Endometrial Carcinoma Patients Research Articles

L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile

BackgroundThe newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.MethodsProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.ResultsExpression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035).ConclusionL1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.

Correlation of MACC1/c-Myc Expression in Endometrial Carcinoma with Clinical/Pathological Features or Prognosis.

BackgroundEndometrial carcinoma (EC) is a type of female reproductive malignant tumor, the incidence of which is generally 20~30%. Multiple factors and genes are involved in the regulation of EC occurrence and progression. This study aimed to measure the expressions of MACC1 and c-Myc in EC patients to analyze their correlation with pathological features of EC.Material/MethodsA total of 60 EC patients were recruited in the experimental group, while another cohort of 30 people with endometrial inflammatory hyperplasia was enrolled in the control group. The levels of serum MACC1 and c-Myc were measured by ELISA, and the protein expressions in EC cancer tissues, tumor-adjacent tissues, and controlled endometrial tissues were detected by immunohistochemistry (IHC). The correlation between gene expression and clinical/pathological features was then determined.ResultsOur data indicate that the level of serum MACC1 and c-Myc in the experimental group was 1.67±0.08 ng/ml and 1.78±0.07 ng/ml, respectively, both of which were significantly higher than that of the control group (p<0.05). However, no significant difference was found among levels of serum MACC1 or c-Myc at different TNM stages (p>0.05). In cancer tissues, the positive rate of MACC1 or c-Myc was 73.3% and 78.3%, respectively, which were significantly higher than that in adjacent or control tissues (p<0.05). MACC1/c-Myc expression was correlated with TNM stage, primary infiltration grade, lymph node metastasis, and distal metastasis (p<0.05).ConclusionsMACC1 and c-Myc are highly expressed in serum and tumor tissues of EC patients. Both are correlated with TNM stage, primary infiltration, and lymph node or distal metastasis, which provides a scientific basis for the development of new biomarkers for the diagnosis of endometrial carcinoma.

The ability of ADC measurements in the assessment of patients with stage I endometrial carcinoma based on three risk categories.

Better selection of patients with intermediate and high-risk stage I endometrial carcinoma (EC) for lymphadenectomy has an important effect on the prognosis. To investigate the role of apparent diffusion coefficient (ADC) measurements in the assessment of stage I EC patients based on three risk categories. We retrospectively studied 80 patients with EC and 28 cervical cancer patients with normal endometrium. 1.5-T conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) (b = 0, 1000 s/mm2) were performed, and ADC values were calculated. Sixty-eight stage I EC patients were divided into three groups: low-risk EC (group 1); intermediate-risk EC (group 2); and high-risk EC (group 3). The remaining 12 EC patients were in stages II and III. Intraclass coefficient, Mann-Whitney U test, Kruskal-Wallis test, and receiver operating characteristics were used for statistical analysis. The mean ADC values ( × 10-3 mm2 /s) were 0.851 ± 0.131, 0.734 ± 0.108, and 0.710 ± 0.108 for groups 1, 2 and 3, respectively. Significant statistical differences were achieved for the three groups ( P = 0.0005). The mean ADC values of group 1 were significantly lower than those in group 2 + 3 (0.725 ± 0.106; P = 0.0001). For the prediction of groups 2 + 3, the area under the curve of 0.786 and the cut-off value of ≤ 0.742 were identified, with a sensitivity, specificity, and accuracy of 66.67%, 84.09%, and 73.53%, respectively. ADC measurements may have the potential to select intermediate-risk and high-risk stage I EC patients for lymphadenectomy.

Establishment of a nine-gene prognostic model for predicting overall survival of patients with endometrial carcinoma.

