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Endometrial carcinoma is a heterogeneous group of malignancies characterized by distinct histopathological features and genetic underpinnings. The 2020 WHO classification has provided a comprehensive framework for the categorization of endometrial carcinoma. However, it has not fully addressed the spectrum of uncommon entities that are currently not recognized by the 2020 WHO and have only been described in the form of small case series and case reports. These neoplasms represent a real diagnostic challenge for pathologists; furthermore, their therapeutic management still remains controversial and information regarding tumor prognosis is very limited. This review aims to elucidate these lesser-known variants of endometrial carcinoma. We discuss the challenges of identifying these rare subtypes and the molecular alterations associated with them. Furthermore, we propose the need for expanded classification systems that include these variants to enhance clinical outcomes and research efforts. We believe that a better histological typing characterization of these entities may lead to more reproducible and accurate diagnoses and more personalized treatments. By raising awareness of these rare entities, we also hope to encourage further investigation and integration into clinical practice to improve patient care in endometrial carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Para-aortic lymphadenectomy can be used for both staging and therapeutic purposes in ovarian, endometrial, gastric and bladder cancers. However, Para-aortic lymphadenectomy is associated with high rates of morbidity and mortality and with no evidence of benefits in terms of overall survival and disease-free survival. A systematic review of the literature was performed to look into the published randomized controlled studies (RCTs) that have reported the effectiveness of lymphadenectomy. The total number of patients was 4231. The 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. Clinicians should inform patients regarding the benefits of para-aortic lymphadenectomy in terms of survival and the potential risks associated with it. 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. [ABSTRACT FROM AUTHOR]

Objectives: To transform the standardized descriptions of the ultrasound characteristics of endometrial and intrauterine lesions devised by the International Endometrial Tumor Analysis (IETA) group into a practical scoring method and to investigate whether application of this method enhances the diagnostic accuracy of ultrasound radiologists with different levels of experience in detecting malignancy compared with subjective assessment. Methods: This was a retrospective study of 855 patients with endometrial and/or intrauterine lesions, who were divided into a training (n = 600) and a validation (n = 255) set. Ultrasound radiologists with varying levels of experience (expert, intermediate and junior) evaluated all lesions by subjective assessment and according to IETA rules. Using IETA rules, the experts identified signs of malignancy in the training set, assigned scores for each indicator and validated the scoring method in the validation set. The intermediate‐level and junior ultrasound radiologists reassessed the malignancy of the lesions using the IETA scoring method and compared their classifications with those made previously by subjective assessment. Postsurgical pathological evaluation was used as the reference standard. Results: Using subjective assessment, the experts demonstrated the highest level of diagnostic accuracy, with a sensitivity of 85.0%, specificity of 94.3% and an area under the receiver‐operating‐characteristics curve (AUC) of 0.897. Applying the IETA scoring method (comprising eight ultrasound characteristics that contributed to the total score) with a threshold of > 25 points for the diagnosis of malignancy achieved a sensitivity of 84.7%, specificity of 94.7% and AUC of 0.9533 in the training set, with similar performance in the validation set, when performed by experts. Using the IETA scoring method, both junior and intermediate ultrasound radiologists showed improvement in sensitivity (from 55.5% to 74.8% and from 70.2% to 77.1%, respectively), specificity (from 88.4% to 91.5% and from 87.4% to 92.2%, respectively) and AUC (from 0.704 to 0.827 and from 0.793 to 0.841, respectively) for diagnosing malignant lesions. Conclusions: The IETA scoring method exhibits high diagnostic efficacy for malignant endometrial and intrauterine lesions. This method compensates for the lack of experience among junior and intermediate‐level ultrasound radiologists, enhancing their diagnostic skill to a level nearing that of experienced senior ultrasound radiologists. Further research is essential to validate the practicality of implementing this method and to confirm its clinical value. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate how L1 cell adhesion molecule (L1CAM) interacting with protein tyrosine kinase 2 (PTK2) affects endometrial cancer (EC) progression and determine its association with the focal adhesion kinase (FAK)–growth factor receptor-bound protein 2 (GRB2)–son of sevenless (SOS)–rat sarcoma (RAS) pathway. EC is a female cancer of major concern in the world, and its incidence has increased rapidly in recent years. L1CAM is considered a reliable marker of poor prognosis in patients with EC. Material and Methods: A single-center and prospective study was conducted using data from the Cancer Genome Atlas and samples from normal and EC tissues to explore the differential expression of L1CAM. Additional experimental models included human immortalized endometrial epithelium cells (hEECs) and EC cell lines such as KLE, RL95-2, and Ishikawa. L1CAM expression was regulated using lentiviruses designed for either overexpression or interference, and PTK2/focal adhesion kinase (FAK) signaling was inhibited with PF431396. Transfected KLE cells were injected into mice, and tumor growth was monitored over 14 days. Cellular proliferation and survival were assessed using cell counting kit, colony formation, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assays. Metastatic behavior was evaluated through Transwell assays for cell migration and invasion. The expression levels of matrix metallopeptidase (MMP) 2 and MMP9 were determined by Western blot. In addition, the activation of the FAK–GRB2–SOS–RAS pathway was examined by assessing the protein levels of FAK, GRB2, SOS, and RAS. Results: There was a significant difference in L1CAM expression between EC tumor tissues and normal tissues, and L1CAM messenger RNA (1.85-fold) and L1CAM protein (2.59-fold) were significantly more expressed in EC tissues (P < 0.01) than in normal tissues. The tumor growth of L1CAM overexpressing EC cells was faster than that of negative control EC cells (6.43 fold; P < 0.001). L1CAM promoted the expression of FAK (1.43-2.72-fold; P < 0.001); enhanced EC cell proliferation (P < 0.01), survival and motility (P < 0.001), migration (P < 0.001), and invasion (P < 0.001); and activated the FAK–GRB2–SOS–RAS pathway, all of which were reversed when FAK expression was not upregulated (P < 0.001). Conclusion: By upregulating PTK2 and its encoded protein FAK, L1CAM was found to promote tumor progression and increase the activation of the FAK–GRB2–SOS–RAS pathway. These findings establish L1CAM and PTK2 as reference genes for poor prognostic prediction in EC and as targets for EC therapy, providing a valuable basis for distinguishing between benign and malignant endometrial conditions and justifying the necessity of targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Despite rapid advances in molecular biology, personalized molecular therapy remains a clinical challenge for endometrial cancer due to its complex and heterogeneous tumor microenvironment. Based on clinical findings, AIB1 is a marker molecule for poor prognosis in endometrial cancer and may serve as a potential therapeutic target. Moreover, it is well known that aerobic glycolysis plays an important role in tumour energy metabolism. It has been previously reported in various hormone-related tumour studies that AIB1 affects glycolysis and promotes tumour development. However, the link between AIB1 and aerobic glycolysis in estrogen-dependent endometrial cancer remains unclear. Methods: We used two endometrial cancer cell lines to validate the high expression of target genes and the effect on the proliferative and invasive capacity of the tumours and verified the pattern of interactions and epigenetic modifications by CHIP and CO-IP techniques. Finally, the conclusions were validated on homozygous mice Results: In this study, we investigated the transcriptional co-activation functions of AIB1, including its acetylation by PCAF, binding to the c-myc transcription factor, and recruitment of glycolysis-related gene promoters. Discussion: Our findings provide new clues that perturbation of normal homeostatic levels of AIB1 is linked with endometrial cancer. These findings suggest that targeting AIB1-mediated regulation of aerobic glycolysis may offer a novel therapeutic approach for endometrial cancer with high AIB1 expression, opening new avenues for personalized diagnostics and treatment strategies in this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Present algorithms for the detection of pelvic sentinel lymph utilizing only tracers may fail to detect metastatic disease as women with nodal metastases overall have an overall lower mapping rate and that nodes at certain anatomic positions of the pelvic lymphatic pathways map less frequently. The study aimed to assess the increase in the diagnosis of pelvic nodal metastases by adding the removal of non-mapped nodes at defined known high-risk anatomic positions despite mapping at other positions. A 4.3% increase in the detection of pelvic nodal metastases was noted by the presence of isolated non-mapped metastatic nodes in the proximal obturator or external interiliac positions, suggesting that a hybrid algorithm combining tracer (ICG) with the removal of non-mapped nodes at either of the aforementioned positions should be utilized. Aim of the study: to investigate the incidence of non-mapped isolated metastatic pelvic lymph nodes at pre-defined anatomical positions. Patients and Methods: Between June 2019 and January 2024, women with uterine-confined endometrial cancer (EC) deemed suitable for robotic surgery and the detection of pelvic sentinel nodes (SLNs) were included. An anatomically based, published algorithm utilizing indocyanine green (ICG) as a tracer was adhered to. In women where no ICG mapping occurred in either the proximal obturator and/or the interiliac positions, defined as "typical positions", those nodes were removed and designated as "SLN anatomy". Ultrastaging and immunohistochemistry were applied to all SLNs. The proportion of isolated metastatic "SLN anatomy" was evaluated. Results: A non-mapping of either the obturator or interiliac area occurred in 180 of the 620 women (29%). In total, 114 women (18.4%) were node-positive and five of these women (4.3%) had isolated metastases in an "SLN anatomy", suggesting a similar lower sensitivity of the ICG-only algorithm. Conclusion: In an optimized SLN algorithm for endometrial cancer, to avoid undetected nodal metastases in 4.3% of node-positive women, if mapping fails in either the proximal obturator or interiliac area, nodes should be removed from those defined anatomic positions, despite mapping at other positions. [ABSTRACT FROM AUTHOR]

