Weibull parametric model for survival analysis in women with endometrial cancer using clinical and T2-weighted MRI radiomic features.

BACKGROUND: Semiparametric survival analysis such as the Cox proportional hazards (CPH) regression model is commonly employed in endometrial cancer (EC) study. Although this method does not need to know the baseline hazard function, it cannot estimate event time ratio (ETR) which measures relative increase or decrease in survival time. To estimate ETR, the Weibull parametric model needs to be applied. The objective of this study is to develop and evaluate the Weibull parametric model for EC patients' survival analysis. METHODS: Training (n = 411) and testing (n = 80) datasets from EC patients were retrospectively collected to investigate this problem. To determine the optimal CPH model from the training dataset, a bi-level model selection with minimax concave penalty was applied to select clinical and radiomic features which were obtained from T2-weighted MRI images. After the CPH model was built, model diagnostic was carried out to evaluate the proportional hazard assumption with Schoenfeld test. Survival data were fitted into a Weibull model and hazard ratio (HR) and ETR were calculated from the model. Brier score and time-dependent area under the receiver operating characteristic curve (AUC) were compared between CPH and Weibull models. Goodness of the fit was measured with Kolmogorov-Smirnov (KS) statistic. RESULTS: Although the proportional hazard assumption holds for fitting EC survival data, the linearity of the model assumption is suspicious as there are trends in the age and cancer grade predictors. The result also showed that there was a significant relation between the EC survival data and the Weibull distribution. Finally, it showed that Weibull model has a larger AUC value than CPH model in general, and it also has smaller Brier score value for EC survival prediction using both training and testing datasets, suggesting that it is more accurate to use the Weibull model for EC survival analysis. CONCLUSIONS: The Weibull parametric model for EC survival analysis allows simultaneous characterization of the treatment effect in terms of the hazard ratio and the event time ratio (ETR), which is likely to be better understood. This method can be extended to study progression free survival and disease specific survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT03543215, https://clinicaltrials.gov/ , date of registration: 30th June 2017.

Upregulation of ESPL1 is associated with poor prognostic outcomes in endometrial cancer.

BACKGROUND: Extra spindle pole bodies-like 1 (ESPL1) is known to play a crucial role in the segregation of sister chromatids during mitosis. Overexpression of ESPL1 is considered to have oncogenic effects in various human cancers. However, the specific biological function of ESPL1 in endometrial cancer (EC) remains unclear. METHODS: The TCGA and GEO databases were utilized to assess the expression of ESPL1 in EC. Immunohistochemistry was utilized to detect separase expression in EC samples. Kaplan-Meier survival analysis and Cox regression analysis were performed to evaluate the diagnostic and prognostic significance of ESPL1 in EC. Gene Set Enrichment Analysis (GSEA) was employed to explore the potential signaling pathway of ESPL1 in EC. Cell proliferation and colony formation ability were analyzed using CCK-8 and colony formation assay. RESULTS: Our analysis revealed that ESPL1 is significantly upregulated in EC, and its overexpression is associated with advanced clinical characteristics and unfavourable prognostic outcomes. Suppression of ESPL1 attenuated proliferation of EC cell line. CONCLUSION: The upregulation of ESPL1 is associated with advanced disease and poor prognosis in EC patients. These findings suggest that ESPL1 has the potential to serve as a diagnostic and prognostic biomarker in EC, highlighting its significance in the management of EC patients.

The expression of ESPL1 was higher in EC tissue than normal endometrial tissue.ESPL1 could be a potential prognostic marker for EC.

Risk assessment of extra-uterine involvement and prognosis in young type I endometrial carcinoma with high or moderate differentiation and less than 1/2 myometrial invasion.

