Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6ß-hydroxycortisol, deoxycholic acid, and 1ß-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

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.

The Possible Role of Mycotoxins in the Pathogenesis of Endometrial Cancer.

Endometrial cancer is one of the most common cancer types among women. Many factors can contribute to the development of this disease, including environmental factors and, thus, eating habits. Our study aims to determine the levels of various mycotoxins and their metabolites in the blood serum and endometrial tissue samples of participants with previously proven endometrial cancer and to find possible contributions to cancer development. In the cohort clinical trial, 52 participants aged between 44 and 86 were studied. The participants were divided into two groups: patients or matched controls. All patients had previously histologically diagnosed endometrial cancer. The cancer patients were divided into low-grade endometrioid and low- plus high-grade endometrioid groups. Controls had no history of endometrial malignancy or premalignancy. Blood serum and endometrial tissue samples were obtained from all study patients. We compared the concentrations of total Aflatoxins (Afs), Deoxynivalenol (DON), Ochratoxin-A (OTA), T2-toxin and HT2 toxin (T2/HT2 toxin), Zearalenone (ZEN), alpha-Zearalenol (α-ZOL), and Fumonisin B1 (FB1) in the serum and endometrium between the different study groups. As a result, we can see a significant correlation between the higher levels of Afs and zearalenone and the presence of endometrial cancer. In the case of Afs, DON, OTA, T2/HT2 toxins, ZEN, and alpha-ZOL, we measured higher endometrial concentrations than in serum. Considering the effect of mycotoxins and eating habits on cancer development, our results might lead to further research exploring the relationship between certain mycotoxins and endometrium cancer.

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.

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).

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.

Preoperative cancer antigen-125 levels as a predictor of recurrence in early-stage endometrial cancer.

OBJECTIVE: Endometrial cancer is the most common gynecological cancer in developed countries, with a majority of cases being low-grade endometrioid endometrial cancer. Identifying risk factors for disease recurrence and poor prognosis is critical. This study aimed to assess the correlation between preoperative cancer antigen-125 levels and disease recurrence in early-stage endometrioid endometrial cancer patients. METHODS: The study was a retrospective analysis of 217 patients diagnosed with endometrioid endometrial cancer who underwent surgical treatment at a university-affiliated tertiary hospital between 2016 and 2022. Patients were divided into two groups based on their preoperative cancer antigen-125 levels and compared with clinicopathological findings and disease recurrence. Disease-free survival rates were calculated, and logistic regression analysis was performed to determine independent factors affecting disease-free survival. RESULTS: The mean age of patients was 61.59±0.75 years, and the mean follow-up time was 36.95±1.18 months. The mean cancer antigen-125 level was 27.80±37.81 IU/mL. The recurrence rate was significantly higher in the group with elevated cancer antigen-125 levels (p=0.025). Disease-free survival was lower in patients with elevated cancer antigen-125 compared with those with normal levels (p=0.005). Logistic regression analysis revealed that elevated cancer antigen-125 levels were associated with disease recurrence (OR: 3.43, 95%CI 1.13-10.37, p=0.029). CONCLUSION: The findings of this study suggest that preoperative cancer antigen-125 levels can be used as a predictor of disease recurrence in early-stage endometrioid endometrial cancer patients. cancer antigen-125 levels may be a useful tool for risk stratification and patient management in endometrial cancer.

Prognostic role of C-reactive protein in patients with endometrial cancer: a meta-analysis.

Background: The present meta-analysis aimed to explore the association between C-reactive protein (CRP) levels and the prognosis of patients with endometrial cancer (EC). Methods: The effect of CRP level on predicting overall survival (OS) and disease-free survival (DFS) in patients with EC was evaluated according to pooled hazard ratios (HRs) and corresponding 95% CIs. Results: High CRP levels were not significantly correlated with OS (HR: 1.32 [95% CI: 0.99-1.77]; p = 0.060) or DFS (HR: 1.05 [95% CI: 0.88-1.25]; p = 0.597) in patients with EC. Conclusion: CRP levels did not significantly predict OS or DFS in patients with EC. However, according to subgroup analyses, higher CRP levels were significantly associated with poor OS in Asian patients with EC.

[Box: see text].

