[Application of PRAME immunohistochemistry in the differential diagnosis of primary endometrial and endocervical adenocarcinomas].

Objective: To investigate the diagnostic value of preferentially expressed antigen in melanoma (PRAME) immunohistochemical staining in differential diagnosis of primary endometrial and endocervical adenocarcinomas. Methods: Eighty-seven cases of endometrial adenocarcinoma and sixty-three cases of cervical adenocarcinoma were collected from May 2018 to November 2023 in the Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School and all the cases were subject to PRAME immunohistochemical staining. The difference of PRAME expression between endometrial and endocervical adenocarcinomas was analyzed. Results: In 87 cases of endometrial adenocarcinoma, patients' age ranged from 35 to 71 years (average 59 years, median 59 years); in 63 cases of cervical adenocarcinoma patients' age ranged from 28 to 80 years (average 49 years, median 47 years). Seventy-eight cases (78/87, 89.7%) of endometrial adenocarcinoma; 2 cases (2/63, 3.2%) of cervical adenocarcinoma showed positive PRAME staining, and both cases of cervical adenocarcinoma were clear cell carcinoma. The sensitivity and specificity of PRAME in distinguishing between endometrial and cervical adenocarcinoma in the cohort were 89.7% and 96.8%, while those in differentiating non-clear cell carcinoma of the uterus from that of the cervix reached up to 91% and 100%, respectively. Conclusions: Immunohistochemical staining for PRAME demonstrates statistically significant differences between endometrial and cervical carcinomas, making it a useful auxiliary diagnostic marker for differentiating cervical and endometrial adenocarcinoma, especially non-clear cell carcinoma.

Clinicopathological Features and Outcomes of Endometrial Cancer: A single institution experience.

Objectives: This study aimed to report the demographic features, clinical presentation, pathological types and long-term outcomes of patients diagnosed with endometrial cancer (EC) in Oman. EC is the sixth most common cancer in women worldwide and the fifth most common cancer in women in Oman. Survival outcomes of EC have not been reported previously from Oman. Methods: This retrospective study was carried out on consecutive patients treated at the Sultan Qaboos University Hospital, Muscat, Oman, between 2008 and 2020. Survival was estimated using the Kaplan and Meier method. Results: A total of 50 patients with EC were included. The median age was 61 years (range: 31-86 years), and 72% of the patients had type I histology. Most patients were diagnosed with stage IA and IB EC (49% and 20%, respectively), and the majority had grade 1 or 2 tumours (40% and 34%, respectively). Overall, the 5-year survival and 10-year survival rates were estimated to be 70% and 56%, respectively. Weight (>75 kg) and body mass index (>30 kg/m2) were significantly associated with better survival. Tumour histology (type I versus type II or carcinosarcoma), grade (1 versus 2 versus 3) and stage (IA or IB versus II-IV) were associated with better overall survival (P = 0.007, P <0.0001 and P <0.0003, respectively). Patients diagnosed with EC with co-morbidities, other than obesity, had inferior survival compared to those without co-morbidities. Conclusion: Median age at presentation, histological sub-type, clinical stage and outcomes are comparable to the published literature. Almost two-thirds of the patients were obese. These data could be used as a benchmark for outcomes of EC in the region.

Correlation between immunohistochemical staining and clinicopathological findings in endometrial carcinoma.

OBJECTIVES: To analyze the immunohistochemical staining pattern of mismatch repair (MMR) proteins and p53 in endometrial carcinoma cases, including different subtypes and stages, to gain insights into their role in the pathogenesis and clinical behaviour of this malignancy. METHODS: In this study, we investigate the association between MMR deficiency, p53 mutational status, and clinical outcomes in various subtypes of endometrial carcinoma. The immunohistochemical staining pattern of MMR proteins in 96 cases of endometrial carcinoma have been analyzed, including 72 endometrioid, 14 papillary serous, 5 clear cell, and 5 mixed Müllerian tumor. RESULTS: The results showed that 36 cases were MMR deficient, with the majority being of endometrioid subtype. The p53 immunostain showed a mutational pattern in a subset of cases, with a documented dismal prognosis. However, aforementioned stains failed to predict synchronous or metachronous cancers in 5 patients. CONCLUSION: These findings highlight the importance of MMR and p53 immunohistochemical staining in the classification, and prognosis of endometrial carcinoma.

Construction and validation of a clinical risk model based on machine learning for screening characteristic factors of lymphovascular space invasion in endometrial cancer.

