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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.

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.

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. 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. 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. 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.

The histology and grade of endometrial cancer are important predictors of disease outcome and of the likelihood of nodal involvement. In most centres, however, surgical staging decisions are based on a preoperative biopsy. The objective of this study was to assess the concordance between the preoperative histology and that of the hysterectomy specimen in endometrial cancer. Patients treated for endometrial cancer during a 10-year period at a tertiary cancer centre were identified from a prospectively collected pathological database. All pathology reports were reviewed to confirm centralised reporting of the original sampling or biopsy specimens; patients whose biopsies were not reviewed by a dedicated gynaecological pathologist at the treating centre were excluded. Surgical pathology data including histology, grade, depth of myometrial invasion, cervical stromal involvement and lymphovascular space invasion (LVSI) as well as preoperative histology and grade were collected. Preoperative and final tumour cell type and grade were compared and the distribution of other high-risk features was analysed. A total of 1329 consecutive patients were identified; 653 patients had a centrally reviewed epithelial endometrial cancer on their original biopsy, and are included in this study. Of 255 patients whose biopsies were read as grade 1 (G1) adenocarcinoma, 45 (18%) were upgraded to grade 2 (G2) on final pathology, 6 (2%) were upgraded to grade 3 (G3) and 5 (2%) were read as a non-endometrioid high-grade histology. Overall, of 255 tumours classified as G1 endometrioid cancers on biopsy, 74 (29%) were either found to be low-grade (G1-2) tumours with deep myometrial invasion, or were reclassified as high-grade cancers (G3 or non-endometrioid histologies) on final surgical pathology. Despite these shifts, we calculate that omitting surgical staging in preoperatively diagnosed G1 endometrioid cancers without deep myometrial invasion would result in missing nodal involvement in only 1% of cases. Preoperative endometrial sampling is only a modest predictor of surgical pathology features in endometrial cancer and may underestimate the risk of disease spread and recurrence. In spite of frequent shifts in postoperative vs preoperative histological assessment, the predicted rate of missed nodal metastases with a selective staging policy remains low.

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). and alterations we found to be good prognostic factors of ES-EC, favouring FST. MSI, , and alterations were found to be fair prognostic factors of ES-EC, favouring FST but carrying a risk of recurrence. , , , , , and 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.

(1) Background: Endometrial cancer (EC) is a common gynecological malignancy, often diagnosed at an early stage with a high overall survival rate. Surgical treatment is the primary approach, guided by pathological and molecular characteristics. Stage IVB EC, characterized by intra and/or extra-abdominal metastasis, presents a significant challenge with no clear consensus on optimal management. (2) Methods: A systematic literature review was conducted from January to May 2023, covering studies from 2000 to 2023. Eligible studies included retrospective case series, prospective trials, and randomized clinical trials. (3) Results: Of 116 studies identified, 21 were deemed relevant: 7 on primary surgery, 10 on neoadjuvant chemotherapy (NACT), and 4 on adjuvant treatment. Notably, the impact of residual tumor after primary surgery was a critical factor affecting survival. The use of NACT followed by interval debulking surgery showed promise, particularly in cases deemed unresectable. Adjuvant treatment, combining radiotherapy and chemotherapy, demonstrated improved survival but lacked consensus regarding its role. (4) Conclusions: Stage IVB EC poses a complex challenge with limited evidence to guide management. Optimal cytoreduction remains crucial, and NACT should be considered for unresectable cases. Multimodality adjuvant therapy may benefit patients, even with disease spread beyond the pelvis. Future advances in molecular classification and targeted therapies are expected to enhance treatment strategies.