Simple Summary: The no specific molecular profile (NSMP) subtype of endometrial cancers remains a poorly understood class from a molecular standpoint, with a wide range of prognoses due to their internal heterogeneity. In this article, we confirm the value of a previously proposed further subdivision of NSMP into two risk classes: low-risk and high-risk; they are characterized by marked differences in oncological outcomes, including both the risk of recurrence and mortality. We are confident that this subdivision could bring significant benefits in the near future, not only in terms of modulating adjuvant therapy but also in standardizing research cohorts for more consistent and reproducible data. (1) Background: Endometrial carcinoma (EC) classified as no specific molecular profile (NSMP) represents a heterogeneous group with variable prognoses. This retrospective, single-center study aims to further stratify NSMP ECs to tailor treatment strategies and improve outcomes. (2) Methods: From 2020 to 2023, we collected data on 51 patients diagnosed with NSMP EC following the introduction of molecular profiling at our institution. Patients were retrospectively analyzed for estrogen receptor (ER) status, histotype, and grade to identify potential prognostic subgroups. (3) Results: Our analysis identified two distinct subgroups within NSMP EC: low-risk and high-risk, based on ER status, histotype, and grade. The low-risk NSMP group demonstrated significantly better survival outcomes compared to the high-risk group. With a median follow-up time of 16 moths (IQR 13.0–29.7), the disease-free survival (DFS) and overall survival (OS) for the low-risk group were 100%. For the high-risk group, the DFS and OS were 71.4% and 78.6%, respectively, which showed a statistically significantly difference (Log-Rank Mantel-Cox < 0.001). In the high-risk group, four patients experienced recurrence, and three of these patients died. (4) Conclusions: Stratifying NSMP EC into low-risk and high-risk categories based on ER status, histotype, and grade can lead to more accurate prognostic assessments. In time, it may require tailored adjuvant therapies and a personalized treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Sentinel lymph node assessment is becoming a standard of care procedure in patients with surgically treatable endometrial cancer due to its cost-effectiveness and the advantages it offers in guiding post-operative management. Unlike in breast cancer, however, several key aspects regarding this technique's employment in endometrial cancer remain unclear, such as tracer injection volume and final pathology interpretation. The aim of this paper is to investigate the current literature on this technique in order to provide simple and clear insight on the matter and to facilitate the reproducibility of this technique, ultimately resulting in improving patients' oncological outcomes. As the number of patients diagnosed with endometrial cancer rises, so does the number of patients who undergo surgical treatment, consisting of radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy or lymph node sampling. The latter entail intra- and post-surgical complications, such as lymphedema and increased intra-operative bleeding, which often outweigh their benefits. Sentinel Lymph Node (SLN) sampling is now common practice in surgical management of breast cancer, as it provides important information about the disease without jeopardizing surgical radicality and patient outcomes. While this technique has also been shown to be feasible in patients with endometrial cancer, there is little consensus on several aspects, such as tracer injection volume and site, pathological ultrastaging, and result interpretation. The aim of this review is to analyze the current literature on SLN assessment in order to help standardize the procedure. [ABSTRACT FROM AUTHOR]

Simple Summary: The RAGE signaling pathway is associated with many chronic disorders. One of them may be endometrial cancer (EC). EC is one of the most common gynecologic cancers among women. The aim of our considerations was to decipher the role of RAGE and its ligands in the progression of EC. We confirmed that disruptions in the RAGE signaling pathways may be a reason for EC progression. The cross-talk between RAGE and Diaph1 plays a crucial role in downstream signaling pathways during EC progression. However, we assume that DNA methylation may regulate the activity of the RAGE signaling pathways in the endometrium. Thus, DNA methylation may create an epigenetic memory that may trigger perturbations in the endometrium. Endometrial cancer (EC) is the most common gynecological malignancy. EC is associated with metabolic disorders that may promote non-enzymatic glycation and activate the receptor for advanced glycation end-products (RAGE) signaling pathways. Thus, we assumed that RAGE and its ligands may contribute to EC. Of particular interest is the interaction between diaphanous-related formin 1 (Diaph1) and RAGE during the progression of human cancers. Diaph1 is engaged in the proper organization of actin cytoskeletal dynamics, which is crucial in cancer invasion, metastasis, angiogenesis, and axonogenesis. However, the detailed molecular role of RAGE in EC remains uncertain. In this review, we discuss epigenetic factors that may play a key role in the RAGE-dependent endometrial pathology. We propose that DNA methylation may regulate the activity of the RAGE pathway in the uterus. The accumulation of negative external factors, such as hyperglycemia, inflammation, and oxidative stress, may interfere with the DNA methylation process. Therefore, further research should take into account the role of epigenetic mechanisms in EC progression. [ABSTRACT FROM AUTHOR]

Simple Summary: In this contribution, we show that, at a natural abundance, the nitrogen, carbon, and sulfur isotopic compositions of uterus cancerous and healthy tissues are different due to various metabolic pathways. These differences indicate that the isotopic composition might be a potential diagnostic and prognostic biomarker. We have tried to correlate the isotopic composition of tissues with that of serum, which would give us access to noninvasive biomarkers. In this respect, the obtained bulk isotopic compositions do not show any systematic correlation between the cancerous tissue and serum. Their application as biomarkers would probably require a position-specific isotopic analysis. Objectives: The metabolic pathway of cancerous tissue differs from healthy tissue, leading to the unique isotopic composition of stable isotopes at their natural abundance. We have studied if these changes can be developed into diagnostic or prognostic tools in the case of endometrial cancer. Methods: Measurements of stable isotope ratios were performed using isotope ratio mass spectrometry for nitrogen, carbon, and sulfur isotopic assessment. Uterine tissue and serum samples were collected from patients and the control group. Results: At a natural abundance, the isotopic compositions of all three of the studied elements of uterus cancerous and healthy tissues are different. However, no correlation of the isotopic composition of the tissues with that of serum was found. Conclusions: Differences in the isotopic composition of the tissues might be a potential prognostic tool. However, the lack of a correlation between the differences in the isotopic composition of the tissues and serum seems to exclude their application as diagnostic biomarkers, which, however, might be possible if a position-specific isotopic analysis is performed. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of endometrial cancer is increasing, creating a need for fast and efficient diagnostic methods. This study explores a new, non-invasive approach using urinary fluorescence spectroscopy to detect endometrial cancer. By analyzing morning urine samples and utilizing advanced machine learning techniques, we identified prospective spectral markers that differentiate between control, benign, and malignant gynecological patients. Our findings indicate good sensitivity and specificity, with high AUC from machine learning models, suggesting this method could significantly improve early cancer detection. This approach is easier and more affordable, especially in resource-limited settings. It has the potential to change the way endometrial cancer is diagnosed, offering a simpler and more accessible option for patients. Endometrial cancer is becoming increasingly common, highlighting the need for improved diagnostic methods that are both effective and non-invasive. This study investigates the use of urinary fluorescence spectroscopy as a potential diagnostic tool for endometrial cancer. Urine samples were collected from endometrial cancer patients (n = 77), patients with benign uterine tumors (n = 23), and control gynecological patients attending regular checkups or follow-ups (n = 96). These samples were analyzed using synchronous fluorescence spectroscopy to measure the total fluorescent metabolome profile, and specific fluorescence ratios were created to differentiate between control, benign, and malignant samples. These spectral markers demonstrated potential clinical applicability with AUC as high as 80%. Partial Least Squares Discriminant Analysis (PLS-DA) was employed to reduce data dimensionality and enhance class separation. Additionally, machine learning models, including Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), and Stochastic Gradient Descent (SGD), were utilized to distinguish between controls and endometrial cancer patients. PLS-DA achieved an overall accuracy of 79% and an AUC of 90%. These promising results indicate that urinary fluorescence spectroscopy, combined with advanced machine learning models, has the potential to revolutionize endometrial cancer diagnostics, offering a rapid, accurate, and non-invasive alternative to current methods. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EC) tissues express CYP7B1, but its association with prognosis needs to be investigated. Methods: Immunohistochemistry and image analysis software were used to assess CYP7B1 protein expression in paraffin-embedded endometrial tumor sections. Associations between CYP7B1 and clinical factors were tested with the Wilcoxon rank-sum test. Kaplan-Meier curves were employed to describe survival, and differences were assessed using the log-rank test. Cox regression analysis was used to assess the association between CYP7B1 expression and the prognosis of patients with EC. Results: A total of 307 patients were enrolled with an average age of 52.6 ± 8.0 years at diagnosis. During the period of follow-up, 46 patients (15.0%) died, and 29 (9.4%) suffered recurrence. The expression of CYP7B1 protein is significantly higher in the cytoplasm than in the nucleus (P < 0.001). Patients aged < 55 years (P = 0.040), ER-positive patients (P = 0.028) and PR-positive patients (P < 0.001) report higher levels of CYP7B1 protein. Both univariate (HR = 0.41, 95% CI: 0.18–0.90, P = 0.025) and multivariate (HR = 0.35, 95%CI:0.16–0.79, P = 0.011) Cox regression analyses demonstrate that high CYP7B1 protein expression predicts longer overall survival (OS). When considering only ER-positive patients (n = 265), CYP7B1 protein expression is more strongly associated with OS (HR = 0.20,95%CI:0.08–0.52, P = 0.001). The 3-year OS and 5-year OS in the low-CYP7B1 subgroup are 81.6% and 76.8%, respectively; while in the high-CYP7B1 subgroup are 93.0% and 92.0%, respectively (P = 0.021). Conclusions: High CYP7B1 protein expression predicted longer OS, suggesting that it may serve as an important molecular marker for EC prognosis. [ABSTRACT FROM AUTHOR]