This study aimed to identify factors that affect lymphovascular space invasion (LVSI) in endometrial cancer (EC) using machine learning technology, and to build a clinical risk assessment model based on these factors. Samples were collected from May 2017 to March 2022, including 312 EC patients who received treatment at Xuzhou Medical University Affiliated Hospital of Lianyungang. Of these, 219 cases were collected for the training group and 93 for the validation group. Clinical data and laboratory indicators were analyzed. Logistic regression and least absolute shrinkage and selection operator (LASSO) regression were used to analyze risk factors and construct risk models. The LVSI and non-LVSI groups showed statistical significance in clinical data and laboratory indicators (P < 0.05). Multivariable logistic regression analysis identified independent risk factors for LVSI in EC, which were myometrial infiltration depth, cervical stromal invasion, lymphocyte count (LYM), monocyte count (MONO), albumin (ALB), and fibrinogen (FIB) (P < 0.05). LASSO regression identified 19 key feature factors for model construction. In the training and validation groups, the risk scores for the logistic and LASSO models were significantly higher in the LVSI group compared with that in the non-LVSI group (P < 0.001). The model was built based on machine learning and can effectively predict LVSI in EC and enhance preoperative decision-making. The reliability of the model was demonstrated by the significant difference in risk scores between LVSI and non-LVSI patients in both the training and validation groups.

Tumor Stiffness Measurement at Multifrequency MR Elastography to Predict Lymphovascular Space Invasion in Endometrial Cancer.

Background Pathologic lymphovascular space invasion (LVSI) is associated with poor outcome in endometrial cancer. Its relationship with tumor stiffness, which can be measured with use of MR elastography, has not been extensively explored. Purpose To assess whether MR elastography-based mechanical characteristics can aid in the noninvasive prediction of LVSI in patients with endometrial cancer. Materials and Methods This prospective study included consecutive adult patients with a suspected uterine tumor who underwent MRI and MR elastography between October 2022 and July 2023. A region of interest delineated on T2-weighted magnitude images was duplicated on MR elastography images and used to calculate c (stiffness in meters per second) and φ (viscosity in radians) values. Pathologic assessment of hysterectomy specimens for LVSI served as the reference standard. Data were compared between LVSI-positive and -negative groups with use of the Mann-Whitney U test. Multivariable logistic regression was used to determine variables associated with LVSI positivity and develop diagnostic models for predicting LVSI. Model performance was assessed with use of area under the receiver operating characteristic curve (AUC) and compared using the DeLong test. Results A total of 101 participants were included, 72 who were LVSI-negative (median age, 53 years [IQR, 48-62 years]) and 29 who were LVSI-positive (median age, 54 years [IQR, 49-60 years]). The tumor stiffness in the LVSI-positive group was higher than in the LVSI-negative group (median, 4.1 m/sec [IQR, 3.2-4.6 m/sec] vs 2.2 m/sec [IQR, 2.0-2.8 m/sec]; P < .001). Tumor volume, cancer antigen 125 level, and tumor stiffness were associated with LVSI positivity (adjusted odds ratio range, 1.01-9.06; P range, <.001-.04). The combined model (AUC, 0.93) showed better performance for predicting LVSI compared with clinical-radiologic model (AUC, 0.77; P = .003) and similar performance to the MR elastography-based model (AUC, 0.89; P = .06). Conclusion The addition of tumor stiffness as measured at MR elastography into a clinical-radiologic model improved prediction of LVSI in patients with endometrial cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ehman in this issue.

New staging of endometrial carcinoma - FIGO 2023.

AIM: To review the changes in the new version of the FIGO 2023 staging system for endometrial cancer. METHODS AND RESULTS: The new FIGO 2023 endometrial cancer staging system provides key updates for the diagnosis and treatment of endometrial cancer. An important step in diagnosis is molecular classification, which allows more accurate risk stratification for recurrence and the identification of targeted therapies. The new staging system, based on the recommendations of the international societies ESGO, ESTRO and ESP, incorporates not only the description of the pathological and anatomical extent of the disease, but also the histopathological characteristics of the tumour, including the histological type and the presence of lymphovascular space invasion. In addition, the staging system uses molecular testing to classify endometrial cancers into four prognostic groups: POLEmut, MMRd, NSMP and p53abn. Each group has its own specific characteristics and prognosis. The most significant changes have occurred in stages I and II, in which the sub-staging better reflects the biological behaviour of the tumour. This update increases the accuracy of prognosis and improves individualized treatment options for patients with endometrial cancer. CONCLUSION: The updated FIGO staging of endometrial cancer for 2023 incorporates different histologic types, tumour features, and molecular classifications to better reflect the current improved understanding of the complex nature of several endometrial cancer types and their underlying bio logic behaviour. The aim of the new endometrial cancer staging system is to better define stages with similar prognosis, allowing for more precise indication of individualised adjuvant radiation or systemic treatment, including the use of immunotherapy.

