MG132-mediated Suppression of the Ubiquitin-proteasome Pathway Enhances the Sensitivity of Endometrial Cancer Cells to Cisplatin.

BACKGROUND: Tumor cell resistance to cisplatin is a common challenge in endometrial cancer chemotherapy, stemming from various mechanisms. Targeted therapies using proteasome inhibitors, such as MG132, have been investigated to enhance cisplatin sensitivity, potentially offering a novel treatment approach. OBJECTIVE: The aim of this study was to investigate the effects of MG132 on cisplatin sensitivity in the human endometrial cancer (EC) cell line RL95-2, focusing on cell proliferation, apoptosis, and cell signaling. METHODS: Human endometrial cancer RL95-2 cells were exposed to MG132, and cell viability was assessed in a dose-dependent manner. The study evaluated the effect of MG132 on cisplatin-induced proliferation inhibition and apoptosis, correlating with caspase-3 activation and reactive oxygen species (ROS) upregulation. Additionally, we examined the inhibition of the ubiquitin-proteasome system and the expression of pro-inflammatory cytokines IL-1ß, IL-6, IL-8, and IL-13 during MG132 and cisplatin co-administration. RESULTS: MG132 exposure significantly reduced cell viability in a dose-dependent manner. It augmented cisplatin- induced proliferation inhibition and enhanced apoptosis, correlating with caspase-3 activation and ROS upregulation. Molecular analysis revealed a profound inhibition of the ubiquitin-proteasome system. MG132 also significantly increased the expression of cisplatin-induced pro-inflammatory cytokines, suggesting a transition from chronic to acute inflammation. CONCLUSION: MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin- proteasome pathway, reducing cell viability, enhancing apoptosis, and shifting the inflammatory response. These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further research is needed to explore detailed mechanisms and clinical applications of this combination therapy.

Effect of hemoglobin, albumin, lymphocyte, and platelet score on prognosis in intermediate-risk endometrial cancer according to molecular-based classification.

OBJECTIVE: The aim of this study is to compare the relationship between molecular classification and HALP score in endometrial cancer (EC). METHODS: Patients who were operated with the diagnosis of EC 2014 and 2024 were included in our study. 150 patients were included in the study. We divided the patients into three groups in terms of molecular classification; group 1 was the patients with POLE mutation, group 2 was the patients with MMRd and NSMP (intermediate prognosis), and group 3 was the patients with p53 mutation. Group 2 participants were divided into two groups, a low HALP score group and a high HALP score group, according to the HALP score cut-off value. RESULTS: Using the value with the highest Youden's index (0.306) as a basis, it was demonstrated that the HALP score with a cut-off value of 33.735 has a sensitivity of 61.86% and a specificity of 68.75% in intermediate-risk EC. The 5-year overall survival (OS) was found to be 75.4% in intermediate-risk EC patients with low HALP scores and 91.5% in intermediate-risk EC patients with high HALP scores (p = 0.008). The 5-year progression-free survival (PFS) was found to be 86% in intermediate-risk EC patients with low HALP scores and 94.4% in intermediate-risk EC patients with high HALP scores (p = 0.089). MMR deficiency and NSMP have been considered intermediate-risk groups for endometrial cancer and are a heterogeneous group. Although the use of the HALP score to reduce this heterogeneity is successful in predicting OS, it is not sufficient for PFS.

Uterine-Conserving Treatment Options for Atypical Endometrial Hyperplasia and Early Endometrial Cancer.

