Differential levels of circulating RNAs prior to endometrial cancer diagnosis.

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

Early detection of uterine corpus endometrial carcinoma utilizing plasma cfDNA fragmentomics.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecologic malignancy with a favorable prognosis if detected early. However, there is a lack of accurate and reliable early detection tests for UCEC. This study aims to develop a precise and non-invasive diagnostic method for UCEC using circulating cell-free DNA (cfDNA) fragmentomics. METHODS: Peripheral blood samples were collected from all participants, and cfDNA was extracted for analysis. Low-coverage whole-genome sequencing was performed to obtain cfDNA fragmentomics data. A robust machine learning model was developed using these features to differentiate between UCEC and healthy conditions. RESULTS: The cfDNA fragmentomics-based model showed high predictive power for UCEC detection in training (n = 133; AUC 0.991) and validation cohorts (n = 89; AUC 0.994). The model manifested a specificity of 95.5% and a sensitivity of 98.5% in the training cohort, and a specificity of 95.5% and a sensitivity of 97.8% in the validation cohort. Physiological variables and preanalytical procedures had no significant impact on the classifier's outcomes. In terms of clinical benefit, our model would identify 99% of Chinese UCEC patients at stage I, compared to 21% under standard care, potentially raising the 5-year survival rate from 84 to 95%. CONCLUSION: This study presents a novel approach for the early detection of UCEC using cfDNA fragmentomics and machine learning showing promising sensitivity and specificity. Using this model in clinical practice could significantly improve UCEC management and control, enabling early intervention and better patient outcomes. Further optimization and validation of this approach are warranted to establish its clinical utility.

Plasma-based proteomic profiling identifies the distinct regulation of proteins in hyperplasia and endometrial cancer.

BACKGROUND: Among gynaecological malignancies, endometrial cancer (EC) is the most prevalent type of uterine cancer affecting women. This study explored the proteomic profiles of plasma samples obtained from EC patients, those with hyperplasia (Hy), and a control group (CO). A combination of techniques, such as 2D-DIGE, mass spectrometry, and bioinformatics, including pathway analysis, was used to identify proteins with modified expression levels, biomarkers and their associated metabolic pathways in these groups. METHODS: Thirty-four patients, categorized into three groups-10 with EC, 12 with Hy, and 12 CO-between the ages of 46 and 75 years old were included in the study. Untargeted proteomic analysis was carried out using two-dimensional difference in gel electrophoresis (2D-DIGE) coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). RESULTS: In all three groups, 114 proteins that were significantly (p ≤ 0.05 and fold change ≥ 1.5) altered were successfully identified using peptide mass fingerprints (PMFs). Compared with those in the control group (CO), the EC samples had 85 differentially expressed proteins (39 upregulated and 46 downregulated), and in the Hy group, 81 proteins were dysregulated (40 upregulated and 41 downregulated) compared to those in the CO group, while 33 proteins exhibited differential regulation (12 upregulated and 21 downregulated) in the EC plasma samples compared to those in the Hy group. Vitamin D binding protein and complement C3 distinguished Hy and EC from CO with the greatest changes in expression. Among the differentially expressed proteins identified, enzymes with catalytic activity represented the largest group (42.9%). In terms of biological processes, most of the proteins were involved in cellular processes (28.8%), followed by metabolic processes (16.7%). STRING analysis for protein interactions revealed that the significantly differentially abundant proteins in the three groups are involved in three main biological processes: signalling of complement and coagulation cascades, regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), and plasma lipoprotein assembly, remodelling, and clearance. CONCLUSION: The identified plasma protein markers have the potential to serve as biomarkers for differentiating between EC and Hy, as well as for early diagnosis and monitoring of cancer progression.

