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.

Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

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.

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.

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.

Is ABO blood group a risk or prognostic factor for patients with endometrioid endometrial cancer? A retrospective analysis in Germany.

BACKGROUND: A relationship is known to exist between gastric and pancreatic cancers and ABO antigens, caused by various immune modulations related to the ABO blood group of the patient. A similar relationship with regard to gynaecological cancers remains controversial. MATERIALS AND METHODS: Patients who underwent surgery for endometrioid endometrial cancer in International Federation of Gynaecology and Obstetrics (FIGO) stage I, II, III or IV from 2006 to 2018 were identified. The research explored the existence of a relationship between the patients' blood group or Rhesus factor and the incidence of endometrial cancer, grade (G1, G2, G3), FIGO stage, nodal status, recurrence, menopausal status, parity, and body mass index. Statistical methods such as the chi-square test, analysis of variance and the Scheffé post-hoc test were used. RESULTS: Two hundred and two patients with endometrioid endometrial cancer were included: 96 had blood group A, 19 blood group B, 75 blood group 0, and 12 had blood group AB. This distribution corresponds to the general blood group distribution in Germany. The vast majority of the dependent variables, such as grade, FIGO stage, nodal status or recurrence were not significantly associated with ABO blood group or Rhesus factor status. The relative frequencies of G1 and G3 endometrial cancers with respect to blood group were similar. Menopausal status, parity, and body mass index were not related to more advanced FIGO stages at initial diagnosis or to ABO blood group. DISCUSSION: Blood group screening would probably not be helpful in the diagnosis of endometrioid endometrial carcinomas in early stages compared to the current gold standard. Furthermore, a specific blood group does not increase either the risk of recurrence or the risk of a dedifferentiated type of endometrial carcinoma.

Vitamin D regulates cell viability, migration and proliferation by suppressing galectin-3 (Gal-3) gene in ovarian cancer cells.

Vitamin D deficiency is identified as a risk factor for the occurrence and recurrence of ovarian cancer. Galectin-3 (Gal-3) participates in many physiological and pathological processes. In present study, serum vitamin D level was detected using chemiluminescence enzyme immunoassay. Gal-3 expression was examined using real-time polymerase chain reaction (PCR), Western blot and immunocytochemistry analysis. SKOV3 cells viability was assessed by the water-soluble tetrazolium salt (WST-1) assay, the migration of SKOV3 cells was detected using transwell assay, and the proliferation of SKOV3 cells was measured by 3H-thymidine incorporation (3H-TdR). Our study demonstrated that vitamin D levels were lower in 40 ovarian cancer patients: vitamin D deficiency is closely related to the pathogenesis of ovarian cancer. Treatment with vitamin D reduced the migration and proliferation of ovarian cancer cells. Gal-3 was overexpressed in ovarian cancer, which could induce the viability, migration and proliferation ability of ovarian cancer cells, and these effects were abrogated by vitamin D downregulating the expression of Gal-3 gene. Therefore, our results support that vitamin D may suppress Gal-3-induced viability, migration and proliferation ability of ovarian cancer cells, which suggests that the use of vitamin D may have beneficial effects in preventing and treating ovarian cancer.

The generally low sensitivity of CA 125 for FIGO stage I ovarian cancer diagnosis increases for endometrioid histotype.

BACKGROUND: The serum marker CA 125 is still the most widely used biomarker for ovarian cancer (OC) diagnosis in gynecological and oncological setting, but its predictive role in early-stage OC is still debated. The aim of this study was to explore the value of CA 125 in distinguishing between early-stage OC and borderline ovarian tumor (BOT) and to evaluate the accuracy of CA 125 in the detection of early stage OC. METHODS: A retrospective cohort study was performed at the University Hospital of Bologna (Italy) on 1296 consecutive women suffering from OC or BOT (diagnosed at histology) between 1988-2017. Patients for whom CA 125 level was determined preoperatively were included. The positive cut-off level used was >35 U/mL. RESULTS: Of 910 patients, 192 (21.1%) were diagnosed with BOT and 718 (78.9%) with OC. The sensitivity of CA 125 for stage I OC was 54.4 (95% CI: 45.3-63.3) (51.5 for IA, 54.6 for IB, 58.3 for IC), but it increased to 78.0 (95% CI: 63.7-88.0) for stage II. Interestingly, in stage I OC, CA 125 presented a significantly higher sensitivity for the endometrioid histotype [72.4 (95% CI: 52.5-86.5) vs. 49.0 (95% CI: 38.6-59.4), P=0.026]. The positive likelihood ratio of CA 125 for early-stage OC compared to BOT was 1.29 (95% CI: 1.06-1.58). CONCLUSIONS: Despite its limited sensitivity for early-stage OCs, CA 125 still represents a useful serum marker to early differentiate between OCs and BOTs. Its sensitivity for stage I OC increases in endometrioid histotype.

Ten years of experience with endometrial cancer treatment in a single Brazilian institution: Patient characteristics and outcomes.

Few reports have described the clinical and prognostic characteristics of endometrial cancer, which is increasing worldwide, in large patient series in Brazil. Our objective was to analyze the clinicopathological characteristics, prognostic factors, and outcomes of patients with endometrial cancer treated and followed at a tertiary Brazilian institution over a 10-year period.This retrospective study included 703 patients diagnosed with endometrial cancer who were treated at a public academic tertiary hospital between 2008 and 2018. The following parameters were analyzed: age at diagnosis, race, body mass index, serum CA125 level before treatment; histological type and grade, and surgical stage. Outcomes were reported relative to histological type, surgical staging, serum CA125, lymph-vascular space involvement (LVSI), and lymph-node metastasis. The median patient age at diagnosis was 63 (range, 27-93) years (6.4% were <50 years). Minimally invasive surgeries were performed in 523 patients (74.4%). Regarding histological grade, 468 patients (66.5%) had low-grade endometrioid histology and 449 patients (63.9%) had stage I tumors. Tumors exceeded 2.0 cm in 601 patients (85.5%). Lymphadenectomy was performed in 551 cases (78.4%). LVSI was present in 208 of the patients' tumors (29.5%). Ninety-three patients (13.2%) had recurrent tumors and 97 (13.7%) died from their malignant disease. The robust prognostic value of FIGO stage and lymph node status were confirmed. Other important survival predictors were histological grade and LVSI [overall survival: hazard ratio (HR) = 3.75, p < 0.001 and HR = 2.01, p = 0.001; recurrence: HR = 2.49, p = 0.004 and HR = 3.22, p = 0.001, respectively). Disease-free (p = 0.087) and overall survival (p = 0.368) did not differ significantly between patients with stage II and III disease. These results indicate that prognostic role of cervical involvement should be explored further. This study reports the characteristics and outcomes of endometrial cancer in a large population from a single institution, with systematic surgical staging, a predominance of minimally invasive procedures, and well-documented outcomes. Prognostic factors in the present study population were generally similar to those in other countries, though our patients' tumors were larger than in studies elsewhere due to later diagnosis. Our unexpected finding of similar prognoses of stage II and III patients raises questions about the prognostic value of cervical involvement and possible differences between carcinomas originating in the lower uterine segment versus those originating in the body and fundus. The present findings can be used to guide public policies aimed at improving the diagnosis and treatment of endometrial cancer in Brazil and other similar countries.

An integrated molecular profile of endometrioid ovarian cancer.

OBJECTIVE: Endometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers. METHODS: Whole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC). RESULTS: EOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases. CONCLUSIONS: We identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.

Preoperative Circulating Lymphocyte and Monocyte Counts Correlate with Patient Outcomes in Type I and Type II Endometrial Cancer.

Tumor-associated macrophages and tumor-infiltrating lymphocytes are associated with survival in solid malignancies. Given the physiological link to peripheral immune cell counts, we evaluated if peripheral immune cell counts were predictors of outcomes in endometrial cancer. A retrospective study was completed for endometrial cancer cases between 2000 and 2010. Kaplan-Meier, bivariate, and multivariable Cox proportion hazard analyses were performed examining the relations between survival and peripheral immune cell counts. Three hundred ten patients were identified. In bivariate analyses, high monocyte counts (> 0.7 × 109 cells/L) trended with decreased progression free survival (PFS) (p = 0.10) and poorer overall survival (OS) (p = 0.16). By contrast, high lymphocyte level (> 1.5 × 109 cells/L) was associated with improved PFS (p = 0.008) and OS (p = 0.006). These findings were consistent for type I and type II endometrial cancers. In a multivariable Cox model, high monocyte level was associated with a greater risk of disease recurrence (hazard ratio (HR) = 1.63, p < 0.035). Other significant predictors of recurrence were age, non-endometrioid histology, and the presence of lymph vascular space invasion (LVSI). In a multivariable Cox model, high lymphocyte count trended with a lower risk of death (HR = 0.66, p = 0.07). Age, surgical stage, non-endometrioid histology, and LVSI were also associated with death in this model. In this sample of endometrial cancer patients, we found that high preoperative lymphocyte counts were associated with improved overall improved survival. High monocyte counts were associated with poorer disease-free survival outcomes. Further studies that focused on understanding tumor-antagonizing and pro-tumoral effects of lymphocytes and monocytes, respectively, in endometrial cancer are recommended.

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.

Serum HSP70 level in patients with endometrial cancer with and without diabetes.

Diabetes mellitus (DM) is associated with an increased risk of endometrial carcinoma (EC). Heat shock proteins have a role in the modulation of both diseases. The aim of this study was to investigate extracellular HSP70 (eHSP70) level alternations in patients with two different types of EC (endometrioid and non-endometrioid) with and without type 2 diabetes. In a case-control study, 88 participants were enrolled in four groups including: 18 EC patients with DM, 19 EC patients without DM, 29 patients with DM, and 22 healthy individuals. Blood samples were taken before surgery in cancer patients. Estradiol, eHSP70, sex hormone-binding globulin (SHBG), FBS, and HbA1c were assessed. Serum HSP70 level was higher in patients with diabetes (52.24 ± 14.2 ng/ml) compared to healthy controls (39.04 ± 6.96) (p < .05). It was lower in EC (26.05 ± 12.28) compared to healthy controls (39.04 ± 6.96) (p < .05). eHSP70 was also lower in endometrioid-type carcinoma (22.57 ± 11) compared to non-endometrioid type (31.55 ± 12.38) (p < .05). Further analysis showed increased levels of eHSP70 in patients having both endometrioid-type carcinoma and diabetes (27.23 ± 11.41) compared to the same patients without DM (17.08 ± 7.78) (p < .05). Presence of diabetes in patients with endometrioid type carcinoma resulted in an increase in eHSP70 approaching the level of eHSP70 in patients with non-endometrioid histology.

Blood steroid levels predict survival in endometrial cancer and reflect tumor estrogen signaling.

OBJECTIVE: Blood-based biomarkers are attractive due to ease of sampling and standardized measurement technology, reducing obstacles to clinical implementation. The objective of this study was to evaluate a clinically available method of steroid hormone measurement for its prognostic potential in endometrial cancer. METHODS: We quantified seven steroid hormones by liquid chromatography-tandem mass spectrometry in 100 endometrial cancer patients from a prospective cohort. Abdominal fat distribution was assessed from abdominal computed tomography (CT) scans. Steroid hormone levels were compared to clinical characteristics, fat distribution and gene expression in primary tumor samples. RESULTS: Low levels of 17OH-progesterone, 11-deoxycortisol and androstenedione were associated with aggressive tumor characteristics and poor disease specific survival (p = .003, p = .001 and p = .02 respectively). Adjusting for preoperative risk based on histological type and grade, low 17OH-progesterone and 11-deoxycortisol independently predicted poor outcome with hazard ratios of 2.69 (p = .033, 95%CI: 1.09-6.68) and 3.40 (p = .020, 1.21-9.51), respectively. Tumors from patients with low steroid level displayed increased expression of genes related to mitosis and cell cycle progression, whereas high steroid level was associated with upregulated estrogen signaling and genes associated with inflammation. Estrone and estradiol correlated to abdominal fat volume in all compartments (total, visceral, subcutaneous, p < .001 for all), but not to the visceral fat proportion. Patients with higher levels of circulating estrogens had increased expression of estrogen signaling related genes. CONCLUSION: Low levels of certain endogenous steroids are associated with aggressive tumor traits and poor survival and may provide preoperative information independent of histological biomarkers already in use.

Circulating Lysophosphatidylcholines, Phosphatidylcholines, Ceramides, and Sphingomyelins and Ovarian Cancer Risk: A 23-Year Prospective Study.

BACKGROUND: Experimental evidence supports a role of lipid dysregulation in ovarian cancer progression. We estimated associations with ovarian cancer risk for circulating levels of four lipid groups, previously hypothesized to be associated with ovarian cancer, measured 3-23 years before diagnosis. METHODS: Analyses were conducted among cases (N = 252) and matched controls (N = 252) from the Nurses' Health Studies. We used logistic regression adjusting for risk factors to investigate associations of lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), ceramides (CERs), and sphingomyelins (SMs) with ovarian cancer risk overall and by histotype. A modified Bonferroni approach (0.05/4 = 0.0125, four lipid groups) and the permutation-based Westfall and Young approach were used to account for testing multiple correlated hypotheses. Odds ratios (ORs; 10th-90th percentile), and 95% confidence intervals of ovarian cancer risk were estimated. All statistical tests were two-sided. RESULTS: SM sum was statistically significantly associated with ovarian cancer risk (OR = 1.97, 95% CI = 1.16 to 3.32; P = .01/permutation-adjusted P = .20). C16:0 SM, C18:0 SM, and C16:0 CERs were suggestively associated with risk (OR = 1.95-2.10; P = .004-.01; permutation-adjusted P = .08-.21). SM sum, C16:0 SM, and C16:0 CER had stronger odds ratios among postmenopausal women (OR = 2.16-3.22). Odds ratios were similar for serous/poorly differentiated and endometrioid/clear cell tumors, although C18:1 LPC and LPC to PC ratio were suggestively inversely associated, whereas C18:0 SM was suggestively positively associated with risk of endometrioid/clear cell tumors. No individual metabolites were associated with risk when using the permutation-based approach. CONCLUSIONS: Elevated levels of circulating SMs 3-23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women. Further studies are required to validate and understand the role of lipid dysregulation in ovarian carcinogenesis.

The investigation of serum levels of ADAMTS 5 and 8 (the A disintegrin and metalloproteinase with thrombospondin motifs) in the etiology of endometrial cancer.

The aim of this study was to investigate the serum levels of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 5 and 8 in patients diagnosed with endometrial cancer. Our study included 41 patients diagnosed with endometrial cancer. The control group consisted of 41 patients diagnosed with benign endometrial pathology. The serum samples were centrifuged and stored at -80 °C. The serum levels of ADAMTS were significantly higher (p<.001), whereas the levels of ADAMTS 8 were significantly lower in patients diagnosed with cancer (p<.001). In addition to the presence of known factors in the aetiology of endometrial cancer, the effect of inflammatory factors and some new proteins has centred on the causes of tumourigenesis in recent years. In this sense, these proteins, called the ADAMTS, are the source of new studies.Impact StatementWhat is already known on this subject? When the recent studies about endometrial cancer are evaluated, it is seen that the effects of chronic inflammation and cytokines have gained importance in its aetiology. The A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) gene family consist of 19 proteases that play essential role in the formation of the extracellular matrix (ECM) and interact with inflammatory cytokines. These proteases and their substrates provide a wide range of functions in different tissues, including ECM remodelling, angiogenesis, fibrosis and coagulation.What the results of this study add? ADAMTS 5, which causes the degradation of the ECM with Aggrecanase activity, was found to be significantly higher in patients diagnosed with cancer and ADAMTS 8 with anti-angiogenesis activity was significantly lower in patients diagnosed with endometrial cancer.What the implications are of these findings for clinical practice and/or further research? In this study, it is understood that the effect of inflammatory mediators is remarkably important in the aetiology of endometrial cancer, as in many types of organ specific cancer.

Pretreatment triglycerides-to-high density lipoprotein cholesterol ratio in postmenopausal women with endometrial cancer.

Raised triglycerides (TG) and reduced high density lipoprotein cholesterol (HDL-c) are components of metabolic syndrome. Both high TG and metabolic syndrome have been reported to be risk factors of endometrial cancer. Therefore, triglycerides-to-high density lipoprotein cholesterol ratio (TG/HDL-c ratio) may be a useful biological indicator in managing endometrial cancer. We aimed to explore the association between pretreatment TG/HDL-c ratio and endometrial cancer in postmenopausal women, and to evaluate its potential role in the disease. Pretreatment serum lipid profile and TG/HDL-c ratio were retrospectively analyzed for 167 postmenopausal women with endometrial cancer and 464 matched noncancer controls. Compared with controls, pretreatment TG/HDL-c ratio in endometrial cancer patients significantly elevated regardless of whether patients had diabetes or overweight/obesity (P < 0.05). Further analyses showed that pretreatment TG/HDL-c ratio increased significantly with advanced tumor stage. Interestingly, TG/HDL-c ratio of type I endometrial cancer patients was higher than those with type II endometrial cancer. A positive association was found between pretreatment TG/HDL-c ratio and tumor stage (adjusted r = 0.176, P = 0.027) in endometrial cancer group. Receiver operating characteristic curve analysis yielded the cut-off value of 1.52 for TG/HDL-c ratio to discriminate patients with cancer from controls (area under the curve, 0.689; sensitivity, 51.5%; specificity, 84.1%). Multivariate logistic regression model identified TG/HDL-c ratio ≥ 1.52 (odds ratio = 4.123; P < 0.001) as an independent predictor of endometrial cancer. TG/HDL-c ratio was positively associated with endometrial cancer clinical features, such as tumor stage and pathogenetic type. Accordingly, pretreatment TG/HDL-c ratio might be a potential marker for endometrial cancer.

Serum calcium is a novel parameter to assess metabolic syndrome in endometrial carcinoma.

OBJECTIVES: To investigate the distribution of serum calcium and the relationship between serum calcium and serum metabolic parameters in endometrial carcinoma (EC) patients. METHODS: Retrospective assessment of patients diagnosed with endometrial cancer from Peking University People's Hospital from 2004 to 2009. Clinical characteristics as well as pretreatment serum calcium, albumin, fasting plasma glucose (FPG), serum triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol (TC) value were extracted from patient records. Serum calcium was corrected for albumin. Unpaired t test and analysis of covariance were used to compare serum calcium among categorical variables. Simple correlation analyses and partial correlation analyses were used to assess the associations between serum calcium and continuous variables. RESULTS: Two-hundred twenty patients were included in this study. After adjusting for confounders, postmenopausal patients had higher total serum calcium (p=0.002) and albumin-corrected serum calcium (p=0.012) than premenopausal patients, endometrioid endometrial carcinoma (EEC) patients had higher total serum calcium than non-endometrioid endometrial carcinoma (NEEC) patients (p=0.037). Significant positive correlations were found between total serum calcium and FPG (p=0.017), TG (p=0.043), HDL (p=0.042), LDL (p<0.001), and TC (p<0.001) after adjusting for multiple variables, and the corrected serum calcium showed no significant correlation with metabolic parameters. CONCLUSION: Total serum calcium might be a more sensitive parameter for metabolic syndrome in endometrioid endometrial cancer patients than lipids.

Quantification of Leydig cells and stromal hyperplasia in the postmenopausal ovary of women with endometrial carcinoma.

Endometrioid endometrial carcinomas (EECs) are correlated with high serum levels of androgens and estrogen. We hypothesized that Leydig cells and ovarian stromal hyperplasia contribute to postmenopausal ovarian androgen production and are observed more frequently in EEC patients. Ovaries of postmenopausal women with EEC (n = 36) or non-endometrioid endometrial carcinoma (NEEC; n = 19) were examined for the presence of hilar Leydig cells and compared with ovaries resected for benign conditions (n = 22). Leydig cells were counted manually, and a Leydig cell density was calculated per millimeter squared hilar surface. Ovarian stromal hyperplasia was scored as atrophic, moderate hyperplastic, or marked hyperplastic. In all endometrial carcinomas, these findings were correlated with the serum levels of sex steroids and hormone receptor expression in their endometrial carcinomas. In EEC patients, mean number of Leydig cells was 282.8 cells compared with 76.3 cells in NEEC patients and 66.4 cells in controls. Leydig cells, marked stromal hyperplasia, and combined presence were observed more frequently in EEC patients compared with NEEC and controls. Combined presence was associated with higher serum sex steroid levels and increased tumor expression of estrogen and progesterone receptor. A cutoff value for Leydig cell hyperplasia could be proposed at a total of 300 Leydig cells bilaterally, examining a representative cross section of both hili. Concluding, we have quantified hilar Leydig cells and demonstrated that Leydig cells may contribute to the development of EEC by increased androgen production in postmenopausal women. The correlation between sex hormone levels and Leydig cell hyperplasia may support endometrial pathology screening in these women.

Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients.

There is currently no blood-based marker in routine use for endometrial cancer patients. Such a marker could potentially be used for early detection, but it could also help to track tumor recurrence following hysterectomy. This is important, as extra-vaginal recurrence of endometrial endometrioid adenocarcinoma is usually incurable. This proof-of-principle study was designed to determine if tumor-associated mutations could be detected in cell-free DNA from the peripheral blood of early and late stage endometrial endometrioid carcinoma patients. Approximately 90% of endometrioid carcinomas have at least one mutation in the genes CTNNB1, KRAS, PTEN, or PIK3CA. Using a custom panel targeting 30 hotspot amplicons in these four genes, next-generation sequencing was performed on cell-free DNA extracted from plasma obtained from a peripheral blood draw at the time of hysterectomy and the matching tumor DNA from 48 patients with endometrioid endometrial carcinomas. At least one mutation in the tumor was detected in 45/48 (94%) of patients. Fifteen of 45 patients (33%) had a mutation in the plasma that matched a mutation in the tumor. These same mutations were not detected in the matched negative control buffy coat. Presence of a plasma mutation was significantly associated with advanced stage at hysterectomy, deep myometrial invasion, lymphatic/vascular invasion, and primary tumor size. Detecting a plasma-based mutation was independent of the amount of cell-free DNA isolated from the plasma. Overall, 18% of early stage patients had a mutation detected in the plasma. These results demonstrate that mutations in genes relevant to endometrial cancer can be identified in the peripheral blood of patients at the time of surgery. Future studies can help to determine the post-operative time course of mutation clearance from the peripheral blood and if mutation re-emergence is predictive of recurrence.