PURPOSE: The aim of this study was to investigate whether young patients with endometrial carcinoma can preserve adnexa and lymph nodes to improve their quality of life without compromising their prognosis. METHODS: A total of 319 patients with type I endometrial carcinoma (high or moderate differentiation and less than 1/2 myometrial invasion) hospitalized in the First Affiliated Hospital of Zhengzhou University from May 2012 to July 2021 were included. The patients were divided into four groups: high differentiation without myometrial invasion group (G1MI-), high differentiation with superficial myometrial invasion group (G1MI+), moderate differentiation without myometrial invasion group (G2MI-), and moderate differentiation with superficial myometrial invasion group (G2MI+). Logistic regression analysis was conducted to identify risk factors for extra-uterine involvement. Kaplan-Meier method was used to draw the survival curve to compare the prognosis in subgroups and rates of extra-uterine involvement were also compared using Chi-square test or Fisher's exact test. RESULTS: Multivariable logistic regression revealed that differentiation (HR = 14.590, 95%CI = 1.778-119.754, p = 0.013) and myometrial invasion (HR = 10.732, 95%CI = 0.912-92.780, p = 0.037) were the independent risk factors for extra-uterine involvement. The overall difference was statistically significant (p < 0.001). In the subgroups analysis, both adnexal metastasis and lymph node metastasis were statistically significant in the G2MI+ group compared with G1MI- (p = 0.007, p = 0.008). There were no significant differences in the overall survival (OS) rate and progression free survival (PFS) rate among the four subgroups (p > 0.05). CONCLUSIONS: Surgery with adnexal preservation and without systematic lymphadenectomy could be employed for the patients who are high differentiation with less than 1/2 myometrial invasion or moderate differentiation without myometrial invasion, but not recommended to the patients with moderate differentiation and superficial myometrial invasion.

Whether surgical procedure can improve the prognosis of endometrial cancer arising in adenomyosis (EC-AIA)? A systematic review and meta-analysis.

PURPOSE: Endometrial cancer arising in adenomyosis (EC-AIA) is frequently detected accidentally following a general hysterectomy for adenomyosis. Whether supplemental lymphadenectomy in patients with EC-AIA can improve the survival outcome remains inconclusive. Herein, the authors summarized the data of patients with EC-AIA and further explored the impact of lymphadenectomy on the prognosis of these patients. METHODS: Five electronic databases, namely MEDLINE, Web of Science, PubMed, Embase, and the Cochrane Library were employed for searching articles from inception to May 2023. RESULTS: In total, 38 eligible studies enrolling 56 patients were included. Of these, 44 patients had a traceable prognosis. Kaplan-Meier curves demonstrated that patients who had undergone lymphadenectomy had a better progression-free survival (PFS) compared with those who had not undergone lymphadenectomy ( P =0.016), but there was no difference in overall survival. Univariable ( P =0.025, HR=0.25, 95% CI=0.08-0.84) and multivariable ( P =0.042, HR=0.13, 95% CI=0.020-0.930) Cox regression analyses revealed that lymphadenectomy was an independent protective factor for PFS. CONCLUSION: For patients diagnosed with EC-AIA following hysterectomy for benign disease, further supplementary lymphadenectomy is recommended to improve PFS.

Trends in endometrial carcinoma: experience of a single institute for four decades.

OBJECTIVE: To determine the current prognosis of endometrial carcinoma in Japan by analyzing long-term trends in endometrial carcinoma at our hospital. METHODS: We divided 1463 patients with endometrial carcinoma who visited our hospital between 1984 and 2022 into group 1984-1991, group 1992-1999, group 2000-2006, group 2007-2014 and group 2015-2022. Trends were determined using the Jonckheere-Terpstra and Cochran-Armitage tests. Data were analyzed using Cox regression analysis. RESULTS: When group 2015-2022 was used as a reference in the univariate analysis, the hazard ratios for the other groups were <1. In particular, the hazard ratio for group 2007-2014 was 0.65 (95% confidence interval, 0.47-0.90, P = 0.009), suggesting that the prognosis of group 2015-2022 was worse than that of group 2007-2014 and seemed to be the worst among all prognoses. In multivariate analysis, the hazard ratios for each group were 1.38, 1.42, 1.88, 1.16 and 1, respectively; the group with the worst prognosis changed from group 2015-2022 to group 2000-2006 (hazard ratio, 1.88; 95% confidence interval, 1.27-2.78, P = 0.001). Age and the rate of non-endometrioid carcinoma exhibited significantly increasing trends (P < 0.001 and P < 0.001, respectively), as did the rates of serous and mixed carcinomas (P = 0.001 and 0.024, respectively). The rates of non-endometrioid carcinoma, serous carcinoma and mixed carcinoma were 19.0%, 5.5% and 3.1% in group 2007-2014 and 28.2%, 10.8% and 4.6% in group 2015-2022, respectively. CONCLUSIONS: The increasing rates of non-endometrioid carcinoma-especially serous and mixed carcinoma-may be associated with the worsening prognosis of endometrial carcinoma at our institution. Careful monitoring is needed to confirm whether this phenomenon is observed throughout Japan.