The inflammatory markers combined with CA125 may predict postoperative survival in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) has a high latency, making prognosis difficult to predict. Cancer antigen 125 (CA125) is not specific as a tumour marker for EC; however, complete blood count (CBC) inflammatory markers are associated with prognosis in various malignancies. Thus, this study investigated the value of CBC inflammatory markers combined with CA125 levels in predicting the prognosis of patients with EC. METHODS: In this study, 517 patients with EC were recruited between January 2015 and January 2022, and clinical characteristics, CBC inflammatory markers, and CA125 levels were assessed. Differences in each index at different EC stages and the correlation between the index and EC stage were analysed, and the influence of the index on EC prognosis was evaluated. RESULTS: Platelet distribution width (PDW) levels were significantly lower in patients with advanced EC than in those with early EC, whereas the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and CA125 levels were significantly higher in patients with advanced EC (all P < 0.05). ROC curve and multivariate logistic regression analyses indicated that decreased PDW and increased CA125 levels were independent risk factors for EC staging progression. In addition, multivariate Cox regression analysis showed that the combination of low PDW and high CA125 (PDW + CA125 = 2) was an independent prognostic factor of survival in EC patients. Kaplan-Meier survival analysis indicated that patients with low PDW and high CA125 had worse overall survival. CONCLUSIONS: The PDW and CA125 score may be an independent prognostic factor for postoperative overall survival in patients with EC and a useful marker for predicting the prognosis of these patients.

Endometrial cancer (EC) has a high latency period, and the prognosis of EC is difficult to predict. The inflammatory response within the tumour microenvironment plays an important role in the occurrence and development of cancer. In our study, various inflammatory indicators in complete blood counts were comprehensively analysed, and cancer antigen 125 (CA125) was further used to predict the stage and prognosis of EC. The results showed that patients with low platelet distribution width (PDW) and high CA125 levels had poorer overall survival. The PDW and CA125 score may be used as a new independent prognostic indicator.

Killer Function of Circulating Neutrophils in Relation to Cytokines in Uterine Myoma and Endometrial Cancer.

The study presents the killer functions of circulating neutrophils: myeloperoxidase activity, the ability to generate ROS, phagocytic activity, receptor status, NETosis, as well as the level of cytokines IL-2, IL-4, IL-6, IL-17A, and IL-18, granulocyte CSF, monocyte chemotactic protein 1, and neutrophil elastase in the serum of patients with uterine myoma and endometrial cancer (FIGO stages I-III). The phagocytic ability of neutrophils in uterine myoma was influenced by serum levels of granulocyte CSF and IL-2 in 54% of the total variance. The degranulation ability of neutrophils in endometrial cancer was determined by circulating IL-18 in 50% of the total variance. In uterine myoma, 66% of the total variance in neutrophil myeloperoxidase activity was explained by a model dependent on blood levels of IL-17A, IL-6, and IL-4. The risk of endometrial cancer increases when elevated levels of monocyte chemotactic protein 1 in circulating neutrophils are associated with reduced ability to capture particles via extracellular traps (96% probability).

Is hemoglobin A1c valuable for predicting concurrent endometrial cancer in diabetic women with endometrial intraepithelial neoplasia?

AIM: The purpose of this study was to determine the predictive value of preoperative hemoglobin A1c (HgA1c) level for endometrial cancer in diabetic women with endometrial intraepithelial neoplasia (EIN). MATERIALS AND METHODS: Six hundred patients with EIN were retrospectively studied in a tertiary referral center in Turkey between January 2014 and December 2021. One hundred and thirteen diabetic patients with EIN who met the inclusion criteria were enrolled in the study and divided into three groups according to the final pathological results: Group 1 with benign findings (n = 29), Group 2 with EIN (n = 34) and Group 3 with endometrial cancer (n = 50). Demographic, clinical and biochemical characteristics were compared among the three groups. Receiver operating characteristic analysis (ROC) was used to evaluate the predictive value of HgA1c for concurrent endometrial cancer in EIN. RESULTS: Mean preoperative HgA1c levels were different among three groups (5.41 ± 0.64, 6.01 ± 0.72, 6.65 ± 1.15, p < 0.001, respectively). The highest value of HgA1c level was found in cancer group and difference within pairs was statistically significant (p < 0.001). Age and duration of menopause were also different among groups (p < 0.005). After adjustment of HgA1c level for age and duration of menopause differences were maintained (p < 0.001), the cutoff value was detected as ≥6.05% for HgA1c and sensitivity, specificity was 60%, 70%, respectively (p < 0.001). CONCLUSIONS: HgA1c could be used in prediction of endometrial cancer. The optimal cutoff value determined in our study could be considered in predicting endometrial cancer in diabetic women with EIN.

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses.

BACKGROUND: Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS: In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS: Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.

