Endometrial Cancer Metastasis Research Articles

Can mismatch repair status be added to sentinel lymph node mapping algorithm in endometrioid endometrial cancer?

ObjectiveTo evaluate the relation between mismatch repair (MMR) status and the risk of lymph node metastasis in endometrial cancer, and whether this additional data can be incorporated to current SLN (sentinel lymph node) algorithm. MethodsWe included a series of 332 women that underwent SLN mapping ± systematic lymphadenectomy from January 2013 to December 2021. Protein expressions of MLH1, MSH2, MSH6, PMS2 were examined by immuno-histochemistry and considered MMRd (deficient) when at least one protein was not expressed. ResultsMMRd was noted in 20.8% of cases and correlated to grade 3 (p = 0.018) and presence of lymphovascular space invasion (p = 0.032). Moreover, MMRd was an independent risk factor for lymph node metastasis (OR 2.76, 95% CI 1.36–5.62). Notably, 21.7% (15/69) cases with MMRd had lymph node metastasis compared to 9.5% (25/263) of cases with MMRp (proficient) (p = 0.005). The overall and bilateral SLN detection rates were 91.9% and 75.9%, respectively. Of the 80 (24%) cases of non-bilateral SLN detection, 66.2% had low-grade tumors (G1/G2) and myometrial invasion <50%. Considering MMR status an independent prognostic factor for lymph node metastasis, a systematic lymphadenectomy (side specific or bilateral) would forgo in 53.7% (43/80) of cases with non-bilateral detection, representing 13% (43/332) of all endometroid tumors. ConclusionMMR status was independently related to lymph node metastasis in endometrioid EC. Moreover, MMR status may help to select patients that can forgo systematic lymphadenectomy in case of undetected SLN.

MiRNA-576-5p promotes endometrial cancer cell growth and metastasis by targeting ZBTB4

PurposeMicroRNAs (miRNAs) have already been shown to have a strong correlation with the invasion and metastasis capacity of tumor cells. The present research examined the function of miRNA-576-5p (miR-576-5p) in the development of endometrial cancer (EC).MethodsmiR-576-5p and ZBTB4 expression in EC and benign endometrial tissues was measured using quantitative real-time PCR (qRT-PCR) and western blot. To evaluate the proliferation ability of tumor cells in vitro, 2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays were carried out. The effect of miR-576-5p on the proliferation ability of EC cells in vivo was measured by the tumor formation in nude mice. The migration and invasion ability of tumor cells was determined using the transwell assay. To confirm the association between expressions of miR-576-5p and zinc finger and BTB domain containing four (ZBTB4), western blot, qRT-PCR, and luciferase assay were carried out.ResultsmiR-576-5p expression increased significantly in EC samples than in benign endometrial tissues. The level of miR-576-5p was significantly higher in the polymerase ε (POLE) ultramutated subgroup compared to the other three subgroups. High levels of miR-576-5p expression were linked to a shorter progression-free interval time in the copy number high subgroup. Furthermore, upregulated miR-576-5p facilitated EC cell invasion and migration in vitro and promoted the proliferation of EC tumor cell lines both in vitro and in vivo. Moreover, this study showed that the expression of ZBTB4 decreased in patients with EC, and the dual-luciferase reporter assay confirmed that miR-576-5p binds directly to the 3′-UTR of ZBTB4 and inhibits the expression of ZBTB4. An increase in miR-576-5p expression leads to a decrease in the mRNA and protein expression level of ZBTB4. The effects of miR-576-5p can be reversed by overexpression of ZBTB4.ConclusionmiR-576-5p promoted proliferation and metastasis capacity of EC cells by inhibiting ZBTB4 expression. We hypothesized that miR-576-5p could be a prospective therapeutic target for EC.