Endometrial carcinoma (EC) is the most common malignant tumor of the female genital tract in developed countries. The prognosis of early stage EC is favorable, but a subset faces high risk of cancer progression or recurrence. EC has a poor prognosis upon progression to advanced or metastatic stages. Therefore, our goal is to build a robust prognostic model for predicting overall survival (OS) in EC patients. In this study, 1571 genes were identified as being associated with OS based on genomewide expression profiles using a training dataset. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that these genes were involved in various cancer‐related signaling pathways. Nine signature genes were further selected using stepwise selection, and their potential role in the development of EC was demonstrated by performing differential expression analysis between EC and normal uterine tissues. A prognostic model that aggregated these nine signature genes was ultimately established and effectively divided EC patients into two risk groups. OS for patients in the high‐risk group was significantly poorer compared with that of the low‐risk group. This nine‐gene model was subsequently validated and evaluated using the TCGA dataset and shown to have a high discriminating power to distinguish EC patients with an elevated risk of mortality based on the FIGO staging system and other prognostic factors. This study provides a novel prognostic model for the identification of EC patients with elevated risk of mortality and will help to improve our understanding of the underlying mechanisms involved in prognostic EC factors.

The PTENP1 Pseudogene, Unlike the PTEN Gene, Is Methylated in Normal Endometrium, As Well As in Endometrial Hyperplasias and Carcinomas in Middle-Aged and Elderly Females

The tumor suppressor PTEN controls multiple cellular functions, including cell cycle, apoptosis, senescence, transcription, and mRNA translation of numerous genes. In tumor cells, PTEN is frequently inactivated by genetic mutations and epimutations. The aim of this study was to investigate the methylation patterns of the PTEN gene and its pseudogene PTENP1 as potential genetic markers of endometrial hyperplasia (EH) and endometrial carcinoma (EC). Methylation of the 5'-terminal regions of the PTEN and PTENP1 sequences was studied using methyl-sensitive PCR of genomic DNA isolated from 57 cancer, 43 endometrial hyperplasia, and normal tissue samples of 24 females aged 17-34 years and 19 females aged 45-65 years, as well as 20 peripheral venous blood samples of EC patients. None of the analyzed DNA samples carried a methylated PTEN gene. On the contrary, the PTENP1 pseudogene was methylated in all analyzed tissues, except for the peripheral blood. Comparison of PTENP1 methylation rates revealed no differences between the EC and EH groups (0.80 < p < 0.50). In all these groups, the methylation level was high (71-77% in patients vs. 58% in controls). Differences in PTENP1 methylation rates between normal endometrium in young (4%) and middle-aged and elderly (58%) females were significant (p < 0.001). These findings suggest that PTENP1 pseudogene methylation may reflect age-related changes in the body and is not directly related to the endometrium pathology under study. It is assumed that, depending on the influence of a methylated PTENP1 pseudogene on PTEN gene expression, the pseudogene methylation may protect against the development of EC and/or serve as a marker of a precancerous condition of endometrial cells.

Type I Versus Type II Endometrial Cancer: Differential Impact of Comorbidity

Two distinct types of endometrial carcinoma (EC) with different etiology, tumor characteristics, and prognosis are recognized. We investigated if the prognostic impact of comorbidity varies between these 2 types of EC. Furthermore, we studied if the recently developed ovarian cancer comorbidity index (OCCI) is useful for prediction of survival in EC. This nationwide register-based cohort study was based on data from 6487 EC patients diagnosed in Denmark between 2005 and 2015. Patients were assigned a comorbidity index score according to the Charlson comorbidity index (CCI) and the OCCI. Kaplan-Meier survival statistics and adjusted multivariate Cox regression analyses were used to investigate the differential association between comorbidity and overall survival in types I and II EC. The distribution of comorbidities varied between the 2 EC types. A consistent association between increasing levels of comorbidity and poorer survival was observed for both types. Cox regression analyses revealed a significant interaction between cancer stage and comorbidity indicating that the impact of comorbidity varied with stage. In contrast, the interaction between comorbidity and EC type was not significant. Both the CCI and the OCCI were useful measurements of comorbidity, but the CCI was the strongest predictor in this patient population. Comorbidity is an important prognostic factor in type I as well as in type II EC although the overall prognosis differs significantly between the 2 types of EC. The prognostic impact of comorbidity varies with stage but not with type of EC.

MELF Pattern for Predicting Lymph Node Involvement and Survival in Grade I-II Endometrioid-type Endometrial Cancer.