Background: Yolk sac tumor (YST) is a highly malignant germ cell tumor, a majority of which originate from the gonads and are extremely rare from endometrium. Case presentation: Here we present a case of a 42-year-old woman suffered from primary pure yolk sac tumor of the endometrium complicated with situs inversus totalis. The patient presented at our hospital with irregular vaginal bleeding. Imageological examination showed a space-occupying lesion in the cervix and the serum Alpha-fetoprotein (AFP) level was significantly high (more than 1210ng/ml). Then she underwent total hysterectomy, bilateral salpingo-oophorectomy and pelvic lymph node dissection. The subsequent postoperative pathological diagnosis was yolk sac tumor arising from the endometrium. Next, the patient was treated with 6 cycles of chemotherapy with Pingyangmycin, etoposide and cisplatin regimen and was alive without evidence of recurrence or distant metastases for 13 months. Conclusions: This rare disease needs to be differentiated from endometrial epithelial neoplasia and the significant increase in AFP is helpful for diagnosis. Combined with previous literature reports, comprehensive staging laparotomy or maximum cytoreductive surgery complemented by standard chemotherapy can usually achieve a good efficacy. [ABSTRACT FROM AUTHOR]

Background & Aims: Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome. Methods: We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer. Results: Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression. Conclusions: This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndromeassociated cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: This review challenges the current ESGO/ESTRO/ESP guidelines on endometrial cancer risk classification, emphasizing the need to have more extensive and differentiated patient cohorts and to carefully consider the length of follow-up evaluation. Since the new guidelines for endometrial cancer risk classification have been released, many reviews have proposed a critical re-evaluation. In this review, we look back to how the molecular classification system has been built and its evolution in time. Since the new guidelines for endometrial cancer risk classification have been published, many reviews have proposed a critical re-evaluation. In this review, we look back to how the molecular classification system was built and its evolution in time to highlight the major flaws, particularly the biases stemming from the inherent limitations of the cohorts involved in the discoveries. A significant drawback in some cohorts is the inclusion criteria, as well as the retrospective nature and the notably sparse numbers, especially in the POLEmut (nonsynonymous mutation in EDM domain of POLE) risk groups, all of which impact the reliability of outcomes. Additionally, a disregard for variations in follow-up duration leads to a non-negligible bias, which raises a substantial concern in data interpretation and guideline applicability. Finally, according to the results that we obtained through a re-analysis of the confirmation cohort, the p53abn (IHC positive for p53 protein) subgroup, which is predominant in non-endometrioid histology (73–80%), loses its predictivity power in the endometrioid cohort of patients. The exclusion of non-endometrioid subtypes from the cohort led to a complete overlap of three molecular subgroups (all except POLEmut) for both overall and progression-free survival outcomes, suggesting the need for a more histotype-specific approach. In conclusion, this review challenges the current ESGO/ESTRO/ESP guidelines on endometrial cancer risk classification and highlights the limitations that must be addressed to better guide the clinical decision-making process. [ABSTRACT FROM AUTHOR]

Simple Summary: The rare ovarian cancer subtypes ovarian clear cell carcinoma (OCCC) and Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), can have mutations in members of a complex known as SWI/SNF that regulates the accessibility of chromatin to factors involved in DNA repair and gene expression. Some mutations in a particular complex member also occur in endometrioid ovarian cancer (EnOC) and endometriosis. Patients with endometriosis have a greater risk of developing OCCC and EnOC, with endometriosis frequently present at the time of diagnosis of these malignancies. The OCCC and SCCOHT ovarian cancer subtypes are notoriously difficult to treat with chemotherapies based on platinum-drugs that are standard-of-care for most cases of ovarian cancer. Mutations in members of this chromatin-remodelling complex offer new opportunities for molecular therapeutics using drugs that inhibit different aspects of cellular processes, including DNA repair, epigenetic regulation, kinase activity, and immune checkpoints. SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

This video article summarizes a case study involving the use of pelvic sentinel lymph node (SLN) biopsy for endometrial cancer (EC) staging and treatment utilizing a multi-modal infrared signal technology. This innovative approach combines cervical injection of fluorescent dye indocyanine green (ICG) and near-infrared imaging to enhance SLN detection rates in early-stage EC patients. The study showcases the successful application of advanced technology in improving surgical staging procedures and reducing postoperative morbidity for patients. Multi-modal infrared signal technology consists of different modes of fluorescence imaging used to identify lymph nodes based on near-infrared signals. Each mode serves a specific purpose: overlay image combines white light and near-infrared signals in green, monochromatic visualization shows near-infrared signal in greyscale, and intensity map combines signals in a color scale to differentiate signal intensity. Yellow denotes strong near-infrared signals while blue represents weaker signals. By utilizing a multi-modal approach, surgeons can accurately identify and remove SLN, thus avoiding unnecessary removal of secondary or tertiary echelons. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time. Methods: We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets. Results: We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and highgrade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors. Conclusions: The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC. [ABSTRACT FROM AUTHOR]

Gynecologic cancer is a critical concern in the field of women's health, and traditional treatment methods have demonstrated limited efficacy for certain advanced and recurrent gynecologic cancers. In recent years, antibody–drug conjugate (ADC) therapy, as an emerging targeted approach, has gained increasing attention as a research hotspot. This review aims to elucidate the structure and mechanism of ADC drugs and explore their application and clinical research progress in gynecologic cancers such as ovarian cancer, cervical cancer, and endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Angiogenesis is a synchronous mechanism of new blood vessel formation that is controlled by pro- and anti-angiogenic factors. Angiogenesis differs from tissue to tissue, especially in pathological conditions. The exact nature of the co-operation between angiogenic markers is still unknown. Herein, we describe the possible critical changes in VEGF-A, TGF-β1, ANG1, ANG2, and HIF-1α in ectopic endometriosis (with elevated pro-angiogenic factors in all studied fields), in ovarian endometrioid adenocarcinoma (showing typical upregulation on the TGF-β1 axis), and two different types of endometrial carcinoma (with an extreme pathological ANG2/ANG1 axis for mixed mesodermal tumors). Understanding the angiogenic mechanism within pathological tissues could help to improve angiogenic treatment strategies and lead to better prognoses. A characteristic feature of uterine pathologies is a specific change in cell metabolism, which predominantly manifests as a shift in the need for nutrients, thereby directing cells to engage in different angiogenic marker activities. Angiogenesis is one of the main signals supporting the survival and development of cells and tissues not only under physiological conditions. Therefore, it is necessary that we understand pathological hyperactivation in all uterine diseases, from endometriosis through ovarian endometrioid adenocarcinoma to malignant transformed cells of the uterine epithelium and body. This work presents the gene expression results of selected angiogenesis targets (VEGF-A, TGF-β1, ANG1/2, and HIF-1α), cell migration, and cell–cell interaction determined in vitro. Our results suggest that angiogenesis varies in the tested pathological conditions (ectopic endometriosis—12Z; ovarian endometrioid adenocarcinoma—A2780; tumors—SK-UT-1 and RL-95-2) compared to physiological angiogenesis (HME1). The differential expression of angiogenic factors may contribute (or is a contributing factor) to the observed differences to acknowledge an inherent variability in angiogenesis among cell lines. Determining the genomic phenomena responsible for processes associated with inadequate angiogenesis in the pelvic region could help us to develop individual treatment strategies and explain resistance to treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: We systematically reviewed the literature on port site metastases in low- and intermediate-risk endometrial carcinoma. We searched six electronic databases and compared data on PSM from the included studies, finding seven studies and 13 cases of PSM in patients with low- or intermediate-risk endometrial carcinoma. Local resection and radiotherapy appear to be the most appropriate treatment approaches. Unfortunately, no consensus has been reached about treatment, and the prognosis appears poor. Background: Port site metastasis (PSM) has been reported as a rare metastasis in women with endometrial carcinoma (EC). However, even more rarely, it has also been described in patients with low- or intermediate-risk EC. Unfortunately, knowledge appears limited on the topic. Objectives: Our objective was to systematically review the literature on PSM in low- or intermediate-risk EC. Search Strategy: A systematic review of the literature was performed by searching six electronic databases from their inception to January 2023. Selection Criteria: We included in our research all peer-reviewed studies which reported PSM in low- or intermediate-risk EC women. Data Collection and Analysis: Data on PSM were collected from the included studies and compared. Results: Seven studies with 13 patients (including our case) were included in the systematic review. PSM was reported in patients with low- or intermediate-risk EC independently from tumor histologic characteristics, endoscopic approach, lymph node staging type, number and site of the port, route of specimen removal, prevention strategies for PSM, and concomitant metastases. Among several proposed treatments, local resection and radiotherapy with or without chemotherapy might be the most appropriate ones. Nevertheless, the prognosis appears poor. Conclusions: In patients with low- or intermediate-risk EC, PSM can occur as a rare metastasis, regardless of tumor characteristics or surgical strategy. Unfortunately, no consensus has been reached regarding treatment, and the prognosis appears poor. Additional cases are needed in order to confirm and further explore this rare EC metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer and mixed Müllerian tumors are different types of uterine malignancies, yet differentiating these diseases can be challenging and often requires surgery. A timely and accurate diagnosis of these conditions is crucial for providing optimal treatment options. The emerging field of radiomics may assist clinicians in diagnosing these conditions preoperatively by extracting complex patterns from clinical imaging to identify features unique to each type of tumor. This study aims to analyze radiomics data from patients with endometrial cancer and mixed Müllerian tumors to identify distinguishing features that could help clinicians diagnose each disease. The objective of this study was to compare the quantitative radiomics data between malignant mixed Müllerian tumors (MMMTs) and endometrial carcinoma (EC) and identify texture features associated with overall survival (OS). This study included 61 patients (36 with EC and 25 with MMMTs) and analyzed various radiomic features and gray-level co-occurrence matrix (GLCM) features. These variables and patient clinicopathologic characteristics were compared between EC and MMMTs using the Wilcoxon Rank sum and Fisher's exact test. The area under the curve of the receiving operating characteristics (AUC ROC) was calculated for univariate analysis in predicting EC status. Logistic regression with elastic net regularization was performed for texture feature selection. This study showed that skewness (p = 0.045) and tumor volume (p = 0.007) significantly differed between EC and MMMTs. The range of cluster shade, the angular variance of cluster shade, and the range of the sum of squares variance were significant predictors of EC status (p ≤ 0.05). The regularized Cox regression analysis identified the "256 Angular Variance of Energy" texture feature as significantly associated with OS independently of the EC/MMMT grouping (p = 0.004). The volume and texture features of the tumor region may help distinguish between EC and MMMTs and predict patient outcomes. [ABSTRACT FROM AUTHOR]