PURPOSE OF REVIEW: This review aims to synthesize available literature on uterine-conserving treatment options for atypical endometrial hyperplasia and grade 1 endometrial carcinoma while highlighting remaining unanswered questions. RECENT FINDINGS: The need for uterine-conserving treatment options for atypical endometrial hyperplasia and grade 1 endometrial carcinoma is growing with the increasing number of cases in younger patients or those who cannot undergo surgery. We reviewed the oncological and reproductive outcomes associated with endocrine therapies used for atypical endometrial hyperplasia and grade 1 endometrial carcinoma. The rising prevalence of delayed childbearing, obesity, and diabetes in reproductive-age individuals and of medical comorbidities associated with high surgical risk continues to amplify the demand for uterine-conserving therapies. Appropriate patient selection for such therapies is imperative to maximize likelihood of treatment response. The ideal candidates are patients with atypical endometrial hyperplasia or early-stage, low-grade endometrial cancer with no evidence of myometrial invasion or extrauterine disease. The most accepted conservative therapeutic approach is hormonal therapy with close surveillance, with or without eventual hysterectomy following childbearing or failure of treatment. Further prospective and randomized trials are needed to address optimal patient and treatment selection, as well as the use of molecular profiling for treatment individualization and prognostication.

Complete response to disitamab vedotin in HER2-low metastatic endometrial carcinoma: a case report and review of the literature.

Endometrial cancer (EC) is one of the most common gynecologic malignancies with increasing morbidity. The prognosis for patients diagnosed with early-stage EC remains favorable; however, for patients with recurrent or metastatic EC, the prognosis is poor and treatment options, until recently, are limited. Antibody drug conjugates (ADCs) represent innovative strategies in cancer treatment; however, there are less investigations regarding their efficacy in EC. This report describes an EC case with low human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) expression score (IHC 2+) that experienced recurrent metastasis in the abdominal and peritoneal following post-surgical chemotherapy and radiotherapy. Subsequently, the commencement of HER2-targeted ADC, disitamab vedotin (RC48; 2.5 mg/kg), administered intravenously every two weeks, was initiated. The tumor lesions shrunk markedly after three cycles of treatment and disappeared by the completion of ten cycles of therapy. The patient is still in remission at present. The current findings imply the potential efficacy of HER2-targeted ADCs for patients with HER2-low metastatic EC.

Endometrial cancer and endometrial changes in transgender men: Insights from Japanese individuals on testosterone.

AIM: Endometrial changes in Japanese transgender men (TGM) on testosterone use remain elucidated. This study aims to present TGM with endometrial cancer and insights from a literature review of similar cases. Furthermore, we investigated the correlation between endometrial cancer and severe obesity in TGM who underwent gender-affirming surgery. METHODS: Between July 2020 and April 2023, two groups were assessed: 2 TGM with endometrial cancer and 43 TGM without cancer who underwent gender-affirming surgery. A literature review for TGM with endometrial cancer was conducted. Clinical data were retrospectively collected, and histopathological evaluation of female genital organs was performed. RESULTS: Two TGM with endometrial cancer and an additional four similar cases were identified through a literature search. These TGM had severe obesity (body mass index [BMI] ≥30 kg/m2) and long-term testosterone use, indicating a possible link between endometrial cancer and these factors. Subsequently, we investigated the 43 TGM without cancer. We revealed 30% with obesity (BMI ≥25), only three cases of severe obesity (BMI ≥30), and a significant correlation between testosterone use duration and BMI in TGM without cancer. Histological examination revealed focal proliferative endometrium in 51% of cases and polycystic ovarian changes in 77%. CONCLUSIONS: Our observations suggest a potential link between severe obesity, prolonged testosterone use, and endometrial cancer in transgender men. Histological changes in the female genital tract highlighted frequent focal proliferative endometrium, even under testosterone therapy. Further research should focus on larger, multi-institutional studies to confirm these findings and establish endometrial cancer screening for Japanese TGM.

Red cell distribution width and mean platelet volume detection in patients with endometrial cancer and endometrial hyperplasia.

