Diagnosis Of Endometrial Cancer Research Articles

Clinical Correlations between Serological Markers and Endometrial Cancer.

Background: Endometrial cancer is associated with changes in blood cell counts and with high levels of inflammatory markers, thus reflecting the tumor's impact on various biological processes and suggesting their potential as biomarkers for endometrial cancer diagnosis, prognosis, and treatment response. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio in peripheral blood sampled preoperatively from patients have been reported to be independently associated with the prognosis of different types of malignancies. Objectives: This study aimed to compare several blood markers-red blood cells, white blood cells, platelet parameters, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, C-reactive protein, and fibrinogen-in patients with benign or malignant endometrial tumors. Material and methods: Our retrospective study included 670 patients (192 diagnosed with endometrial cancer and 478 with endometrial hyperplasia), and we compared the serological parameters discussed above with those sampled the day before surgery. Results: Analysis of complete blood count indices revealed no significant differences in red blood cell or total white blood cell parameters between the endometrial cancer group and the endometrial hyperplasia group. However, a distinct pattern emerged in the white blood cell differential. The endometrial cancer group showed a statistically significant decrease in lymphocyte count compared with the endometrial hyperplasia group. In contrast, the endometrial cancer group showed significantly higher mean platelet counts and increased mean platelet volume compared with controls. Furthermore, the endometrial cancer group demonstrated a marked inflammatory response, as evidenced by significantly elevated levels of C-reactive protein, fibrinogen, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio compared with the endometrial hyperplasia group. Conclusions: The current research revealed statistically significant differences in multiple serological biomarkers between the two groups. These findings support the initial hypothesis regarding the potential utility of these biomarkers in endometrial cancer diagnosis, prognosis, and treatment response, highlighting the existence of biomarkers affordable for analysis under any health system, regardless of the country's level of development.

Polycystic ovary syndrome and endometrial cancer risk: results from a nationwide cohort study.

Most previous studies have found an elevated risk of endometrial cancer among women with polycystic ovary syndrome (PCOS). However, these have highly varying methods for ascertainment of PCOS diagnoses and have limitations such as few exposed women and short follow-up. In this cohort study, we investigated the association between PCOS and endometrial cancer among women born in Denmark between January 1, 1940, and December 31, 1993 (N=1,719,121). Data in this study, including PCOS and endometrial cancer diagnoses and covariates, were derived from nationwide registers. We used cox proportional hazard regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7862 endometrial cancer cases were identified during 23.7 years of follow-up (inter quartile range 37.7-61.9). We found an increased risk of endometrial cancer among women with PCOS compared with women without PCOS (HR: 3.02, 95% CI; 2.03-4.49). The risk was increased for premenopausal women (HR5.82, 95% CI: 3.64-9.30) whereas no marked association was seen for postmenopausal women. However, for postmenopausal women, results were limited by few cases and young age at end of follow-up. Mounting evidence of an increased risk for endometrial cancer among women with PCOS reinforces the need for prevention and early detection.

Differential levels of circulating RNAs prior to endometrial cancer diagnosis.

Endometrial cancer (EC) is one of the most common female cancers and there is currently no routine screening strategy for early detection. An altered abundance of circulating microRNAs (miRNAs) and other RNA classes have the potential as early cancer biomarkers. We analyzed circulating RNA levels using small RNA sequencing, targeting RNAs in the size range of 17-47 nucleotides, in EC patients with samples collected prior to diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to EC diagnosis, and 316 matched controls, both from the Janus Serum Bank cohort in Norway. We identified differentially abundant (DA) miRNAs, isomiRs, and small nuclear RNAs between EC cases and controls. The top EC DA miRNAs were miR-155-5p, miR-200b-3p, miR-589-5p, miR-151a-5p, miR-543, miR-485-5p, miR-625-p, and miR-671-3p. miR-200b-3p was previously reported to be among one of the top miRNAs with higher abundance in EC cases. We observed 47, 41, and 32 DA miRNAs for EC interacting with BMI, smoking status, and physical activity, respectively, including two miRNAs (miR-223-3p and miR-29b-3p) interacting with all three factors. The circulating RNAs are altered and show temporal dynamics prior to EC diagnosis. Notably, DA miRNAs for EC had the lowest q-value 4.39-6.66 years before diagnosis. Enrichment analysis of miRNAs showed that signaling pathways Fc epsilon RI, prolactin, toll-like receptor, and VEGF had the strongest associations.