Context.--: Molecular stratification of endometrial carcinoma provides more accurate prognostic information than traditional clinicopathologic features. However, because next-generation sequencing is typically recommended for polymerase tifilon (POLE) mutation detection, the practical application of a test based on molecular stratification is limited in the clinical setting. Objective.--: To evaluate a polymerase chain reaction (PCR)-based assay for POLE mutation detection in endometrial carcinoma. Design.--: We developed a PCR-based technology called Dalton Mutation Identifier Technology (Dalton-MIT) that targets 9 mutation sites within POLE exons. Endometrial carcinoma specimens from 613 patients were tested for POLE mutations. Correlations between POLE mutations and patient clinicopathologic characteristics and prognosis were analyzed. Results.--: PCR detection data showed that the incidence rate of POLE mutation was 11.4% (70 of 613). Patients with POLE mutations had better clinicopathologic characteristics and prognosis than those with non-POLE mutations. Comparison between Dalton-MIT and next-generation sequencing in 59.5% (365 of 613) of specimens showed that the sensitivity of Dalton-MIT for detecting POLE pathogenic mutations was 100%, the specificity was 99.3%, the Youden index was .993, and the k value was .981 (P < .001). Conclusions.--: Our data demonstrate that POLE mutation detection by Dalton-MIT correlates with next-generation sequencing. This suggests that Dalton-MIT represents a promising alternative assay for detecting POLE mutations and will facilitate the wider application of molecular stratification tools for endometrial carcinoma in the clinic. [ABSTRACT FROM AUTHOR]

Objective: The incidence of endometrial cancer is increasing, and oxidative stress has been suggested to play a vital role in its carcinogenesis. Statins have an impact on the cellular redox-state. The aim of this study was to determine the effects of statin use on redox-state regulating enzymes in endometrial cancer in women with type 2 diabetes. Materials and methods: This retrospective study consisted of 119 women with type 2 diabetes who were diagnosed with endometrial cancer at Oulu University Hospital in Finland between 2007 and 2014. There were 58 statin users and 61 non-users based on medication use at the time of endometrial cancer diagnosis. The expression of redox-state regulating proteins nuclear factor erythroid 2- related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in the tumor samples was assessed immunohistochemically, and manganese superoxide dismutase (MnSOD) levels were measured both immunohistochemically and from serum samples. Results: High MnSOD expression predicted better progression-free survival (PFS) in statin non-users in a univariate analysis (p=0.02). There was no statistical difference in overall survival (OS) or PFS between strong and weak expression of Nrf2 and Keap1. After adjusting for stage and statin use, the results were similar. Conclusion: Statin non-users with strong MnSOD expression had better PFS compared to statin users which proves that statins have impact on redox-state regulating enzymes. However, these findings are preliminary and require further research. [ABSTRACT FROM AUTHOR]

Simple Summary: This study compares the survival and surgical outcomes of patients who underwent conventional versus robot-assisted laparoscopy for aggressive histologic types of uterine cancer. While there is no association between the use of robotic assistance and overall survival, robot-assisted laparoscopy is associated with a decreased risk for conversion to laparotomy and a higher rate of surgical lymph node evaluation. The objective of this study is to compare the overall survival (OS) and surgical outcomes between conventional laparoscopy and robot-assisted laparoscopy (RAL) in women with type II endometrial cancer. We identified a large cohort of women who underwent hysterectomy for type II endometrial cancer between January 2010 and December 2014 using the National Cancer Database (NCDB). The primary outcome was to compare the OS of conventional laparoscopy versus RAL. Secondary outcomes included the length of hospital stay, 30-day readmission rate, 90-day mortality, rates of lymph node retrieval, rates of node positivity, and rates of conversion to laparotomy. Cohorts were compared and multivariable logistic regression was used to determine characteristics with statistically significant predictors of outcome. We identified 7168 patients with stage I–III type II endometrial cancer who had minimally invasive surgery as primary treatment between 2010 and 2014. A total of 5074 patients underwent RAL. Women who underwent RAL were less likely to have stage III disease (26.4% vs. 29.9%, p = 0.008) and had smaller primary tumors (4.6 vs. 4.1 cm, p < 0.001). In a multivariable model, there was no difference in OS between conventional laparoscopy and RAL. With regard to postoperative outcomes, RAL was associated with a decreased risk for conversion to laparotomy (2.7% vs. 12%, p < 0.001), a shorter hospital stay (1 vs. 2 days, p < 0.001), a decreased 90-day mortality (1.3% vs. 2.2%, p = 0.004), and an increased number of lymph nodes sampled (14 vs. 12, p < 0.001). In multivariable analysis, the use of RAL was independently associated with a reduced rate of conversion to laparotomy. In conclusion, there was no difference in OS between conventional laparoscopy and RAL in type II endometrial cancer in a large retrospective cohort of patients from the NCDB. RAL was associated with a decreased risk of conversion to laparotomy. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is a common cancer among women worldwide. In rare occasions, it can be caused by mutations in genes that can be inherited, and, mostly, as part of the Lynch syndrome that can also increase the risk of developing other cancers, mostly colorectal. In this study, we analyzed genetic alterations in 130 Arab patients with endometrial cancer. Among the whole group, 18 (13.8%) patients had positive mutations in MLH1, PMS2, MSH2, ATM, MUTYH, and BRCA2. Such mutations were more common in younger patients and in patients with specific endometrial cancers like carcinosarcoma and clear cell carcinoma. Most of endometrial cancers are sporadic, with 5% or less being attributed to inherited pathogenic germline mutations and mostly related to the Lynch syndrome. To our knowledge, this is the first study to investigate patterns and frequencies of germline mutations in patients with endometrial cancer in an Arab region. Consecutive patients with endometrial cancer (n = 130), regardless of their age and family history, were enrolled. Germline genetic testing, using an 84-gene panel, was performed on all. Almost half of the patient population (n = 64, 49.2%) was tested based on international guidelines, while the remaining patients (n = 66, 50.8%) were tested as part of an ongoing universal germline genetic testing program. Among the whole group, 18 (13.8%) patients had positive pathogenic or likely pathogenic (P/LP) germline variants. The most common variants encountered were in MLH1 (n = 4, 22.2%), PMS2 (n = 3, 16.7%), ATM, MSH2, MUTYH, and BRCA2 (n = 2, 11.1% each). In addition, three (2.3%) patients were found to have an increased risk allele of the APC gene. P/LP variants were more common among patients with carcinosarcoma and clear cell carcinoma, younger patients (age ≤ 50 years), and in patients with a non-metastatic disease. We conclude that germline genetic variants, mostly in genes related to the Lynch syndrome, are relatively common among Arab patients with endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: High-grade endometrial stromal sarcoma (HG-ESS) is a rare malignant tumor with poor prognosis. To overcome the limitations of current treatment for advanced patients, the intervention of targeted drug therapy is urgently needed. Case presentation: A 74-year-old married woman who presented with abdominal distension and lower abdominal pain was admitted to Hebei General Hospital. After surgery, immunohistochemical staining revealed a malignant tumor which was consistent with HG-ESS. Tumor recurrence occurred 2 months after surgery. Then the patient underwent chemotherapy with two courses but responded poorly. Subsequently we observed ATM, BLM, and CDH1 co-mutations by Next Generation Sequencing (NGS). Then the patient received pamiparib, which resulted in a 10-month progression-free survival (PFS) and is now stable with the administration of sintilimab in combination with pamiparib and anlotinib. Conclusions: Due to the successful use of poly ADP-ribose polymerase inhibitor (PARPi) on HG-ESS, we suggest that the selection of effective targeted drugs combined with anti- programmed death-1 (PD-1) drug therapy based on genetic testing may become a new option for the treatment of homologous repair deficient (HR-deficient) HG-ESS. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify high- and low-risk subgroups of patients with lymph node (LN) metastasis in presumed early-stage endometrioid endometrial cancer (EC) patients. Methods: Clinicopathologic data of presumed early-stage endometrioid EC patients (n=361) treated with lymphadenectomy between March 2000 and July 2022 were analyzed. None of the patient had definite evidence of LN metastasis in a preoperative magnetic resonance imaging (MRI). A received operating characteristic curve analysis was conducted to define the sensitivity and specificity for the combined preoperative risk factors for LN metastasis, which was determined by multivariate analysis. Results: Nineteen patients (5.3%) had LN metastasis. Multivariate analysis identified cervical stromal invasion on MRI (odds ratio [OR]=4.386; 95% confidence interval [CI]=1.020-18.852; p=0.047), cornual location of tumor on MRI (OR=36.208; 95% CI=7.902-165.913; p<0.001), and lower uterine segment/isthmic location of tumor on MRI (OR=8.454; 95% CI=1.567-45.610; p=0.013) as independent prognostic factors associated with LN metastasis. Patients were categorized into low- and high-risk groups according to risk criteria. Significant differences in the rates of LN metastasis were observed between the two groups (0.4% vs. 22.2%, p<0.001). Conclusion: Approximately 95% of presumed early-stage endometrioid EC patients did not have LN metastasis. A model using tumor location was significantly correlated with the risk of LN metastasis. Even in presumed early-stage endometrioid EC patients, therefore, tumor location should be investigated to determine whether to perform LN assessment. [ABSTRACT FROM AUTHOR]

Objective: As an indolent malignant tumor, the long-term management of low-grade endometrial stromal sarcoma (LGESS) patients required awareness, especially the management of recurrences. Unfortunately, few studies focused on the treatment of recurrent LGESS. Our study aimed to investigate the prognostic factors and the value of recurrent surgery on recurrent LGESS. Methods: This retrospective study consecutively recruited patients with pathologically diagnosed recurrent LGESS at our center from April 1, 2004 to April 1, 2020. Results: After a median follow-up of 137.0 months (95% confidence interval=85.4-188.6), the 5-year cumulative survival rate of the cohort of 38 patients with recurrent LGESS was 71.1%. The median overall survival (OS) and post-recurrence survival (PRS) was 156 and 89.0 months. Survival analysis showed that patients with younger age, positive estrogen receptor (ER) and optimal abdominopelvic debulking in the first recurrent surgery had better prognosis (p<0.05). Multivariate analysis showed that optimal abdominopelvic debulking in the first recurrent surgery was the only independent prognostic factor for OS and PRS (OS=216.0/35.0 months, hazard ratio [HR]=5.319, p=0.034; PRS=not reached/4.0 months, HR=10.900, p=0.006). There was no significant difference in OS and PRS between patients recurred only once and those recurred at least twice (p>0.05). Conclusions: The prognosis of recurrent LGESS was favorable. Optimal debulking of no residual tumor in abdominal and pelvic cavity should be the first choice of treatment for recurrent patients, while preservation of ovary or fertility should not be recommended. [ABSTRACT FROM AUTHOR]

Objective: In this study, we collected data over 8 years (2012-2019) from the Japan Society of Obstetrics and Gynecology (JSOG) tumor registry to determine the status of endometrial cancer in Japan, and analyzed detailed clinicopathological factors. Methods: The JSOG maintains a tumor registry that gathers information on endometrial cancer treated at the JSOG-registered institutions. Data from the patients whose endometrial cancer treatment was initiated from 2012 to 2019 were analyzed retrospectively. Results: A total of 82,969 patients with endometrial cancer underwent treatment from 2012 to 2019. Chemotherapy alone or in combination with hormonal therapy is more common among endometrial cancer patients under 40 years compared with those over 40 years. The number of patients with endometrial cancer, treated with laparoscopic or robot-assisted surgery was observed to have increased yearly. Small cell carcinomas and undifferentiated carcinomas were more likely to be diagnosed at an advanced stage. Lymphadenectomy was most commonly performed for stage IIIC2 disease, whereas positive peritoneal washing cytology was most common for stage IVB and serous carcinoma. Conclusion: Multi-year summary reports provided detailed clinicopathological information regarding endometrial cancer that could not be obtained in a single year. These reports were useful in understanding treatment strategies and trends over time based on age, histology, and stage. [ABSTRACT FROM AUTHOR]

Simple Summary: Various diagnostic methods exist for EC, with traditional biopsy being common but invasive. Endometrial cytology using liquid specimens shows promise for non-invasive detection. Morphological features like fractal dimension, circularity, and solidity in cell clusters could potentially enhance diagnostic accuracy and predict prognosis. Circularity and fractal dimension demonstrated significant associations with EC and AEH, regardless of age and cytology results. An ROC analysis revealed improved diagnostic accuracy when combining fractal dimension with cytology, particularly in menopausal age groups. Moreover, circularity, solidity, and fractal dimension may serve as prognostic indicators for endometrial cancer. This study showed that the morphological characteristics of cell clusters in liquid-based cytology may improve endometrial cancer diagnosis and predict prognosis. Endometrial cancer (EC) in women is increasing globally, necessitating improved diagnostic methods and prognosis prediction. While endometrial histology is the conventional approach, liquid-based endometrial cytology may benefit from novel analytical techniques for cell clusters. A clinical study was conducted at the University of Fukui Hospital from 2012 to 2018, involving 210 patients with endometrial cytology. The liquid-based cytology images were analyzed using cell cluster analysis with Image J software. Logistic regression, ROC analysis, and survival analysis were employed to assess the diagnostic accuracy and prognosis between cell cluster analysis and EC/atypical endometrial hyperplasia (AEH). Circularity and fractal dimension demonstrated significant associations with EC and AEH, regardless of age and cytology results. The ROC analysis revealed improved diagnostic accuracy when combining fractal dimension with cytology, particularly in menopausal age groups. Lower circularity and solidity were independently associated with poor overall survival, while higher fractal dimension values correlated with poorer overall survival in Grades 2 and 3 endometrial cancers. The combination of circularity and fractal dimension with cytology improved diagnostic accuracy for both EC and AEH. Moreover, circularity, solidity, and fractal dimension may serve as prognostic indicators for endometrial cancer, contributing to the development of more refined screening and diagnostic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: In the past few years, the endometrial cancer field has been revolutionized, following the integration of molecular classification into clinical practice. Endometrial carcinoma is currently molecularly categorized into four main subgroups: POLE-mutated, mismatch repair-deficient, p53-mutated, and no specific molecular profile. The POLE-mutated subgroup is characterized by an excellent prognosis notwithstanding bad conventional prognostic factors, including high-grade and TP53 mutations. On the other hand, the p53-mutated subgroup demonstrates the worst outcome. However, the remaining subgroups are more prevalent and display variable clinical outcomes. In this review, we describe the evolution of the endometrial carcinoma classification, its strengths and limitations, clinical implications, and foreseen perspectives. Endometrial carcinoma (EC) is the most frequent gynecological cancer, with an increasing incidence and mortality in recent times. The last decade has represented a true revolution with the development of the integrated histo-molecular classification of EC, which allows for the stratification of patients with morphologically indistinguishable disease into groups with different prognoses. Particularly, the POLE-mutated subgroup exhibits outstanding survival. Nevertheless, the indiscriminate application of molecular classification appears premature. Its prognostic significance has been proven mainly in endometrioid EC, the most common histotype, but it has yet to be convincingly confirmed in the other minor histotypes, which indeed account for a relevant proportion of EC mortality. Moreover, its daily use both requires a mindful pathologist who is able to correctly evaluate and unambiguously report immunohistochemical staining used as a surrogated diagnostic tool and is hampered by the unavailability of POLE mutation analysis. Further molecular characterization of ECs is needed to allow for the identification of better-tailored therapies in different settings, as well as the safe avoidance of surgery for fertility preservation. Hopefully, the numerous ongoing clinical trials in the adjuvant and metastatic settings of EC will likely produce evidence to refine the histo-molecular classification and therapeutic guidelines. Our review aims to retrace the origin and evolution of the molecular classification for EC, reveal its strengths and limitations, show clinical relevance, and uncover the desired future developments. [ABSTRACT FROM AUTHOR]

Simple Summary: We have performed a systematic review of the literature about the expression of miRNAs in the endometrium and their potential regulatory roles under pathological conditions such as endometriosis, recurrent implantation failure and endometrial cancer. Our systematic review focused on the potential of miRNAs as non-invasive biomarkers for diagnosing and prognosing endometrial cancer (EC), guiding surgical therapies, and enhancing understanding of EC carcinogenesis. The human endometrium experiences significant cyclic morphological and biochemical changes throughout the menstrual cycle to prepare for embryo implantation. These processes are meticulously regulated by ovarian steroids and various locally expressed genes, encompassing inflammatory reactions, apoptosis, cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. MicroRNAs (miRNAs) have been recognized as crucial regulators of gene expression, with their altered expression being linked to the onset and progression of various disorders, including cancer. This review examines the expression of miRNAs in the endometrium and their potential regulatory roles under pathological conditions such as endometriosis, recurrent implantation failure and endometrial cancer. Given miRNAs' critical role in maintaining gene expression stability, understanding the regulatory mechanisms of endometrial miRNAs and identifying their specific target genes could pave the way for developing preventive and therapeutic strategies targeting specific genes associated with these reproductive disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial endometrioid carcinoma (EEC) is generally considered to have a good prognosis. However, a subset of patients die of their disease. For this reason, it is essential to reveal and define all prognostic factors that can guide optimal treatment. Because lymphovascular space invasion (LVSI) is now related to staging, and blood vascular invasion seems to be more important than lymphovascular invasion, it could be important to encourage pathologists to distinguish between the two. The morphologic pattern of myometrial invasion may also be related to biological behavior. Myometrial invasion with an infiltrative pattern is associated with advanced-stage LVSI and recurrence. A specific pattern of myometrial invasion characterized by microcystic, elongated, and fragmented (MELF) glands is known to be associated with LVSI and lymph node metastases. This study investigated the relationship between these three closely related parameters, particularly the importance of blood vessel invasion (BVI), lymphatic vessel invasion (LVI), and MELF invasion as prognostic factors for endometrial cancer. This may be of great importance for the therapeutic approach in EEC. We studied 115 cases of EEC diagnosed on hysterectomy specimens. Double immunohistochemical staining (D2-40/CD31) was performed in all 115 cases to show LVI and BVI on the same slide. MELF pattern invasion was present in 24/115 (21%) cases. MELF-positive tumors had a higher frequency of LVI than MELF-negative tumors (58% and 23%, respectively); the frequency of BVI was twice as high in MELF-positive tumors in comparison to MELF-negative tumors (25% and 12%, respectively). These differences were significant (p ˂ 0.0001). All tumors with positive BVI also had a concomitant LVI. The presence of MELF invasion had no impact on overall survival, confirming previous studies. 5-year survival rates were almost equal in cases with negative LVSI and cases with positive isolated LVI (98% vs. 97%). However, in cases where BVI was also present, the 5-year survival rate was significantly lower, 63% (p ˂ 0.0001). Furthermore, BVI proved to be an independent prognostic factor for overall survival, disease-free survival, and recurrence in the multivariate analysis. In conclusion, MELF pattern invasion is a good predictor of lymphatic and blood vessel invasion but has no prognostic value. Our results suggest that BVI in EEC has greater clinical value than isolated LVI or myometrial invasion patterns, and the therapeutic approach should be guided by BVI presence. Therefore, we hope this study will promote the routine evaluation of BVI in the context of EEC diagnostic procedures. [ABSTRACT FROM AUTHOR]

Simple Summary: Germline and somatic deficiencies of mismatch repair proteins (MMRd) are related to colorectal and endometrial cancers, but the survival impact in Asian patients remains unclear. We investigated the prevalence and outcomes of patients with germline and/or somatic MMRd. Germline and somatic MMRd were determined by gene sequencing and protein staining of tumor samples, respectively. We found that colorectal and endometrial cancer patients with germline MMRd have favorable survival outcomes compared to those without, regardless of somatic MMRd status. These findings highlight the importance of germline genetic testing when tumor MMRd is detected. Germline (Lynch syndrome, LS) and somatic deficiencies of mismatch repair proteins (MMRd) are linked to colorectal and endometrial cancer; however, their prognostic impact in Asian populations remains unclear. This prospective cohort study aimed to determine the prevalence and outcome of germline and somatic MMRd in cancer patients suspected of LS. Patients with colorectal or endometrial cancer suspected of LS were enrolled and underwent gene sequencing for germline MMRd (gMMRd) and immunohistochemistry staining of MMR proteins in a subset of the pathological samples (pMMRd). Among the 451 enrolled patients, 36 patients were gMMRd (+). Compared with gMMRd (−) patients, the 10-year relapse-free survival in gMMRd (+) patients was significantly higher (100% vs. 77.9%; p = 0.006), whereas the 10-year overall survival was similar (100% vs. 90.9%; p = 0.12). Among the 102 gMMRd (−) patients with available pMMR status, 13.7% were pMMRd (+). The 5-year relapse-free survival was 62.9% in gMMRd (−) pMMRd (+) patients and 35.0% in gMMRd (−) pMMRd (−) patients, both lower than gMMRd (+) patients (100%; p < 0.001). This study showed that having LS confers a favorable outcome in colorectal and endometrial cancer patients and highlights the importance of germline genetic testing following the detection of somatic MMRd. [ABSTRACT FROM AUTHOR]

Background: Budd–Chiari syndrome (BCS) is a rare condition, usually associated with hematological disorders such as thrombotic diathesis and hypercoagulability. Serum CA-125 level is an established tumor marker of ovarian malignancy; however, cases of primary BCS may also show raised CA-125 levels. BCS in a case of ovarian carcinoma is usually primary in nature due to hypercoagulable state, and raised CA-125 levels with tender hepatomegaly in a treated case of ovarian carcinoma usually imply metastatic recurrence in the liver. However, our case demonstrates an atypical secondary cause of BCS in such a patient caused by extrinsic compression of IVC due to recurrent disease. Case presentation: We report an unusual case of a 69-year-old female who presented with nausea and abdominal pain. She had a 7-year-old history of endometrioid carcinoma of the right ovary for which she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and pelvic lymph node dissection along with adjuvant chemotherapy. Currently, she had right hypochondrium tenderness, deranged liver function tests (LFT) and raised CA-125 levels, which raised suspicion of hepatic metastasis. However, CECT abdomen revealed peripheral mottled enhancement of liver with multifocal extrahepatic tumor deposits, one of them causing compression of inferior vena cava (IVC) implying a diagnosis of secondary Budd–Chiari syndrome. Conclusions: In a background of treated ovarian malignancy with raised CA-125 levels and deranged LFT, primary suspicion is of hepatic tumor recurrence. However, in our case, radiological investigation revealed diagnosis of secondary Budd–Chiari syndrome due to perihepatic metastatic recurrence with the absence of frank intrahepatic lesions. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the efficacy of immunocytochemistry in diagnosing abdominopelvic washings (APWs) and evaluate the superiority of cytology combined with immunocytochemistry over cytology alone. Material and Methods: Data on APW cytology and available cell blocks from patients who underwent radical surgery for endometrial cancer between January 2021 and December 2022 were reviewed. Cytology was re-evaluated according to a five-tier system. Immunocytochemistry analysis for targets such as Sry box transcription factor 1(SOX17), Paired box gene 2 (Pax-2) protein, Phosphatase and tensin (PTEN), and β-catenin was performed on each case with non-negative cytology. Mismatch repair (MMR) protein and P53 immunocytochemistry analyses were performed using cell blocks from cases with abnormal MMR or P53 expression in their primary lesion. The accuracies of cytology combined with immunocytochemistry and cytology alone were calculated. Results: Overall, 126 patients were included in this study, 18 of whom demonstrated non-negative cytology of APW. Cell blocks were successfully prepared for 16 cases. SOX17 positivity was observed in 16 cases, including 1 of serous carcinoma, 1 of clear cell carcinoma, and 14 of endometrioid carcinoma (EC). Loss of Pax-2 and PTEN expression was observed in the APWs of the 14 patients with EC. MMR deficiency was noted in two patients with EC, and P53 mutation was noted in another two patients with EC. Compared with 10 metastatic carcinomas (10/18, 55.56%) diagnosed by cytology alone, 15 malignant APWs (15/18, 83.33%) were confirmed through combination cytology and immunocytochemistry. APWs were more likely to be observed in cases with more than half myometrial invasion than those with no or less than half myometrial invasion (P = 0.0067). The probability of malignant APW occurrence was slightly elevated in cases of EC exhibiting microcystic, elongated, and fragmented(MELF) infiltrative growth (P = 0.039). Conclusion: SOX17 is a useful Müllerian marker for distinguishing endometrial epithelium in APW. Loss of Pax-2 and PTEN expression offers evidence of metastatic endometrial carcinoma. Furthermore, positive APWs retained molecular features similar to primary lesions. The use of multiple immunocytochemical markers can effectively enhance the diagnostic efficiency of APWs. [ABSTRACT FROM AUTHOR]

Purpose: Myometrial invasion of endometrial cancer (EC) impairs the effectiveness of progestin-based treatment and results in high risks of disease progression and relapse. However, it is difficult to decide whether myometrial invasion exists when suspected endometrial invasion is detected on magnetic resonance imaging (MRI). This study developed an MRI-guided hysteroscopic precise en bloc resection method to actually diagnose myometrial invasion in patients with EC and suspected myometrial invasion on MRI. The fertility-preserving outcomes of patients with EC and suspected myometrial invasion on MRI but negative pathological findings after en bloc resection was also evaluated. Materials and methods: EC patients with suspected myometrial invasion on MRI (n = 38) were prospectively enrolled and evaluated. Suspected myometrial invasion was identified on MR images and resected via an en bloc resection technique (resecting the endometrial lesion, basal layer, and underneath myometrium en bloc) under hysteroscopy for pathological examination. Patients with negative pathological findings received progestin-based conservative therapy. The clinical characteristics and fertility-preserving outcomes of these patients were compared with those of patients without any evidence of myometrial invasion on MRI (n = 98, reference group). Results: Among patients with suspected myometrial invasion on MRI, myometrial invasion was pathologically excluded in 29 patients (non-MI group). The cumulative complete response rate was lower in the non-MI group than in the reference group at the 8th month (43.4% vs. 64.9%, P = 0.040) and was not significant at the 18th month (87.5% vs. 96.8%, P = 0.11). The 24-month cumulative relapse rate was 31.2% in the non-MI group, versus 0% in the reference group (P < 0.0001). Conclusion: Myometrial invasion was pathologically confirmed in approximately one-fourth of patients with suspected myometrial invasion on MRI. However, suspected myometrial invasion on MRI with negative pathological findings was correlated with worse fertility-preserving outcomes in young women with endometrial cancer. [ABSTRACT FROM AUTHOR]

The clinical heterogeneity of early-stage endometrial cancer (EC) is worthy of further study to identify high-quality prognostic markers and their potential role in aggressive tumor behavior. Mutation of TP53 was considered as an important primary triage in modified molecular typing for EC, it still cannot precisely predict the prognosis of EC. After proteomic analysis of cancer and para-cancerous tissues from 24 early-stage endometrioid EC patients with different survival outcomes, 13 differentially expressed proteins were screen out while 2 proteins enriched in p53 signaling pathway were further identified by single-cell transcriptome (scRNA-seq). Interestingly, tumor necrosis factor type-1 receptor-associated protein (TRAP1) and calmodulin-regulated spectrin-associated protein family member 3 (CAMSAP3) were found to be significantly downregulated in the specific cell cluster. Expectedly, the signature genes of TRAP1low/CAMSAP3low cluster included classical oncogenes. Moreover, close cellular interactions were observed between myeloid cells and the TRAP1low/CAMSAP3low cluster after systematically elucidating their relationship with tumor microenvironment (TME). The expression of TRAP1 and CAMSAP3 was verified by immunohistochemistry. Thus, a novel prediction model combining TRAP1, CAMSAP3 and TP53 was construct by multi-omics. Compared with the area under the curve, it demonstrated a significantly improvemrnt in the diagnostic efficacy in EC patients from TCGA bank. In conclusion, this work improved the current knowledge regarding the prognosis of early-stage EC through proteomics and scRNA-seq. These findings may lead to improvements in precise risk stratification of early-stage EC patients. [ABSTRACT FROM AUTHOR]

The vagina hosts a community of microorganisms known as the vaginal microbiota. This community is relatively stable and straightforward, with Lactobacillus species being the most dominant members. The vaginal microbiota has various functions that are essential for maintaining human health and balance. For example, it can metabolise dietary nutrients, produce growth factors, communicate with other bacteria, modulate the immune system, and prevent the invasion of harmful pathogens. When the vaginal microbiota is disrupted, it can lead to diseases and infections. The observed disturbance is distinguished by a reduction in the prevalence of Lactobacillus and a concurrent rise in the number of other bacterial species that exhibit a higher tolerance to low oxygen levels. Gynecologic cancers are a group of cancers that affect the female reproductive organs and tissues, such as the ovaries, uterus, cervix, vagina, vulva, and endometrium. These cancers are a major global health problem for women. Understanding the complex interactions between the host and the vaginal microorganisms may provide new insights into the prevention and treatment of gynecologic cancers. This could improve the quality of life and health outcomes for women. [ABSTRACT FROM AUTHOR]

Simple Summary: Gynecological cancers affect many women of reproductive age, necessitating the development of fertility preservation methods to fulfill family planning. Consequently, providing treatment options that preserve fertility in women diagnosed with gynecological cancers has become a crucial component of care for survivors. This leads to improved quality of life, allowing survivors to become mothers even in the seemingly adverse circumstances posed by cancers. However, although there are guidelines on fertility preservation in the context of neoplasms, physicians do not routinely consider it and do not discuss these options with their patients. It is important for patients to be informed about the available options for fertility preservation and to be encouraged to make informed decisions in collaboration with their medical team. Standardized guideline recommendations for onco-fertility should be considered in the future. We explore possible methods that can be employed for obtaining a pregnancy after gynecologic cancer treatment, including more exotic ones like uterine transplant. (1) Background: Currently, an increasing number of women postpone pregnancy beyond the age of 35. Gynecological cancers affect a significant proportion of women of reproductive age, necessitating the development of fertility preservation methods to fulfill family planning. Consequently, providing treatment options that preserve fertility in women diagnosed with gynecological cancers has become a crucial component of care for survivors. (2) Methods: We conducted an extensive search of relevant scientific publications in PubMed and Embase databases and performed a narrative review, including high-quality peer-reviewed research on fertility after being treated for gynecologic cancers, reporting pregnancy rates, birth rates, and pregnancy outcomes in cancer survivors as well as therapeutic options which partially preserve fertility and methods for obtaining a pregnancy in survivors. (3) Discussion: The medicine practiced today is focused on both treating the neoplasm and preserving the quality of life of the patients, with fertility preservation being an important element of this quality. This leads to an improved quality of life, allowing these women to become mothers even in the seemingly adverse circumstances posed by such a pathology. However, although there are guidelines on female fertility preservation in the context of neoplasms, an analysis shows that physicians do not routinely consider it and do not discuss these options with their patients. (4) Conclusions: Advancements in medicine have led to a better understanding and management of gynecological neoplasms, resulting in increased survival rates. Once the battle against these neoplasms is won, the issue of preserving the quality of life for these women arises, with fertility preservation being an important aspect for women who have not yet fulfilled their family planning desires at the time of diagnosis. It is important for patients to be informed about the available options for fertility preservation and to be encouraged to make informed decisions in collaboration with their medical team. Standardized recommendations for onco-fertility into guidelines should be taken into consideration in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Obesity significantly contributes to endometrial cancer (EC) incidence and mortality. Weight loss interventions are pivotal in mitigating endometroid EC risk, showing notable improvements in obesity-related metabolic perturbations, including insulin resistance, dyslipidemia, and inflammation. This review aimed to assess the efficacy of weight loss strategies, including lifestyle modifications, surgical interventions, and pharmacological approaches, on key biological indicators associated with endometroid EC. Findings reveal the assessment of weight loss for reducing inflammatory markers linked to endometroid EC, with bariatric surgery emerging as a prominent intervention. These insights can inform clinical practice, refine therapeutic strategies, and introduce tailored interventions to promote equitable healthcare and enhance outcomes for individuals affected by endometroid EC. Endometrial cancer (EC) includes various histologic types, with estrogen-dependent endometrioid carcinoma being the most common. Obesity significantly increases the risk of developing this type, especially in postmenopausal women, due to elevated estrogen production by adipocytes. This review examines the impact of weight loss from different interventions on reducing obesity-related risk factors for endometrioid EC. A systematic review and meta-analysis were conducted on three weight loss interventions: bariatric surgery, pharmacotherapy, and lifestyle changes. The effects of these interventions on inflammatory biomarkers (CRP, TNF-α, IL-6) and hormones (leptin, estrogen) were analyzed. Data from controlled studies were pooled to assess the significance of weight loss in reducing these biomarkers. Despite heterogeneity, bariatric surgery resulted in an overall 25.8% weight reduction, outperforming lifestyle and pharmacotherapy interventions. Weight loss reduced CRP levels by 33.5% and IL-6 levels by 41.9%. TNF-α levels decreased by 13% with percent weight loss over 7%. Leptin levels also decreased significantly, although the exact weight loss percentage was not statistically significant. Weight loss effectively reduces proinflammatory markers and hormones associated with increased risk of endometrioid EC. The strengths of this review include a comprehensive examination of different weight-loss interventions and a large pool of participants. However, limitations include high heterogeneity among studies and only 43% of the participants being postmenopausal. Limited data on sex hormones and racial disparities underscore the need for further research. [ABSTRACT FROM AUTHOR]

Objective: Endometrial cancer (EC) is an oestrogen-dependent tumour, the occurrence of which is closely related to an imbalance of oestrogen homeostasis. Our previous studies explored the effects of Resveratrol(Res) on oestrogen metabolism. However, systematic research on the exact mechanism of action of Res is still lacking. Based on network pharmacology, molecular docking and animal experiments, the effects and molecular mechanisms of Res on endometrial cancer were investigated. Methods: The target of Res was obtained from the high-throughput experiment and reference-guided database of TCM (HERB) and the Encyclopedia of Traditional Chinese Medicine (ETCM) databases, and the target of endometrial cancer was obtained by using the Genecards database. Venny map was used to obtain the intersection target of Res in the treatment of endometrial cancer, and the protein interaction network of the intersection target was constructed by importing the data into the STRING database. Then, the drug–disease–target interaction network was constructed based on Cytoscape 3.9.1 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for intersection targets using the OmicShare cloud platform. Res and core targets were analysed by molecular docking. EC model mice induced by MNNG were randomly divided into the control group, Res group, MNNG group, MNNG + Res group, and MNNG + Res + MAPK/ERKi group. The protein levels of ERK and p-ERK in the mouse uterus were detected by Western blot. The levels of E1, E2, E3, 16-epiE3, 17-epiE3, 2-MeOE1, 4-MeOE1, 2-MeOE2, 4-MeOE2, 3-MeOE1, 2-OHE1, 4-OHE1, 2-OHE2, 4-OHE2, and 16α-OHE1 in the serum and endometrial tissue of mice were measured by LC‒MS/MS. Results: A total of 174 intersection targets of Res anti-endometrial cancer were obtained. The signalling pathways analysed by KEGG enrichment included the AGE-RAGE signalling pathway in diabetic complications, the PI3K-Akt signalling pathway and the MAPK signalling pathway. The top 10 core targets were MAPK3, JUN, TP53, CASP3, TNF, IL1B, AKT1, FOS, VEGFA and INS. Molecular docking showed that in addition to TNF, other targets had good affinity for Res, and the binding activity with MAPK3 was stable. Western blot results showed that Res increased the phosphorylation level of ERK and that MAPK/ERKi decreased ERK activation. In the LC-MS/MS analysis, the levels of 2-MeOE1, 2-MeOE2 and 4-MeOE1 in serum and uterine tissue showed a significantly decreasing trend in the MNNG group, while that of 4-OHE2 was increased (P < 0.05). The concentrations of 4-MeOE1 in serum and 2-MeOE1 and 2-MeOE2 in the endometrial tissue of mice were significantly increased after Res treatment, and those of 4-OHE2 in the serum and uterus of mice were significantly decreased (P < 0.05). Meanwhile, in the MAPK/ERKi intervention group, the effect of Res on the reversal of oestrogen homeostasis imbalance was obviously weakened. Conclusion: Res has multiple targets and multiple approaches in the treatment of endometrial cancer. In this study, it was found that Res regulates oestrogen metabolism by activating the MAPK/ERK pathway. This finding provides a new perspective for subsequent research on the treatment of endometrial cancer. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a type of non-coding RNA (ncRNA) that possesses a unique single-stranded circular structure. They are primarily formed through alternative splicing of pre-mRNA (messenger RNA). The primary biological function of circRNAs is to regulate gene expression at both the transcriptional and post-transcriptional levels. Recent studies have increasingly demonstrated a close association between the dysregulation of circRNAs and the progression of diverse cancers, where they can function as either tumor suppressors or oncogenes. circWHSC1 (circNSD2) is a circular ncRNA that originates from the first 2 exons of the Wolf-Hirschhorn syndrome candidate gene (WHSC1). As Chen 2019 discovery that circWHSC1 (circNSD2) functions as a sponge for miRNAs and promotes cancer, this circRNA has garnered significant interest among researchers. circWHSC1 (circNSD2) has been found to be up-regulated in various malignant tumors, including nasopharyngeal carcinoma, lung cancer, breast cancer, liver cancer, colorectal cancer, ovarian cancer, cervical cancer, and endometrial cancer. It exerts its effects on cancer by either inhibiting or promoting the expression of related genes through direct or indirect pathways, ultimately affecting cancer proliferation, invasion, and prognosis. This article provides a comprehensive review and discussion of the biological roles of circWHSC1 (circNSD2) and its target genes in various cancers, as well as the latest research progress on related molecular biological regulatory mechanisms. Furthermore, the potential significance of circWHSC1 (circNSD2) in future clinical applications and transformations is thoroughly analyzed and discussed. [ABSTRACT FROM AUTHOR]

The high incidence of cancer and the prevalence of chemoresistance are serious problems worldwide, underscoring the urgency of novel research focused on understanding the underlying mechanisms and finding new therapeutic targets. Recently, the G protein-coupled estrogen receptor (GPER) has received increasing attention, and it has been studied in various models, including physiological and pathological conditions, using appropriate pharmacological and molecular biological strategies. Numerous studies indicate that GPER plays an important role in cancer progression and resistance. This review focuses on the structure of GPER, the diversity of its ligands and GPER-activated signaling pathways, the role of GPER in cancer progression, and mechanisms of chemoresistance, with special emphasis on different cancer types and the tumor microenvironment. GPER was evidenced to exhibit conformational plasticity and different ligand binding modes. Therefore, GPER-mediated effects can be triggered by estrogens or various estrogen mimetics, including synthesized compounds, licensed drugs, or exogenous environmental compounds. We found multiple reports evidencing that GPER is differentially expressed in healthy tissues and tumors and plays a protumor role in breast, ovarian, lung, thyroid, and endometrial cancers. Additionally, there are several studies that indicate that GPER expression in cells of the tumor microenvironment may also contribute to cancer progression. Among the major mechanisms of GPER-mediated chemoresistance are the epithelial-mesenchymal transition, the overexpression of multidrug resistance pumps, and autophagy regulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Sentinel lymph node (SLN) mapping for the surgical staging of endometrial and cervical cancer is commonly performed by laparoscopy, but recently, a new retroperitoneal transvaginal natural orifice transluminal endoscopic surgery approach has been described and developed by Jan Baekelandt. This technique provides easy visualization of lymphatic afferent vessels and pelvic lymph nodes, early SLN assessment, and a coherent mapping methodology following the lymphatic flow from caudal to cranial. However, only a few publications have reported it. Following the IDEAL (Idea Development Exploration Assessment Long-term follow-up) framework, research concerning this technique is in Stage 2a, with only small case series as evidence of its feasibility. Provided that the standardized description of this surgical technique appears necessary to provide the homogeneity required to move further in its investigation, here, we describe a 10-step approach for performing it successfully. This could help other surgeons approach this new technique, and it proposes a common methodology necessary for evolving through future studies. (1) Background: Sentinel lymph node (SLN) mapping represents an accurate and feasible technique for the surgical staging of endometrial and cervical cancer. This is commonly performed by conventional laparoscopy or robotic-assisted laparoscopy, but in recent years, a new retroperitoneal transvaginal natural orifice transluminal endoscopic surgery (vNOTES) approach has been described and developed by Jan Baekelandt. This technique provides easy visualization of lymphatic afferent vessels and pelvic lymph nodes, early SLN assessment, and a coherent mapping methodology following the lymphatic flow from caudal to cranial. However, only a few publications have reported it. Following the IDEAL (Idea Development Exploration Assessment Long-term follow-up) framework, research concerning this technique is in Stage 2a, with only small case series as evidence of its feasibility. Its standardized description appears necessary to provide the surgical homogeneity required to move further. (2) Methods: Description of a standardized approach for retroperitoneal pelvic SLN mapping by vNOTES. (3) Results: We describe a 10-step approach to successfully perform retroperitoneal vNOTES SLN mapping, including pre-, intra-, and postoperative management. (4) Conclusions: This IDEAL Stage 2a study could help other surgeons approach this new technique, and it proposes a common methodology necessary for evolving through future IDEAL Stage 2b (multi-center studies) and Stage 3 (randomized controlled trials) studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer has emerged as the main gynecological malignant tumour in developed countries. The development of molecular techniques allows the precise profiling of each case. This affects the selection of a therapy and the patient's prognosis. Long non-coding RNAs, which influence tumour development, are a novelty in endometrial cancer. They can both stimulate and inhibit the progression of the disease. Their number is constantly growing, and the mechanisms of action are not fully discovered. Some of them may become targets for new molecular therapies in the future. Endometrial cancer is one of the most common malignant tumours in women. The development of this tumour is associated with several genetic disorders, many of which are still unknown. One type of RNA molecules currently being intensively studied in many types of cancer are long non-coding RNAs (lncRNAs). LncRNA-coding genes occupy a large fraction of the human genome. LncRNAs regulate many aspects of cell development, metabolism, and other physiological processes. Diverse types of lncRNA can function as a tumour suppressor or an oncogene that can alter migration, invasion, cell proliferation, apoptosis, and immune system response. Recent studies suggest that selected lncRNAs are important in an endometrial cancer course. Our article describes over 70 lncRNAs involved in the development of endometrial cancer, which were studied via in vivo and in vitro research. It was proved that lncRNAs could both promote and inhibit the development of endometrial cancer. In the future, lncRNAs may become an important therapeutic target. The aim of this study is to review the role of lncRNAs in the development of carcinoma of uterine body. [ABSTRACT FROM AUTHOR]

Simple Summary: MLH1 methylation status was accessed by a Pyrosequencing (PSQ) assay, and the results point to the efficacy of PSQ for evaluating MLH1 methylation. While unmethylation appears to be associated with a higher relapse rate, the survival rate does not seem to be influenced by methylation. Quantitative percentages suggest that elevated MLH1 methylation is linked to relapse and mortality, though a study with a larger sample size would be essential for statistically significant results. Background: In cancer care, the MLH1 gene is crucial for DNA mismatch repair (MMR), serving as a vital tumor suppressor. Evaluating MLH1 protein expression status, followed by analysis of MLH1 promoter methylation, has become a key diagnostic and prognostic approach. Our study investigates the complex link between MLH1 methylation and prognosis in endometrial adenocarcinoma (EA) patients. Methodology: MLH1 methylation status was accessed by a Pyrosequencing (PSQ) assay. Qualitative positivity for methylation was established if it exceeded the 11% cut-off; as well, a quantitative methylation analysis was conducted to establish correlations with clinicopathological data, relapse-free survival, and disease-free survival. Results: Our study revealed that 33.3% of patients without MLH1 methylation experienced relapses, surpassing the 23.3% in patients with methylation. Furthermore, 16.7% of patients without methylation succumbed to death, with a slightly higher rate of 17.6% in methylated patients. Qualitative comparisons highlighted that the mean methylation rate in patients experiencing relapse was 35.8%, whereas in those without relapse, it was 42.2%. This pattern persisted in disease-specific survival (DSS), where deceased patients exhibited a higher mean methylation level of 49.1% compared to living patients with 38.8%. Conclusions: Our findings emphasize the efficacy of PSQ for evaluating MLH1 methylation. While unmethylation appears to be associated with a higher relapse rate, the survival rate does not seem to be influenced by methylation. Quantitative percentages suggest that elevated MLH1 methylation is linked to relapse and mortality, though a study with a larger sample size would be essential for statistically significant results. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, scientists investigated how pathologists test for a protein called HER2 in a type of cancer called endometrial cancer (EC). They checked samples from 180 patients tested over the first two years following approval of the test in the clinic. They found that 28% of the samples had HER2 overexpression, which makes them eligible for HER2-targeted therapies. They also noticed that in some cases, the test results were different depending on the method used. This study shows that there are challenges in testing for HER2 in endometrial cancer and suggests that we need standardized guidelines to help doctors make better decisions about endometrial cancer treatment. HER2-targeted therapies have transformed the management of advanced or recurrent serous endometrial cancer (EC), leading to an increased clinical demand for HER2 testing. Despite its adoption in select academic centers, the global extent of such tumor testing is unclear. In this study, we report on the initial two-year experience of HER2 testing at a major academic center with a reference gynecologic oncology service and biomarker reference laboratory. All patients who underwent HER2 testing based on physician discretion, reflex HER2 testing, and reference laboratory requests were included. From February 2021 to October 2023, HER2 testing was performed on 192 tumor tissue samples from 180 EC patients. Serous carcinoma constituted 52% of samples, reflecting diagnostic challenges and limited therapeutic options for advanced EC. HER2 positivity was found in 28% of all cases and 30% of p53-aberrant cases. An immunohistochemistry (IHC) score of 3+ was found in 15% of samples, while IHC 2+ was found in 45% (13% IHC 2+/ISH+ and 32% IHC 2+/ISH−). The newly identified 'HER2-low' category comprised 46% of the samples. Heterogeneity was noted in 42% of HER2-positive cases, with complex patterns in 3%. NGS and HER2 IHC-FISH showed a 24% discordance, attributed to intratumoral heterogeneity, tumor cellularity, a small number of amplified cells, and the HER2/CEP17 ratio near the cut-off. This study offers real-world insights into HER2 testing in EC, highlighting the challenges and underscoring the need for standardized guidelines in specimen handling, proficiency testing, and scoring criteria to enhance patient management and therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Simple Summary: Oestrogen and progesterone are two sex hormones that are important in the development of cancer of the inner lining of the uterus and endometrial cancer (EC). Oestrogen binds to the oestrogen receptor (ER) and progesterone to the progesterone receptor (PR). The presence of these receptors is important because the response to hormonal therapy is higher when the receptors are present. However, as EC grows and spreads throughout the body, ER and PR may be lost. In this study, we found that tumours that have spread to other organs throughout the blood and tumours that have spread in the abdomen have a relatively high presence of ER/PR, while tumours located in the lymph nodes have a lower presence of PR. ER/PR-IHC were not lower in tumours that had previously been treated with radiotherapy. This might influence the application of hormonal therapy in the future. Background: Response to hormonal therapy in advanced and recurrent endometrial cancer (EC) can be predicted by oestrogen and progesterone receptor immunohistochemical (ER/PR-IHC) expression, with response rates of 60% in PR-IHC > 50% cases. ER/PR-IHC can vary by tumour location and is frequently lost with tumour progression. Therefore, we explored the relationship between ER/PR-IHC expression and tumour location in EC. Methods: Pre-treatment tumour biopsies from 6 different sites of 80 cases treated with hormonal therapy were analysed for ER/PR-IHC expression and classified into categories 0–10%, 10–50%, and >50%. The ER pathway activity score (ERPAS) was determined based on mRNA levels of ER-related target genes, reflecting the actual activity of the ER receptor. Results: There was a trend towards lower PR-IHC (33% had PR > 50%) and ERPAS (27% had ERPAS > 15) in lymphogenic metastases compared to other locations (p = 0.074). Hematogenous and intra-abdominal metastases appeared to have high ER/PR-IHC and ERPAS (85% and 89% ER-IHC > 50%; 64% and 78% PR-IHC > 50%; 60% and 71% ERPAS > 15, not significant). Tumour grade and previous radiotherapy did not affect ER/PR-IHC or ERPAS. Conclusions: A trend towards lower PR-IHC and ERPAS was observed in lymphogenic sites. Verification in larger cohorts is needed to confirm these findings, which may have implications for the use of hormonal therapy in the future. [ABSTRACT FROM AUTHOR]