Histological assessment of endometrial polyps resected by hysteroscopy.

OBJECTIVE: This study aimed to analyze the clinical data and pathologic aspects of endometrial polyps (EMPs) excised completely during surgical hysteroscopy and assess the connection between premalignant and malignant EMPs. PATIENTS AND METHODS: This retrospective study includes 489 participants who underwent hysteroscopy due to endometrial polyps, and the clinical features and histological findings of the resected polyps analyzed. RESULTS: Participants with EMPs were divided into six groups according to histologic findings. The histologic finding of most cases was simple benign endometrial polyp [397 patients (81.2%)]. Malignant polyp was detected in 3 patients (0.6%). The histologic findings according to age, menopausal status, and menstrual bleeding patterns at the time of presentation to the outpatient clinic were compared; however, no significant difference was observed. 237 patients were observed to have menometrorrhagia, which was the most prevalent symptom reported. The distribution of polyp sizes observed at hysteroscopy according to histologic findings was compared, but no significant difference was observed. CONCLUSIONS: EMPs are often benign but can include premalignant or malignant tissue changes. Hysteroscopy is used for direct observation of the uterine cervix and resection of existing polyps, considering the increasing frequency of its use as a diagnostic and treatment tool.

Glycometabolism and lipid metabolism related genes predict the prognosis of endometrial carcinoma and their effects on tumor cells.

BACKGROUND: Glycometabolism and lipid metabolism are critical in cancer metabolic reprogramming. The primary aim of this study was to develop a prognostic model incorporating glycometabolism and lipid metabolism-related genes (GLRGs) for accurate prognosis assessment in patients with endometrial carcinoma (EC). METHODS: Data on gene expression and clinical details were obtained from publicly accessible databases. GLRGs were obtained from the Genecards database. Through nonnegative matrix factorization (NMF) clustering, molecular groupings with various GLRG expression patterns were identified. LASSO Cox regression analysis was employed to create a prognostic model. Use rich algorithms such as GSEA, GSVA, xCELL ssGSEA, EPIC,CIBERSORT, MCPcounter, ESTIMATE, TIMER, TIDE, and Oncoppredict to analyze functional pathway characteristics of the forecast signal, immune status, anti-tumor therapy, etc. The expression was assessed using Western blot and quantitative real-time PCR techniques. A total of 113 algorithm combinations were combined to screen out the most significant GLRGs in the signature for in vitro experimental verification, such as colony formation, EdU cell proliferation, wound healing, apoptosis, and Transwell assays. RESULTS: A total of 714 GLRGs were found, and 227 of them were identified as prognostic-related genes. And ten GLRGs (AUP1, ESR1, ERLIN2, ASS1, OGDH, BCKDHB, SLC16A1, HK2, LPCAT1 and PGR-AS1) were identified to construct the prognostic model of patients with EC. Based on GLRGs, the risk model's prognosis and independent prognostic value were established. The signature of GLRGs exhibited a robust correlation with the infiltration of immune cells and the sensitivity to drugs. In cytological experiments, we selected HK2 as candidate gene to verify its value in the occurrence and development of EC. Western blot and qRT-PCR revealed that HK2 was substantially expressed in EC cells. According to in vitro experiments, HK2 knockdown can increase EC cell apoptosis while suppressing EC cell migration, invasion, and proliferation. CONCLUSION: The GLRGs signature constructed in this study demonstrated significant prognostic value for patients with endometrial carcinoma, thereby providing valuable guidance for treatment decisions.

FIGO 2023 endometrial staging: a leap of faith into the new "prognostic based' rather than "anatomical based" staging-too fast too furious??