Comprehensive Assessment of ERα, PR, Ki67, P53 to Predict the Risk of Lymph Node Metastasis in Low-Risk Endometrial Cancer

Purpose According to international guidelines, selective lymph node dissection can be performed on patients with early-stage endometrial cancer. However, some patients at early stage have already occurred lymph node metastasis at the time of diagnosis. This study was aimed to find a method to predict the risk of lymph node metastasis in this part of patient. Methods We collected data from 571 patients as training cohort and 351 patients as validation cohort for this study. Then we performed univariate and multivariate analyses to confirm the correlation of frequently used factors and lymph node metastasis. Combined analysis of four commonly indicators (ERα, PR, P53 and Ki67) from pathological parameter sources was mainly carried out, and the combined ratio is defined as (ERα + PR)/(Ki67 + P53). Then the accuracy of the combined ratio and other factors in prediction were compared by AUC value. Also, the optimal truncation value was searched. Finally, patients followed up for more than two years were divided into groups by the threshold value, and their difference in survival was explored. Results This study showed that CA125, grade, LVSI, ERα, PR, P53, Ki67 have statistical significance (P-value <0.05). The AUC value of combined ratio is 0.876, which is the best. The best cutoff value of combined ratio is 1.38 Conclusion The combined ratio cutoff value of 1.38 in this study can be used for prediction of risk of lymph node metastasis in early-stage endometrial cancer patients and provide a reference for therapeutic planning.

Prediction of high-risk factors for ovarian metastasis in patients with endometrial cancer: A large-sample retrospective case-control study.

To determine the high-risk factors of ovarian metastasis of endometrial cancer and their impact on prognosis. A retrospective case-control study was conducted on a large cohort of patients with endometrial cancer. A total of 1240 patients with endometrial cancer were eligible for analysis, of whom 120 (9.7%) had ovarian metastasis. The patients with endometrial cancer with ovarian metastasis were more likely to have deep myometrial infiltration, lymph node metastasis, and elevated levels of CA125. The median survival was 39 months in patients with ovarian metastasis and 111 months in those without ovarian metastasis (P< 0.001). According to the stratified analysis, the progression-free survival (PFS) and overall survival in the low-risk group and PFS in the high-risk group of patients with endometrial cancer with ovarian metastasis were significantly shorter than those without ovarian metastasis (P< 0.0001, P= 0.0034, and P< 0.0001, respectively). Deep myometrial invasion, lymph node metastasis, and elevated levels of CA125 may be independent high-risk factors for ovarian metastasis in patients with endometrial cancer. Ovarian metastasis has a greater impact on the prognosis of patients with low-risk endometrial cancer.

Comparing the efficacy of imaging techniques in detecting myometrial invasion, cervical involvement and pelvic lymph-nodal metastasis in endometrial cancer

Aim: To compare sensitivity, specificity, positive predictive and negative predictive value of preoperative imaging techniques for detecting myometrial invasion, cervix involvement, and alsopelvic lymph nodal metastasis in endometrial cancer Materials and Methods: The medical records of patients who underwent an operation for endometrial cancer in the years between 2005 and 2017 were collected from the database at our institution. Preoperative imaging reports of 252 ultrasonography (USG), 89 computerized tomographies (CT),147 magnetic resonance imaging (MRI) of patients with endometrial cancer, and postoperative pathologic reports were collected and compared. Results: In our study 252 ultrasonography (USG), 89 computerized tomography (CT), 147 magnetic resonance imaging (MRI) examinations were evaluated. Among deep myometrial invasion; all imaging modalities have low specificities (respectively 26.7%, 37.9%, and 32.4%) but higher sensitivities (respectively 68.5%, 79.1%, and 89.4%). To rule out cervical invasion all modalities have high and comparable sensitivities (respectively 98.3%, 95.0%, and 87.0%). On the other hand, USG has superiority to detect cervical invasion over CT and MRI (respectively 71.4%, 15.4%, and 22.7%). CT has much highersensitivity than MRI for detection of pelvic lymph node metastasis (87.5% vs 53.1%). Conclusion: Preoperative imaging modalities have high sensitivities for deep myometrial invasion, but low detection rates for cervical involvement and pelvic lymph node metastasis. MRI should be the preferred modality for myometrial invasion, on the other hand, The USG is much better to detect cervical involvement. CT has superiority on other imaging modalities among lymph node metastasis.