Prognosis of uterine and extrauterine low-grade endometrial stromal sarcoma: an observational cohort study.

OBJECTIVE: Little is known about the survival differences between uterine and extrauterine low-grade endometrial stromal sarcoma (LGESS). Survival outcomes, consisting of disease-free survivals and overall survivals (OS), were compared in these two entities. METHODS: From February 2012 to June 2019, all primary LGESS cases and LGESS cases with first recurrence in the study center were reviewed. The clinicopathological characteristics and survival outcomes of extrauterine and uterine LGESS patients were compared for both primary and recurrent diseases. RESULTS: During the study period, 143 patients with primary LGESS and 56 patients with recurrent LGESS were included and followed up to 1 June 2020, among whom 8 (5.6%) and 10 (17.8%) patients were identified as having extrauterine LGESS. Patients with primary and recurrent extrauterine LGESS had similar clinicopathological characteristics to those of patients with uterine LGESS. In primary or in recurrent LGESS cases, in univariate analysis, patients with uterine and extrauterine LGESS had similar disease-free intervals after the last treatment, and they also had similar OSs after the diagnosis. Ovarian preservation led to significantly increased recurrence for primary LGESS [hazard ratio (HR) 4.9, 95% CI: 2.3-10.1, P <0.001) and repeated recurrence for recurrent LGESS (HR 3.1, 95% CI: 1.3-7.3, P =0.009). Surgical treatment for recurrent LGESS decreased repeated recurrence after the first recurrence (HR 0.2, 95% CI: 0.1-0.7, P =0.006). No factors were found to be associated with the OS of primary or recurrent LGESS. CONCLUSION: The clinical characteristics and survival outcomes of extrauterine LGESS are similar to those of uterine LGESS. Surgery is the treatment of choice for recurrent LGESS. Ovarian preservation is detrimental to disease-free survival but not to OS in both uterine and extrauterine LGESS.

Effect of time interval between surgery and the initiation of adjuvant therapy on the oncologic outcomes of early-stage endometrial cancer.

OBJECTIVE: To identify the impact of time interval between surgery and initial adjuvant radiotherapy on oncologic outcomes in early-stage endometrial cancer. METHODS: This retrospective cohort study included patients with stage I/II endometrial cancer who underwent surgical staging and adjuvant therapy at Songklanagarind Hospital from January 1, 2007, to December 31, 2017. Patients were categorized into two groups: TI <6 weeks and TI ≥6 weeks. The effects of TI and clinicopathological factors on recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox proportional-hazards regression. RESULTS: In total, 177 patients were enrolled, with 52% receiving adjuvant radiotherapy at <6 weeks (overall median TI 5.7 weeks). The recurrence and death rates were 13% and 10.2%, respectively. The median follow-up time was 46.6 months. The overall 3-year RFS and OS rates were 88.2% and 85.2%, respectively. The TI significantly affected the 3-year RFS (94.4% vs 81.2%; P = 0.008) and 3-year OS (95.5% vs 83.2%; P = 0.012) in patients with TI <6 and ≥6 weeks, respectively. In multivariate analysis, the depth of myometrial invasion (MI), presence of lymphovascular space invasion, and TI were independent prognostic factors for both RFS and OS. Delaying the TI (≥6 weeks) was significantly associated with a worse RFS (hazard ratio [HR] 3.70; 95% confidence interval [CI]: 1.34-10.22; P = 0.012) and an inferior OS (HR 3.80; 95% CI: 1.23-11.69; P = 0.02). CONCLUSION: A delay in the TI between surgery and the initiation of adjuvant radiotherapy of ≥6 weeks negatively affected the oncologic outcomes in early-stage endometrial cancer.