Stage II endometrial cancer: The diagnostic power of hysteroscopic excisional biopsy and MRI in the pre-operative cervical stroma assessment

Introduction/backgroundStage II Endometrial cancer (EC) accounts only for 12% of cases. Recent evidences redraw the weight of radicality in this stage as it would seem to have no impact on survival outcomes claiming for radicality when free surgical margins are not ensured to be achieved by simple hysterectomy. Thus, an accurate pre-operative evaluation might be crucial. This study aims to estimate the diagnostic power of Hysteroscopic excisional biopsy (HEB) of cervical stroma alone and combined with Magnetic resonance imaging (MRI) to predict the stage and concealed parametrial invasion in patients with preoperative stage II EC. MethodologyFrom January 2019 to November 2023, all patients evaluated at the Department of Gynaecology Oncology of Humanitas, Istituto Clinico Catanese, Catania, Italy, with a diagnosis of EC and evidence of cervical stromal diffusion on preoperative MRI and/or office hysteroscopy evaluation, considered suitable for laparoscopic modified type B hysterectomy, were consecutively included in the study. These underwent endometrial and cervical hysteroscopy excisional biopsy (HEB) for histological evaluation before definitive surgery. The data obtained were compared with the definitive histological examination (reference standard). ResultsSixteen patients met the including/excluding criteria and were considered into the study. Stage II endometrial cancer were confirmed in 3 cases (18.7%). We reported 2 (12,5%) parametrial involvement (IIIB), 4 (25%) cases of lymph nodes metastasis (IIIc), 7 (43,7%) cases of I stage. MRI had a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy (95% CIs) of 71%, 44%, 50%, 66% and 56.2 % respectively.HEB showed sensitivity, specificity, PPV, NPV and accuracy (95 % CI) of 85 %, 89 %, 85 %, 88 % and 87 % respectively. Comparing HEB + MRI to HEB alone, no statistical differences were noted in all fields. Considering parametrial invasion, MRI had better sensitivity but there were no statistical differences to HEB in other fields, showing both a worthy NPV. ConclusionHEB was accurate in all fields for cervical stroma assessment and had a fine NPV to exclude massive cervical involvement up to parametrial. Considering the new FIGO staging a preoperative molecular and histological evaluation of the cervical stroma may be useful. Operative hysteroscopy seems to be a feasible and accurate method for this purpose.

The usefulness of p16 and COX-2 expression on the prediction of progression to endometrial cancer.

Endometrial cancer (EC) is the most commonly diagnosed gynecological cancer. Endometrial hyperplasia (EH) is a more common diagnosis than EC. Endometrial hyperplasia is found in approximately 1.5% of all women presenting with abnormal bleeding. Endometrial hyperplasia progresses to EC, and especially, cancer risk increases in cases with atypical hyperplasia. p16, one of the tumor suppressor proteins involved in the cell cycle, and COX-2, one of the key enzymes of prostaglandin synthesis, are important markers for the diagnosis of both EH and EC. There is lack of consensus in the classification, diagnosis and treatment of EH. The subject of changes in the cell cycle in the progression of endometrial pathologies may help to identify and prevent these affected pathways in the treatment stage. The aim of this study is to investigate the expression of p16 and COX-2 during the development of EC from EH. We investigated COX-2 and P16 expressions in patients with proliferative endometrium, complex/simple endometrial hyperplasia and endometrioid adenocarcinoma. p16 expression increased in EH and EC (p<0.001). COX-2 expression was increased in endometrial cancer compared to other groups, but this increase was not found to be statistically significant. Although p16 and COX-2 expression were increased in patients with advanced grade/stage, lymphovascular invasion, and >50% of myometrial invasion, this increase was not statistically significant. More detailed studies are needed to investigate the prognostic significance of the COX-2 molecule. COX-2 might be a potential biomarker for the prognosis of endometrial cancer and a potential therapeutic target for EC treatment. Also, it might be used to prevent the progression of precursor lesions to invasive EC.

