0.221) and LBR per warmed blastocyst (31.6% and 26.3%; P = 0.137) were not statistically different between the case and control groups. No significant difference in preterm births (11.1% versus 15.7%), birthweights (3333 ± 723 g versus 3304 ± 609 g) or sex ratio (49.3% versus 50.7% boys) was observed between the two groups. No major malformations were detected in the study population. CONCLUSIONS: Compared with vitrification of intact blastocysts, collapsed blastocysts resulted in a significantly higher optimal survival rate, and although they resulted in a 5% higher LBR, this was not significant for the chosen sample size. Neonatal outcomes were comparable in the two groups.

Molecular signature of eutopic endometrium in endometriosis based on the multi-omics integrative synthesis.

PURPOSE: To synthesise data from genome-wide studies reporting molecular signature of eutopic endometrium through the phases of the menstrual cycle in endometriosis. METHODS: Extraction of data from publications reporting genetic signatures characterising endometrium associated with endometriosis. The nomenclature of extracted differentially expressed transcripts and proteins was adopted according to the HUGO Gene Nomenclature Committee (HGNC). Loci were further sorted according to the different phases of the menstrual cycle, i.e. menstrual (M), proliferative (P), secretory (S), early-secretory (ES), mid-secretory (MS), late-secretory (LS), and not specified (N/S) if the endometrial dating was not available. Enrichment analysis was performed using the DAVID bioinformatics tool. RESULTS: Altered molecular changes were reported by 21 studies, including 13 performed at the transcriptomic, 6 at proteomic, and 2 at epigenomic level. Extracted data resulted in a catalogue of total 670 genetic causes with available 591 official gene symbols, i.e. M = 3, P = 188, S = 81, ES = 82, MS = 173, LS = 36, and N/S = 28. Enriched pathways included oestrogen signalling pathway, extracellular matrix organization, and endothelial cell chemotaxis. Our study revealed that knowledge of endometrium biology in endometriosis is fragmented due to heterogeneity of published data. However, 15 genes reported as dysregulated by at least two studies within the same phase and 33 significantly enriched GO-BP terms/KEGG pathways associated with different phases of the menstrual cycle were identified. CONCLUSIONS: A multi-omics insight into molecular patterns underlying endometriosis could contribute towards identification of endometrial pathological mechanisms that impact fertility capacities of women with endometriosis.

Cumulative live birth rate after GnRH agonist trigger and elective cryopreservation of all embryos in high responders.

Elective embryo cryopreservation after using gonadotrophin-releasing hormone (GnRH) antagonist protocols and GnRH agonist triggering is becoming an increasingly important part of medically assisted reproduction. We designed a single-centre retrospective study to assess the cumulative probability of achieving a live birth through consecutive transfers of vitrified-warmed blastocysts after elective embryo cryopreservation in high-responding patients. Hence, 123 women identified to be at high risk for developing ovarian hyperstimulation syndrome were included. They were stimulated using GnRH antagonist protocol, and GnRH agonist was used to trigger final oocyte maturation. All embryos were vitrified at the blastocyst stage and transferred in the subsequent menstrual cycles. Using the Kaplan-Meier survival analysis, a total of 65.9% (95% CI 57.5 to 74.3) women achieved a live birth after a maximum of six embryo transfer cycles using the 'conservative' approach. Applying the 'optimistic' approach, presuming that women who still had cryopreserved embryos and did not return for embryo transfer had the same chance of achieving a live birth as those returning for transfer, the cumulative live birth rate estimated in six embryo transfer cycles was 76.6% (95% CI 69.1 to 84.1). No cases of severe ovarian hyperstimulation syndrome were recorded.

Endometrial injury, the quality of embryos, and blastocyst transfer are the most important prognostic factors for in vitro fertilization success after previous repeated unsuccessful attempts.

PURPOSE: The purpose of this study was to find out the most important prognostic factors for achieving a pregnancy after in vitro fertilization (IVF) in women with history of repeated unsuccessful IVF attempts. METHODS: We analyzed factors affecting pregnancy rate in a retrospective study including 429 IVF/ICSI cycles performed in women younger than 40 years with at least three previous consecutive failed IVF/ICSI attempts. RESULTS: Clinical pregnancy was observed in 140/429 (32.6%) cycles. Clinical pregnancy rate (CPR) was significantly higher in cycles with LEI compared to cycles without LEI before embryo transfer (44.4 vs 26.54%, p = 0.007). The CPR was also higher in cycles with day 5 blastocyst- compared with day 3 cleavage-stage embryo transfers (45.51 vs 26.54%, p < 0.001). In multivariate logistic regression model, only transfer of at least one good quality embryo (OR = 4.32, 95% CI 2.41-7.73), local endometrial injury (OR = 1.73, 95% CI 1.02-2.92), and transfer on day 5 (OR = 3.02, 95% CI 1.53-5.94) remained important independent prognostic factors for clinical pregnancy. CONCLUSIONS: These results suggest that hysteroscopy with local injury to the endometrium prior to ovarian stimulation for IVF/ICSI can improve implantation and pregnancy rates in women experiencing recurrent IVF failure. However, large studies are needed to confirm these findings.

