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.

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.

Endometrial regeneration cell-derived exosomes loaded with siSLAMF6 inhibit cardiac allograft rejection through the suppression of desialylation modification.

BACKGROUNDS: Acute transplant rejection is a major component of poor prognoses for organ transplantation. Owing to the multiple complex mechanisms involved, new treatments are still under exploration. Endometrial regenerative cells (ERCs) have been widely used in various refractory immune-related diseases, but the role of ERC-derived exosomes (ERC-Exos) in alleviating transplant rejection has not been extensively studied. Signaling lymphocyte activation molecule family 6 (SLAMF6) plays an important role in regulating immune responses. In this study, we explored the main mechanism by which ERC-Exos loaded with siSLAMF6 can alleviate allogeneic transplant rejection. METHODS: C57BL/6 mouse recipients of BALB/c mouse kidney transplants were randomly divided into four groups and treated with exosomes. The graft pathology was evaluated by H&E staining. Splenic and transplanted heart immune cell populations were analyzed by flow cytometry. Recipient serum cytokine profiles were determined by enzyme-linked immunosorbent assay (ELISA). The proliferation and differentiation capacity of CD4+ T cell populations were evaluated in vitro. The α-2,6-sialylation levels in the CD4+ T cells were determined by SNA blotting. RESULTS: In vivo, mice treated with ERC-siSLAMF6 Exo achieved significantly prolonged allograft survival. The serum cytokine profiles of the recipients were significantly altered in the ERC-siSLAMF6 Exo-treated recipients. In vitro, we found that ERC-siSLAMF6-Exo considerably downregulated α-2,6-sialyltransferase (ST6GAL1) expression in CD4+ T cells, and significantly reduced α-2,6-sialylation levels. Through desialylation, ERC-siSLAMF6 Exo therapy significantly decreased CD4+ T cell proliferation and inhibited CD4+ T cell differentiation into Th1 and Th17 cells while promoting regulatory T cell (Treg) differentiation. CONCLUSIONS: Our study indicated that ERC-Exos loaded with siSLAMF6 reduce the amount of sialic acid connected to α-2,6 at the end of the N-glycan chain on the CD4+ T cell surface, increase the number of therapeutic exosomes endocytosed into CD4+ T cells, and inhibit the activation of T cell receptor signaling pathways, which prolongs allograft survival. This study confirms the feasibility of using ERC-Exos as natural carriers combined with gene therapy, which could be used as a potential therapeutic strategy to alleviate allograft rejection.

Evaluation of lymphovascular space invasion in endometrial carcinoma by APTw and mDixon-Quant.

BACKGROUND: Lymphovascular space invasion (LVSI) is a strong and independent risk factor that increases the probability of endometrial carcinoma (EC) recurrence and reduces the survival rate of patients. PURPOSE: To investigate the value of amide proton transfer weighted (APTw) and mDixon-Quant techniques in evaluating EC lymphovascular space invasion (LVSI). MATERIAL AND METHODS: Data of 50 EC patients (18 LVSI+ and 32 LVSI-) confirmed by surgery and pathology were retrospectively analyzed. Preoperative magnetic resonance imaging (MRI) scans included APTw and mDixon-Quant imaging. APT, transverse relaxation rate (R2*), and fat fraction (FF) plots were obtained by postprocessing. The APT, R2*, and FF values of the two groups of cases were measured by two observers. RESULTS: The agreement between the two observers was good. The mean APT, R2*, and FF values of LVSI+ EC were 2.947% ± 0.399%, 20.605 /s (range = 18.525-27.953), and 2.234% ± 1.047%, respectively, while the parameters of LVSI- EC were 2.628% ± 0.307%, 18.968 /s (range = 16.225-20.544), and 2.103% ± 1.070%, respectively. The APT and R2* values of LVSI+ EC were higher than those of LVSI- EC (P < 0.05). There was no significant difference in FF value between the two groups. The AUC values of APT, R2*, and APT + R2* for LVSI were 0.751, 0.713, and 0.781, respectively (all P > 0.05). APT value was moderately correlated with R2* value (r = 0.528, P < 0.001) and weakly correlated with FF value (r = 0.312, P = 0.027). CONCLUSION: APTw and mDixon-Quant techniques could evaluate the LVSI status of EC, and their combined application could improve diagnostic efficiency.

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.

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.

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.

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.

Clinical outcomes analysis of image-guided brachytherapy as definitive treatment for inoperable endometrial cancer.

OBJECTIVES: This study evaluates the efficacy and toxicity of image-guided brachytherapy combined with or without external beam radiotherapy (IGBT ± EBRT) as definitive treatment for patients with inoperable endometrial cancer (IOEC), in addition to establishing a risk classification to predict prognosis. METHODS: Fifty-one IOEC patients who underwent IGBT ± EBRT at Peking Union Medical College Hospital from January 2012 to December 2021 were retrospectively analyzed, of which 42 patients (82.4%) were treated with IGBT + EBRT and 9 patients (17.6%) with IGBT alone. Establishing risk classification based on FIGO 2009 staging and biopsy pathology, stage III/IV, non-endometrioid, or Grade 3 endometrioid cancer were included in the high-risk group (n = 25), and stage I/II with Grade 1-2 endometrioid cancer was included in the low-risk group (n = 26). RESULTS: The median follow-up time was 58.0 months (IQR, 37.0-69.0). Clinical complete remission (CR) was achieved in 92.2% of patients after radiotherapy (n = 47). The cumulative incidences of locoregional and distant failure were 19.6% (n = 10) and 7.8% (n = 4), respectively. A total of 20 patients died (39.2%), including 10 cancer-related deaths (19.6%) and 10 comorbidity-related deaths (19.6%). The 5-year locoregional control (LRC), time to progression (TTP), overall survival (OS), and cancer-specific survival (CSS) were 76.9%, 71.2%, 59.4%, and 77.0%, respectively. No Grade 3 or above acute or late toxicities were reported. In univariate analysis, LRC, TTP, and CSS were significantly higher in the low-risk group than in the high-risk group (P < 0.05). After adjusting for age, number of comorbidities, radiotherapy modality, and chemotherapy, the low-risk group was still significantly better than the high-risk group in terms of LRC (HR = 6.10, 95% CI: 1.18-31.45, P = 0.031), TTP (HR = 8.07, 95% CI: 1.64-39.68, P = 0.010) and CSS (HR = 6.29, 95% CI: 1.19-33.10, P = 0.030). CONCLUSIONS: IGBT ± EBRT is safe and effective as definitive treatment for IOEC patients, achieving satisfactory locoregional control, favorable survival outcomes, and low toxicity. Risk classification based on FIGO 2009 staging and biopsy pathology is an independent prognostic factor for LRC, TTP, and CSS.