Multiparametric magnetic resonance imaging-based assessment of the effect of adenomyosis on determining the depth of myometrial invasion in endometrial cancer.

Accurate preoperative diagnosis of endometrial cancer (EC) with deep myometrial invasion (DMI) is critical to deciding whether to perform lymphadenectomy. However, the presence of adenomyosis makes distinguishing DMI from superficial myometrial invasion (SMI) on magnetic resonance imaging (MRI) challenging. We aimed to evaluate the accuracy of multiparametric MRI (mpMRI) in diagnosing DMI in EC coexisting with adenomyosis (EC-A) compared with EC without coexisting adenomyosis and to evaluate the effect of different adenomyosis subtypes on myometrial invasion (MI) depth in EC. Patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage I EC who underwent preoperative MRI were consecutively included in this 2-center retrospective study. Institution 1 was searched from January 2017 to November 2022 and institution 2 was searched from June 2017 to March 2021. Patients were divided into 2 groups: group A, patients with EC-A; group B, EC patients without coexisting adenomyosis, matched 1:2 according to age ±5 years and tumor grade. A senior radiologist assessed the MRI adenomyosis classification in group A. Then, 2 radiologists (R1/R2) independently interpreted T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), T1-weighted contrast-enhanced (T1CE), and a combination of all images (mpMRI) respectively, and then assessed MI depth. Accuracy, sensitivity, specificity, and the areas under the receiver operating curve (AUC) were calculated. The chi-square test was used to compare the accuracy of diagnosing DMI. Interobserver agreement was evaluated using the Kappa test. A total of 70 cases in group A and 140 cases in group B were included. The accuracy, sensitivity, and specificity of consensus were 94.3% [95% confidence interval (CI): 88.9-99.7%] vs. 92.1% (95% CI: 87.7-96.6%), 60.0% (95% CI: 17-92.7%) vs. 86.7% (95% CI: 68.4-95.6%), and 96.9% (95% CI: 88.4-95.5%) vs. 93.6% (95% CI: 86.8-97.2%) (group A vs. group B, respectively). There was no significant difference in the diagnostic accuracy of DMI on each sequence between the groups (Reviewer 1/Reviewer 2): PT2WI=0.14/0.17, PDWI=0.50/0.33, PT1CE=0.90/0.18, PmpMRI=0.50/0.37. The AUC for T2WI, DWI, T1CE, and mpMRI (Reviewer 1/Reviewer 2), respectively, were 0.54 (95% CI: 0.42-0.66)/0.78 (95% CI: 0.67-0.87), 0.63 (95% CI: 0.50-0.74)/0.77 (95% CI: 0.65-0.86), 0.69 (95% CI: 0.57-0.80)/0.79 (95% CI: 0.68-0.88), and 0.91 (95% CI: 0.82-0.97)/0.89 (95% CI: 0.79-0.95) (group A) and 0.83 (95% CI: 0.76-0.89)/0.85 (95% CI: 0.78-0.90), 0.83 (95% CI: 0.76-0.89)/0.86 (95% CI: 0.79-0.91), 0.88 (95% CI: 0.82-0.93)/0.86 (95% CI: 0.80-0.92), and 0.91 (95% CI: 0.85-0.95)/0.87 (95% CI: 0.80-0.92) (group B). Interobserver agreement was highest with mpMRI [κ=0.387/0.695 (case/control)]. The consensus results of MRI categorization of adenomyosis revealed no significant difference in the accuracy of diagnosing DMI by adenomyosis subtype (Pspatial relationship>0.99, Paffected area=0.52, Paffected pattern=0.58, Paffected size>0.99). The presence of adenomyosis or adenomyosis subtype had no significant effect on the interpretation of the depth of MI. T1CE can increase the contrast between adenomyosis and cancer foci; therefore, the information provided by T1CE should be valued.