Tamoxifen Regulates Epithelial-Mesenchymal Transition in Endometrial Cancer via the CANP10/NRP1 Signaling Pathway.

Tamoxifen, which is used to treat advanced gynecological tumors, has been associated with tumor cell metastasis. Herein, we investigated the effect of tamoxifen on epithelial-mesenchymal transition in endometrial cancer and the associated signaling mechanism. Wound healing and invasion chamber assays, respectively, were performed to determine the migrative capacity and invasiveness of tamoxifen-stimulated endometrial carcinoma (RL95-2) cells. Western blotting and immunofluorescence were used to evaluate the expression of vimentin, E-cadherin, calpain 10 (CANP10), and neuropilin-1 (NRP1). Transfection of a CAPN10-harboring plasmid was used to overexpress CANP10 in RL95-2 cells, and small interfering RNAs were used to silence CANP10 and NRP1 expression. Tamoxifen induced migration, invasion, and morphological changes in RL95-2 cells. It also downregulated E-cadherin expression and upregulated vimentin, CANP10, and NRP1 expression. CANP10 silencing inhibited tamoxifen-induced NRP1 upregulation, and CANP10 or NRP1 silencing inhibited the migration and invasion of RL95-2 cells. CANP10 overexpression upregulated vimentin expression and downregulated that of E-cadherin and also increased cell migration and invasion. Silencing NRP1 protein expression inhibited the induction effect of CANP10 overexpression. In conclusion, tamoxifen promotes the epithelial-mesenchymal transition of RL95-2 cells via the CANP10/NRP1 signaling pathway. Thus, targeting CANP10 or NRP1 may be a novel strategy for preventing tamoxifen-induced endometrial cancer metastasis.

Clinical and Pathological Profiles of Vertebral Bone Metastases from Endometrial Cancers: Evidence from a Twenty-Year Case Series.

Patients with endometrial cancer (EC) frequently have metastases to lungs, extra-pelvic nodes, and liver. Although an uncommon occurrence, cases of EC metastasis to bone, prevalently in vertebral bone, have also been reported. The objective of this study was to analyze clinical and pathological profiles of patients with EC metastatic to vertebral bone. We carried out a retrospective case series on surgically treated patients for this pathology. From 2001 to 2021, out of 775 patients with bone metastasis, 1.6% had bone metastasis from EC. The median time between the diagnosis of primary tumor and that of bone metastases was 31.5 months. Solitary bone lesion was present in 7 patients and lumbar vertebrae were the segments most affected. Pathological fractures in 46.2% of patients and spinal pain in all were present. In terms of location, 46.2% of bone metastases resided within the anterior section of the vertebra, while the remaining presented an extension within the anterior and posterior sections, with 46.1% of cases showing an extradural extra-osseous extension and paraspinous envelope. Median survival after diagnosis of bone metastasis was 11.5 months. Vertebral bone metastasis in EC is a rare phenomenon, with severe prognosis. An in-depth understanding of this topic may guide future management and treatment decisions, thus improving life expectancy and quality.

Follicle-Stimulating Hormone Promotes the Development of Endometrial Cancer In Vitro and In Vivo.

Endocrine disruptors as risk factors for endometrial cancer (EC) are positively correlated with serum follicle-stimulating hormone (FSH) levels. Additionally, increased FSH is associated with EC. However, its exact mechanism is not yet clear. Therefore, this study investigated how FSH affects the occurrence of EC. Using immunohistochemistry (IHC), immunofluorescence (IF), and Western blot (WB), we found that FSH receptor (FSHR) was expressed in both EC tissues and cell lines. To explore the effect of FSH on EC in vitro, Ishikawa (ISK) cells were cultured in different doses of FSH, and it was found that FSH could promote the proliferation and migration of ISK cells. Furthermore, the detection of key molecules of migration and apoptosis by WB showed that FSH promoted cell migration and inhibited apoptosis. Additionally, FSH decreased AMPK activation. To clarify the effect of FSH on EC in vivo, we subcutaneously planted ISK cells into ovariectomized mice and then gave two of the groups oestradiol (E2). In comparison with the OE (ovariectomy plus E2) and sham groups, the growth rates and weights of the tumors in the OE plus FSH group were significantly higher. The findings above suggest that FSH promotes the proliferation and metastasis of EC, providing a new strategy for the treatment of EC.