What is the value of anti-Müllerian hormone in predicting the response to ovarian stimulation with GnRH agonist and antagonist protocols?

BACKGROUND: Anti-Müllerian hormone (AMH) is a marker of the ovarian reserve with promising prognostic potential in reproductive medicine. We aimed to evaluate the prognostic ability of AMH for predicting excessive or poor responses to ovarian stimulation using gonadotrophin-releasing hormone (GnRH) agonist and GnRH antagonist protocols in patients undergoing medically assisted reproduction (MAR) procedures. METHODS: This retrospective analysis included 623 women who underwent ovarian stimulation for medically assisted reproduction. AMH level measurements were acquired from all couples within six months of the initiation of ovarian stimulation. RESULTS: AMH was significantly correlated with the number of retrieved oocytes, and age was not relevant in a multivariate regression analysis (unstandardized regression coefficient of 1.130, 95 % confidence interval 0.977-1.283). AMH was a better predictor of both excessive (>19 oocytes) and poor (<4 oocytes) ovarian response than age (areas under the curve (AUCs) of 0.882 and 0.816, respectively). When stratified according to the stimulation protocol (a long GnRH agonist versus a GnRH antagonist protocol), AMH retained its high predictive value for excessive and poor responses in both groups. Serum AMH levels exhibited a strong correlation with the level of the response to ovarian stimulation. CONCLUSIONS: AMH is an independent and an accurate predictor of excessive and poor responses to GnRH agonist and GnRH antagonist protocols for ovarian stimulation.

Simultaneous determination of phthalates, their metabolites, alkylphenols and bisphenol A using GC-MS in urine of men with fertility problems.

A GC-MS method was successfully applied to measure simultaneously the concentrations of endocrine disrupting compounds (5 dialkyl phthalates, 9 phthalate monoesters, 3 alkylphenols and bisphenol A) in 136 male urine samples. In the present study the method was validated and concentrations of EDCs were determined. The results were compared with results from other studies. Correlations between endocrine disrupting compounds and also correlations of endocrine disrupting compounds with two semen quality parameters are presented and evaluated. Significant positive correlations were found between almost all the endocrine disrupting compounds. The parameter sum of DEHP (SUM DEHP) was positively correlated to all the endocrine disrupting compounds but negatively to two semen quality parameters. Negative correlations between the endocrine disrupting compounds and the semen quality parameters could indicate that endocrine disrupting compounds could cause reproductive problems by decreasing the semen count and quality. This research will have helped to evaluate human exposure to endocrine disrupting compounds.

Obstetric outcomes in women with pelvic endometriosis: a prospective cohort study.

OBJECTIVE: To determine whether obstetric outcomes differ between women with endometriosis and those without, where all women undergo first-trimester screening for endometriosis. DESIGN: A prospective observational cohort study. SETTING: The Early Pregnancy Unit at University College London Hospital, United Kingdom. PATIENTS: Women with a live pregnancy progressing beyond 12 weeks' gestation and concurrent endometriosis (n = 110) or no endometriosis (n = 393). INTERVENTION: All women underwent a pelvic ultrasound examination in early pregnancy to examine for the presence of endometriosis and uterine abnormalities. MAIN OUTCOME MEASURES: The primary outcome of interest was preterm birth, defined as delivery before 37 completed weeks' gestation. Secondary outcomes included late miscarriage, antepartum hemorrhage, placental site disorders, gestational diabetes, hypertensive disorders of pregnancy, neonates small for gestational age, mode of delivery, intrapartum sepsis, postpartum hemorrhage, and admission to the neonatal unit. RESULTS: Women with a diagnosis of endometriosis did not have statistically significantly higher odds of preterm delivery (adjusted odds ratio [aOR] 1.85 [95% confidence interval {CI} 0.50-6.90]), but they did have higher odds of postpartum hemorrhage during cesarean section (aOR 3.64 [95% CI 2.07-6.35]) and admission of their newborn infant to the neonatal unit (aOR 3.24 [95% CI 1.08-9.73]). Women with persistent or recurrent deep endometriosis after surgery also had higher odds of placental site disorders (aOR 8.65 [95% CI 1.17-63.71]) and intrapartum sepsis (aOR 3.47 [95% CI 1.02-11.75]). CONCLUSION: We observed that women with endometriosis do not have higher odds of preterm delivery, irrespective of their disease subtype. However, they do have higher odds of postpartum hemorrhage during the cesarean section and newborn admission to the neonatal unit.

Endocrine-disrupting chemicals and male reproductive health.

Endocrine-disrupting chemicals are substances present in the environment that can interfere with normal hormonal balance and thus exert potentially adverse health effects on the human organism. Male reproductive system development and function may be susceptible to the effects of such environmental toxicants. Bisphenol A, phthalates and alkylphenols are important components of multiple products and are thus ubiquitously present in the environment. It has been demonstrated under laboratory conditions that they can exert detrimental effects on the male reproductive system. However, human exposure data are scarce and do not uniformly support toxicity of these substances at environmental concentrations. Despite substantial research efforts, the final answer to the problem of endocrine-disrupting chemicals is not yet in sight.

Comparison of embryo transfer strategies and assisted reproduction outcome in Slovenian and cross-border patients.

A reduction in the number of embryos transferred is the most important step in decreasing multiple gestation rates after medically assisted reproduction. Slovenia has implemented insurance company regulations that regulate single-embryo transfer in selected good-prognosis couples. The aim of the present study was to evaluate its effects on the Slovenian population compared with cross-border patients, who are not affected by the insurance company policy. Ultimately, 2403 couples undergoing IVF or intracytoplasmic sperm injection were included in the retrospective analysis. Patients were classified according to their origin. The decision about the number of embryos transferred and the treatment success were evaluated. The implementation of the policy favouring single-embryo transfer resulted in a significant decrease in the twin birth rate in Slovenian patients (24.4% before policy versus 6.7% after policy implementation, P<0.001). Although in cross-border patients twin birth rates have declined through the study period, they remained significantly higher compared with Slovenian patients (23.1% versus 6.7%, P<0.001). The data demonstrate that insurance company policies favouring single-embryo transfer are an effective tool in decreasing multiple gestation rates. Similar mechanisms should be implemented in the cross-border patient population.

Human chorionic gonadotropin levels are equally predictive for pregnancy outcome after fresh and vitrified-warmed blastocyst transfer.

PURPOSE: The aim of the present study was to evaluate if the live birth predictive values of ß-hCG levels differ in fresh and vitrified-warmed blastocyst transfer cycles. METHODS: In the retrospectively designed study, 775 cycles with positive ß-hCG values 13 days after fresh blastocyst transfer (fresh ET; n = 568) or vitrified-warmed blastocyst transfer (FET; n = 207) were selected for analysis. Average ß-hCG levels stratified according to pregnancy outcome (biochemical pregnancy, spontaneous abortion, ectopic pregnancy, and singleton or twin birth) were compared between fresh ET and FET cycles. To determine the optimal sensitivity and specificity of ß-hCG levels for live birth prediction, a ROC curve was constructed. Fisher's exact test was used to compare the positive predictive values (PPV). RESULTS: Average ß-hCG levels stratified according to pregnancy outcome were not statistically different between fresh ET and FET cycles. In fresh ET and in FET group, the ß-hCG levels were significantly higher in pregnancies resulting in live birth compared to non-viable pregnancies (1,035 vs. 462 IU/L, p < 0.001 and 968 vs. 411 IU/L, p < 0.001). Optimal cut-off level for live birth prediction was 495 IU/L (sensitivity 83.0 %, specificity 71.8 %) after ET and 527 IU/L (sensitivity 80.0 % and specificity 76.6 %) after FET. The PPV for live birth rate in the groups after ET and FET were 90.6 % and 84.9 % respectively, without statistically significant difference (p > 0.05). CONCLUSION: Beta-hCG levels after fresh and vitrified-warmed blastocyst transfer are equally predictive for pregnancy outcome. Clinicians can be encouraged to interpret ß-hCG results in the same manner.

What Role do Androgens Play in Endometrial Cancer?

The role of estrogens and progesterone in the development and progression of endometrial cancer is well-established, but there are very little data about the role of androgens. There are five different androgens produced in women: dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T) and dihydrotestosterone (DHT). The most potent hormones are T and DHT, the latter being mainly produced from T in peripheral tissues, including endometrium. Although they are considered to exert antiproliferative effects in many settings and the expression of their receptors is more often associated with a good prognosis in EC, it is still unknown in which specific settings androgens have carcinogenic or protective effects in EC.

Ultra-High-Risk Gestational Choriocarcinoma of the Ovary Associated with Ectopic Pregnancy.