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.

Intra-racial disaggregation reveals associations between nativity and overall survival in women with endometrial cancer.

OBJECTIVE: Prior studies have demonstrated survival differences between Black women with endometrial cancer (EC) born in the US and Caribbean. Our objective was to determine if country of birth influences EC overall survival (OS) in disaggregated subpopulations of Black women. METHODS: Using the Florida Cancer Data System, women with EC diagnosed from 1981 to 2017 were identified. Demographic and clinical information were abstracted. Women who self-identified as Black and born in the US (USB), Jamaica (JBB), or Haiti (HBB) were included. Statistical analyses were performed using chi-square, Cox proportional hazards models, and Kaplan-Meier methods with significance set at p < 0.05. RESULTS: 3817 women met the inclusion criteria. Compared to USB, JBB and HBB had more high-grade histologies, more advanced stage disease, had a greater proportion of uninsured or Medicaid insured, and had a higher proportion of women who received chemotherapy (all p < 0.05). In multivariate analyses, age (HR 1.03 [1.02-1.05]), regional stage (HR 1.52 [1.22-1.89]), distant stage (HR 3.73 [2.84-4.89]), lymphovascular space invasion (HR 1.96 [1.61-2.39]), receipt of surgery (HR 0.47 [0.29-0.75]), and receipt of chemotherapy (HR 0.77 [0.62-0.95]) were independently associated with OS. Compared to USB, Haitian nativity was an independent negative predictor of OS when evaluating all histologies together (HR 1.54 [1.18-2.00]) and for endometrioid EC specifically (HR 1.77 [1.10-2.83]). Among women with serous EC, HBB had markedly worse median OS (18.5 months [13.4-46.5]) relative to USB (29.9 months [26.3-35.9]) and JBB (41.0 months, [34.1-82.6], p = 0.013). CONCLUSION: Country of birth is associated with endometrial cancer survival in Black women, with HBB demonstrating worse outcomes.

The association of black race with receipt of hysterectomy and survival in low-risk endometrial cancer.

OBJECTIVE: To determine whether Black race is associated with treatment and survival among women with low-risk endometrial cancer. METHODS: Black and White women with Stage IA grade 1-2 endometrioid endometrial carcinoma diagnosed from 2010 to 2016 in the SEER 18 dataset were identified (n = 23,431), and clinical and socioeconomic attributes obtained. Five-year cancer-specific survival (CSS) and relative survival (RS) were calculated using SEER*Stat 8.3.9. Cox proportional hazards model was used to determine predictors of overall survival (OS) and CSS. RESULTS: There was a significantly higher proportion of Black women who did not have surgery compared to White women (3% vs 1%, respectively; p < 0.0001). Residing in the South, being insured with Medicaid, and residing in a county with low median income were also associated with non-receipt of surgery. Black women remained less likely to undergo hysterectomy on multivariable analysis (OR 0.44, 95% CI 0.32-0.60). Non-receipt of hysterectomy was predictive of decreased CSS (HR 0.14, 95% CI 0.09-0.21) and OS (HR 0.18, 95% 0.14-0.23) on adjusted analysis. Black race was also an independent predictor of increased cancer-specific death (HR 2.07, 95% CI 1.50-2.86) as well as death from any cause (HR 1.74, 95% CI 1.44-2.09) on adjusted analysis. CONCLUSIONS: Black women with low-risk endometrial cancer were less likely to undergo hysterectomy and experienced decreased survival relative to White women. Further investigation is warranted to better understand the socioeconomic, geographic, and biologic factors that influence this disparity.