The aim of this study was to examine the associations between microcystic, elongated, and fragmented (MELF) pattern and other prognostic factors and lymph node involvement, disease-free survival, and overall survival (OS) using a case-control group consisting of grade I-II endometrioid endometrial carcinoma (EEC) patients with/without lymph node involvement. The files of the patients were searched electronically for all hysterectomy specimens with a diagnosis of grade I-II EEC of the uterine body from January 1, 2008 to July 31, 2014. Lymph node involvement was detected in 27 patients who were histologically diagnosed with grade I-II EEC, and these patients made up the case group. Using a dependent random sampling method, 28 grade I-II EEC patients without lymph node involvement were selected. According to multivariate regression analysis, lymphovascular space invasion [odds ratio, 23.5; 95% confidence interval (CI), 2.4-223.5] and MELF pattern (odds ratio, 13.3; 95% CI, 1.4-121.8) were significant predictors of lymph node involvement. There was recurrence in 15.8% of cases that showed a MELF pattern and in 19.4% of those that did not (P=0.738). According to Kaplan-Meier analysis, the MELF pattern revealed no significant differences in disease-free survival (hazard ratio, 1.0; 95% CI, 0.1-36.5), whereas the effect on OS was significant (hazard ratio, 2.2; 95% CI, 1.3-4.2). The presence of MELF pattern was a substantial risk factor for detecting lymph node involvement in patients with grade I-II EEC. The MELF pattern may be important for identifying which patients need staging surgery, in addition to its effect on the OS.

ABO Blood Group and Endometrial Carcinoma: A Preliminary Single-Center Experience from Saudi Arabia.

Introduction: Inherited ABO blood groups have been shown to play possible contributions in the pathogenesis of various gynecologic and non-gynecologic carcinomas. With regard to gynecologic carcinomas, there is a confined number of studies that explored the relationship between ABO blood group and endometrial carcinoma (EC) in the PubMed-indexed literature. To the best of our knowledge, no such study has ever been conducted in Saudi Arabia.Objectives: Our study has two objectives: (I) to determine the prevalence of ABO blood groups among Saudi patients with EC, and (II) to explore the relationship between ABO blood group and several clinico-pathological prognostic parameters (namely: menopausal status [age], body mass index [BMI], tumor grade, FIGO [Fédération Internationale de Gynécologie et d'Obstétrique] stage and recurrence) in Saudi patients with EC.Materials and Methods: A retrospective cross-sectional study from 01-January-2010 to 31-July-2014 was conducted at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia — a referral tertiary healthcare institute. One-hundred and fourteen patients (n=114) were included in the study. Clinico-pathological data were extrapolated from medical records, and their association with ABO blood groups were evaluated. Categorical data were presented as number of cases (n) and percentages (%). Two-tailed Chi-square test was used for univariate analysis. For all purposes, p values <0.05 were regarded as statistically significant.Results: The mean age and BMI were 59.5 ± 10.8 years (range: 31 – 90) and 36.6 ± 8.6 kg/m2 (range: 17 – 60), respectively. The vast majority of patients were post-menopausal (86%), had BMI >28 kg/m2 (84.2%), diagnosed with early FIGO stage I-II (76.3%) and developed no recurrence (86.8%). The frequencies of ABO blood group types A, B, AB, and O were 28.1%, 12.3%, 3.5% and 56.1%, respectively. When ABO blood groups were analyzed as four different types (A, B, AB and O), O-type was the most common ABO blood group in pre- and post-menopausal EC patients (43.8% and 58.2%, respectively; p=0.14). There were no statistically significant correlations between ABO blood groups and all the examined clinico-pathological factors. Moreover, when ABO blood groups were analyzed as two different types (O and non-O), similar results were obtained; no statistically significant correlations were found between ABO blood groups and all the examined clinico-pathological factors.Conclusions: O-type was the most prevalent ABO blood group among Saudi Arabian patients with EC, and our finding was different from the existing literature, probably highlighting an ethnic-related variance. Furthermore, no statistically significant correlations were identified between ABO blood groups and all the examined clinico-pathological factors. Also, routine ABO blood group may emerge as a clinically accessible, beneficial and economical biomarker for a possible EC vulnerability. A large-sized case-control study is needed to withdraw solid conclusions.