BACKGROUND: In 2023 FIGO revised the endometrial cancer staging system after 13 years. There is a lacuna of data regarding the performance and practicality of the revised 2023 FIGO staging schema for endometrial cancer from Low Middle-Income Countries (LMIC). OBJECTIVE: To estimate the shift of stage and adjuvant management of endometrial cancer based on the FIGO 2023 system compared to the FIGO 2009 system and assess the predictive potential of the FIGO 2023 system. MATERIAL AND METHODS: A retrospective study was conducted from 1st January 2017 to 31st December 2022. All patients with endometrial cancer were staged according to the FIGO 2023 and FIGO 2009 staging system. Follow-up of patients was done to determine recurrence. RESULTS: A total of 152 patients were included. Aggressive histology was seen in 66 (45%) patients. Eighteen (11%) had subserosal involvement. Substantial LVSI was noted in 23 (15%) of patients. Twenty-four (47%) patients of FIGO 2009 Stage IA and 26 patients (63%) of FIGO 2009 Stage IB were upstaged. Eleven (50%) patients of FIGO 2009 Stage IIIA were down staged to IA3. Overall 23 patients (15%) had a shift of stage. Fifteen out of 152 patients (15%) would have had a possible risk stratification change which would imply 23 patients (15%) would have needed a more radical treatment. Molecular classification was done in 32 patients; however, only 2 patients could afford POLE testing. Kaplan-Meier curves showed significant PFS differences in FIGO 2009 Stage IB and Stage IIIA when restaged according to the FIGO 2023 system. CONCLUSION: The FIGO 2023 endometrial staging is a more robust prognosticator; however, the practicality of molecular classification in LMICs is still a distant dream.

Tailoring postoperative management through sentinel lymph node biopsy in low- and intermediate-risk endometrial cancer - the SENTRY clinical trial.

BACKGROUND: While total hysterectomy and bilateral salpingo-oophorectomy without lymph node staging are standard for low- and intermediate-risk endometrial cancer, certain histopathologic factors revealed after surgery can necessitate additional interventions. Our study assessed the influence of sentinel lymph node biopsy on postoperative decision-making. MATERIALS AND METHODS: In the SENTRY trial (July 2021 - February 2023), we enrolled patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IA-IB low-grade endometrioid endometrial cancer. Laparoscopic sentinel lymph node mapping using indocyanine green was performed alongside total hysterectomy with bilateral salpingo-oophorectomy. Subsequent management changes based on sentinel lymph node biopsy results were evaluated. The trial was registered at ClinicalTrials.gov (NCT04972682). RESULTS: Of the 100 enrolled participants, a bilateral detection rate of 91% was observed with a median detection time of 10 min (interquartile range 8-13 min). Sentinel lymph node metastases were found in 8% (N = 8) of participants. Postoperative FIGO staging increased in 15% (N = 15) and decreased in 5% (N = 5) of patients. Sentinel lymph node biopsy results altered the adjuvant treatment plan for 20% (N = 20): external beam radiotherapy was omitted in 12% (N = 12) while 6% (N = 6) had external beam radiotherapy +/- systemic chemotherapy added due to sentinel lymph node metastases. In 2% (N = 2), the external beam radiotherapy field was expanded with the paraaortic region. No intraoperative complications were reported and no 30-day major morbidity and mortality occurred. Throughout a median follow-up of 14 (95% CI 12-15 months, neither patient-reported lymphedema nor pelvic recurrence surfaced in the cohort. CONCLUSIONS: Sentinel lymph node biopsy using indocyanine green is a safe procedure and allows tailoring adjuvant therapy in presumed low- and intermediate-risk endometrial cancer. It assists in avoiding external beam radiotherapy overtreatment and introducing additional modalities when necessary.

Predictive models for lymph node metastasis in endometrial cancer: A systematic review and bibliometric analysis.

BACKGROUND: Lymph node metastasis is associated with a poorer prognosis in endometrial cancer. OBJECTIVE: The objective was to synthesize and critically appraise existing predictive models for lymph node metastasis risk stratification in endometrial cancer. DESIGN: This study is a systematic review. DATA SOURCES AND METHODS: We searched the Web of Science for articles reporting models predicting lymph node metastasis in endometrial cancer, with a systematic review and bibliometric analysis conducted based upon which. Risk of bias was assessed by the Prediction model Risk Of BiAS assessment Tool (PROBAST). RESULTS: A total of 64 articles were included in the systematic review, published between 2010 and 2023. The most common articles were "development only." Traditional clinicopathological parameters remained the mainstream in models, for example, serum tumor marker, myometrial invasion and tumor grade. Also, models based upon gene-signatures, radiomics and digital histopathological images exhibited an acceptable self-reported performance. The most frequently validated models were the Mayo criteria, which reached a negative predictive value of 97.1%-98.2%. Substantial variability and inconsistency were observed through PROBAST, indicating significant between-study heterogeneity. A further bibliometric analysis revealed a relatively weak link between authors and organizations on models predicting lymph node metastasis in endometrial cancer. CONCLUSION: A number of predictive models for lymph node metastasis in endometrial cancer have been developed. Although some exhibited promising performance as they demonstrated adequate to good discrimination, few models can currently be recommended for clinical practice due to lack of independent validation, high risk of bias and low consistency in measured predictors. Collaborations between authors, organizations and countries were weak. Model updating, external validation and collaborative research are urgently needed. REGISTRATION: None.