Circular RNA hsa_circ_0023404 promotes the proliferation, migration and invasion in endometrial cancer cells through regulating miR-217/MAPK1 axis

BackgroundEmerging studies indicated that circular RNA hsa_circ_ 0023404 and its target miR-217/MARK1 axis play a critical role in cancer progression such as non-small cell lung cancer and cervical cancer. However, the role of hsa_circ_0023404/miR-217/MARK1 involved in endometrial cancer (EC) was not investigated yet. The aim of this study is to investigate the functions of hsa_circ_0023404 in endometrial cancer (EC) and the potential molecular mechanism.MethodsWe used RT-qPCR and Western blot approach to detect the expressed levels of related genes in EC cell lines. Transfected siRNAs were applied to knockdown the level of related mRNA in cells. Cell proliferation by CCK-8 assay and colony formation assay were applied to detect cell proliferation. Transwell migration and invasion assay was for detecting the migration and invasion of the cells.ResultsRT-qPCR showed that the levels of hsa_circ_0023404 and MARK1 mRNA were upregulated, but mirR-217 was decreased in three endometrial cancer cell lines. Knockdown of hsa_circ_0023404 by siRNA markedly increased the level of miR-217 and reduced the proliferation of the Ishikawa cells. It also inhibited the cell migration and invasion. Anti-miR-217 can reverse the promoted proliferation, migrations and invasion of Ishikawa cells mediated by si-circ_0023404. si-MARK1 restored the inhibited cell proliferation, migration and invasion of the co-transfected Ishikawa cells with si- circ_0023404 and anti-miR-217.Conclusionhsa_circ_0023404 exerts a tumor-promoting role in endometrial cancer by regulating miR-217/MARK1 axis. hsa_circ_0023404 inhibit miR-217 as sponge which inhibit endometrial cancer cell growth and metastasis. MARK1 is downstream target of miR217 and upregulated by hsa_circ_ 0023404/miR-217 axis and involved in the endometrial cancer progression.

Predictive model for the preoperative assessment and prognostic modeling of lymph node metastasis in endometrial cancer

Lymph node metastasis (LNM) is a well-established prognostic factor in endometrial cancer (EC). We aimed to construct a model that predicts LNM and prognosis using preoperative factors such as myometrial invasion (MI), enlarged lymph nodes (LNs), histological grade determined by endometrial biopsy, and serum cancer antigen 125 (CA125) level using two independent cohorts consisting of 254 EC patients. The area under the receiver operating characteristic curve (AUC) of the constructed model was 0.80 regardless of the machine learning techniques. Enlarged LNs and higher serum CA125 levels were more significant in patients with low-grade EC (LGEC) and LNM than in patients without LNM, whereas deep MI and higher CA125 levels were more significant in patients with high-grade EC (HGEC) and LNM than in patients without LNM. The predictive performance of LNM in the HGEC group was higher than that in the LGEC group (AUC = 0.84 and 0.75, respectively). Patients in the group without postoperative pathological LNM and positive LNM prediction had significantly worse relapse-free and overall survival than patients with negative LNM prediction (log-rank test, P < 0.01). This study showed that preoperative clinicopathological factors can predict LNM with high precision and detect patients with poor prognoses. Furthermore, clinicopathological factors associated with LNM were different between HGEC and LGEC patients.