The expression of ER, PR in endometrial cancer and analysis of their correlation with ERK signaling pathway.

Endometrial carcinoma (EC) is a common malignant tumor in gynecology. Its incidence and development are closely associated with the levels of estrogenic and progesterone hormone. Extracellular signal-regulated kinase (ERK) signaling pathway abnormity is associated with a variety of tumors. This study detected estrogen receptor (ER), progesterone receptor (PR), ERK1, and ERK2 expression in EC and analyzed their correlations. A total of 40 EC patients in our hospital were selected as test group, while another 40 healthy volunteers were enrolled as control group. ER, PR, ERK1, and ERK2 expression in EC tissue, para-carcinoma tissue, and normal endometrial tissue were detected by immunohistochemistry and Western blot. The positive rate of ER, PR, ERK1, and ERK2 in the test group was 50%, 40%, 60%, and 65%, respectively, which were significantly higher than those in the control (P< 0.05). ER, PR, ERK1, and ERK2 protein expressions in EC cell were significantly higher than those in the control (P< 0.05). ERK1 and ERK2 presented positive correlation with ER and PR (P< 0.05). In conclusion, EC patients presented higher expressions of ER, PR, which were correlated with higher levels of ERK1 and ERK2, suggesting they might be involved in the pathogenesis of EC.

Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients.

BackgroundProstaglandin E2 (PGE2) receptor 3 (EP3) regulates tumor cell proliferation, migration, and invasion in numerous cancers. The role of EP3 as a prognostic biomarker in endometrial cancer remains unclear. The primary aim of this study was to analyze the prognostic significance of EP3 expression in endometrial cancer.MethodsWe analyzed the EP3 expression of 140 endometrial carcinoma patients by immunohistochemistry. RL95-2 endometrial cancer cell line was chosen from four endometrial cancer cell lines (RL95-2, Ishikawa, HEC-1-A, and HEC-1-B) according to EP3 expression level. Treated with PGE2 and EP3 antagonist, RL95-2 cells were investigated by MTT, BrdU, and wound healing assay for functional assessment of EP3.ResultsEP3 staining differed significantly according to WHO tumor grading in both whole cohort (p = 0.01) and the subgroup of endometrioid carcinoma (p = 0.01). Patients with high EP3 expression in their respective tumors had impaired progression-free survival as well as overall survival in both cohorts above. EP3 expression in the overall cohort was identified as an independent prognostic marker for progression-free survival (HR 1.014, 95%CI 1.003-1.024, p = 0.01) when adjusted for age, stage, grading, and recurrence. Treatment with EP3 antagonists induced upregulation of estrogen receptor β and decreased activity of Ras and led to attenuated proliferation and migration of RL95-2 cells.ConclusionsEP3 seems to play a crucial role in endometrial cancer progression. In the context of limited systemic treatment options for endometrial cancer, this explorative analysis identifies EP3 as a potential target for diagnostic workup and therapy.

PGK1 and GRP78 overexpression correlates with clinical significance and poor prognosis in Chinese endometrial cancer patients.

The aim of this study was to measure the expression patterns of PGK1 and GRP78 in normal endometrial tissues and endometrial carcinoma, and associations between their combined effects and the pathological features of endometrial carcinoma. We used 30 normal endometrial tissue samples and 130 endometrial carcinoma samples, and separately evaluated PGK1 and GRP78 protein expression by immunohistochemistry. Scores ranging from 0 to 9 were obtained by multiplying the percentage of positive cells by the staining intensity (0–3). Immunohistochemical analysis revealed increased PGK1 and GRP78 expression in the cytoplasm of endometrial carcinoma cells compared with that in normal endometrial tissues. High PGK1 expression positively correlated with the FIGO stage (P < 0.001), histological grade (P = 0.002), and lymph node status (P < 0.001). High GRP78 expression positively correlated with the pathological type (P = 0.0125), FIGO stage (P < 0.001), and lymph node status (P < 0.001). In addition, PGK1 overexpression was positively correlated with GRP78 overexpression in endometrial carcinoma patients (P < 0.001), and the concurrent expression of both oncogenes in endometrial carcinoma patients correlated significantly with the lymph node status (P < 0.001) and FIGO stage (P < 0.001). Patients with high PGK1 and GRP78 expression levels had poorer overall survival rates than those with low expression levels of both proteins (P < 0.001). Our results suggested that the co-occurrence of PGK1 and GRP78 expression is potentially an unfavorable factor for endometrial carcinoma progression.

Prognostic roles of L1-cell adhesion molecule up-regulation in association with p53 overexpression and E-cadherin down-regulation in endometrial carcinoma patients

Prognostic roles of L1-cell adhesion molecule up-regulation in association with p53 overexpression and E-cadherin down-regulation in endometrial carcinoma patients

Estrogen and insulin synergistically promote type 1 endometrial cancer progression

ABSTRACTDespite evidence that estrogens and insulin are related to type 1 endometrial carcinoma (EC), their synergistic role has not been analyzed. Here, we investigated how estrogens cooperate with insulin to promote type 1 EC progression. We examined the clinical significance of serum estrogen and insulin levels using type 1 EC patients and control subjects. Univariate and multivariate logistic regression analyses for total, premenopausal, and postmenopausal subjects were performed. Type 1 EC risk was evaluated with respect to estrone, estradiol, and insulin levels based on odds ratios (ORs) using stratified data. Cell growth in vitro and in vivo, effects of insulin and estradiol on apoptosis and cell cycle distribution were measured after estradiol and insulin stimulation. Estrone and insulin concentrations were significantly high in type 1 EC patients and retained positive associations with type 1 EC after adjustment for BMI, WHR, diabetes, and hypertension. The odds ratio was significantly high for type 1 EC patients with higher levels of estrone/estradiol and insulin than for patients with higher levels of either estrone/estradiol or insulin, suggesting that estrogen and insulin play a synergistic role in type 1 EC carcinogenesis and progression. Compared to EC cells and cell-based xenografts treated with estradiol or insulin alone, those treated with estradiol and insulin exhibited stronger stimulation. Estrogen and insulin play synergistic roles in type 1 EC carcinogenesis and progression, extending our understanding of EC risks.

The prognostic significance of preoperative serum cancer antigen 15-3 levels in endometrial carcinomas.

Objectives:To determine the associations between serum cancer antigen 15-3 levels and prognostic factors in patients with endometrial carcinomas. Additionally, we investigated the clinical utility of serum cancer antigen 15-3 levels in the selection of low-risk patients with endometrioid type, tumor size <2 cm, myometrial invasion ≤50%, and histological grade 1-2.Methods:Ninety-six patients, who were surgically staged at Ankara Yildirim Beyazit University, Ankara, Turkey, between 2007 and 2016, were retrospectively analyzed. Demographic, clinical, and surgical characteristics were retrieved from the patients’ hospital records. A p<0.05 was considered significant.Results:Fifteen patients had advanced (≥Stage II) disease, 14 patients had Type 2 histology, 20 patients had Grade 3 tumors, 23 patients had lymphovascular space invasion, and 10 patients had positive lymph node involvement. Serum cancer antigen 15-3 levels were significantly higher in patients with advanced (≥Stage II) disease, Type 2 histology, Grade 3 tumors, lymp°hovascular space invasion, and positive lymph node involvement (p<0.05). Serum cancer antigen 15-3 levels were also significantly correlated with tumor size (p=0.006). Serum cancer antigen 15-3 levels were significantly lower (95% confidence interval: 0.57−0.79; p=0.03) in low-risk patients compared to other endometrial carcinoma patients. A cutoff of 25.0 IU/mL was used to identify high-risk patients with a specificity of 100%.Conclusion:Serum cancer antigen 15-3 levels significantly correlated with prognostic factors and were a useful diagnostic tool for endometrial carcinomas.

Asparaginase-like protein 1 is an independent prognostic marker in primary endometrial cancer, and is frequently lost in metastatic lesions

ObjectiveLoss of Asparaginase-like protein 1 (ASRGL1) has been suggested as a prognostic biomarker in endometrial carcinoma. Our objective was to validate this in a prospectively collected, independent patient cohort, and evaluate ASRGL1 expression in endometrial carcinoma precursor lesion and metastases. Methods782 primary endometrial carcinomas, 90 precursor lesions (complex atypical hyperplasia), and 179 metastases (from 87 patients) were evaluated for ASRGL1 expression by immunohistochemistry in relation to clinical and histopathological data. ASRGL1 mRNA level was investigated in 237 primary tumors and related to survival and ASRGL1 protein expression. ResultsLow expression of ASRGL1 protein and ASRGL1 mRNA predicted poor disease specific survival (P<0.001). In multivariate survival analyses ASRGL1 had independent prognostic value both in the whole patient cohort (Hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.04–2.26, P=0.031) and within the endometrioid subgroup (HR: 2.64, CI: 1.47–4.74, P=0.001). Low ASRGL1 expression was less frequent in patients with low grade endometrioid primary tumors compared to high grade endometrioid and non-endometrioid primary tumors, and ASRGL1 was lost in the majority of metastatic lesions. ConclusionsIn a prospective setting ASRGL1 validates as a strong prognostic biomarker in endometrial carcinoma. Loss of ASRGL1 is associated with aggressive disease and poor survival, and is demonstrated for the first time to have independent prognostic value in the entire endometrial carcinoma patient population.

Study on the relationship between laparoscopic operation and pseudo vascular invasion in stage Ⅰa endometrial carcinoma

Objective: To explore relations between pseudo vascular invasion (PVI) and laparoscopic operation in patients with stage Ⅰa endometrial carcinoma. Methods: Details of stage Ⅰa endometrial carcinoma patients' clinical information and pathological sections who received operation treatment between January 2008 and October 2015 were obtained from the Dalian Maternal and Child Health Hospital. There were 515 cases entrolled into this study, including 332 (64.5%) cases performed surgery by laparoscopy and 183 (35.5%) cases undergone abdominal surgery. The vascular invasion rate and the microscopic manifestations of PVI in two groups were retrospectively compared and analyzed. The follow-up period ended February 2017, the adjuvant treatment and prognosis of patients with lympho-vascular space invasion (LVSI) and PVI were analysed. Results: (1) Seventy-five of 515 cases with stage Ⅰa endometrial carcinoma, there were seven-five cases found with tumor cells in lympho-vascular space, including 52 cases of LVSI and 25 cases of PVI (2 cases of both). The incidence of cancer emboli in lympho-vascular space and LVSI in laparoscopic group and laparotomy group were respectively 15.4% (51/332) vs 13.1% (24/183) and 9.6% (32/332) vs 10.9% (20/183), there were no significant differences (all P>0.05). But the rate of PVI between the two group was significantly different [6.3% (21/332) vs 2.2% (4/183), P=0.036], laparoscopic group was higher than that in laparotomy group. (2) Of 332 cases in laparoscopic group, 21 cases was found PVI, containing 8 cases showed tumor tissue with mesenchyme or papillary structures located in large thick wall vessels of the outer lateral myometrium, 13 cases showed the tumor tissue was away from the vessel wall. Among 183 cases in laparotomy group, 3 cases with PVI which the tumor tissue was away from the vessel wall, and 1 with interstitial tissue. (3) During the follow-up period, 7 of 75 cases (both LVSI and PVI) were lost, and 66 cases were relapse-free survival, 2 cases recurred at fifth months and died respectively at 7, 20 months after the operation. This 2 cases were both PVI of laparoscopic group, and the pathological type was endometrioid adenocarcinoma grade 3, and adjuvant treatment was not accepted after the operation. The relapse-free survival with LVSI was 49 months and 46 months for cases with PVI. Conclusion: s Laparoscopic operation could increase PVI in patients with stage Ⅰa endometrial carcinoma, while does not increase LVSI. It is not yet possible to demonstrate that PVI affects the prognosis of patients.

Extended Duration of Dilator Use Beyond 1 Year May Reduce Vaginal Stenosis After Intravaginal High-Dose-Rate Brachytherapy

Vaginal stenosis (VS) is a late toxicity associated with vaginal or pelvic radiotherapy (RT). Vaginal dilators are recommended after RT to prevent VS though the time course of this toxicity is not fully understood and the optimal duration of dilator use is unknown. We examined rates of VS among women treated with intravaginal brachytherapy (IVBT) for endometrial carcinoma (EC) and evaluated the effect of dilator use duration on VS. We reviewed the records of 243 stage IA-II EC patients who received adjuvant IVBT in a departmental database. The typical high-dose-rate IVBT dose was 18-21 Gy in 3 fractions delivered weekly. Patients were instructed to begin dilator use 2 weeks after the final IVBT fraction, 2-3 times/week, 10 minutes/session, for at least 1 year duration. The primary outcome was development of grade ≥ 1 VS as assessed by physical examination at any follow-up in the radiation oncology clinic (typically 3-6 months after final IVBT fraction and then yearly thereafter) and was graded using CTCAE v4.0. The Kaplan-Meier method was used to estimate VS over time. The log-rank test and multivariable Cox proportional hazards modeling were used to evaluate the effect of dilator use (noncompliance vs. standard compliance [up to 1 year] vs. extended compliance [over 1 year]) on VS. The median follow-up time was 14.8 months (range: 1.9-38.1). The median age was 65 years (range: 43-94) and the majority (70.2%) were not sexually active. At 12 and 24 months, freedom from VS was 71.1% and 53.3%, respectively. Regarding dilator compliance, 98 (40.3%) were noncompliant, 97 (39.9%) had standard compliance, and 48 (19.8%) had extended compliance. Freedom from VS at 12 months was 63.5% for noncompliant patients, 70.2% in those with standard compliance, and 81.2% in those with extended compliance (log-rank, P = 0.04). At 24 months, freedom from VS was 39.8%, 50.2% and 72.1%, respectively. The median time to VS was 17.5 months for noncompliant patients, 27 months for standard compliance, and was not yet reached for extended compliance. On multivariable analysis, after adjusting for other significant variables (gravidity, sexual activity, cylinder size, and vaginal percent length treated), there was a trend towards a difference in grade ≥ 1 VS based on dilator compliance (P = 0.069), with a statistically significant decrease in grade ≥ 1 VS for patients with extended compliance vs. noncompliance (hazard ratio 0.43, 95% confidence interval 0.20 – 0.89, P = 0.024). Among the 74 patients with recorded VS, 62 had grade 1, 11 had grade 2, and 1 had grade 3. Of all grade ≥ 2 VS, 7/12 (58.3%) cases were noted in noncompliant patients. Grade ≥ 2 VS was not observed among those with extended compliance. The risk of VS persists beyond 1 year after IVBT. Extended vaginal dilator compliance beyond 1 year may mitigate this risk. Further studies are needed to determine the optimal frequency and duration of vaginal dilator use, as well as factors affecting compliance.

RERT: A Novel Regression Tree Approach to Predict Extrauterine Disease in Endometrial Carcinoma Patients

Some aspects of endometrial cancer (EC) preoperative work-up are still controversial, and debatable are the roles played by lymphadenectomy and radical surgery. Proper preoperative EC staging can help design a tailored surgical treatment, and this study aims to propose a new algorithm able to predict extrauterine disease diffusion. 293 EC patients were consecutively enrolled, and age, BMI, children’s number, menopausal status, contraception, hormone replacement therapy, hypertension, histological grading, clinical stage, and serum HE4 and CA125 values were preoperatively evaluated. In order to identify before surgery the most important variables able to classify EC patients based on FIGO stage, we adopted a new statistical approach consisting of two-steps: 1) Random Forest with its relative variable importance; 2) a novel algorithm able to select the most representative Regression Tree (RERT) from an ensemble method. RERT, built on the above mentioned variables, provided a sensitivity, specificity, NPV and PPV of 90%, 76%, 94% and 65% respectively, in predicting FIGO stage > I. Notably, RERT outperformed the prediction ability of HE4, CA125, Logistic Regression and single cross-validated Regression Tree. Such algorithm has great potential, since it better identifies the true early-stage patients, thus providing concrete support in the decisional process about therapeutic options to be performed.