ObjectiveHigh grade and non-endometrioid endometrial cancers carry a poor prognosis, and the lack of randomized prospective data has led to a wide range of practice regarding adjuvant therapy. The objective of this study was to evaluate the outcomes of different treatment strategies in patients with high-risk, early-stage endometrial cancer.MethodsPatients with high-grade endometrioid, serous endometrial cancer and carcinosarcoma diagnosed between 2000 and 2012 were identified from databases in three gynecologic oncology divisions, in Toronto and in Israel. Adjuvant treatment practices differed across the centers, creating a heterogeneous cohort. A comparison of stage I patients stratified by adjuvant treatment was undertaken. Log-rank tests and Cox proportional hazards models were employed to compare recurrence and survival across treatment groups.Results490patients with high risk endometrial cancer were identified, among them 213 patients with stage I disease. Israeli patients received more chemotherapy (41% vs 10% in stage I disease; P<0.001) than patients in Toronto. Chemotherapy was not associated with improved disease-free, disease-specific or overall survival, nor was it associated with fewer distant recurrences (50% vs 54%). Radiation was also not associated with improved recurrence or survival, nor did it affect the pattern of recurrence. On Cox multivariable analysis, neither radiation treatment nor chemotherapy were significantly associated with outcome (HR for recurrence, 0.72 for pelvic radiation (P=0.46) and 1.99 for chemotherapy (P=0.09); HR for death, 0.67 for pelvic radiation (P=0.29) and 1.03 for chemotherapy (P=0.94)).ConclusionsIn this retrospective analysis, neither adjuvant radiation nor chemotherapy were associated with improved outcome in stage I, high risk endometrial cancer.

This review article explores the possibility of developing an integrated approach to the management of the different needs of endometrial cancer (EC) patients seeking to become pregnant. Life preservation of the woman, health preservation of the baby, a precocious and-as much as possible-minimally invasive characterization of the health and fertility parameters of the patient, together with the concerns regarding the obstetric, neonatal, and adult health risks of the children conceived via assisted reproductive techniques (ART) are all essential aspects of the problem to be taken into consideration, yet the possibility to harmonize such needs through a concerted and integrated approach is still very challenging. This review aims to illustrate the main features of EC and how it affects the normal physiology of pre-menopausal women. We also focus on the prospect of a miR-based, molecular evaluation of patient health status, including both EC early diagnosis and staging and, similarly, the receptivity of the woman, discussing the possible evaluation of both aspects using a single specific panel of circulating miRs in the patient, thus allowing a relatively fast, non-invasive testing with a significantly reduced margin of error. Finally, the ethical and legal/regulatory aspects of such innovative techniques require not only a risk-benefit analysis; respect for patient autonomy and equitable health care access allocation are fundamental issues as well.

Metformin is an oral biguanide commonly used for treating type II diabetes and has recently been reported to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study shows a marked loss of AMP‐activated protein kinase (AMPK) phosphorylation and nuclear human Forkhead box O1 (FOXO1) protein in estrogen‐dependent endometrial cancer (EC) tumors compared to normal control endometrium. Metformin treatment suppressed EC cell growth in a time‐dependent manner in vitro; this effect was cancelled by cotreatment with an AMPK inhibitor, compound C. Metformin decreased FOXO1 phosphorylation and increased FOXO1 nuclear localization in Ishikawa and HEC‐1B cells, with non‐significant increase in FOXO1 mRNA expression. Moreover, compound C blocked the metformin‐induced changes of FOXO1 and its phosphorylation protein, suggesting that metformin upregulated FOXO1 activity by AMPK activation. Similar results were obtained after treatment with insulin. In addition, transfection with siRNA for FOXO1 cancelled metformin‐inhibited cell growth, indicating that FOXO1 mediated metformin to inhibit EC cell proliferation. A xenograft mouse model further revealed that metformin suppressed HEC‐1B tumor growth, accompanied by downregulated ki‐67 and upregulated AMPK phosphorylation and nuclear FOXO1 protein. Taken together, these data provide a novel mechanism of antineoplastic effect for metformin through the regulation of FOXO1, and suggest that the AMPK–FOXO1 pathway may be a therapeutic target to the development of new antineoplastic drugs. Metformin may exert its anti‐proliferative effect on EC cells by activating AMPK and thus decreasing phosphorylation of FOXO1 protein, thereby triggering the relocalization of FOXO1 protein from the cytoplasm to the nucleus and resulting in increased FOXO1 activity. This study provide a novel mechanism of anti‐neoplastic effect for metformin through the regulation of FOXO1, and suggest that AMPK‐FOXO1 pathway may be a therapeutic target to the development of new anti‐neoplastic drugs.