ODP548 Fatty acid metabolism-related factors in breast and endometrial cancers

Abstract Obesity is a well-known risk factor for gynecological malignant tumors such as breast and endometrial cancers. In the cancer microenvironment, the interaction between cancer cells and adipocytes reportedly contributes to the malignant behavior of cancer. In breast cancer, the fatty acid transporter CD36, also known as fatty acid translocase, has been shown to mediate fatty acid uptake into cancer cells and activate signaling pathways that promote tumor progression. Fatty acids are speculated to play important roles in breast and endometrial cancer; however, detailed mechanisms remain unclear. In the present study, we first examined the expression of CD36 and acyl-CoA dehydrogenase long chain (ACADL) in breast (30 cases) and endometrial (35 cases) cancer tissues using immunohistochemistry. CD36 is a membrane protein that transports long-chain fatty acids, and ACADL catalyzes the initial β-oxidation reaction. We detected no correlation between the CD36 status and clinicopathological factors, including the estrogen receptor status in breast cancer tissues. CD36 status revealed a significant positive correlation with lymph node metastasis in endometrial cancer. There was no immunoreactivity for CD36 in morphologically normal mammary glands. Otherwise, CD36 immunoreactivity was detected in the endometrial glandular cells. In both cancers, ACADL expression did not correlate with any clinicopathological factor. Both CD36 and ACADL showed higher positivity rates in endometrial cancer than in breast cancer. In addition, the effect of lipid addition on cell proliferation was examined using breast (T-47D) and endometrial (AN3CA) cancer cell lines exhibiting equivalent CD36 levels. Lipid (Refeed JNS) was obtained from Remembrane, Italy. Lipid addition promoted cell proliferation in both T-47D and AN3CA cells. Intracellular fatty acid β-oxidation (FAO) was visualized using FAOBlue (Funakoshi, Tokyo, Japan), a nonanoic acid (C9) derivative of coumarin, a blue fluorescence dye. Following FAOBlue decomposition in the fourth FAO cycle, coumarin is released from propionic acid, and released coumarin shows strong blue fluorescence excited at 405 nm. T-47D cells showed blue fluorescence in the lipid-supplemented medium, indicating β-oxidative activity. Conversely, AN3CA cells exhibited weak fluorescence under the same conditions. It can be postulated that intracellular lipid uptake and subsequent β-oxidation are mediated via a specific pathway in breast and endometrial cancers. Lipid-mediated effects differ between breast and endometrial cancers, and further investigations are needed to elucidate intracellular signals mediating these effects. Presentation: No date and time listed

The association of tumor diameter with lymph node metastasis and recurrence in patients with endometrial cancer: a systematic review and meta-analysis.

Tumor diameter (TD)/original lesion area has been reported to have a certain predictive effect on lymph node metastasis (LNM) and recurrence of endometrial cancer (EC) patients, but there is still controversy about their relationship. Therefore, we conducted a meta-analysis to provide reference for clinical management and follow-up studies of patients with EC. The databases of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang were searched, from inception to 27 October 2022, for studies regarding the association of TD with LNM risk and recurrence rate in EC. The search strategy was developed using a combination of free terms and medical subject headings (MeSH). Stata 15.0 was used to conduct the statistical analysis. Odds ratio (OR) with the 95% confidence interval (CI) were calculated to evaluate the association of TD and the risk of LNM and recurrence in EC patients. The OR value obtained from the multivariate analysis is first extracted; the results of univariate analysis were extracted for articles without the results of multivariate analysis. Newcastle-Ottawa Scale (NOS) assessed the quality of the included articles, publication bias was evaluated by Egger's test with funnel plots. There was a total of 69 studies 123,383 EC patients included. Meta-analysis showed higher LNM risk in EC patients with the TD >2 cm, which was 2.88 times higher than that in those with ≤2 cm, and the difference was statistically significant (OR =2.88; 95% CI: 2.12-3.89; P<0.001), publication bias had no effect on the results. The risk of recurrence in EC patients with a TD >2 cm was 2.45 times higher than that in those with ≤2 cm (OR =2.45; 95% CI: 1.73-3.48; P<0.001), publication bias exerted influence over the results. TD is associated with LNM and recurrence in patients with EC. Therefore, TD should be considered in the scope of surgery and adjuvant therapy.

Incorporation of Tumor-Free Distance and Other Alternative Ultrasound Biomarkers into a Myometrial Invasion-Based Model Better Predicts Lymph Node Metastasis in Endometrial Cancer: Evidence and Future Prospects.