Racial/ethnic differences in anthropometric and hormone-related factors and endometrial cancer risk: the Multiethnic Cohort Study.

BACKGROUND: Anthropometric and hormone-related factors are established endometrial cancer risk factors; however, little is known about the impact of these factors on endometrial cancer risk in non-White women. METHODS: Among 110,712 women participating in the Multiethnic Cohort (MEC) Study, 1150 incident invasive endometrial cancers were diagnosed. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with endometrial cancer risk for race/ethnicity and for risk factors across racial/ethnic groups were calculated. RESULTS: Having a higher body mass index (BMI) at baseline or age 21 years was strongly associated with increased risk (pint race/ethnicity ≥ 0.36). Parity (vs nulliparity) was inversely associated with risk in all the groups except African Americans (pint 0.006). Current use of postmenopausal hormones at baseline (PMH-E; vs never use) was associated with increased risk in Whites and Japanese Americans (pint 0.002). Relative to Whites, endometrial cancer risk was lower in Japanese Americans and Latinas and non-significantly higher in Native Hawaiians. Risk in African Americans did not differ from that in Whites. CONCLUSIONS: Racial/ethnic differences in endometrial cancer risk were not fully explained by anthropometric or hormone-related risk factors. Further studies are needed to identify reasons for the observed racial/ethnic differences in endometrial cancer risk.

Increasing serum gamma-glutamyltransferase level accompanies a rapid increase in the incidence of endometrial cancer in Korea: A nationwide cohort study.

OBJECTIVE: This study aimed to determine the association of serum GGT levels with the risk of developing endometrial cancer. Women's obesity and menopausal status were also taken into account in our analysis. METHODS: We used a nationwide cohort to examine the association between serum GGT levels and endometrial cancer development in Korean women. Data were retrieved from the Korean National Health Insurance Service (NHIS) healthcare system. Women aged over 19 years who participated in the Korea National Health Screening Examination in 2009 and were not diagnosed with endometrial cancer 1-year post-examination were included in our study (n = 2,736,588). RESULTS: Obese (BMI, ≥25 kg/m2) women with increased GGT levels were at high risk of endometrial cancer (HR = 1.415, 95% CI: 1.236-1.621). Interestingly, in pre-menopausal women, high GGT level (Q4) was associated with the increased endometrial cancer risk only for obese women (HR = 1.482, 95% CI: 1.205-1.821). In post-menopausal women, only a high GGT level (Q4) was also associated with the increased cancer risk for obese women (HR = 1.313, 95% CI: 1.096-1.573). We observed a significant association between high GGT levels and increased risk of endometrial cancer in pre-menopausal women with abdominal obesity (WC, ≥85 cm) (HR = 1.647, 95% CI: 1.218-2.227). CONCLUSIONS: Increased GGT level is an independent risk factor of endometrial cancer, especially for post-menopausal women and obese pre-menopausal women. These results may suggest that serum GGT levels might be useful in the risk stratification of endometrial cancer. Adopting a healthy lifestyle for lowering serum GGT level is warranted, especially for women with a higher risk of developing endometrial cancer.

Prospective analysis of circulating metabolites and endometrial cancer risk.

BACKGROUND: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. RESULTS: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80-0.99; OR1SD: 0.89, 95% CI: 0.79-1.00 and OR1SD: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. CONCLUSION: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.

Lymphadenectomy is associated with an increased risk of postoperative venous thromboembolism in early stage endometrial cancer.