High-Grade Endometrial Cancer: Molecular Subtypes, Current Challenges, and Treatment Options.

Although many recent advancements have been made in women's health, perhaps one of the most neglected areas of research is the diagnosis and treatment of high-grade endometrial cancer (EnCa). The molecular classification of EnCa in concert with histology was a major step forward. The integration of profiling for mismatch repair deficiency and Human Epidermal Growth Factor 2 (HER2) overexpression, can further inform treatment options, especially for drug resistant recurrent disease. Recent early phase trials suggest that regardless of subtype, combination therapy with agents that have distinct mechanisms of action is a fruitful approach to the treatment of high-grade EnCa. Unfortunately, although the importance of diagnosis and treatment of high-grade EnCa is well recognized, it is understudied compared to other gynecologic and breast cancers. There remains a tremendous need to couple molecular profiling and biomarker development with promising treatment options to inform new treatment strategies with higher efficacy and safety for all who suffer from high-grade recurrent EnCa.

A new perspective on Endometrial Carcinoma classification and management strategies in context of molecular subtypes.

Endometrial cancer is the most common gynecological cancer and the second most prevalent female malignancy in the developed world. It is typically diagnosed in postmenopausal women, presenting with the characteristic clinical symptom of uterine abnormal bleeding. In the past, only two histological types were considered. However, it has become increasingly evident that endometrial cancer is a clinically heterogeneous disease, and this heterogeneity is closely associated with the diversity of underlying molecular alterations. The Cancer Genome Atlas classification has significantly advanced the diagnosis, risk stratification, and management of endometrial cancer by categorizing it into four molecular subgroups, each characterized by distinct mutational burdens and copy number alterations.

New staging of endometrial carcinoma - FIGO 2023.

To review the changes in the new version of the FIGO 2023 staging system for endometrial cancer. 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. 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.

Potential application of body fluids autofluorescence in the non-invasive diagnosis of endometrial cancer.

Endometrial carcinoma (EC) is the most common cancer of the female reproductive tract in developed countries. The prognosis and 5-year survival rates are closely tied to the stage diagnosis. Current routine diagnostic methods of EC are either lacking specificity or are uncomfortable, invasive and painful for the patient. As of now, the gold diagnostic standard is endometrial biopsy. Early and non-invasive diagnosis of EC requires the identification of new biomarkers of disease and a screening test applicable to routine laboratory diagnostics. The application of untargeted metabolomics combined with artificial intelligence and biostatistics tools has the potential to qualitatively and quantitatively represent the metabolome, but its introduction into routine diagnostics is currently unrealistic due to the financial, time and interpretation challenges. Fluorescence spectral analysis of body fluids utilizes autofluorescence of certain metabolites to define the composition of the metabolome under physiological conditions. This review highlights the potential of fluorescence spectroscopy in the early detection of EC. Data obtained by three-dimensional fluorescence spectroscopy define the quantitative and qualitative composition of the complex fluorescent metabolome and are useful for identifying biochemical metabolic changes associated with endometrial carcinogenesis. Autofluorescence of biological fluids has the prospect of providing new molecular markers of EC. By integrating machine learning and artificial intelligence algorithms in the data analysis of the fluorescent metabolome, this technique has great potential to be implemented in routine laboratory diagnostics.

EnBloc Resection of Sentinel Lymph Nodes with the Hysterectomy Specimen in Endometrial Cancer.