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

A nomogram for predicting overall survival in patients with type II endometrial carcinoma: a retrospective analysis and multicenter validation study.

OBJECTIVE: Type II endometrial cancer (EC) is associated with high risk of metastasis and poor prognosis. We aimed to develop a nomogram for predicting survival probability in patients with type II EC. PATIENTS AND METHODS: Data from a total of 4,117 patients with confirmed type II EC were pulled from the Surveillance, Epidemiology, and End Results (SEER) database, and were randomly divided into a training set and an internal verification set. A nomogram was constructed based on the training set. The concordance index (C-index), area under the ROC curve, and calibration plots were used to evaluate the identification and calibration of the nomogram. The SEER internal validation set and the Chinese multicenter data set (74 patients) were used to verify discriminations and corrections of the model. RESULTS: Multivariate analysis indicated that age, marital status, tumor size, T stage, N stage, M stage, surgery, radiotherapy, and chemotherapy were independent factors affecting the prognosis of type II EC patients (p<0.001). The corresponding nomogram has showed excellent calibration and discrimination (C-index [95% CI], 0.752 [0.738-0.766]). The model was verified in the internal verification set (0.760 [0.739-0.781]) and the Chinese multicenter set (0.784 [0.607-0.961]). In addition, the AUC further confirmed the accuracy of the nomogram in predicting survival. The calibration curve of OS within 5 years confirmed good calibration of the nomogram. CONCLUSIONS: This model and the corresponding risk classification system may provide useful tools for clinicians to evaluate the long-term prognosis of patients and carry out personalized clinical evaluation.

Impact of pre-treatment prognostic nutritional index and the haemoglobin, albumin, lymphocyte and platelet (HALP) score on endometrial cancer survival: A prospective database analysis.

PURPOSE: The Onodera's prognostic nutritional index (PNI) and the haemoglobin, albumin, lymphocyte and platelet (HALP) score are immune-nutritional indices that correlate with survival outcomes in several adult solid malignancies. The aim of this study was to investigate whether PNI and HALP are associated with survival outcomes in endometrial cancer. PATIENTS AND METHODS: Women undergoing management for endometrial cancer were recruited to a single centre prospective cohort study. Pre-treatment PNI and HALP scores were computed for study participants and analysed as continuous variables and by selecting cut-off values based on previous publications. Both parameters were analysed in relation to overall, endometrial cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox proportional regression. RESULTS: A total of 439 women, with a median age of 67 years (interquartile range (IQR), 58, 74) and BMI of 31kg/m2 (IQR 26, 37) were included in the analysis. Most had low-grade (63.3%), early-stage (84.4% stage I/II) endometrial cancer of endometrioid histological subtype (72.7%). Primary treatment was surgery in 98.2% of cases. Adjusted overall mortality hazard ratios for PNI and HALP as continuous variables were 0.97(95%CI 0.94-1.00, p = 0.136) and 0.99(95%CI 0.98-1.01, p = 0.368), respectively. Women with pre-treatment PNI ≥45 had a 45% decrease in both overall (adjusted HR = 0.55, 95% CI 0.33-0.92, p = 0.022) and cancer-specific mortality risk (adjusted HR = 0.55, 95%CI 0.30-0.99, p = 0.048) compared to those with PNI <45. There was no evidence for an effect of PNI on recurrence free survival. HALP scores were associated with adverse clinico-pathologic factors, but not overall, cancer-specific or recurrence-free survival in the multivariable analysis. CONCLUSION: PNI is an independent prognostic factor in endometrial cancer and has the potential to refine pre-operative risk assessment.

Conditional estimates for uterine serous cancer: Tools for survivorship counseling and planning.

OBJECTIVES: Develop conditional survival and risk-assessment estimates for uterine serous carcinoma (USC) overall and stratified by stage as tools for annual survivorship counseling and care planning. METHODS: Patients in the National Cancer Data Base diagnosed between 2004 and 2014 with stage I-IV USC were eligible. Individuals missing stage or survival data or with multiple malignancies were excluded. Five-year conditional survival was estimated using the stage-stratified Kaplan-Meier method annually during follow-up. A standardized mortality ratio (SMR) estimated the proportion of observed to expected deaths in the U.S. adjusted for year, age, and race. The relationships between prognostic factors and survival were studied using multivariate Cox modeling at diagnosis and conditioned on surviving 5-years. RESULTS: There were 14,575 participants, including 43% with stage I, 8% with stage II, 29% with stage III, and 20% with stage IV USC. Five-year survival at diagnosis vs. after surviving 5-years was 52% vs. 75% overall, 77% vs. 81% for stage I, 57% vs. 72% for stage II, 40% vs. 66% for stage III, and 17% vs. 60% for stage IV USC, respectively (P < 0.0001). Incremental improvements in 5-year conditional survival and reductions in SMR tracked with annual follow-up and higher stage. The adjusted risk of death at diagnosis vs. after surviving 5-years was 1.15 vs. 1.40 per 5-year increase of age, 1.26 vs. 1.68 for Medicaid insurance, 3.92 vs. 2.48 for stage III disease, and 6.65 vs. 2.79 for stage IV disease, respectively (P < 0.0001). CONCLUSION: In USC, the evolution of conditional survival permits annual reassessments of prognosis to tailor survivorship counseling and care planning.

Significance of a PTEN Mutational Status-Associated Gene Signature in the Progression and Prognosis of Endometrial Carcinoma.

BACKGROUND: PTEN mutations have been reported to be involved in the development and prognosis of endometrial carcinoma (EC). However, a prognostic gene signature associated with PTEN mutational status has not yet been developed. In this study, we generated a PTEN mutation-associated prognostic gene signature for EC. METHODS: We obtained the single-nucleotide variation and transcriptomic profiling data from The Cancer Genome Atlas database as training data and implemented the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm to establish a PTEN mutation-associated prognostic gene signature. The overall survival rates of the high-risk and low-risk groups were determined with the Kaplan-Meier (K-M) method, and the accuracy of risk score prediction was tested by using the receiver operating characteristic (ROC) curve. RESULTS: The K-M curves revealed that the EC patients with PTEN mutations augured favorable survival outcomes. Differential expression analysis between the EC patients with PTEN mutation and wild-type PTEN identified 224 differentially expressed genes (DEGs). Eighty-four DEGs that manifested prognostic value were fitted into the LASSO-Cox analysis, and a PTEN gene signature with seven mutation-associated prognostic genes that showed robust prognostic ability was constructed; this signature was then successfully validated in the other two datasets from the cBioPortal database as well as with 60 clinical specimens. Furthermore, the PTEN mutation-associated prognostic gene signature proved to be an independent prognostic predictor of EC. Remarkably, the EC patients in the high-risk group were characterized by higher tumor stages and grades as well as lower tumor mutation burden with respect to EC, with a poor survival outcome. Collectively, the PTEN mutation-associated prognostic gene signature that we developed could now be used as a favorable prognostic biomarker for EC. CONCLUSION: In summary, we developed and validated a prognostic predictor for EC associated with PTEN mutational status that may be used as a favorable prognostic biomarker and therapeutic target for EC.

Overview of adjuvant radiotherapy on survival, failure pattern and toxicity in stage I to II endometrial carcinoma: a long-term multi-institutional analysis in China.