Myometrial invasion (MI) is a parameter currently used in transvaginal ultrasound (TVS) in endometrial cancer (EC) to determine local staging; however, without molecular diagnostics, it is insufficient for the selection of high-risk cases, i.e., those with a high risk of lymph node metastases (LNM). The study’s objective was to answer the question of which TVS markers, or their combination, reflecting the molecular changes in EC, can improve the prediction of LNM. Methods: The TVS examination was performed on 116 consecutive EC patients included in this prospective study. The results from the final histopathology were a reference standard. Univariate and multivariate logistic models of analyzed TVS biomarkers (tumor [T] size, T area [AREA], T volume [SPE-VOL], MI, T-free distance to serosa [TFD], endo-myometrial irregularity, [EMIR], cervical stromal involvement, CSI) were evaluated to assess the relative accuracy of the possible LNM predictors., Spline functions were applied to avoid a potential bias in assuming linear relations between LNM and continuous predictors. Calculations were made in R using libraries splines, glmulti, and pROC. Results: LNM was found in 20 out of the 116 (17%) patients. In univariate analysis, only uMI, EMIR, uCSI and uTFD were significant predictors of LNM. The accuracy was 0.707 (AUC 0.684, 95% CI 0.568−0.801) for uMI (p < 0.01), 0.672 (AUC 0.664, 95% CI 0.547−0.781) for EMIR (p < 0.01), 0.776 (AUC 0.647, 95% CI 0.529−0.765) for uCSI (p < 0.01), and 0.638 (AUC 0.683, 95% CI 0.563−0.803) for uTFD (p < 0.05). The cut-off value for uTFD was 5.2 mm. However, AREA and VOL revealed a significant relationship by nonlinear analysis as well. Among all possible multivariate models, the one comprising interactions of splines of uTFD with uMI and splines of SPE-VOL with uCSI showed the most usefulness. Accuracy was 0.802 (AUC 0.791, 95% CI 0.673−0.91) Conclusions: A combination of uTFD for patients with uMI > 50%, and SPE-VOL for patients with uCSI, allows for the most accurate prediction of LNM in EC, rather than uMI alone.

Altered Gut Microbial Profile Accompanied by Abnormal Fatty Acid Metabolism Activity Exacerbates Endometrial Cancer Progression.

Endometrial cancer (EC) is the most prevalent gynecological malignancy, with a higher risk in obese woman, indicating the possibility of gut microbiota involvement in EC progression. However, no direct evidence of a relationship between EC and gut microbiota in humans has been discovered. Here, we performed 16S rRNA sequencing to explore the relationship between dysbiosis of gut microbiota and cancer development in different types of EC patients. The results clearly show the differential profiles of gut microbiota between EC patients and normal participants as well as the association between gut microbiota and EC progression. Targeted metabolomics of plasma revealed an increased level of C16:1 and C20:2, which was positively associated with the abundance of Ruminococcus sp. N15.MGS-57. The higher richness of Ruminococcus sp. N15.MGS-57 in EC subjects not only was positively associated with blood C16:1 and C20:2 but also was negatively correlated with betalain and indole alkaloid biosynthesis. Furthermore, the combined marker panel of gut bacteria, blood metabolites, and clinical indices could distinguish the EC patients under lean and overweight conditions from normal subjects with high accuracy in both discovery and validation sets. In addition, the alteration of tumor microenvironment metabolism of EC was characterized by imaging mass microscopy. Spatial visualization of fatty acids showed that C16:1 and C18:1 obviously accumulate in tumor tissue, and C16:1 may promote EC cell invasion and metastasis through mTOR signaling. The aberrant fecal microbiome, more specifically, Ruminococcus sp. N15.MGS-57 and spatially distributed C16:1 in EC tissues, can be used as a biomarker of clinical features and outcomes and provide a new therapeutic target for clinical treatment. IMPORTANCE A growing number of studies have shown the connection between gut microbiota, obesity, and cancer. However, to our knowledge, the association between gut microbiota and endometrial cancer progression in humans has not been studied. We recruited EC and control individuals as research participants and further subgrouped subjects by body mass index to examine the association between gut microbiota, metabolites, and clinical indices. The higher richness of Ruminococcus sp. N15.MGS-57 in EC subjects was not only positively associated with blood C16:1 but also negatively correlated with betalain and indole alkaloid biosynthesis. Spatial visualization of fatty acids by imaging mass microscopy showed that C16:1 obviously accumulates in tumor tissue, and C16:1 may promote the EC cell invasion and metastasis through mTOR signaling. The aberrant fecal microbiome, more specifically, Ruminococcus sp. N15.MGS-57 and spatially distributed C16:1, can be used as a biomarker of clinical features and outcomes and provide a new therapeutic target for clinical treatment.