We demonstrate the surgical technique of removing the sentinel lymph nodes with its afferent lymphatic vessels attached to the hysterectomy specimen. Stepwise demonstration of the technique with narrated video footage. Sentinel lymph node sampling has been established as an acceptable staging method in endometrial cancer cases.1 Lymphatic anatomy has been described according to three consistent channels for endometrial cancer dissemination: (1) an upper paracervical pathway draining external or obturator lymph nodes; (2) a lower pathway draining internal iliac lymph nodes; and (3) the infundibulo-pelvic pathway with a course along the broad ligament.2 A study in patients with cervical cancer identified tumor cells in the afferent lymphatic vessels of the upper pathway, even when the corresponding sentinel node was negative (3/20 patients).3 This could be an important prognostic factor in patients with cervical cancer. Since the typical position of sentinel nodes is the same in both endometrial and cervical cancers, we aimed to assess the feasibility of removing 'enbloc' the sentinel node with its afferent lymphatic vessels, and the uterus.4 INTERVENTIONS: The Da Vinci Xi surgical system was used. Indocyanine green was injected cervically, the pelvic surgical spaces were developed, and the sentinel lymph nodes, along with the afferent lymphatic vessels, were identified using the Firefly infrared camera. The lymphovascular tissue was mobilized and separated from the uterine artery, which was skeletonized and ligated. Colpotomy was performed and the specimen was retrieved vaginally. Emerging evidence regarding diagnosis, characterization, and treatment of endometrial cancer has introduced a new era, based on minimally invasive techniques for staging through sentinel lymph node biopsy, molecular classification, and personalized treatment algorithms that include immune checkpoint inhibitors and targeted therapies.5 Lymph node staging is one of the most significant prognostic factors in endometrial cancer patients and is a guide for adjuvant treatment. Sentinel lymph node biopsy is not inferior to conventional lymphadenectomy and is in fact a better way of identifying low-volume cancer through the use of ultrastaging, as part of the sentinel node algorithm.6 The dissection technique described in this video could offer an improvement in the staging of endometrial cancer, ensuring that the true sentinel lymph node is identified and that potential cancer cells inside the afferent lymphatic vessels are also excised. Therefore, it could be utilized as a more accurate way of planning adjuvant treatment and consequently improving recurrence and survival; however more studies are needed to further evaluate the feasibility and sensitivity of identifying disease in the afferent lymphatic vessels. This novel surgical technique emphasizes the importance of anatomical knowledge and offers inspiration for studies with potential clinical benefit that should follow.

The association between endometrial cancer and subsequent diabetic retinopathy severity: A retrospective nationwide study.

The endometrial cancer is a disorder with elevated oxidative stress. The high oxidative stress resulting from hyperglycemia can lead to diabetic retinopathy (DR) development which is a complication of type 2 diabetes mellitus. Accordingly, we aim to evaluate the potential relationship between the endometrial cancer and following DR development. A retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD) of Taiwan. Individuals diagnosed with endometrial cancer were matched to the non-endometrial cancer patients in a 1:4 ratio. The major outcomes are the presence of DR, diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) according to diagnostic codes. Cox proportional hazard regression was used to show the adjusted hazard ratio (aHR) with 95% confidence interval (CI) of major outcomes between groups. There were 99 (2.3%), 20 (0.5%), and 14 (0.3%) cases with DR, DME and PDR in the endometrial cancer group, respectively. Another 303 (1.8%), 35 (0.2%), and 27 (0.2%) with DR, DME and PDR were observed in the control group, respectively. The endometrial cancer group revealed a significantly higher incidence of DR compared with the control group (aHR 1.51, 95% CI 1.20-1.90, P < 0.001). The cumulative probability of DR was also higher in the endometrial cancer group than in the control group (P < 0.001). The relationship between endometrial cancer and DR was significantly higher in patients aged over 70 years (P = 0.008). In addition, a higher incidence of DR was found during the first 5 years after the endometrial cancer diagnosis (P < 0.001). The endometrial cancer correlates to a higher incidence of subsequent DR, especially within first 5 years of endometrial cancer diagnosis.

Multiparametric ultrasound Diagnosis of Endometrial Cancer in the Preoperative Preparation of Menopausal Patients

Multiparametric ultrasound Diagnosis of Endometrial Cancer in the Preoperative Preparation of Menopausal Patients

Real-world treatment patterns and clinical outcomes from a retrospective chart review study of patients with recurrent or advanced endometrial cancer who progressed following prior systemic therapy in Europe

ObjectiveTo evaluate real-world treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer patients who progressed following prior systemic therapy in clinical practice in Europe.DesignEndometrial Cancer Health Outcomes-Europe (ECHO-EU) is a...

Discovery of the potential biomarkers for early diagnosis of endometrial cancer via integrating metabolomics and transcriptomics

Endometrial cancer (EC) is one of the most common malignant tumors in women, and the increasing incidence and mortality pose a serious threat to the public health. Early diagnosis of EC could prolong the survival period and optimize the survivorship, greatly alleviating patients’ suffering and social medical pressure. In this study, we collected urine and serum samples from the recruited patients, analyzed the samples using LC-MS approach, and identified the differential metabolites through metabolomic analysis. Then, the differentially expressed genes were identified through the systematic transcriptomic analysis of EC-related dataset from Gene Expression Omnibus (GEO), followed by network profiling of metabolic-reaction-enzyme-gene. In this experiment, a total of 83 differential metabolites and 19 hub genes were discovered, of which 10 different metabolites and 3 hub genes were further evaluated as more potential biomarkers based on network analysis. According to the KEGG enrichment analysis, the potential biomarkers and gene-encoded proteins were found to be involved in the arginine and proline metabolism, histidine metabolism, and pyrimidine metabolism, which was of significance for the early diagnosis of EC. In particular, the combination of metabolites (histamine, 1-methylhistamine, and methylimidazole acetaldehyde) as well as the combination of RRM2, TYMS and TK1 exerted more accurate discrimination abilities between EC and healthy groups, providing more criteria for the early diagnosis of EC.

Accuracy of endometrial sampling in the diagnosis of endometrial cancer: a multicenter retrospective analysis of the JAGO-NOGGO

BackgroundAccurate preoperative molecular and histological risk stratification is essential for effective treatment planning in endometrial cancer. However, inconsistencies between pre- and postoperative tumor histology have been reported in previous studies. To address this issue and identify risk factors related to inaccurate histologic diagnosis after preoperative endometrial evaluation, we conducted this retrospective analysis.MethodsWe conducted a retrospective analysis involving 375 patients treated for primary endometrial cancer in five different gynaecological departments in Germany. Histological assessments of curettage and hysterectomy specimens were collected and evaluated.ResultsPreoperative histologic subtype was confirmed in 89.5% of cases and preoperative tumor grading in 75.2% of cases. Higher rates of histologic subtype variations (36.84%) were observed for non-endometrioid carcinomas. Non-endometrioid (OR 4.41) histology and high-grade (OR 8.37) carcinomas were identified as predictors of diverging histologic subtypes, while intermediate (OR 5.04) and high grading (OR 3.94) predicted diverging tumor grading.ConclusionWhen planning therapy for endometrial cancer, the limited accuracy of endometrial sampling, especially in case of non-endometrioid histology or high tumor grading, should be carefully considered.

Abstract 941: Patient-derived model systems of endometrial cancers for disease modeling and drug sensitivity testing

Abstract Background: Endometrial cancer (EC) is the most common gynecological cancer in the US, with increasing incidence and mortality rates. The survival rate lags behind four decades ago (81% vs 87%), underscoring the critical need for more effective treatment strategies. The heterogeneous nature of EC contributes to varied outcomes with current treatments. This project aims to establish reliable EC models for characterizing each individual tumor, distinguish optimal drug treatment, and determine specific drug effect mechanisms for personalized therapy. Methods: Freshly collected tumors were used for patient-derived xenograft models (PDXs) and patient-derived primary cancer cells (PDCs). Immunohistochemistry (IHC) staining was used to confirm the tumors grown in mice faithfully replicate the characteristics of patient tumor tissues. FDA-approved anticancer drugs were used to screen the optimal drugs to inhibit tumor cell proliferation and further utilized to inhibit tumor growth using PDXs. Results: We have collected 26 EC tumors and characterize them by DNA mutation and RNA-seq analysis. We implanted them in NSG mice, and 16 tumor samples have successfully grown in mice with a success rate of 61%. Most PDXs can be faithfully passaged to three generations. From the 16 PDXs, we created six novel PDCs. Using 2D and 3D spheroid cell culture, we screened 133 FDA-approved oncology drugs in the EC-PDC models. The drug screening results clearly highlighted several standout drugs, including CUDC-907 (a dual PI3K/HDAC inhibitor), two histone deacetylase (HDAC) inhibitors including romidepsin and panobinostat, four topoisomerase II (TOP II) inhibitors including mitoxantrone, daunorubicin, doxorubicin, and epirubicin, two proteasome inhibitors including carfilzomib and bortezomib, 2 DNA-directed RNA synthesis inhibitor dactinomycin and plicamycin, omacetaxine mepesuccinate (protein synthesis inhibitor), and valrubicin (DNA synthesis inhibitor). These drugs have demonstrated a significant capacity to inhibit tumor cell proliferation. Our pilot studies using single drugs, CUDC-907, romidepsin and mitoxantrone, achieved moderate drug effects. Combine mitoxantrone with romidepsin or CUDC-907 show surprisingly synergistic effects in multiple PDC models. The combination strategy will be tested in PDXs in the near future. Conclusion: Our unique PDXs and PDCs are excellent models for representing various characteristics of EC and testing novel therapeutics. This current study presents a promising direction for developing personalized therapy options for EC patients and provides a platform for further investigation of drug mechanisms and tumor development. Future studies will also involve etiology, such as chronic psychological stress, DNAm age and intratumoral microbiome. This information will help with endometrial cancer prevention, diagnosis, and prognosis. Citation Format: Tianyue Li, Xiaohao Huang, Riley Rosenmeyer, Samuel Robinson, Kazi Salsabil, Yiqin Xiong, Xiangbing Meng, Shujie Yang. Patient-derived model systems of endometrial cancers for disease modeling and drug sensitivity testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 941.

Single-cell analysis reveals landscape of endometrial cancer response to estrogen and identification of early diagnostic markers.

The development of endometrial cancer (EC) is closely related to the abnormal activation of the estrogen signaling pathway. Effective diagnostic markers are important for the early detection and treatment of EC. We downloaded single-cell RNA sequencing (scRNA-seq) and spatial transcriptome (ST) data of EC from public databases. Enrichment scores were calculated for EC cell subpopulations using the "AddModuleScore" function and the AUCell package, respectively. Six predictive models were constructed, including logistic regression (LR), Gaussian naive Bayes (GaussianNB), k-nearest neighbor (KNN), support vector machine (SVM), extreme gradient boosting (XGB), and neural network (NK). Subsequently, receiver-operating characteristics with areas under the curves (AUCs) were used to assess the robustness of the predictive model. We classified EC cell coaggregation into six cell clusters, of which the epithelial, fibroblast and endothelial cell clusters had higher estrogen signaling pathway activity. We founded the epithelial cell subtype Epi cluster1, the fibroblast cell subtype Fib cluster3, and the endothelial cell subtype Endo cluster3 all showed early activation levels of estrogen response. Based on EC cell subtypes, estrogen-responsive early genes, and genes encoding Stage I and para-cancer differentially expressed proteins in EC patients, a total of 24 early diagnostic markers were identified. The AUCs values of all six classifiers were higher than 0.95, which indicates that the early diagnostic markers we screened have superior robustness across different classification algorithms. Our study elucidates the potential biological mechanism of EC response to estrogen at single-cell resolution, which provides a new direction for early diagnosis of EC.

Association of tet methylcytosine dioxygenase 2 and 5-hydroxymethylcytosine in endometrioid adenocarcinoma and its clinical significance

BackgroundAberrant DNA methylation is a vital molecular alteration commonly detected in type I endometrial cancers (EC), and tet methylcytosine dioxygenase 2 (TET2) and 5-hydroxymethylcytosine (5hmC) play significant roles in DNA demethylation. However, little is known about the function and correlation of TET2 and 5hmC co-expressed in EC. This study intended to investigate the clinical significance of TET2 and 5hmC in EC.MethodsThe levels of TET2 and 5hmC were detected in 326 endometrial tissues by immumohistochemistry, and the correlation of their level was detected by Pearson analysis. The association between the levels of TET2 and 5hmC and clinicopathologic characteristics was analyzed. Prognostic value of TET2 and 5hmC was explored by Kaplan–Meier analysis. The Cox proportional hazard regression model was used for univariate and multivariate analyses.ResultsBased on the analysis results, TET2 protein level was positively correlated with 5hmC level in EC tissues (r = 0.801, P < 0.001). TET2+5hmC+ (high TET2 and high 5hmC) association was significantly associated with well differentiation, myometrial invasion, negative lymph node metastasis, and tumor stage in EC. Association of TET2 and 5hmC was confirmed as a prognostic factor (HR = 2.843, 95%CI = 1.226–3.605, P = 0.007) for EC patients, and EC patients with TET2−5hmC− level had poor overall survival.ConclusionsIn summary, the association of TET2 and 5hmC was downregulated in EC tissues, and may be a potential poor prognostic indicator for EC patients. Combined detection of TET2 and 5hmC may be valuable for the diagnosis and prognosis of EC.

Accuracy of Frozen Section Biopsy in the Diagnosis of Endometrial Cancer: A Systematic Review and Meta-Analysis.

The early and accurate diagnosis of endometrial cancer is of paramount importance for the survival of these patients. The aim of this study was to systematically appraise the available data regarding the accuracy of frozen section biopsy in diagnosing endometrial cancer. A thorough literature search was performed in PubMed/Medline, Scopus and the Cochrane Central Register of Controlled Trials databases from inception up to January 2023, with the use of specific, relevant key terms. A quality evaluation for each study was performed with the QUADAS-2 tool, whereas a bivariate random-effect model was performed to generate a summary receiver-operated curve. Heterogeneity was evaluated with Cochrane Q and Higgins' I2 statistics. Subgroup analyses were performed for studies focused on atypical hyperplasia and those focused on endometrial cancer. The search yielded 47 studies, involving 7790 patients with endometrial cancer. Among them, only 11 could be included in the quantitative analysis. QUADAS-2 evaluation resulted in rather high quality among the included studies. Quantitative synthesis resulted in a pooled sensitivity of 0.863 and pooled specificity of 0.916. The AUC was 0.948, the Q statistic was 10.488 (10 df, p = 0.399) and Higgins' I2 (4.655%) reported no significant heterogeneity. Subgroup analyses based on the diagnosis revealed a pooled sensitivity 0.886, specificity 0.862 and AUC 0.934 for endometrial cancer versus a sensitivity of 0.816, specificity of 0.962 and AUC 0.939 for atypical hyperplasia. Frozen section appears as a valid and reliable diagnostic tool for endometrial cancer. Its reliability seems to be even higher for the diagnosis of atypical hyperplasia. Therefore, this method may be considered in clinical practice and in settings with appropriate resources.