Background: Endometrial cancer is the most common malignancy in women in developed countries, and its incidence is increasing annually. Due to the availability and cost-effectiveness of serum markers of red cell distribution width (RDW), and mean platelet volume (MPV), we decided to investigate these two important markers in patients with endometrial cancer and assess their role in diagnosing the tumor and differentiate it from endometrial hyperplasia and other causes of bleeding. Methods: This is a case-control study that examined the data of patients who were referred to Al-Zahra Hospital during 2022-2023 with complaints of abnormal bleeding and underwent diagnostic curettage. Based on the pathology findings, the patients were divided into 3 groups, including endometrial cancer, endometrial hyperplasia, and control. The clinical characteristics and results of MPV and RDW were compared in these three groups. The IBM SPSS Statistics for Windows, Version 21.0. was used for data analysis. Results: In this study, 87 women were examined in three groups endometrial cancer, endometrial hyperplasia, and control with a mean age of 52.70 ± 11.63 years. The results showed that the endometrial cancer group, had higher gravida, underlying disease, history of radiation therapy, anticoagulant therapy, blood transfusion, surgery, and family history of cancer (p < 0.05). Meanwhile, the endometrial cancer group had lower menstrual age and history of using contraceptives than other groups (p < 0.05). In addition, in this study, the results indicated that the levels of MPV and RDW in the endometrial cancer group were significantly higher than in the endometrial hyperplasia and control groups (p < 0.05). Conclusion: Since MPV and RDW are cheap and accessible and can be easily obtained from complete blood count panels, they can be used as suitable diagnostic markers for endometrial cancer. However, conducting comprehensive multicenter prospective studies with a larger sample size can be helpful.

Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer.

OBJECTIVE: Interventions that combat obesity and its associated metabolic perturbations may decrease incidence and improve outcomes of endometrial cancer (EC). Potential options for weight loss include pharmacotherapeutic interventions such as tirzepatide, a dual-acting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist. Given this, we explored the anti-obesity and anti-tumorigenic effects of tirzepatide in our pre-clinical mouse model of endometrioid EC. METHODS: Starting at 4 weeks of age, Lkb1fl/flp53fl/fl mice were fed a low-fat diet vs a high-fat diet to generate a lean or obese phenotype. Nine weeks after induction of EC, obese and lean mice were randomized to receive tirzepatide for 4 weeks. Body and tumor weights, tumor transcriptomic and metabolomic profiles, and serum metabolic markers and chemokines were assessed. RESULTS: Both obese and lean mice began to lose body weight after 2 weeks of tirzepatide treatment, ultimately achieving a significant weight loss of 20.1 % in obese mice and 16.8 % in lean mice. Tirzepatide improved obesity-induced serum adiponectin, leptin, GIP, and C-reactive protein levels. Furthermore, tirzepatide relative to vehicle, effectively reduced tumor growth in obese and lean mice, inhibited the ErbB signaling and glycolysis/gluconeogenesis in tumors of obese mice, and increased O-linked glycosylation biosynthesis and phospholipase D signaling in tumors of lean mice. CONCLUSION: Tirzepatide decreased both mouse weight and tumor growth via effects on metabolic and immune pathways in the EC tumors that differed between obese and lean mice. This novel weight loss treatment deserves further evaluation as an innovative strategy in the management of EC.

Role of Pyroptosis in Endometrial Cancer and Its Therapeutic Regulation.

Pyroptosis is an inflammatory cell death induced by inflammasomes that release several pro-inflammatory mediators such as interleukin-18 (IL-18) and interleukin-1ß (IL-1ß). Pyroptosis, a type of programmed cell death, has recently received increased interest both as a therapeutic and immunological mechanism. Numerous studies have provided substantial evidence supporting the involvement of inflammasomes and pyroptosis in a variety of pathological conditions including cancers, nerve damage, inflammatory diseases and metabolic conditions. Researchers have demonstrated that dysregulation of pyroptosis and inflammasomes contribute to the progression of endometriosis and gynecological malignancies. Current research also indicates that inflammasome and pyroptosis-dependent signaling pathways may further induce the progression of endometrial cancer (EC). More specifically, dysregulation of NLR family pyrin domain 3 (NLRP3) and caspase-1-dependent pyroptosis play a contributory role in the pathogenesis and development of EC. Therefore, pyroptosis-regulated protein gasdermin D (GSDMD) may be an independent prognostic biomarker for the detection of EC. This review presents the molecular mechanisms of pyroptosis-dependent signaling pathways and their contributory role and function in advancing EC. Moreover, this review offers new insights into potential future applications and innovative approaches in utilizing pyroptosis to develop effective anti-cancer therapies.

Targeting KRAS in gynecological malignancies.

Cervical, endometrial, and ovarian cancers stand prominently as the leading gynecological malignancies of the female reproductive system. The conventional therapeutic modalities for gynecological malignancies have predominantly encompassed surgery, chemotherapy, and radiotherapy. However, efficacy of these approaches remains limited in cases of relapse or drug resistance. KRAS is one of the most frequently mutated oncogenes in human cancers. The KRAS gene encodes a small guanosine triphosphatase protein that acts as a molecular switch for crucial intracellular signaling pathways. KRAS mutations are deeply involved in the occurrence and development of gynecological malignancies. The present review aims to expound upon the role of oncogenic KRAS as a biomarker, elucidating various therapeutic approaches under investigation targeting the KRAS pathway in gynecological tumors.

[Retracted] LncRNA TTN­AS1 promotes endometrial cancer by sponging miR­376a­3p.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell cell migration and invasion assay data in Fig. 2E and F and 4E and F, tumor images in Fig. 7B and western blotting data shown in Fig. 4D had already appeared in previously published articles written by different authors at different research institutes (a few of which have been retracted). Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 44: 1343­1354, 2020; DOI: 10.3892/or.2020.7691].

Preoperative prediction of lymph node metastasis in endometrial cancer patients via an intratumoral and peritumoral multiparameter MRI radiomics nomogram.

Introduction: While lymph node metastasis (LNM) plays a critical role in determining treatment options for endometrial cancer (EC) patients, the existing preoperative methods for evaluating the lymph node state are not always satisfactory. This study aimed to develop and validate a nomogram based on intra- and peritumoral radiomics features and multiparameter magnetic resonance imaging (MRI) features to preoperatively predict LNM in EC patients. Methods: Three hundred and seventy-four women with histologically confirmed EC were divided into training (n = 220), test (n = 94), and independent validation (n = 60) cohorts. Radiomic features were extracted from intra- and peritumoral regions via axial T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) mapping. A radiomics model (annotated as the Radscore) was established using the selected features from different regions. The clinical parameters were statistically analyzed. A nomogram was developed by combining the Radscore and the most predictive clinical parameters. Decision curve analysis (DCA) and the net reclassification index (NRI) were used to assess the clinical benefit of using the nomogram. Results: Nine radiomics features were ultimately selected from the intra- and peritumoral regions via ADC mapping and T2WI. The nomogram combining the Radscore, serum CA125 level, and tumor area ratio achieved the highest AUCs in the training, test and independent validation sets (nomogram vs. Radscore vs. clinical model: 0.878 vs. 0.850 vs. 0.674 (training), 0.877 vs. 0.838 vs. 0.668 (test), and 0.864 vs. 0.836 vs. 0.618 (independent validation)). The DCA and NRI results revealed the nomogram had greater diagnostic performance and net clinical benefits than the Radscore alone. Conclusion: The combined intra- and peritumoral region multiparameter MRI radiomics nomogram showed good diagnostic performance and could be used to preoperatively predict LNM in patients with EC.

UBE2T is a diagnostic and prognostic biomarker for endometrial cancer.

BACKGROUND: Endometrial cancer (UCEC) is one of the most common malignant tumors in gynecology, and early diagnosis is crucial for its treatment. Currently, there is a lack of early screening tests specific to UCEC, and treatment advances are limited. It is crucial to identify more sensitive biomarkers for screening, diagnosis, and predicting UCEC. Previous studies have shown that UBE2T is involved in the development of various tumors such as breast cancer and liver cancer, but research on the role of UBE2T in UCEC is limited. METHODS: Using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and UALCAN databases, we analyzed the differential expression of UBE2T mRNA and protein in endometrial cancer (UCEC), along with its clinical relevance. A total of 113 clinical samples were collected, and immunohistochemistry and Western blot analysis were employed to validate bioinformatics analysis results. Volcano plots were generated using UBE2T and its differentially expressed genes, and a protein-protein interaction (PPI) network was constructed. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and immune infiltration analysis were used to predict the functional role of UBE2T in UCEC progression. Correlation between UBE2T expression and patient survival was analyzed using TCGA data, and Kaplan-Meier survival curves were plotted. RESULTS: UBE2T is significantly overexpressed in UCEC and correlates with poor prognosis. Its overexpression is closely associated with mitosis, cell cycle regulation, and histological grade in UCEC patients. CONCLUSION: UBE2T is highly expressed in UCEC and suppresses anti-tumor immune responses in UCEC patients. It serves as a key participant in UCEC progression, associated with a range of adverse outcomes, and holds potential as a clinical diagnostic and prognostic biomarker.

Development of a disulfidptosis-related prognostic model for endometrial cancer with potential therapeutic target.

Prognosis biomarkers for endometrial cancer (EC) are in need. Recent evidence demonstrated the critical role of disulfidptosis, a novel cell death modality, in cancer. However, limited studies have developed a disulfidptosis-related gene model for EC. Disulfidptosis prognosis score of EC (disulfidptosis-PSEC) were constructed using disulfidptosis-related differently expression genes with the RNA data of 544 EC patients from The Cancer Genome Atlas (TCGA) dataset. Model was evaluated using time-dependent receiver operating characteristic curve analysis for overall survival (OS) and disease-free survival (DFS), along with the hazard ratio (HR) between risk groups. Then, the cellular and molecular profile for different risk groups were performed, along with drug target inference. Disulfidptosis-PSEC demonstrated outstanding prognostic value for OS and DFS, with 5-year area under curve of 0.71 (95% CI, 0.58-0.75) and 0.69 (95% CI, 0.62-0.76), respectively. Low risk group demonstrated better survival with an HR of 0.38 (95% CI, 0.24-0.59) and 0.46 (95% CI, 0.32-0.66) for OS and DFS, respectively. The model was independent of TCGA subtype. Low risk group were featured with more immune cell infiltration and less gene mutation. Serval drug targets, and the therapeutic value of serotonin receptor among copy number (CN)-low subpopulation, were identified. Disulfidptosis-PSEC was a potential prognosis biomarker for EC with targetable biological process.

Impact of estradiol in inducing endometrial cancer using RL95-2.

BACKGROUND: Endometrial cancer is the most common gynecological malignancy that originates from the inner lining of the uterus and predominantly affects postmenopausal women. Prolonged exposure to estrogen, family history of endometrial cancer, obesity, and hormonal imbalance are some of the risk factors associated with endometrial cancer. In our study, we investigated the effect of estradiol, a potent form of estrogen at various concentrations on endometrial cell line RL95-2. METHODS: Endometrial cell RL95-2 were cultured in DMEM medium with optimal conditions required to maintain the cells. MTT assay and colony formation assay were further performed after treating the cells with different concentrations of estradiol (1, 10, and 100 nM) and TAM (100 nM). Moreover, the effect of genes regulated by estradiol was also examined using microarray and validated using real-time polymerase chain reaction (qRT-PCR). RESULTS: Time-dependent MTT assay shows a significant change in the ability of the cells to survive relative to concentrations. Colony formation was found to be directly proportional to the concentration of the estradiol (p < 0.05). Among genes, MMP14 (p = 0.03), SPARCL1 (p = 0.005), and CLU (p = 0.06) showed a significant up-regulation in their expression after estradiol treatment while NRN1 (p < 0.001) showed significant downregulation in expression pattern compared to control. However, the TAM treatment was found to be significantly effective after 72 h (p < 0.001) compared to control and 100 nM E2 (p = 0.0206). CONCLUSION: Our study suggests that estradiol significantly contributes to regulating the viability, colony formation, and expression of genes associated with endometrial cancer.

Evaluating pretreatment serum CA-125 levels as prognostic biomarkers in endometrial cancer: a comprehensive meta-analysis.

Background: In recent years, the incidence of endometrial cancer (EC) has been rising. This meta-analysis aims to clarify the prognostic significance of serum CA-125 levels in EC. Methods: Articles up to March 1, 2024, were systematically searched in EMBASE, Cochrane Library, PubMed, and Web of Science. This analysis pooled hazard ratios (HR) and 95% confidence intervals (CI) from qualifying studies to evaluate the association of CA-125 levels with overall survival (OS), progression-free survival (PFS), disease-free/relapse-free survival (DFS/RFS), and disease-specific survival (DSS). Results: 25 studies involving 7,716 patients were included. The analysis revealed that elevated CA-125 levels correlate with poorer OS (HR = 1.848, 95% CI: 1.571-2.175, p < 0.001). This association persisted across various study regions and sample sizes, and was notably strong in subgroups with a CA-125 cut-off value of less than 35 (HR = 2.07, 95% CI: 1.13-3.80, p = 0.019) and equal to 35 (HR = 2.04, 95% CI: 1.49-2.79, p < 0.001), and among type II pathology patients (HR = 1.72, 95% CI: 1.07-2.77, p = 0.025). Similarly, high CA-125 levels were linked to reduced PFS, particularly in subgroups with a CA-125 cut-off value less than 35 (HR = 1.87, 95% CI: 1.15-3.04, p = 0.012) and equal to 35 (HR = 4.94, 95% CI: 2.56-9.54, p < 0.001), and in endometrioid endometrial cancer patients (HR = 2.28, 95% CI: 1.18-4.40, p = 0.014). Elevated CA-125 levels were also indicative of worse DFS/RFS (HR = 2.17, 95% CI: 1.444-3.262, p < 0.001) and DSS (HR = 2.854; 95% CI: 1.970-4.133, p < 0.001). Conclusion: Serum CA-125 levels before treatment was highly associated with prognosis of EC patients.

Assessing para-aortic nodal status in high-grade endometrial cancer patients with negative pelvic sentinel lymph node biopsy.

OBJECTIVE: To determine the accuracy of pelvic sentinel lymph node biopsy (SLN) in detecting positive para-aortic (PA) lymph nodes in high-grade uterine cancer, and to determine the recurrence rate in patients with high-grade uterine cancers who did not receive adjuvant chemotherapy based on negative pelvic SLNs. METHODS: This was a retrospective cohort study of patients with newly diagnosed, high-grade endometrial cancer who underwent surgery, including pelvic SLNs with or without PA node dissection, at a tertiary care institution between 2015 and 2020. Baseline demographics, surgical management, pathology data, and outcomes were analyzed using descriptive statistics, and survival analysis. RESULTS: Postoperative histology of the 110 patients meeting inclusion criteria was 45.5% grade 3 endometrioid, 36.4% serous, 10.9% clear cell, and 7.3% carcinosarcoma. On final pathology, 63.7% were stage 1, and 23.6% were stage 3C with positive nodes. A total of 63 patients (57.3%) had a PA lymph node dissection (56 bilateral, 7 unilateral) in addition to the pelvic SLN. Among this group, 5.8% (95% confidence interval 1.2%-16.0%) had a positive PA node despite a negative pelvic SLN. Among those with a negative pelvic SLN and no adjuvant chemotherapy (n = 75), the rate of distant recurrence was 14.7%, and 3-year recurrence-free survival was 71.9%. CONCLUSION: The rate of isolated PA node metastasis in high-grade endometrial cancers despite a negative pelvic SLN may be significantly higher than the accepted rate of isolated PA node metastasis in low-grade endometrial cancer. This supports adjuvant treatment decisions continuing to incorporate primary tumor pathology and molecular classification.