OBJECTIVES: In patients undergoing surgery for early stage endometrial cancer, we sought to evaluate the effect of lymphadenectomy (LND), as well as surgical route, on the risk of postoperative venous thromboembolism (VTE). METHODS: The Surveillance, Epidemiology, and End Results cancer registries (2000-2013) linked to Medicare claims follow up from 1999 to 2014 was accessed to identify those with stage I-II endometrioid endometrial cancer who underwent hysterectomy. Performance of LND, 90-day incidence of postoperative VTE, open vs minimally invasive surgery (MIS), demographics, comorbidities, grade, and stage were collected. A washout period of 12 months with no prior VTE was required. t-test, Chi square test, univariate and multivariable Poisson regression with robust variance estimator were used. RESULTS: A total of 15,101 patients had hysterectomy for early stage endometrial cancer. LND was performed in 9004 (60%) patients. VTE was found in 486 patients. There were 346 VTEs (3.8%) in the LND group vs 140 (2.3%) in those without LND (RR = 1.67, p < 0.0001). Adjusting for age, stage, grade, comorbidities and surgical approach, LND remained a significant risk for VTE (RR = 1.7, p < 0.001). In those who underwent MIS, LND was associated with a two-fold increase in the risk of VTE (p = 0.0008) (adjusted RR = 1.99, p = 0.0014) and had a statistically comparable rate of VTE when compared to the open surgical approach (p = 0.054). CONCLUSIONS: LND is associated with an increased 90-day risk of postoperative VTE in patients undergoing surgery for early stage endometrial cancer. The need for extended postoperative VTE prophylaxis in patients undergoing LND via MIS needs further exploration.

Dasatinib, paclitaxel, and carboplatin in women with advanced-stage or recurrent endometrial cancer: A pilot clinical and translational study.

PURPOSE: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. PATIENTS AND METHODS: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. RESULTS: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%-77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). CONCLUSIONS: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.

HE4 and CA125 as preoperative risk stratifiers for lymph node metastasis in endometrioid carcinoma of the endometrium: A retrospective study in a cohort with histological proof of lymph node status.

OBJECTIVES: To investigate whether HE4 and CA125 could identify endometrioid adenocarcinoma patients who might most benefit from full staging surgery with lymphadenectomy. METHODS: Sequential patients with a preoperative banked serum and histology of endometrioid adenocarcinoma of endometrium who had undergone surgical staging with lymph node dissection over a 5-year period between 2011 and 2016 were included from a tertiary Gynaecological Cancer Centre, Dublin, Ireland. Preoperative serum HE4 and CA125 were measured using ELISA, with the cut-offs HE4 81 pmol/L and CA125 35 U/ml. Predictive values were estimated using AUC, sensitivity, specificity and odds ratios. RESULTS: 9.5% of the cohort had lymph node metastases. A HE4 cut-off of 81 pmol/L yielded a sensitivity of 78.6% and specificity of 53.4% for predicting lymph node metastases. Sensitivity of CA125 at 35 U/ml was 57% and specificity 91.4%. The AUC was 0.66 (0.52-0.80) for HE4 and 0.74 (0.58-0.91) for CA125. Sensitivity was 92.8% and specificity 51.1% when an elevation of either HE4 or CA125 was included, AUC was 0.72 (0.61-0.83), this combination yielded the highest NPV of 98.6%. Sensitivity was 42.9% and specificity 93.8% if both markers were elevated simultaneously, AUC was 0.68 (0.51-0.86). Preoperative clinical predictors of high-grade preoperative histology and radiology had sensitivities of 21.4% and 41.7%, respectively. Patients with a HE4 above 81 pmol/L had an odds ratio of 4.2 (1.12-15.74), p < 0.05, of lymph node metastases and CA125 had an odds ratio of 14.2 (4.16-48.31), p < 0.001. CONCLUSIONS: Serum HE4 and CA125 improved on existing methods for risk stratification of endometrioid carcinomas and warrant further investigation.

Circulating miRNA 27a and miRNA150-5p; a noninvasive approach to endometrial carcinoma.

The search for novel non-invasive biomarkers such as epigenetic molecular markers is new hope for common and burdensome cancers. We aim to assess serum expression of miRNA 27a and miRNA150-5p in endometrial cancer patients. Serum was drawn for 36 un-intervened endometrial cancer patients scheduled for hysterectomy and 35 controls. miRNA 27a and miRNA150-5p were measured by real time reverse transcription polymerase chain reaction. Significant overexpression of both miRNA in patients (p < 0.001). At cutoffs 0.2872 & > 1.02, miRNA 27a showed 100% sensitivity, specificity, positive and negative predictive values. miRNA150-5p showed 88.89% sensitivity, 100% specificity, 100% positive and 78.9% negative predictive values. Areas under curve were 1.0 for miRNA 27a, 0.982 for miRNA 150 performing much better than Ca125. miRNA 27a was significantly associated with type I endometroid endometrial cancer. Conclusion: miRNA 27a and miRNA-150-5P can be suggested as promising biomarkers of endometrial cancer possibly part of a miRNA panel for management.