Integration of pretreatment tumor markers in a nomogram model for prognostic prediction of FIGO stage I endometrial cancer: A multi-institutional cohort study.

OBJECTIVE: Traditionally, the prognosis of patients with FIGO stage I endometrial cancer is determined by clinicopathological risk factors. In this study, we assessed the potential contribution of pretreatment carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) levels to estimating the prognosis of these patients and aimed to develop and validate a prognostic nomogram. METHODS: This retrospective study included patients with FIGO stage I endometrial cancer who underwent treatment between January 2009 and December 2021 in the four institutes of Chang Gung Memorial Hospital. To identify optimal cutoff values of CEA and CA-125 for predicting survival, receiver operating characteristic (ROC) curves were generated, the Kaplan-Meier method was used to estimate survival, and a Cox regression model was used to analyze the independent prognostic factors. Finally, a nomogram and calibration curve were constructed to predict patient survival probability. RESULTS: Of the 1559 patients evaluated, the optimal cutoff values of CEA and CA-125 were 1.44 ng/mL (area under the ROC curve [AUC] 0.601) and 39.77 U/mL (AUC 0.503), respectively. Multivariate Cox regression analysis showed that pretreatment CEA (hazard ratio [HR] 2.11, 95% confidence interval [95% CI] 1.35-3.28), CA-125 (HR 2.07, 95% CI 1.31-3.27), age >70 years (HR 12.54, 95% CI 5.05-31.11), myometrial invasion >50% (HR 1.69, 95% CI 1.03-2.73), non-endometrioid histology (HR 1.83, 95% CI 1.14-2.95), high-grade tumor (HR 2.41, 95% CI 1.46-3.97), and lymphovascular space invasion (HR 2.32, 95% CI 1.26-4.25) were significant variables associated with overall survival. These factors were used to construct the nomogram model, which showed good concordance and accuracy. CONCLUSIONS: Integration of pretreatment CEA and CA-125 in a prognostic nomogram is feasible. Our prediction model has the potential to assist clinicians in guiding appropriate clinical practice.

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.

Evaluation of Tissue Expression of Vaspin and Serum Vaspin Concentration as a Prognostic and Risk Factor in Endometrial Cancer.

Adipose tissue is a multifunctional endocrine organ. One of the biologically active substances is vaspin, which is part of the serpin family. The purpose of the following study is to determine the possibility of using vaspin as a prognostic and risk factor in endometrial cancer. The study included 127 patients with abnormal uterine bleeding. To determine the value of adipokine, the study used Kaplan-Meier curves to estimate patients survival. Univariate and multivariate analyses were performed simultaneously using the Cox regression model. Tissue expression of vaspin was assessed in patients from the study group (endometrial cancer) and the control group (non-cancerous). We found that higher levels of vaspin are found in obese people, with lower staging (FIGO I and II), lower grading (G1), no LVSI metastases and no lymph node metastases. Higher serum vaspin levels are an independent protective factor for endometrial cancer. We concluded that endometrial cancer patients with serum vaspin concentrations above the median have longer DFS compared to patients with concentrations below the median. Considering multivariate analysis, vaspin concentrations above the median are independent favourable prognostic factors for endometrial cancer. Tissue expression of vaspin cannot be a histological marker to distinguish between cancer and non-cancerous lesions and between different grading levels.

Correlation of Preoperative Serum and Intraoperative Peritoneal Lavage Fluid Ca-125 Levels with Postoperative Tumor Histology in Patients with Endometrial Cancer: A Prospective-Controlled Study.