Introduction to predictive models for lymph node metastasis in endometrial cancerLymph node metastasis of endometrial cancer is associated with a poor prognosis. There are currently many predictive models. We summarized and evaluated them in this article.

Validating the 2023 FIGO staging system: A nomogram for endometrioid endometrial cancer and adenocarcinoma.

BACKGROUND: To find the factors impacting overall survival (OS) prognosis in patients with endometrioid endometrial carcinoma (EEC) and adenocarcinoma and to establish a nomogram model to validate the 2023 International Federation of Obstetrics and Gynecology (FIGO) staging system for endometrial cancer. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) training cohort. An independent validation cohort was obtained from the First Affiliated Hospital of Anhui Medical University between 2008 and 2023. Cox regression analysis identified independent prognostic factors for OS in EEC and adenocarcinoma patients. A nomogram predicting OS was developed and validated utilizing the C-index, calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The relationship between the tumor grade and prognosis of EEC and adenocarcinoma was quantified using net reclassification improvement (NRI), propensity score matching (PSM), and Kaplan-Meier curves. RESULTS: Cox regression analysis identified age, race, marital status, tumor grade, tumor stage, tumor size, and chemotherapy as independent prognostic factors for OS. A nomogram for predicting OS was developed based on these factors. The C-indexes for the OS nomogram was 0.743 and 0.720 for the SEER training set and external validation set, respectively. The area under the ROC (AUC) for the OS nomogram was 0.755, 0.757, and 0.741 for the SEER data subsets and 0.844, 0.719, and 0.743 for the external validation subsets. Calibration plots showed high concordance between the nomogram-predicted and observed OS. DCA also demonstrated the clinical utility of the OS nomogram. NRI, PSM, and survival analyses revealed that tumor grade was the most important histopathological factor for EEC and adenocarcinoma prognosis. CONCLUSION: Seven independent prognostic variables for the OS of patients with EEC and adenocarcinoma were identified. The established OS nomogram has good predictive ability and clinical utility and validates the 2023 endometrial cancer FIGO staging system.

Synchronous Well-Differentiated Papillary Mesothelioma and Endometrioid Adenocarcinoma Arising From Endometriosis.

Well-differentiated papillary mesothelioma (WDPM) is a rare mesothelial tumor of uncertain malignant potential. We present a unique case of a woman with synchronous WDPM and well-differentiated endometrioid adenocarcinoma (EA) arising from extraovarian endometriosis. A 56-year-old postmenopausal woman presented with a several-month history of right lower quadrant abdominal pain. She had a history of supracervical hysterectomy and bilateral salpingo-oophorectomy secondary to endometriosis. Imaging reported a mass in the right lower quadrant originating from the distal ileum. At laparotomy, the patient underwent a right colectomy with resection of the terminal ileum and excision of a solitary peritoneal nodule. Pathology was consistent with a diagnosis of well-differentiated EA (arising from extraovarian endometriosis) and WDPM. Further treatment consisted of complete surgical staging/debulking and adjuvant chemotherapy directed toward metastatic well-differentiated EA. Surgeons should be familiar with WDPM as a potential finding in women of reproductive age undergoing abdominal surgery for any indication.

Diagnostic and therapeutic challenges in a recurrent endometrial carcinoma in lung, 15 years after primary treatment.

Endometrial carcinoma (EC) is the sixth most common cancer in females. Most ECs are detected in stage 1 and have a 5-year survival rate of more than 90%. Recurrence rates are highest within 5 years after treatment and are exceptionally rare after 10 years. Here, we describe a woman in her late 70s with endometrial cancer who was treated in 2008 and was diagnosed with a relapse in her left lung in 2023. Due to her advanced age and comorbidities, she was deemed inoperable. However, she received sequential chemotherapy and radiotherapy with a good partial response. She has now been started on hormonal therapy with an alternate megestrol and tamoxifen regime. There is a lack of follow-up imaging guidelines to detect late relapse, a dilemma in preferred treatment sequencing at relapse and an enigma in selecting chemotherapy or hormonal therapy.