Identification of candidate genes for endometrial cancer in multi-omics: a Mendelian randomization analysis.

Endometrial cancer is the most common malignant tumor of the uterus, but the underlying genetic mechanisms of EC remain unclear. To identify candidate genes and investigate genetic mechanisms for endometrial cancer, we utilized the summary-data-based Mendelian randomization (SMR) method to investigate causal associations between genetic variants, gene expression, DNA methylation, and endometrial cancer. Three main analyses were conducted utilizing cis-expression and methylation quantitative trait loci (eQTLs and mQTLs) as instrumental variables to examine causal relationships with endometrial cancer, and assessing the causal relationship between DNA methylation and gene expression. Data sources included genetic association data from O'Mara et al. eQTL data from the GTEx database, and mQTL data from McRae et al. Analysis involved the HEIDI test to distinguish pleiotropy, SMR analysis with multiple testing correction, and colocalization analysis to assess associations driven by linkage disequilibrium. Functional enrichment analysis was performed by the Metascape tool. Our study showed that three genes, SNX11, LINC00243, and EVI2A, were identified as causally related to endometrial cancer. SNX11 exhibited a positive causal relationship, while LINC00243 and EVI2A showed negative ones. Furthermore, 24 CpG sites were identified as causally related to endometrial cancer, with cg14424631 (CYP19A1) being the most significant. The study revealed common genes implicated in endometrial cancer, gene expression, and methylation sites, with LINC00243 playing a key role. Colocalization analysis confirmed significant causal relationships between LINC00243, SNX11, and endometrial cancer. Enrichment analysis uncovered pathways like interferon gamma signaling enriched in both endometrial cancer GWAS and e/mQTL. These findings shed light on the molecular mechanisms underlying endometrial cancer development. The study identified candidate genes and DNA methylation loci causally associated with endometrial cancer, which are expected to serve as potential targets for treatment.

Para-Aortic Lymphadenectomy in Ovarian, Endometrial, Gastric, and Bladder Cancers: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Para-aortic lymphadenectomy can be used for both diagnostic and therapeutic purposes as it aids in staging, provides prognostic data, and influences the patient's options for adjuvant therapy. However, there is still contention over its potential in treating cancer. A systematic review of the literature was performed to look into the published randomized controlled studies (RCTs) that have reported the effectiveness of lymphadenectomy. METHODS: Five different electronic databases, including PubMed, Cochrane Library, Clinical trials.gov, ICTRP, and Embase, were used to conduct a comprehensive search. Original RCTs reporting on the impact of lymphadenectomy on the overall survival in various cancers were included. Information related to the study population, intervention, type of cancer, primary endpoints, and key findings of the study were extracted. Quality assessment of the selected studies was conducted using the Revised Cochrane Risk of Bias Tool Rob 2 for randomized trials. RESULTS: A total of 1693 citations, with 1511 from PubMed, 80 from the Cochrane Library, 67 from Embase, 18 from ICTRP, and 17 from Clinicaltrials.gov were retrieved. Preliminary screening was performed, and after applying selection criteria, nine articles were included in the final qualitative analysis. The total number of patients was 4231, and the sample size ranged from 70 to 1408. Among these nine studies, four studies were on genital cancers (two ovarian cancers, one endometrial cancer, and one cervical cancer); four on digestive cancers (advanced gastric cancers); and one on urinary cancer (advanced bladder cancer). These studies reported that para-aortic lymphadenectomy did not improve overall survival and disease-free survival in advanced ovarian cancers, early endometrial cancers, advanced gastric, and bladder cancers. All of the studies had a low risk of bias. CONCLUSIONS: Para-aortic lymphadenectomy is not advised in advanced ovarian cancers, early endometrial cancers with low risks, advanced gastric cancers, and bladder cancers. SNB could be an alternative to lymphadenectomy for ovarian cancer in the future. Clinicians should inform patients regarding the benefits of para-aortic lymphadenectomy in terms of survival and the potential risks associated with it.