BACKGROUND: The role of Ca-125 in endometrial cancer is not fully known. Some authors have reported high Ca-125 levels in patients with recurrent or advanced endometrial cancer, whereas others have stated that Ca-125 levels and the advance of the disease were not correlated in endometrial cancer. This makes it inevitable for clinicians to search for different measurement methods or interpretation of the present tumor markers. The aim of this study was to evaluate the relationship between Ca-125 values of the serum and abdominal lavage fluid and postoperative histopathological parameters in patients with endometrial carcinoma. METHODS: The study included patients who were diagnosed with endometrial cancer in the Gynecology Clinic and were planned to undergo surgery. The correlations of clinicopathological parameters with preoperative values of Ca-125 measured from serum and abdominal lavage fluid were investigated. The Spearman correlation test was applied in the analysis of correlations of serum and abdominal lavage fluid Ca-125 values with postoperative tumor characteristics. RESULTS: The serum Ca-125 values were determined to be positively correlated with surgical stage, tumor diameter, and lymph node involvement (p = 0.03; p = 0.04; and p = 0.01, respectively). No correlation was determined between tumor grade and serum Ca-125 level. The level of Ca-125 in the abdominal lavage fluid was observed to be correlated with surgical stage and tumor grade, but not with tumor diameter or lymph node involvement (p = 0.01, p = 0.04, respectively). CONCLUSIONS: The value of Ca-125 in the abdominal lavage fluid has a positive correlation with the surgical stage and tumor grade in patients with endometrial carcinoma.

Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study.

CONTEXT: The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear. OBJECTIVE: This Mendelian randomization study assessed the causal associations of endogenous 17ß-estradiol (E2), the most potent estrogen, with cancer risk in women. METHODS: As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio. RESULTS: Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10-3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10-13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10-11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers. CONCLUSION: This study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women.

Serum HE4 and CA125 combined to predict and monitor recurrence of type II endometrial carcinoma.

There is no recognized serum biomarker to predict the recurrence of endometrial carcinoma (EC). We aimed to explore serum human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) as the biomarkers to predict and monitor recurrence of type II EC. 191 patients diagnosed with type II EC were involved for this retrospective study. Comparing recurrent with non-recurrent patients, HE4 levels resulted a statistically significant difference at primary diagnosis and recurrence, respectively (P = 0.002 and P = < 0.001), while CA125 levels resulted statistically significant (P = < 0.001) at recurrence. According to receiver operating characteristic curve analysis, the areas under the curve were significant for HE4 levels at primary diagnosis and recurrence predicting recurrence. Furthermore, CA125 levels at recurrence were significant. And the combination of both markers showed the higher sensitivity and specificity than single one. Patients with higher HE4 levels were associated with worse disease-free survival and overall survival, the opposite was true for patients with lower HE4 levels. The preoperative HE4 levels could be used to evaluate the risk factors of type II EC. Which suggested that HE4 levels might associated with the prognosis of type II EC. And combination of HE4 and CA125 could be applied to monitor recurrence during follow-up.

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.

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.

Expression of Delta Like Ligand 4 (DLL4) in endometrial carcinomas and tumor vasculature.

PURPOSE: Delta like ligand 4 (DLL4) is a transmembrane ligand of the Notch Signalling pathway, that regulates blood vessel sprouting and maturation. We investigated the expression of DLL4 in endometrial cancer. METHODS: DLL4 was assessed in the plasma (with ELISA) and tissues (with immunohistochemistry) 33 patients with endometrial cancer, treated with radical hysterectomy for stage I endometroid carcinoma. The angiogenic activity (AA) of endometrial cancer was quantified by assessing the CD31+ microvessel density (MVD) in the invading tumor front. Vascular maturation index (VMI), defined as the percentage of CD31+ microvessels expressing DLL4, was calculated as the ratio of the CD31+ MVD to the DLL4+ MVD. RESULTS: The angiogenic activity was directly related with the histological grade (p=0.01). The VMI ranged from 0.1 to 0.7 (median 0.34). The concentration of DLL4 in the plasma ranged from 55-81pg/ml (mean 62.8) before, and dropped to 55-62 (mean 58.2) after hysterectomy (p<0.05). DLL4 was also expressed by cancer cells in 17/33 cases. No correlation between DLL4-related parameters with histopathological variables was noted. CONCLUSION: This pilot study shows that DLL4 is overexpressed in endometrial cancer cells, vasculature and is also elevated in the plasma of a fraction of patients before surgery. The percentage of DLL4+ vessels in the penetrating sample ranged from 10-70%, indicating a large difference in the quality of angiogenesis produced between the endometrial tumors of the same histological type and differentiation.

Association of Endogenous Pregnenolone, Progesterone, and Related Metabolites with Risk of Endometrial and Ovarian Cancers in Postmenopausal Women: The B∼FIT Cohort.

BACKGROUND: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. METHODS: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. RESULTS: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01]. CONCLUSIONS: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. IMPACT: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

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.

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.