Clinical factors associated with failed sentinel lymph node mapping in endometrial cancer

ObjectiveSentinel lymph node (SLN) mapping is a highly accurate surgical technique for detecting metastases in endometrial cancer. The objective of this study was to identify clinical factors associated with failed mapping. MethodsAll patients with endometrial cancer undergoing minimally-invasive staging and planned SLN biopsy from 1/1/2017 to 12/31/2020 at a single institution were identified retrospectively. Demographic, clinicopathologic and treatment data were obtained. Data were compared using descriptive statistics. Univariate and multivariable logistic regression were performed to identify predictors of failed mapping. Results819 patients were identified with a mean age of 64.6 years (range 26–93) and mean BMI of 35.6 kg/m2 (range 18–68). Most (88.5 %, 725/819) had early-stage disease and endometrioid histology (82.3 %, 674/819). A majority (74.2 %, 608/819) had successful bilateral mapping, and 54 (6.6 %) had unsuccessful bilateral mapping. Increasing BMI was significantly associated with unsuccessful bilateral mapping: patients with BMI > 30 were more likely to have unsuccessful SLN mapping (p = 0.033). Among patients with known lymph node status (799/819), patients with macrometastases and micrometastases were more likely to have failed bilateral mapping compared to those with negative SLNs or isolated tumor cells (p = 0.013). On multivariable analysis, higher BMI and histology were associated with failed bilateral mapping (OR = 1.023, 95 % CI (1.005, 1.041) and OR = 1.678, 95 % CI (1.177, 2.394), respectively). ConclusionSLN mapping has a high success in patients undergoing minimally-invasive surgical staging for endometrial cancer. Increasing BMI, high risk histology, and lymph node metastases are risk factors for failed mapping.

Advances in Exosomes as Diagnostic and Therapeutic Biomarkers for Gynaecological Malignancies.

Simple SummaryThe three major gynaecological cancers are ovarian cancer, endometrial cancer, and cervical cancer, which endanger women’s health worldwide. Significant progress has been made in the study of exosomes, which have been proven to be an important form of intercellular communication, as well as an important carrier for the uptake, transport, and release of cargo. Exosomes may also be promising diagnostic or prognostic markers for gynaecologic malignancies, which may improve the level of treatment of gynaecologic malignancies. This article reviews the latest research progress and systematic knowledge of exosomes in gynaecological malignant tumours in recent years, in order to provide a new perspective for the treatment of gynaecological tumours and promote the clinical application of exosomes in gynaecological malignancies.Background: Exosomes are extracellular vesicles that can be released by practically all types of cells. They have a diameter of 30–150 nm. Exosomes control the exchange of materials and information between cells. This function is based on its special cargo-carrying and transporting functions, which can load a variety of useful components and guarantee their preservation. Recently, exosomes have been confirmed to play a significant role in the pathogenesis, diagnosis, treatment, and prognosis of gynaecological malignancies. Particularly, participation in liquid biopsy was studied extensively in gynaecological cancer, which holds the advantages of noninvasiveness and individualization. Literature Review: This article reviews the latest research progress of exosomes in gynaecological malignancies and discusses the involvement of humoral and cell-derived exosomes in the pathogenesis, progression, metastasis, drug resistance and treatment of ovarian cancer, cervical cancer, and endometrial cancer. Advances in the clinical application of exosomes in diagnostic technology, drug delivery, and overcoming tumour resistance are also presented. Conclusion: Exosomes are potentially diagnostic and prognostic biomarkers in gynaecological malignancies, and also provide new directions for the treatment of gynaecological tumours, showing great clinical potential.