Drp1 mediates high glucose-induced mitochondrial dysfunction and epithelial-mesenchymal transition in endometrial cancer cells.

This study aims to clarify the role and molecular mechanism of dynamin-related protein 1 (Drp1)-mediated mitochondrial homeostasis in high glucose (HG)-induced endometrial cancer (EC). Normal endometrium and tumor tissues of EC patients with normal and HG levels were collected, and Drp1 and p-Drp1 expression levels were detected by immunohistochemistry. Human EC cells were cultured with different glucose concentrations, and Drp1 and p-Drp1 expression levels were evaluated by Western blotting. Cell models of control and siDrp1 groups under normal and HG conditions were established, and subsequent functional experiments were conducted. Histology and in vitro experiments showed that the HG environment increased Drp1 activation, which could lead to mitochondrial dysfunction. Moreover, the imbalance of mitochondrial homeostasis mediated by Drp1 resulted in cell dysfunction, including altered glucose metabolism and increased epithelial-mesenchymal transition (EMT), migration and invasion. All these changes caused by HG could be partially alleviated by Drp1 knockdown. This study revealed that Drp1 was involved in the progression of EC associated with HG, and Drp1 might be a new potential therapeutic target for EC patients with diabetes.

Prognostic significance of pretreatment thrombocytosis in endometrial cancer: an Israeli Gynecologic Oncology Group study.

OBJECTIVE: Endometrial cancer prognosis is related to stage, histology, myometrial invasion, and lymphovascular space invasion. Several studies have examined the association between pretreatment thrombocytosis and patient outcomes with contrasting results regarding prognosis. Our aim was to evaluate the association of pretreatment platelet count with outcomes in endometrial cancer patients. METHODS: This is an Israeli Gynecologic Oncology Group multicenter retrospective cohort study of consecutive patients with endometrial cancer, who underwent surgery between January 2002 and December 2014. Patients were grouped as low risk (endometrioid G1-G2 and villoglandular) and high risk (endometrioid G3, uterine serous papillary carcinoma, clear cell carcinoma, and carcinosarcoma). Those with stage I disease were compared with stages II-IV. Disease stages were reviewed and updated to reflect International Federation of Gynecology and Obstetrics (FIGO) 2009 staging. All patients underwent pelvic washings for cytology and total abdominal or laparoscopic hysterectomy with bilateral salpingo-oophorectomy. Pelvic lymph node assessment was performed in patients with tumors of moderate-high risk histology or deep myometrial invasion. Para-aortic sampling was performed at the surgeon's discretion. Patients were categorized by pretreatment platelet count into two groups: ≤400×109/L and >400×109/L (defined as thrombocytosis). Clinical and pathological features were compared using Student t-test, χ2 or Fisher's exact test. Survival measures were plotted with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariable comparison of associations. RESULTS: Of the 1482 patients included, most had stage I disease (961; 74.8%) and most had endometrioid histology (927; 64.1%). A total of 1392 patients (94%) had pretreatment platelet counts ≤400×109/L and 90 (6%) had pretreatment thrombocytosis. Patients with thrombocytosis had a significantly higher rate of high-grade malignancy, advanced stage, lymphovascular space invasion, low uterine segment involvement, and lymph node metastases. They also had shorter 5 year disease-free survival (65% vs 80%, p=0.003), disease-specific survival (63% vs 83%, p<0.05) and overall survival (59% vs 77%, p<0.05). On multivariate analysis, an elevated pretreatment thrombocyte count remained a significant independent predictor for disease-specific survival and overall survival. CONCLUSIONS: Pretreatment thrombocytosis is an independent prognostic factor for decreased disease-specific survival and overall survival among patients with endometrial cancer, and can serve as a predictor of poor outcome.

Preoperative neutrophil-to-lymphocyte, platelet-to-lymphocyte and monocyte-to-lymphocyte ratio as a prognostic factor in non-endometrioid endometrial cancer.

