Expression of Intracellular Galectin-8 and -9 in Endometrial Cancer.

Endometrial cancer (EC) is a common gynecological cancer worldwide. Treatment has been improved in recent years; however, in advanced stages, therapeutic options are still limited. The expression of galectins is increased in several tumor types and that they are involved in important cell processes. Large studies on endometrial cancer are still pending; Specimens of 225 patients with EC were immunohistochemically stained with antibodies for Gal-8 and Gal-9. Expression was correlated with histopathological variables. The cytosolic expression of both galectins is associated with grading and survival. Cytosolic Galectin-8 expression is a positive prognostic factor for overall survival (OS) and progression-free survival (PFS), while nuclear Gal-8 expression correlates only to OS. The cytosolic presence of Galectin-9 is correlated with a better prognosis regarding OS. Our results suggest that expression of both galectins is associated with OS and PFS in EC. Further studies are needed to understand the underlying molecular mechanisms.

Mismatch Repair (MMR) Gene Mutation Carriers Have Favorable Outcome in Colorectal and Endometrial Cancer: A Prospective Cohort Study.

Germline (Lynch syndrome, LS) and somatic deficiencies of mismatch repair proteins (MMRd) are linked to colorectal and endometrial cancer; however, their prognostic impact in Asian populations remains unclear. This prospective cohort study aimed to determine the prevalence and outcome of germline and somatic MMRd in cancer patients suspected of LS. Patients with colorectal or endometrial cancer suspected of LS were enrolled and underwent gene sequencing for germline MMRd (gMMRd) and immunohistochemistry staining of MMR proteins in a subset of the pathological samples (pMMRd). Among the 451 enrolled patients, 36 patients were gMMRd (+). Compared with gMMRd (-) patients, the 10-year relapse-free survival in gMMRd (+) patients was significantly higher (100% vs. 77.9%; p = 0.006), whereas the 10-year overall survival was similar (100% vs. 90.9%; p = 0.12). Among the 102 gMMRd (-) patients with available pMMR status, 13.7% were pMMRd (+). The 5-year relapse-free survival was 62.9% in gMMRd (-) pMMRd (+) patients and 35.0% in gMMRd (-) pMMRd (-) patients, both lower than gMMRd (+) patients (100%; p < 0.001). This study showed that having LS confers a favorable outcome in colorectal and endometrial cancer patients and highlights the importance of germline genetic testing following the detection of somatic MMRd.

Diagnostic Value and Molecular Function of MicroRNAs in Endometrial Diseases: A Systematic Review.

The human endometrium experiences significant cyclic morphological and biochemical changes throughout the menstrual cycle to prepare for embryo implantation. These processes are meticulously regulated by ovarian steroids and various locally expressed genes, encompassing inflammatory reactions, apoptosis, cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. MicroRNAs (miRNAs) have been recognized as crucial regulators of gene expression, with their altered expression being linked to the onset and progression of various disorders, including cancer. This review examines the expression of miRNAs in the endometrium and their potential regulatory roles under pathological conditions such as endometriosis, recurrent implantation failure and endometrial cancer. Given miRNAs' critical role in maintaining gene expression stability, understanding the regulatory mechanisms of endometrial miRNAs and identifying their specific target genes could pave the way for developing preventive and therapeutic strategies targeting specific genes associated with these reproductive disorders.

Unsolved Issues in the Integrated Histo-Molecular Classification of Endometrial Carcinoma and Therapeutic Implications.

Endometrial carcinoma (EC) is the most frequent gynecological cancer, with an increasing incidence and mortality in recent times. The last decade has represented a true revolution with the development of the integrated histo-molecular classification of EC, which allows for the stratification of patients with morphologically indistinguishable disease into groups with different prognoses. Particularly, the POLE-mutated subgroup exhibits outstanding survival. Nevertheless, the indiscriminate application of molecular classification appears premature. Its prognostic significance has been proven mainly in endometrioid EC, the most common histotype, but it has yet to be convincingly confirmed in the other minor histotypes, which indeed account for a relevant proportion of EC mortality. Moreover, its daily use both requires a mindful pathologist who is able to correctly evaluate and unambiguously report immunohistochemical staining used as a surrogated diagnostic tool and is hampered by the unavailability of POLE mutation analysis. Further molecular characterization of ECs is needed to allow for the identification of better-tailored therapies in different settings, as well as the safe avoidance of surgery for fertility preservation. Hopefully, the numerous ongoing clinical trials in the adjuvant and metastatic settings of EC will likely produce evidence to refine the histo-molecular classification and therapeutic guidelines. Our review aims to retrace the origin and evolution of the molecular classification for EC, reveal its strengths and limitations, show clinical relevance, and uncover the desired future developments.

Uterine cancer restaging according to the updated 2023 FIGO Guidelines does not uniformly affect prognosis: An institutional retrospective cohort study.

OBJECTIVE: Efforts have been made to better risk stratify patients given the rise in incidence of endometrial cancer (EC). The 2023 FIGO staging now incorporates histologic subtype and molecular classification into determination of EC stage. We sought to elucidate if the new staging system demonstrated prognostic differences compared to the 2009 staging system. METHODS: A retrospective chart review was performed on women treated for EC at our institution from September 2013 to May 2023 and combined with the publicly available TCGA Nature 2013 dataset. Detailed clinical information was captured. Patients were restaged according to the 2023 guidelines. Survival estimates were obtained using Kaplan-Meier method, and the log-rank test was used to compare survival curves for progression-free survival (PFS). RESULTS: 919 patients were included in our analysis. The datasets were comparable regarding histologic grade, stage, and age at diagnosis. 175 (31.5%) of patients in the institution dataset and 115 (31.6%) patients in the TCGA dataset experienced a stage change. Most patients whose stage changed were upstaged (275/290; 94.8%). 3-year PFS estimates for stage IA patients with no stage change versus those upstaged were 92.3% (95% CI: 87.2, 95.4) v. 72.0% (95% CI: 68.4, 84.9), p = 0.002. No significant differences in survival difference were seen in other stage subsets. CONCLUSION: Modest survival differences exist in patients with EC originally staged as IA who underwent upstaging. No significant survival difference is observed in patients who are restaged to stage II or III subsets. Improved risk stratification is needed in assessing prognosis and adjuvant therapy for patients with endometrial cancer.

Associations between Serum Metabolites and Female Cancers: a Bidirectional Two-sample Mendelian Randomization Study.

Female cancers, especially breast, ovarian, cervical and endometrial cancers, constitute a major threat to women's health worldwide. In view of the complex genetic background of cancers cannot be fully explained with current genetic information, we used a bidirectional two-sample mendelian randomization approach to explore the causal associations between serum metabolites and four major female cancers-breast, ovarian, cervical and endometrial cancers. We analyzed the metabolites dataset from the Canadian Longitudinal Study of Aging and cancer datasets from the 10th round of the Finngen project. Replication analyses was performed with Cancer Association Consortium and Leo's studies. Instrumental variables were analyzed using methods including the Wald ratio, inverse-variance weighted, MR-Egger, and weighted median. To ensure robustness, sensitivity analyses were performed using Cochrane's Q, Egger's intercept, MR-PRESSO, and leave-one-out methods. After meticulous analysis, we obtained levels of 3-hydroxyoleoylcarnitine, hexadecanedioate, tetradecanedioate and carnitine C14 with robust causal associations with breast cancer, levels of 5alpha-androstan-3alpha,17beta-diol monosulfate (1), androstenediol (3beta,17beta) monosulfate (1), androsterone sulfate, and 5alpha-androstan-3beta,17beta-diol disulfate causal associations with endometrial cancer. The reverse analysis showed that breast, ovarian, and endometrial cancer and survival of breast and ovarian cancer were found to have causal relationships with 8, 5, 2, 6, and 3 metabolites, respectively. These insights underscore the potential roles of specific metabolites in the etiology of female cancers, providing new biomarkers for early detection, risk stratification, and disease progression monitoring. Further research could elucidate how these metabolites influence specific pathways in cancer development, offering theoretical foundations for prevention and treatment strategies.

Lower limb lymphedema after surgical staging for endometrial cancer: Current insights and future directions.

Lower extremity lymphedema (LEL) is a common complication following surgical staging of endometrial cancer. LEL is a chronic condition associated with significant impact on patient morbidity and quality of life (QoL). This review aimed to report the current evidence in the literature on secondary LEL after surgical staging for endometrial cancer, focusing on the incidence based on different approaches to lymph node staging, diagnosis, risk factors, and the impact on QoL. Due to the absence of a standardized agreement regarding the methodology for evaluating LEL, the documented frequency of occurrence fluctuates across different studies, ranging from 0% to 50%. Systematic pelvic lymphadenectomy appears to be the primary determinant associated with the emergence of LEL, whereas the implementation of sentinel lymph node biopsy has notably diminished the occurrence of this lymphatic complication after endometrial cancer staging. LEL is strongly associated with decreased QoL, lower limb function, and negative body image, and has a detrimental impact on cancer-related distress reported by survivors. Standardization of lymphedema assessment is needed, along with cross-cultural adaptation of subjective outcome measures for self-reported LEL. The advent of sentinel lymph node mapping represents the ideal approach for accurate nodal assessment with less short- and long-term morbidity. Further research is needed to definitively assess the prevalence and risk factors of LEL and to identify strategies to improve limb function and QoL in cancer survivors with this chronic condition.

The impact of hysterectomy on subsequent colonoscopy in women with Lynch Syndrome.

BACKGROUND AND AIMS: Women with Lynch Syndrome (LS) have a high risk of colorectal and endometrial cancer. They are recommended regular colonoscopies, and some choose prophylactic hysterectomy. The aim of this study was to determine the impact of hysterectomy on subsequent colonoscopy in these women. MATERIALS AND METHODS: A total of 219 LS women >30 years of age registered in the clinical registry at Section for Hereditary Cancer, Oslo University Hospital, were included. Data included hysterectomy status, other abdominal surgeries, and time of surgery. For colonoscopies, data were collected on cecal intubation rate, challenges, and level of pain. Observations in women with and without hysterectomy, and pre- and post-hysterectomy were compared. RESULTS: Cecal intubation rate was lower in women with hysterectomy than in those without (119/126 = 94.4% vs 88/88 = 100%, p = 0.025). Multivariate regression analysis showed an increased risk of challenging colonoscopies (OR,3.58; CI: 1.52-8.43; p = 0.003), and indicated a higher risk of painful colonoscopy (OR, 3.00; 95%CI: 0.99-17.44, p = 0.052), in women with hysterectomy compared with no hysterectomy. Comparing colonoscopy before and after hysterectomy, we also found higher rates of reported challenging colonoscopies post-hysterectomy (6/69 = 8.7% vs 23/69 = 33.3%, p < 0.001). CONCLUSIONS: Women with hysterectomy had a lower cecal intubation rate and a higher number of reported challenging colonoscopy than women with no hysterectomy. However, completion rate in the hysterectomy group was still as high as 94.4%. Thus, LS women who consider hysterectomy should not be advised against it.

CircABHD2 Inhibits Malignant Progression of Endometrial Cancer by Regulating NAD+/NAMPT Metabolism Axis.

Circular RNAs (circRNAs) perform important functions in the regulation of diverse physiological and pathological processes. CircABHD2 exhibits down-regulation in both endometrial cancer (EC) cells and tissues, but the biological roles and mechanisms of action in EC are still unclear. This study aims to provide a theoretical basis for the role of circABHD2 in EC and potential targets for individualized precision therapy. Dysregulated circRNAs were identified using RNA sequencing (RNA-Seq) from EC tissues and validated using RT-qPCR. CCK-8, colony formation assay, wound healing assay, transwell assay, cell cycle, and apoptosis assay were used to evaluate the effects of circABHD2 on EC cells. Metabolomics assay and western blot analyses were used to investigate the potential mechanisms of circABHD2. From sequencing of RNA (RNA-Seq) analysis of EC tissues, we obtained 19 dysregulated circRNAs, including 8 upregulated ones and 11 downregulated ones. Using RT-qPCR on 32 EC tissues and 19 normal endometrial tissues, we confirmed that circABHD2 was downregulated in EC tissues. The expression levels of circABHD2 were closely relevant to the International Federation of Gynecology and Obstetrics (FIGO) stage and differentiation degree of EC. Functional experiments demonstrated that overexpression of circABHD2 decreased proliferation, migration, invasion, and promoted cell apoptosis. Un-targeted metabolomic assay revealed 31 differential metabolites in EC cells overexpressing circABHD2. KEGG analysis of differential metabolites indicated that NAD+ is the core metabolite regulated by circABHD2. NAMPT is one key enzyme involved in the synthetic pathway responsible for NAD+. Subsequent experiments confirmed that by inhibiting NAMPT protein expression in EC cells, cirABHD2 can inhibit NAD+ level, suggesting that circABHD2 may inhibit EC by regulating the metabolic axis of NAD+/NAMPT. CircABHD2, a downregulated circRNA in EC cells and tissues, inhibits the malignant progression of EC via the NAD+/NAMPT metabolic axis. This discovery presents a promising diagnostic biomarker and potential therapeutic target for EC.

Development and validation of a circulating tumor DNA-based optimization-prediction model for short-term postoperative recurrence of endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is a common gynecological malignancy that typically requires prompt surgical intervention; however, the advantage of surgical management is limited by the high postoperative recurrence rates and adverse outcomes. Previous studies have highlighted the prognostic potential of circulating tumor DNA (ctDNA) monitoring for minimal residual disease in patients with EC. AIM: To develop and validate an optimized ctDNA-based model for predicting short-term postoperative EC recurrence. METHODS: We retrospectively analyzed 294 EC patients treated surgically from 2015-2019 to devise a short-term recurrence prediction model, which was validated on 143 EC patients operated between 2020 and 2021. Prognostic factors were identified using univariate Cox, Lasso, and multivariate Cox regressions. A nomogram was created to predict the 1, 1.5, and 2-year recurrence-free survival (RFS). Model performance was assessed via receiver operating characteristic (ROC), calibration, and decision curve analyses (DCA), leading to a recurrence risk stratification system. RESULTS: Based on the regression analysis and the nomogram created, patients with postoperative ctDNA-negativity, postoperative carcinoembryonic antigen 125 (CA125) levels of < 19 U/mL, and grade G1 tumors had improved RFS after surgery. The nomogram's efficacy for recurrence prediction was confirmed through ROC analysis, calibration curves, and DCA methods, highlighting its high accuracy and clinical utility. Furthermore, using the nomogram, the patients were successfully classified into three risk subgroups. CONCLUSION: The nomogram accurately predicted RFS after EC surgery at 1, 1.5, and 2 years. This model will help clinicians personalize treatments, stratify risks, and enhance clinical outcomes for patients with EC.

A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Our current understanding of the biological impact of endometrial cancer mtDNA genome mutations and their potential use as a biomarker.

Endometrial cancer (EC) is a devastating and common disease affecting women's health. The NCI Surveillance, Epidemiology, and End Results Program predicted that there would be >66,000 new cases in the United States and >13,000 deaths from EC in 2023, and EC is the sixth most common cancer among women worldwide. Regulation of mitochondrial metabolism plays a role in tumorigenesis. In proliferating cancer cells, mitochondria provide the necessary building blocks for biosynthesis of amino acids, lipids, nucleotides, and glucose. One mechanism causing altered mitochondrial activity is mitochondrial DNA (mtDNA) mutation. The polyploid human mtDNA genome is a circular double-stranded molecule essential to vertebrate life that harbors genes critical for oxidative phosphorylation plus mitochondrial-derived peptide genes. Cancer cells display aerobic glycolysis, known as the Warburg effect, which arises from the needs of fast-dividing cells and is characterized by increased glucose uptake and conversion of glucose to lactate. Solid tumors often contain at least one mtDNA substitution. Furthermore, it is common for cancer cells to harbor mixtures of wild-type and mutant mtDNA genotypes, known as heteroplasmy. Considering the increase in cancer cell energy demand, the presence of functionally relevant carcinogenesis-inducing or environment-adapting mtDNA mutations in cancer seems plausible. We review 279 EC tumor-specific mtDNA single nucleotide variants from 111 individuals from different studies. Many transition mutations indicative of error-prone DNA polymerase γ replication and C to U deamination events were present. We examine the spectrum of mutations and their heteroplasmy and discuss the potential biological impact of recurrent, non-synonymous, insertion, and deletion mutations. Lastly, we explore current EC treatments, exploiting cancer cell mitochondria for therapy and the prospect of using mtDNA variants as an EC biomarker.

Efficacy of ABCA1 Transporter Proteins in Patients with Endometrial Cancer: an In Vitro Study.

Objectives: Endometrial carcinoma (EC) is a typical gynecological malignant tumor that occurs more frequently every year. Obesity is a significant contributor to the development of EC and its prognosis. Lipid metabolism and malignant tumors have a long history of association. Elevated cholesterol levels are made possible by adenosine triphosphate-binding cassette protein A1 (ABCA1) deficiency, which eventually promotes cancer cell survival. The aim of this study was to examine at the ABCA1 gene expression levels in EC patients. The relationship between ABCA1 and the occurrence, progression, and prognosis of EC is discussed in this article as a potential mechanism. Materials and Methods: The samples of 45 endometrial adenocarcinoma patients were retrospectively included in this study and they were further divided into Grade 1 (15), Grade 2 (15), Grade 3 (15) tumors, control group. Twenty-nine endometrial tissues without a confirmed diagnosis of endometrial cancer made up the control group. ABCA1 gene expression was examined using real-time polymerase chain reaction. Results: According to the results, the gene expressions of the patient group were higher than the control group When each Grade was compared with the control group, statistically significant results were obtained. After analyzing the data, it was found that the patient group was generally higher than the control group (p < 0.05) and there were differences in the grades of the patient group (p < 0.05). When the ABCA1 expressions of the grade groups and control groups were compared separately, a difference was found between Grade 1, Grade 2 and Grade 3 and the control group (p= 0.0001). Conclusion: According to the findings of our study, a key component in the growth of EC tumors is the increase in cholesterol production caused by a reduction in ABCA1.

Comparative Assessment of miR-185-5p and miR-191-5p Expression: From Normal Endometrium to High-Grade Endometrial Cancer.

Endometrial cancer (EC) is a significant cause of cancer-related deaths in women. MicroRNAs (miRs) play a role in cancer development, acting as oncogenes or tumor suppressors. This study evaluated the diagnostic potential of hsa-miR-185-5p and hsa-miR-191-5p in EC and their correlation with clinical and histopathological features. A cross-sectional study analyzed formalin-fixed, paraffin-embedded tissue samples from 59 patients: 18 with EC, 21 with endometrial hyperplasia (EH), 17 with normal endometrium (NE), and 3 with endometrial polyps (EPs). Quantitative reverse transcription-polymerase chain reaction and TaqMan probes were used for miR expression analysis. The Shapiro-Wilk test was used to analyze the normal distribution of the data. Subsequently, parametric or non-parametric tests were used to evaluate the associations between the expression levels of each miR and clinical parameters. Both miRs were underexpressed in some precursor and malignant lesions compared to certain NE subtypes and benign lesions. Specifically, hsa-miR-185-5p showed underexpression in grade 3 EC compared to some NE and EH subtypes (FC: -57.9 to -8.5, p < 0.05), and hsa-miR-191-5p was underexpressed in EH and EC compared to secretory endometrium and EPs (FC: -4.2 to -32.8, p < 0.05). SETD1B, TJP1, and MSI1 were common predicted target genes. In conclusion, hsa-miR-185-5p and hsa-miR-191-5p are underexpressed in EC tissues, correlating with histopathological grades, highlighting their potential as diagnostic biomarkers and their role as tumor suppressors in EC.

Vaginal lacerations during laparoscopic hysterectomy for endometrial cancer and local recurrence risk.

Objective: Laparoscopic surgery (MIS) offers equivalent oncologic outcomes as compared to open surgery, while causing lesser morbidity and resulting in a faster recovery. Vaginal extraction of specimens may cause vaginal or perineal lacerations (VL). The objective of this retrospective study was to assess local recurrence rates compared between cases with vaginal laceration (VL) or without vaginal lacerations (NL). Methods: We identified patients with endometrial cancer who underwent MIS between 2014 and 2018. We assessed the rate of local recurrence between patients in VL and NL cohorts. The study included all histologic subtypes and stages while benign final pathology, synchronous primaries or cases that required laparotomy for extraction were excluded. Results: 338 MIS cases were evaluable of which 40 cases had a vaginal laceration during specimen extraction. There was no significant difference in age, race, presence of LVSI, stage, grade, histology or use of vaginal brachytherapy between cohorts. Cases with vaginal lacerations were significantly associated with a higher median BMI and larger uterine size. The VL cohort was more likely to have received adjuvant treatment. In early stage disease, more cases had non-endometrioid histology in the VL group and had increased incidence of chemotherapy and radiation use as well. There were no cases of isolated vaginal recurrence (0/40) in the VL group as compared to an incidence of 2 % (7/298) in the NL group with a relative risk of 0.48 (CI: 0.03-8.36, p = 0.62). There were 4 cases of pelvic recurrence (4/40) in the VL group and 2 cases in the NL group (2/298) with a relative risk of 2.13 (CI: 0.46-9.89, p = 0.34). Conclusions: In endometrial cancer cases, we did not observe a significantly increased risk of vaginal or pelvic recurrence after a vaginal laceration at the time of specimen removal.

Metformin as an Adjunct to Progestin Therapy in Endometrial Hyperplasia and Early-Stage Endometrial Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Background and Objective: Metformin has been studied for its anti-proliferative effects on endometrial cells, and it is hypothesized to have a synergistic effect with progestin therapy in suppressing endometrial cell proliferation. This systematic review and meta-analysis aimed to determine the efficacy of adjunctive metformin in the clinical regression of endometrial hyperplasia and early-stage endometrial carcinoma. There have been previous systematic reviews that investigated the role of metformin with progesterone for endometrial hyperplasia and endometrial cancer, but they have included retrospective cohorts, and are thus have higher risk of bias. Methods: This meta-analysis followed the Cochrane methodology and adhered to the PRISMA 2020 guidelines. Randomized controlled trials (RCTs) were included if they enrolled reproductive-aged women with endometrial hyperplasia (with and without atypia) and endometrial carcinoma who were treated with progestin and metformin. The primary outcome was the complete response rate at 12-16 weeks, and secondary outcomes included relapse rate, clinical pregnancy rate, and live birth rate. Subgroup analysis of endometrial hyperplasia without atypia vs hyperplasia with atypia and early endometrial cancer was also included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for dichotomous data. Results: Six RCTs were included. The addition of metformin to progestin therapy may increase the complete response rate of endometrial hyperplasia without atypia (OR 5.12, 95% CI 1.17 to 22.41; n = 102) and live birth rates (OR 2.51, 95% CI 1.34 to 4.69; n = 188) compared to progestin therapy alone, but the certainty of the evidence is low. Metformin did not have a significant effect on the clinical response of endometrial hyperplasia with atypia and endometrial carcinoma, relapse rates, and clinical pregnancy rates. Conclusion: Current evidence is uncertain on the potential benefit of metformin with progestin in endometrial hyperplasia and carcinoma. Future high-quality randomized controlled trials with larger sample sizes and longer follow-up periods are needed to support practice recommendations.

Cost-effectiveness of dostarlimab plus chemotherapy for primary advanced or recurrent endometrial cancer.

Objective: In the double-blind, phase III, placebo-controlled RUBY randomized clinical trial, dostarlimab plus carboplatin-paclitaxel significantly increased survival among patients with primary advanced or recurrent endometrial cancer (EC). We conducted a cost-effectiveness analysis of dostarlimab in combination with chemotherapy in these patients stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups from the perspective of a United States payer. Materials and methods: A Markov model with three states was employed to simulate patients who were administered either dostarlimab in combination with chemotherapy or chemotherapy based on the RUBY trial. Quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were calculated with a willingness-to-pay (WTP) threshold of $150,000 per QALY. Both univariate and probabilistic sensitivity analyses were carried out to explore the robustness of the model. Results: In dMMR EC, the combination of dostarlimab and chemotherapy achieved an additional 5.48 QALYs at an incremental cost of $330,747 compared to chemotherapy alone, resulting in an ICER of $60,349.30 per QALY. In pMMR EC, there were 1.51 additional QALYs gained at an extra cost of $265,148, yielding an ICER of $175,788.47 per QALY. With a 15.2% discount on dostarlimab, the ICER decreased to $150,000 per QALY in the pMMR EC. The univariate sensitivity analysis revealed that the cost of dostarlimab, utility of progression-free survival (PFS), and progressive disease (PD) had the most significant impacts on the outcomes. Probabilistic sensitivity analysis revealed that dostarlimab had a 100% likelihood of being considered cost-effective for patients at a WTP threshold of $150,000 per QALY for dMMR EC, whereas this likelihood was only 0.5% for pMMR EC. Conclusion: Dostarlimab in combination with chemotherapy was cost-effective for primary advanced or recurrent dMMR EC from the perspective of a United States payer at a WTP threshold of $150,000 per QALY, but not for pMMR EC. Lowering the prices of dostarlimab could potentially enhance the cost-effectiveness of treatment for pMMR EC.

Chronic endometritis - a constantly discussed issue in infertile women.

OBJECTIVE: A review of current knowledge on the pathophysiology, diagnostic and treatment options for chronic endometritis in infertile women. METHODS AND RESULTS: One of the major causes of failed in vitro fertilization (IVF) is undiagnosed intrauterine pathologies, including chronic inflammation of the uterine mucosa - chronic endometritis. However, some authors relativize the negative impact of chronic endometritis on reproductive outcomes. The etiopathogenesis of chronic endometritis is due to qualitative and quantitative changes in the endometrial microbiome with abnormal multiplication of microorganisms naturally occurring in the uterine cavity or vagina. There is no uniform consensus on the most common pathogen causing chronic endometritis. It is characterized by infiltration of plasma cells into the endometrial stroma outside the menstrual cycle, accompanied by hyperaemia and endometrial oedema. Clinical symptoms are very mild or absent. The diagnosis of chronic endometritis is often difficult because there is no specific clinical or laboratory diagnostic method. The following investigative options are commonly used for the diagnosis of chronic endometritis: diagnostic hysteroscopy, histopathological examination of the endometrium including CD 138 immunohistochemistry and culture from the uterine cavity. However, standardised international hysteroscopic and histopathological criteria for accurate diagnosis of chronic endometritis are still lacking. Empirically administered antibiotic therapy improves the success rate of pregnancy and delivery of a viable foetus in infertile patients with proven chronic endometritis. In addition to reviewing the current knowledge of chronic endometritis, this article discusses the importance of hysteroscopy in the diagnostic process. CONCLUSION: Chronic endometritis is often a clinically silent disease with negative impact on reproduction in infertile women. Although there are still many unresolved issues, the introduction of hysteroscopy into the diagnostic process is important for clinical practice; however, hysteroscopy even in combination with histological examination of the endometrium, often does not allow an unequivocal diagnosis of chronic endometritis. Further prospective randomised studies in a selected group of women with proven chronic endometritis and repeated failure to implant proven euploid embryos should refine this knowledge.

Clinical significance of TROAP in endometrial cancer and the antiproliferative and proapoptotic effects of TROAP knockdown in endometrial cancer cells: integrated utilization of bioinformatic analysis and in vitro test verification.

Trophinin-associated protein (TROAP), a cytoplasmic protein essential for spindle assembly and centrosome integrity during mitosis, has been reported to serve as an oncogene in various tumors. However, its role in endometrial cancer (EC) progression is still undefined. TROAP expression in EC was analyzed via GEPIA and HPA databases. The diagnostic and prognostic values of TROAP were examined by ROC curve analysis and Kaplan-Meier plotter, respectively. Cell proliferation was evaluated using CCK-8 and EdU incorporation assays. Apoptosis was assessed using TUNEL and flow cytometry assays. GSEA was performed to explore TROAP-related pathways in EC. Expression of TROAP, proliferating cell nuclear antigen (PCNA), Ki-67, cleaved-caspase-3 (cl-caspase-3), caspase-3, active ß-catenin, and total ß-catenin was detected using western blot analysis. TROAP was upregulated in EC. TROAP served as a potential diagnostic and prognostic marker in EC patients. TROAP silencing suppressed proliferation and enhanced apoptosis in EC cells. GSEA revealed that EC and Wnt signaling pathways were related to the expression of TROAP. We further demonstrated that TROAP knockout repressed the Wnt/ß-catenin pathway in EC cells. Moreover, SKL2001, a Wnt/ß-catenin activator, partially abrogated the effects of TROAP silencing on EC cell proliferation and apoptosis, while the signaling inhibitor XAV-939 had the opposite effect. In conclusion, TROAP knockout retarded proliferation and elicited apoptosis in EC cells by blocking the Wnt/ß-catenin pathway.

Long noncoding RNA VPS9D1-AS1 promotes the progression of endometrial cancer via regulation of the miR-187-3p/S100A4 axis.

VPS9D1-AS1 functions as an oncogene in many cancers. However, its role and potential mechanism in the progression of endometrial cancer (EC) are not fully understood. VPS9D1-AS1 levels in EC and adjacent normal tissues were investigated using the TCGA-UCEC cohort and 24 paired clinical samples. The roles of VPS9D1-AS1 and miR-187-3p in cell cycle, proliferation, and apoptosis were evaluated by loss- and gain-of-function experiments. In addition, the effect of VPS9D1-AS1 on tumor growth was further investigated in vivo. Rescue experiments were performed to investigate the involvement of the miR-187-3p/S100A4 axis in VPS9D1-AS1 knockdown-mediated antitumor effects. VPS9D1-AS1 was highly expressed in EC tissues. VPS9D1-AS1 knockdown, similar to miR-187-3p overexpression, significantly inhibited cell proliferation, inhibited colony formation, induced cell cycle arrest, and facilitated apoptosis of KLE cells. MiR-187-3p bound directly to VPS9D1-AS1 and the 3'UTR of S100A4. Furthermore, VPS9D1-AS1 negatively regulated miR-187-3p while positively regulating S100A4 expression in EC cells. MiR-187-3p knockdown or S100A4 overexpression partially reversed the tumor suppressive function of VPS9D1-AS1 knockdown. The results suggest that VPS9D1-AS1 affects EC progression by regulating the miR-187-3p/S100A4 axis. This may provide a promising therapeutic target to help treat EC.