Pituitary Gland Metastasis of Endometrial Cancer: A Case Report

Pituitary Gland Metastasis of Endometrial Cancer: A Case Report

Proteomic and functional characterization of intra-tumor heterogeneity in human endometrial cancer

SummaryEndometrial cancer is one of the most frequently diagnosed gynecological cancers worldwide, and its prevalence has increased by more than 50% over the last two decades. Despite the understanding of the major signaling pathways driving the growth and metastasis of endometrial cancer, clinical trials targeting these signals have reported poor outcomes. The heterogeneous nature of endometrial cancer is suspected to be one of the key reasons for the failure of targeted therapies. In this study, we perform a sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based comparative proteomic analysis of 63 tumor biopsies collected from 20 patients and define differences in protein signature in multiple regions of the same tumor. We develop organoids from multiple biopsies collected from the same tumor and show that organoids capture heterogeneity in endometrial cancer growth. Overall, using quantitative proteomics and patient-derived organoids, we define the heterogeneous nature of endometrial cancer within a patient’s tumor.

Prognostic features of endometrial cancer metastasis to the central nervous system.

Central nervous system metastases (CNSm) secondary to endometrial cancer (EC) are rare. As a result, prognostic factors for this patient population are not well described. EC patients with CNSm were identified retrospectively from two academic centers. EC patients without CNSm (non-CNSm) were used as controls. Chi-square and Fisher's exact tests were used for analysis of categorial variables. Wilcoxon tests were used for quantitative measures. Overall survival (OS) was compared with Log-rank test. Cox proportional hazard models were used to estimate hazard ratios for OS. 22 EC patients with CNSm and 354 non-CNSm patients were included. Compared to non-CNSm EC, the CNSm cohort was younger (58.5 vs 62.0 years, p = 0.018) with lower BMI (27.7 vs. 33.7 kg/m2, p = 0.005), and had more advanced stages (p = ≤ 0.001), grade 3 tumors (81.8% CNSm vs 25.1% non CNSm, p≤0.001) and serous histology (22.7% vs 8.5%, p = 0.010). Median survival after CNSm diagnosis was 9 months (95% CI 4, NA). CNSm was a strong poor prognostic factor (HR death 4.96, p = 0.022). Improved OS was seen with CNS as the only disease site (83m CNSm only vs 30m additional sites, p = 0.007) and less than five CNSm (49m <5 vs. 23m ≥5, p = 0.004). Surgical resection of CNSm (OS 83m surgery vs 33m no surgery, p = 0.003) or multimodal therapy (83m multimodal vs 33m single therapy, p = 0.027) resulted in longer OS. CNSm is a poor prognostic factor in EC, however, low volume disease with aggressive treatment may result in more favorable survival outcomes.

Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study.

Simple SummaryJudging the chance (risk) of cancer spread and bad outcome in endometrial cancer continues to be a challenge. Molecular and clinical factors offer the hope of improving the accuracy of judging the danger of cancer spread (metastasis) and a bad outcome (prognosis) to help guide patient care. The aim of this research was to develop a risk score for cancer spread and bad outcome for the most common type of endometrial cancer, endometrioid endometrial cancer, using molecular features and clinical factors in endometrial cancers removed during surgery. The molecular score, referred to as MS7, was more accurate at judging the chance of nodal and distant metastasis than clinical factors like grade 3 disease and myometrial invasion. MS7 score was also better than aggressive molecular subtypes or endometrial cancer-associated genes identified by other research groups. The combination of MS7 score and myometrial invasion was the best at accurately judging the chance of nodal and distant metastasis in the most common type of endometrial cancer. The MS7 score was also shown to accurately indicate bad outcome including cancer progression and death. This research hopes to help guide patient care stopping overtreatment in lower-risk and undertreatment in higher-risk endometrial cancer patients. Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80–0.98) for MS7 compared with 0.69 (0.59–0.80) and 0.71 (0.58–0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool.