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Endometrial cancer represents one of the most common gynecological cancers in women. In recent years, there has been increasing interest in immunotherapy, including the use of pembrolizumab, particularly for the treatment of cancers with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H). A systematic review of the literature from 2020 to 2025 was conducted according to the PICO model. Six studies were included in this review, comprising four randomized clinical trials (RCTs) and two pre-specified subgroup analyses derived from previous RCTs involving a total of 3684 patients with early-stage or advanced disease or metastatic or recurrent endometrial cancer. Interventions included the use of pembrolizumab in monotherapy and in combination with chemotherapy or lenvatinib. Pembrolizumab showed a significant improvement in progression-free survival (PFS) and overall survival (OS) in the dMMR patient groups. Therapeutic benefit was limited in the proficient mismatch repair (pMMR) groups. The incidence of side effects was high but comparable to the control group. Pembrolizumab, especially in combination therapy with lenvatinib, is a promising therapeutic option for patients with dMMR/MSI-H endometrial cancer. The results suggest a potential long-term treatment effect, although the limitations of the RCT and the variability in the therapeutic regimens require further research.

Abstract Context Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged females, and women with PCOS are at increased risk for endometrial cancer (EndoCA), the most common gynecological malignancy. Objective Our study sought to assess the economic burden associated with EndoCA in PCOS. Method Using PRISMA systematic review guidelines, we evaluated studies on EndoCA rates in patients with PCOS. Excluded studies were reviews and case reports, those with nonhuman subjects, without controls, without full text available, or reporting solely on other conditions. Selected studies were assessed for quality using the Newcastle-Ottawa Scale. Meta-analysis used DerSimonian-Laird random effects model to assess pooled risk ratio (RR). Excess cost was assessed in US dollars (USD). Result Of 98 studies screened, 9 were included. Pooled RR for EndoCA in PCOS was 3.46 (95% CI, 2.28-5.23), P ≤ .001. In the United States, prevalence of EndoCA in patients with PCOS in 2020 was 1.712%, compared with a baseline estimated prevalence in all women of 0.489%. The excess prevalence of EndoCA attributable to PCOS was 1.223%, approximately 98 348 affected women. A population attributable fraction of EndoCA for PCOS was 24.4%. Given estimated costs of EndoCA exceeding $1.9 billion (in 2023 USD), the economic burden of EndoCA attributable to PCOS exceeds $467 million/year. Conclusion The excess annual US healthcare cost for EndoCA attributable to PCOS exceeds $467 million/year (2023 USD). Although a concerning morbidity of PCOS, it is notable that the economic burden of EndoCA attributable to the disorder represents only a small fraction of its total healthcare burden.

ObjectiveIn the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin–paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin–paclitaxel, with manageable toxicity, in patients with primary advanced or recurrent endometrial cancer. Here we report on patient-reported outcomes in the mismatch repair-deficient/microsatellite instability-high population, a secondary endpoint in the trial.MethodsPatients were randomized 1:1 to dostarlimab+carboplatin–paclitaxel or placebo+carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo monotherapy every 6 weeks for ≤3 years or until disease progression. Patient-reported outcomes, assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Endometrial Cancer Module, were prespecified secondary endpoints. A mixed model for repeated measures analysis, a prespecified exploratory analysis, was conducted to generate least-squares means to compare between-treatment differences while adjusting for correlations across multiple time points within a patient and controlling for the baseline value. Results are provided with 2-sided, nominal p values.ResultsOf 494 patients enrolled, 118 were mismatch repair-deficient/microsatellite instability-high. In this population, mean change from baseline to end of treatment showed visual improvements in global quality of life (QoL), emotional and social function, pain, and back/pelvis pain for dostarlimab+carboplatin–paclitaxel. Meaningful differences (least-squares mean [standard error]) favoring the dostarlimab arm were reported for change from baseline to end of treatment for QoL (14.7 [5.45]; p=0.01), role function (12.7 [5.92]); p=0.03), emotional function (14.3 [4.92]; p<0.01), social function (13.5 [5.43]; p=0.01), and fatigue (−13.3 [5.84]; p=0.03).ConclusionsPatients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin–paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin–paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin–paclitaxel as a standard of care in this setting.Trial registrationClinicalTrials.gov NCT03981796

The AT-rich interacting domain-containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome-wide analyses with next-generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis-associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis-associated carcinoma in ovarian cancer and also from atypical endo-metrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis-associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular-targeted drug can inhibit proliferation of ARID1A-mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.

IntroductionMolecular characterization is important to inform treatment decisions for patients with endometrial cancer (EC). Wild type TP53 (TP53wt) is found in ~50% of advanced/recurrent EC and of those, ~70% are microsatellite stable (MSS/pMMR).MethodsENGOT-EN5/GOG-3055/SIENDO (NCT03555422) is a randomized double-blind, phase 3 trial evaluating selinexor vs placebo as a maintenance treatment for advanced/recurrent EC following response to prior systemic therapy. Here we report the updated efficacy and safety of a prespecified exploratory subgroup analysis of patients with TP53wt EC.Results113 patients with TP53wt EC received selinexor (n=77) or placebo (n=36) as maintenance therapy. As of March 2023, the median follow-up was 25.3 months, and 26 patients remain on treatment. Median PFS (mPFS) was 27.4 months with selinexor vs 5.2 months with placebo (HR 0.42; 95% CI [0.25–0.70], nominal one-sided p=0.0003). PFS improvement was observed regardless of microsatellite instability status; in the TP53wt/MSS(pMMR) subgroup, the mPFS was not reached with selinexor vs 4.9 months with placebo. In patients with TP53wt, the most common adverse events (AEs) were nausea, vomiting, and diarrhea; most common grade ≥3 AEs were neutropenia, thrombocytopenia, and nausea; 16% of patients discontinued selinexor due to AEs. No grade 5 AEs occurred. No immune-related AEs were observed.Abstract PO006LBA/#1520 Figure 1Conclusion/ImplicationsTP53wt status may represent a robust predictive biomarker for selinexor efficacy in EC. Additionally, a strong PFS signal was observed in the TP53wt/MSS(pMMR) subgroup, a patient population with high unmet need. Both additional data and updated data will be presented at the conference.

(1) Objective: Artificial intelligence (AI) has become an important tool in medicine in diagnosis, prognosis, and treatment evaluation, and its role will increase over time, along with the improvement and validation of AI models. We evaluated the applicability of AI in predicting the depth of myometrial invasion in MRI studies in women with endometrial cancer. (2) Methods: A systematic search was conducted in PubMed, SCOPUS, Embase, and clinicaltrials.gov databases for research papers from inception to May 2023. As keywords, we used: “endometrial cancer artificial intelligence”, “endometrial cancer AI”, “endometrial cancer MRI artificial intelligence”, “endometrial cancer machine learning”, and “endometrial cancer machine learning MRI”. We excluded studies that did not evaluate myometrial invasion. (3) Results: Of 1651 screened records, eight were eligible. The size of the dataset was between 50 and 530 participants among the studies. We evaluated the models by accuracy scores, area under the curve, and sensitivity/specificity. A quantitative analysis was not appropriate for this study due to the high heterogeneity among studies. (4) Conclusions: High accuracy, sensitivity, and specificity rates were obtained among studies using different AI systems. Overall, the existing studies suggest that they have the potential to improve the accuracy and efficiency of the myometrial invasion evaluation of MRI images in endometrial cancer patients.

Background High-grade endometrioid and serous endometrial cancers (ECs) are an aggressive subtype of ECs without effective therapies. The reciprocal communication between tumor cells and their surrounding microenvironment drives tumor progression. Long noncoding RNAs (lncRNAs) are key mediators of tumorigenesis and metastasis. However, little is known about the role of lncRNAs in aggressive EC progression and tumor microenvironment remodeling. Methods We performed an array-based lncRNA analysis of a parental HEC-50 EC cell population and derivatives with highly invasive, sphere-forming, and paclitaxel (TX)-resistant characteristics. We characterized the roles of the lncRNA NEAT1 in mediating aggressive EC progression in vitro and in vivo and explored the molecular events downstream of NEAT1. Results We identified 10 lncRNAs with upregulated expression (NEAT1, H19, PVT1, UCA1, MIR7-3HG, SNHG16, HULC, RMST, BCAR4 and LINC00152) and 10 lncRNAs with downregulated expression (MEG3, GAS5, DIO3OS, MIR155HG, LINC00261, FENDRR, MIAT, TMEM161B-AS1, HAND2-AS1 and NBR2) in the highly invasive, sphere-forming and TX-resistant derivatives. NEAT1 expression was markedly upregulated in early-stage EC tissue samples, and high NEAT1 expression predicted a poor prognosis. Inhibiting NEAT1 expression with small hairpin RNAs (shRNAs) diminished cellular proliferation, invasion, sphere formation, and xenograft tumor growth and improved TX response in aggressive EC cells. We showed that NEAT1 functions as an oncogenic sponge for the tumor suppressor microRNA-361 (miR-361), which suppresses proliferation, invasion, sphere formation and TX resistance by directly targeting the oncogene STAT3. Furthermore, miR-361 also suppressed the expression of multiple prometastatic genes and tumor microenvironment-related genes, including MEF2D , ROCK1 , WNT7A , VEGF-A , PDE4B, and KPNA4 . Conclusions NEAT1 initiates a miR-361-mediated network to drive aggressive EC progression. These data support a rationale for inhibiting NEAT1 signaling as a potential therapeutic strategy for overcoming aggressive EC progression and chemoresistance.

Endometrial cancer is one of the most common malignant diseases in women worldwide, with an incidence of 5.9%. Thus, it is the most frequent cancer of the female genital tract, with more than 34,000 women dying, in Europe and North America alone. Endometrial Cancer Stem Cells (CSC) might be drivers of carcinogenesis as well as metastatic and recurrent disease. Therefore, targeting CSCs is of high interest to improve prognosis of patients suffering of advanced or recurrent endometrial cancer. This review describes the current evidence of molecular mechanisms in endometrial CSCs with special emphasis on MYC and NF-κB signaling as well as mitochondrial metabolism. Furthermore, the current status of immunotherapy targeting PD-1 and PD-L1 in endometrial cancer cells and CSCs is elucidated. The outlined findings encourage novel therapies that target signaling pathways in endometrial CSCs as well as immunotherapy as a promising therapeutic approach in the treatment of endometrial cancer to impede cancer progression and prevent recurrence.

Endometrial cancer occurs in up to 29% of women before 40 years of age. Seventy percent of these patients are nulliparous at the time. Decision making regarding fertility preservation in early stage endometrial cancer (ES-EC) is, therefore, a big challenge since the decision between the risk of cancer progression and a chance to parenthood needs to be made. Sixty-two percent of women with complete remission of ES-EC after fertility-sparing treatment (FST) report to have a pregnancy wish which, if not for FST, they would not be able to fulfil. The aim of this review was to identify and summarise the currently established biomolecular and genetic prognostic factors that can facilitate decision making for FST in ES-EC. A comprehensive search strategy was carried out across four databases; Cochrane, Embase, MEDLINE, and PubMed; they were searched between March 1946 and 22nd December 2022. Thirty-four studies were included in this study which was conducted in line with the PRISMA criteria checklist. The final 34 articles encompassed 9165 patients. The studies were assessed using the Critical Appraisal Skills Program (CASP). PTEN and POLE alterations we found to be good prognostic factors of ES-EC, favouring FST. MSI, CTNNB1, and K-RAS alterations were found to be fair prognostic factors of ES-EC, favouring FST but carrying a risk of recurrence. PIK3CA, HER2, ARID1A, P53, L1CAM, and FGFR2 were found to be poor prognostic factors of ES-EC and therefore do not favour FST. Clinical trials with bigger cohorts are needed to further validate the fair genetic prognostic factors. Using the aforementioned good and poor genetic prognostic factors, we can make more confident decisions on FST in ES-EC.

Purpose Incidence and mortality rates of uterine cancer are increasing and, obesity, which is also rising, has been associated with uterine cancer development and mortality. A recent study found that poor sleep quality is common among endometrial cancer survivors and those with obesity had more sleep disturbances than those having normal weight. However, it is unclear if higher levels of obesity (Class III, BMI ≥ 40 kg/m 2 ), which are rising rapidly, are differentially associated with sleep as well as depression and quality of life in endometrial cancer survivors. Methods We evaluated sleep, depression, and quality of life in 100 Stage I endometrial cancer survivors with obesity seeking weight loss enrolled in a lifestyle intervention (NCT01870947) at baseline. Results The average age was 60 years and mean BMI was 42.1 kg/m 2 with 58% having a BMI ≥ 40 kg/m 2 . Most survivors (72.3%) had poor sleep quality and most (71.2%) reported sleeping < 7 h/night. Survivors with class III compared with class I obesity had significantly more sleep disturbances and daytime dysfunction; and, those with poor sleep had higher depression and lower quality of life. Survivors with a BMI ≥ 50 kg/m 2 (~ 25%) had the highest levels of depression and lowest physical and emotional well-being. Conclusions Our results reveal that endometrial cancer survivors with class III compared with class I obesity have poorer sleep quality, higher depression, and lower quality of life. Given the rising rates of obesity and uterine cancer mortality, interventions to combat both obesity and poor sleep are needed.