Objective: Evaluate the prognostic value of neutrophil-lymphocyte ratio (NMR), platelet-lymphocyte ratio (PLR), and monocyte-lymphocyte ratio (MLR) in patients with non-endometrioid endometrial cancer. Method: Laboratory and clinicopathological data from 118 patients with non-endometrioid endometrial cancer who underwent surgical resection between January 2010 and December 2019 were reviewed. NLR, PLR and MLR were analyzed for correlations with recurrence and survival. The receiver operating characteristic (ROC) curves were generated for the NLR, PLR, and MLR. Optimal cut-off values were determined as the points at which the Youden index (sensitivity + specificity - 1) was maximal. Based on the results of the ROC curve analysis, the patients were grouped into high MLR and low MLR groups. Recurrence rate, disease-free survival, and overall survival were compared between the two groups. The prognostic factors were investigated using univariate and multivariate Cox proportional hazards model. Results: The optimal cut-off value of MLR was 0.191 (AUC, 0.718; p < 0.001). Significantly more patients in the high MLR group experienced recurrence (60.3% vs. 15.6%, p < 0.0001) and cancer-related deaths (46.6% vs. 13.3%, p = 0.003). In multivariate analysis, advanced stage and high MLR were independent prognostic factors for disease-free survival and overall survival. Conclusion: Elevated MLR was significantly associated poor clinical outcomes in patients with non endometrioid endometrial cancer. Our findings suggest that MLR may be clinically reliable and useful as an independent prognostic marker for patients with non-endometrioid endometrial cancer.

What is the predictive value of preoperative CA 125 level on the survival rate of type 1 endometrial cancer?

Background/aim: To investigate the utility of preoperative serum cancer antigen 125 (CA 125) levels in type 1 endometrial carcinoma (EC) as a marker for determining poor prognostic factors and survival. Material and methods: All patients with endometrial cancer, who had been treated between 2012 and 2020, were retrospectively reviewed, and finally, 256 patients with type 1 endometrium carcinoma were included in the study. The relationship between the clinicopathological characteristics, CA 125 level, and survival rates were analyzed. The cut-off value for the preoperative serum CA 125 level was defined as 16 IU/L. Results: The median serum CA 125 levels were significantly higher in patients with deep myometrial invasion, lymph node metastasis, lymphovascular space invasion, cervical stromal and adnexal involvement, advanced stage, positive peritoneal cytology, recurrence, and adjuvant therapy requirement. Serum CA 125 cut-off values determined according to clinicopathologic factors ranged from 15.3 to 22.9 IU/L (sensitivity 61%­77%, specificity 52%­73%). The disease-specific survival rate was significantly higher in patients with CA 125 levels < 16 IU/L (P = 0.047). Conclusion: The data showed that choosing a lower threshold value for the CA 125 level (16 IU/L) instead of 35 IU/L, could be more useful in type 1 EC patients with negative prognostic factors.

Detection of somatic mutations in peritoneal lavages and plasma of endometrial cancer patients: A proof-of-concept study.

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Although most patients are diagnosed at early stages, 15-20% will relapse despite local treatment. Presently, there are no reliable markers to identify patients with worse outcomes who may benefit from adjuvant treatments, such as chemotherapy, and liquid biopsies may be of use in this setting. Peritoneal lavages are systematically performed during endometrial surgery but little data are available about their potential as liquid biopsies. We analyzed KRAS and PIK3CA mutations in paired surgical biopsies, blood and cytology-negative peritoneal lavages in a cohort of 50 EC patients. Surgical biopsies were submitted to next-generation sequencing (NGS) while circulating-free DNA (cfDNA) purified from plasma and peritoneal lavages was analyzed for KRAS and PIK3CA hotspot mutations using a sensitive quantitative polymerase chain reaction (PCR) assay. NGS of biopsies revealed KRAS, PIK3CA or concomitant KRAS + PIK3CA mutations in 33/50 (66%) EC patients. Of those, 19 cases carried hotspot mutations. Quantitative PCR revealed KRAS and/or PIK3CA mutations in the lavages of 9/19 (47.4%) hotspot EC patients. In contrast, only 2/19 (10.5%) blood samples from hotspot EC patients were positive. Mutations found in cfDNA consistently matched those in paired biopsies. One of the two patients positive in plasma and lavage died in less than 6 months. In conclusion, mutational analysis in peritoneal lavages and blood from early stage EC is feasible. Further studies are warranted to determine if it might help to identify patients with worse prognosis. Human genes discussed: KRAS, KRAS proto-oncogene, GTPase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.