Palmitic Acid Exerts Anti-Tumorigenic Activities by Modulating Cellular Stress and Lipid Droplet Formation in Endometrial Cancer.

Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer.

Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3ß/ß-catenin signaling.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers. METHODS: Bioinformatics analyses were performed to reveal EC patients' prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively. RESULTS: Machine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3ß-mediated ß-catenin ubiquitination and degradation, thus facilitating the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/ß-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects. CONCLUSIONS: Herein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/ß-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.

Analysis of CDO1, PITX2, and CDH13 Gene Methylation in Early Endometrial Cancer for Prediction of Medical Treatment Outcomes.

An observational cohort study of patients diagnosed with endometrial cancer (EC) stage IA G1, or atypical endometrial hyperplasia (AEH), undergoing organ-preserving treatment, was conducted. OBJECTIVE OF THE STUDY: To determine CDO1, PITX2, and CDH13 gene methylation levels in early endometrial cancer and atypical hyperplasia specimens obtained before organ-preserving treatment in the patients with adequate response and with insufficient response to hormonal treatment. MATERIALS AND METHODS: A total of 41 endometrial specimens obtained during diagnostic uterine curettage in women with EC (n = 28) and AEH (n = 13), willing to preserve reproductive function, were studied; 18 specimens of uterine cancer IA stage G1 from peri- and early postmenopausal women (comparison group) were included in the study. The control group included 18 endometrial specimens from healthy women obtained by diagnostic curettage for missed abortion and/or intrauterine adhesions. Methylation levels were analyzed using the modified MS-HRM method. RESULTS: All 13 women with AEH had a complete response (CR) to medical treatment. In the group undergoing organ-preserving treatment for uterine cancer IA stage G1 (n = 28), 14 patients had a complete response (EC CR group) and 14 did not (EC non-CR group). It was found that all groups had statistically significant differences in CDO1 gene methylation levels compared to the control group (p < 0.001) except for the EC CR group (p = 0.21). The p-value for the difference between EC CR and EC non-CR groups was <0.001. The differences in PITX2 gene methylation levels between the control and study groups were also significantly different (p < 0.001), except for the AEH group (p = 0.21). For the difference between EC CR and EC non-CR groups, the p-value was 0.43. For CDH13 gene methylation levels, statistically significant differences were found between the control and EC non-CR groups (p < 0.001), and the control and EC comparison groups (p = 0.005). When comparing the EC CR group with EC non-CR group, the p-value for this gene was <0.001. The simultaneous assessment of CDO1 and CDH13 genes methylation allowed for an accurate distinction between EC CR and EC non-CR groups (AUC = 0.96). CONCLUSION: The assessment of CDO1 and CDH13 gene methylation in endometrial specimens from patients with endometrial cancer (IA stage G1), scheduled for medical treatment, can predict the treatment outcome.

VOLTA: an enVironment-aware cOntrastive ceLl represenTation leArning for histopathology.

In clinical oncology, many diagnostic tasks rely on the identification of cells in histopathology images. While supervised machine learning techniques necessitate the need for labels, providing manual cell annotations is time-consuming. In this paper, we propose a self-supervised framework (enVironment-aware cOntrastive cell represenTation learning: VOLTA) for cell representation learning in histopathology images using a technique that accounts for the cell's mutual relationship with its environment. We subject our model to extensive experiments on data collected from multiple institutions comprising over 800,000 cells and six cancer types. To showcase the potential of our proposed framework, we apply VOLTA to ovarian and endometrial cancers and demonstrate that our cell representations can be utilized to identify the known histotypes of ovarian cancer and provide insights that link histopathology and molecular subtypes of endometrial cancer. Unlike supervised models, we provide a framework that can empower discoveries without any annotation data, even in situations where sample sizes are limited.

Prognostic impact and causality of age on oncological outcomes in women with endometrial cancer: a multimethod analysis of the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials.

BACKGROUND: Numerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials. METHODS: In this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used. FINDINGS: Median follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9-12·6) for PORTEC-1, 10·5 years (10·2-10·7) for PORTEC-2, and 6·1 years (5·9-6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01-1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01-1·05; p=0·0012) and was identified as a significant causal variable. INTERPRETATION: This study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone. FUNDING: None.