Significance of matrix metalloproteinase-1 and -3 gene polymorphisms and their expression in normal and neoplastic endometrium

BackgroundMatrix metalloproteinases (MMPs) play a fundamental role in tissue degradation or remodeling and involved in all stages of tumor progression. However, the role of the MMPs polymorphisms with endometrial carcinoma has not been fully examined in Egyptian patients. Therefore, we planned this study to evaluate associations of the MMP-1 (−1607 1G/2G) and MMP-3 (−1171 5A/6A) polymorphisms and their immune reactive protein combinations with endometrial carcinoma susceptibility and prognosis in Egyptian patients. MethodsParaffin-embedded tissue samples from 40 women with endometrial carcinoma and 30 controls were immunohistochemically stained for MMP-1and MMP-3 expression. Tissue MMPs levels were analyzed by ELISA technique, and tissue samples were genotyped for MMP-1 and MMp-3 gene polymorphisms by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Resultswe recorded a significant increase of MMP-1 levels in endometrial carcinoma patients more than controls, to be more increased with advanced stages and grades of the carcinoma. Whereas, the MMP-3 tissue levels showed non-significant changes among patients and controls and even among different stages and grades of cancer.Patients with endometrial carcinoma exhibited a higher distribution of MMP-11G/2G or 2G/2G genotypes compared with controls. Tumors containing the 2G allele expressed MMP-1 protein more frequently than those of 1G/1G genotype. The overall genotype and alleles distribution of the MMP-3 polymorphism in patients was not different from that of controls. The haplotype 2G-6A was associated with a significantly increased risk of endometrial carcinoma as compared with the 1G-5A haplotype. ConclusionThe MMP-1 (−1G/2G) SNP and MMP 2G/6A haplotype may modify susceptibility and are associated with a higher risk of endometrial carcinoma. Otherwise, the MMP-3 (5A/6A) promoter SNP is unlikely to be associated with endometrial carcinoma in the Egyptian population.

Disseminated tumor cells are not associated with established risk factors, L1CAM immunoreactivity and outcome in endometrial carcinoma.

The presence of disseminated tumor cells (DTC) in the bone marrow of endometrial carcinoma patients has been demonstrated previously. In contrast to breast cancer, no prognostic significance or association with clinicopathological features was revealed for endometrial carcinoma so far. The aim of this study was to investigate DTC in a large patient cohort with in-depth pathology review data available and to study DTC occurrence in the context of L1CAM and long-term disease specific follow-up. Patients treated for endometrial carcinoma at the Tuebingen University Women's hospital between 2003 and 2013 were identified. Cases with previous expert central pathology review including L1CAM immunohistochemistry and bone marrow aspirates available were selected. The presence of DTC and L1CAM expression was studied immunohistochemically. In 395 cases with a confirmed diagnosis of endometrial carcinoma, bone marrow aspirates were available. DTC were detected in 17.2%. The presence of DTC was independent from tumor histology, grade, lymphovascular space involvement (LVSI), FIGO stage, myoinvasion, L1CAM immunoreactivity, and nodal metastasis. DTC occurred less frequently in cases with a microcystic elongated and fragmented (MELF) pattern of invasion (2.2 vs. 21.8%, p=0.0003). Disease progression was distributed equally among patients with and without DTC present. We were able to confirm previous findings of DTC presence in a large well-characterized cohort of endometrial carcinoma patients. DTC are detectable in almost one-fifth of endometrial carcinoma and occur less frequently with a MELF pattern of invasion. Further studies investigating the role of DTC in endometrial carcinoma are warranted.