The Impact of Positive Peritoneal Cytology on the Survival of Endometrial Cancer Patients.

Background: Since the revision of the FIGO staging of endometrial cancer in 2009, patients with positive peritoneal cytology are no longer upstaged to stage IIIA. However, several studies demonstrated poorer outcomes in patients with positive washings. We conducted a survival analysis with the aim of evaluating the impact of positive peritoneal cytology on the survival of EC patients. Methods: We performed a retrospective analysis of prospectively collected data on patients with endometrial cancer operated in our institution between 2008 and 2014. We analysed the impact of positive peritoneal cytology and other established prognostic factors on survival. Results: A total of 227 patients with a median follow-up of 6.9 years were included in the study. A total of 12.8% had positive peritoneal cytology. Positive peritoneal cytology was significantly associated with worse overall survival (HR 1.82; 95% CI 1.02-3.26; p 0.043) but not with worse recurrence-free survival (HR 1.64; 95% CI 0.92-2.93; p 0.091) in univariate analyses. In addition, tumour stage, histologic subtype, lymphovascular space invasion, grade, and the depth of myometrial invasion were all significant prognostic factors for overall survival in univariate analyses. In multivariate survival analysis, only the histologic subtype, tumour stage, and myometrial invasion remained in the model at the last step. Conclusions: Positive peritoneal cytology was associated with worse overall survival in our series of endometrial cancer patients. However, other traditional prognostic factors had a more important prognostic role for survival in a multivariate model.

Lenvatinib Plus Pembrolizumab versus Doxorubicin for Advanced or Recurrent Endometrial Cancer with Short Treatment-Free Intervals Following First-Line Carboplatin Plus Paclitaxel.

Background: The treatment-free interval is a significant predictor of worse prognosis and poor response rates of the second-line treatment in patients with carboplatin and paclitaxel (PT)-pretreated, advanced, or recurrent endometrial cancer (EC). Whether lenvatinib plus pembrolizumab still confers a survival benefit compared with doxorubicin in patients with platinum-free intervals of <6 months remains unclear. Methods: This multi-institutional retrospective analysis was performed using de-identified electronic health records from the TriNetX Research Network. Patients with advanced or recurrent ECs who received lenvatinib plus pembrolizumab or doxorubicin within six months of first-line PT were identified. A 1:1 propensity score matching (PSM) was conducted to control for potential confounding variables. Overall survival (OS) and adverse event profile were the primary and secondary outcomes. Results: Between January 2018 and February 2024, 130 patients with PT-treated, advanced, or recurrent ECs who received lenvatinib plus pembrolizumab and 122 patients who received doxorubicin at a platinum-free interval of <6 months were identified across 31 healthcare organizations. In the balanced cohort following PSM with 117 patients in each group, treatment with lenvatinib plus pembrolizumab was associated with improved OS compared with treatment with doxorubicin (12.8 vs. 8.2 months, p = 0.012, hazard ratio: 0.65, 95% confidence interval: 0.46-0.91). Regarding adverse event analysis, a higher incidence of hypothyroidism and proteinuria was observed with lenvatinib plus pembrolizumab, and more hematological toxicities were observed with doxorubicin. Conclusions: in patients with treatment-free intervals of <6 months, lenvatinib plus pembrolizumab still confers improved survival compared with doxorubicin in PT-treated, advanced, or recurrent ECs.