Gestational choriocarcinoma of the ovary is an exceptionally rare and highly aggressive tumor. Preoperative diagnosis of extrauterine choriocarcinoma is difficult due to nonspecific clinical presentation and its resemblance to ectopic pregnancy. Without molecular genetic analysis, it is not possible to reliably differentiate gestational from non-gestational choriocarcinoma. Here, we present a case of a 44-year-old woman who presented to our emergency department with complaints of pelvic pain, vaginal bleeding, and amenorrhea. Because of a recent history of conservatively managed ectopic pregnancy, the patient underwent emergency laparoscopy. Right-sided salpingo-oophorectomy was performed due to intraoperatively suspected ovarian ectopic pregnancy. Histopathology results revealed the diagnosis of ovarian choriocarcinoma of possible gestational origin. It was classified as FIGO stage IV and WHO ultra-high-risk, and she underwent multi-agent chemotherapy without major complications. She has remained in complete remission after a 12-month follow-up. Considering the rarity of this diagnosis, we conducted a literature review including all published cases of suspected gestational choriocarcinomas of the ovary. We conclude that due to the rarity of this entity, preoperative differentiating between ovarian ectopic pregnancy and ovarian choriocarcinoma is extremely challenging, and without molecular genetic analysis, it is not possible to identify the genetic origin of the tumor.

The association of Wnt-signalling and EMT markers with clinical characteristics in women with endometrial cancer.

Endometrial cancer is the most common gynecologic malignancy in the developed world. Risk stratification and treatment approaches are changing due to better understanding of tumor biology. Upregulated Wnt signaling plays an important role in cancer initiation and progression with promising potential for development of specific Wnt inhibitor therapy. One of the ways in which Wnt signaling contributes to progression of cancer, is by activating epithelial-to-mesenchymal transition (EMT) in tumor cells, causing the expression of mesenchymal markers, and enabling tumor cells to dissociate and migrate. This study analyzed the expression of Wnt signaling and EMT markers in endometrial cancer. Wnt signaling and EMT markers were significantly correlated with hormone receptors status in EC, but not with other clinico-pathological characteristics. Expression of Wnt antagonist, Dkk1 was significantly different between the ESGO-ESTRO-ESP patient risk assessment categories using integrated molecular risk assessment.

Endometrial Cancer Individualized Scoring System (ECISS): A machine learning-based prediction model of endometrial cancer prognosis.

OBJECTIVE: To establish a prognostic model for endometrial cancer (EC) that individualizes a risk and management plan per patient and disease characteristics. METHODS: A multicenter retrospective study conducted in nine European gynecologic cancer centers. Women with confirmed EC between January 2008 to December 2015 were included. Demographics, disease characteristics, management, and follow-up information were collected. Cancer-specific survival (CSS) and disease-free survival (DFS) at 3 and 5 years comprise the primary outcomes of the study. Machine learning algorithms were applied to patient and disease characteristics. Model I: pretreatment model. Calculated probability was added to management variables (model II: treatment model), and the second calculated probability was added to perioperative and postoperative variables (model III). RESULTS: Of 1150 women, 1144 were eligible for 3-year survival analysis and 860 for 5-year survival analysis. Model I, II, and III accuracies of prediction of 5-year CSS were 84.88%/85.47% (in train and test sets), 85.47%/84.88%, and 87.35%/86.05%, respectively. Model I predicted 3-year CSS at an accuracy of 91.34%/87.02%. Accuracies of models I, II, and III in predicting 5-year DFS were 74.63%/76.72%, 77.03%/76.72%, and 80.61%/77.78%, respectively. CONCLUSION: The Endometrial Cancer Individualized Scoring System (ECISS) is a novel machine learning tool assessing patient-specific survival probability with high accuracy.

The Role of CTNNB1 in Endometrial Cancer.

Endometrial cancer (EC) is the most common gynaecologic malignancy in the developed countries. Recent evidence suggests that histopathological subtyping together with molecular subgrouping can lead to more accurate assessment of the risk profile for the patient. Clinical studies suggest the currently used molecular classification improves the risk assessment of women with endometrial cancer but does not explain the differences in recurrence profiles clearly. This could be improved by novel markers. One of such are mutations in the ß-catenin (CTNNB1) gene, a frequently mutated gene in endometrial cancer. This shows mutations mostly at phosphorylation sites of the ß-catenin and almost exclusively in the endometrial subgroup of no specific molecular profile. CTNNB1 mutations lead to alterations in the Wnt/ß-catenin signalling pathway, involved in the carcinogenesis and progression of EC by inducing transcription of target genes, whose function is to regulate the cell cycle. Although tumours with mutations in CTNNB1 tend to have low-risk characteristics, they are related to worse outcomes with significantly increased rate of disease recurrence and lower overall survival.