BACKGROUND: This research aimed to provide an overview of the impact of adjuvant vaginal brachytherapy (VBT) and external beam pelvic radiotherapy (EBRT) with or without VBT on survival in stage I to II EC patients in China from a long-term multi-institutional analysis. METHODS: We retrospectively analyzed stage I to II EC patients from 13 institutions treated between 2003 and 2015. All patients underwent surgical staging and received adjuvant RT. Patients were divided into groups of low-risk (LR), intermediate-risk (IR), high-intermediate-risk (HIR) and high-risk (HR). Survival statistics, failure pattern, and toxicity of different radiation modalities in different risk groups were analyzed. RESULTS: A total of 1048 patients were included. HR disease represented 27.6%, HIR 17.7%, IR 27.7% and LR 27.1%, respectively. Endometrioid adenocarcinoma (EAC) and non-endometrioid carcinoma (NEC) accounted for 92.8 and 7.2%. A total of 474 patients received VBT alone and 574 patients received EBRT with or without VBT. As for EAC patients, the 5-year overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rate was: 94.6, 90.4, 93.0 and 91.6%, respectively. For LR patients, EBRT (with or without VBT) seemed to be a risk factor. With the higher risk category, the survival benefit of EBRT gradually became remarkable. EBRT (with or without VBT) significantly increased DFS, LRFS and DMFS compared to VBT alone in the HR group (p < 0.05). Distant metastasis was the main failure pattern for all risk groups. As for NEC patients, the 5-year OS, DFS, LRFS and DMFS rate was: 93.4, 87.2, 91.7 and 89.3%, respectively. As for toxicity, EBRT (with or without VBT) significantly increased the incidence of grade 1-2 gastrointestinal, urinary, and hematological toxicity. CONCLUSIONS: For stage I to II EC patients, EAC accounted for the majority and had better prognosis than NEC. For EAC patients, VBT alone resulted in comparable survival to EBRT in the LR, IR and HIR groups, while EBRT significantly increased survival in the HR group. EBRT had higher rate of toxicity than VBT.

Diagnostic and prognostic value of genomic instability-derived long non-coding RNA signature of endometrial cancer.

OBJECTIVE: To investigate whether genomic instability (GI)-derived long non-coding RNAs (lncRNAs) have a prognostic impact on the patients with endometrial cancer. MATERIAL AND METHODS: Patients with Uterine Corpus Endometrial Carcinoma (UCEC) were selected from The Cancer Genome Atlas (TCGA) database. Systematic bioinformatics analyses were performed, including Pearson correlations, GO and KEGG enrichment analysis, bivariate and multiple logistic regression analysis, and Kaplan-Meier (KM) method. RESULTS: A total of 552 UCEC samples were included in the study. The differentially expressed lncRNAs (DELs) were identified, including 79 down-regulated lncRNAs and 31 up-regulated lncRNAs. Bivariate logistic regression analysis showed that 19 GI-derived lncRNAs were prognostic factors. By further multivariate logistic regression analysis, AC005256.1 (estimated coefficient = -0.474), AC026336.3 (estimated coefficient = -0.030), AL161618.1 (estimated coefficient = -1.661), and BX322234.1 (estimated coefficient = 1.511) were used to construct a prognostic risk model. In the train set and test set, the risk model was shown to have both a high prognostic and a diagnostic value. CONCLUSION: We developed a novel GI-derived 4-lncRNA signature for the diagnosis and prognosis of patients with endometrial cancer. These findings offered a novel perspective in the clinical management of endometrial cancer.

The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis.

BACKGROUND: Endometrial carcinoma (EC) is classified into four distinct molecular subgroups. Patients with polymerase epsilon exonuclease domain mutated (POLE-EDM) tumors have the best prognosis of all. This meta-analysis consolidated the clinicopathology variations reported in the POLE-mutant subtype and survival parameters in patients with EC. METHODS: The following internet data bases were searched: PubMed, Web of science, Embase and Scimage directory. Data was extracted from eligible studies including sample size, number of positive POLE-mutant cases, EDM sequencing information, clinicopathologic, and survival data. Meta-analysis and a random-effects model produced pooled estimates of POLE prognostic parameters using 95% confidence intervals (CI), hazard ratios (HR), and odds ratios (OR). RESULTS: The meta-analysis included 11 cohort studies comprising 5508 EC patients (442 POLE EDM tumors). Patients with POLE mutant EC were associated with improved disease specific survival (HR = 0.408, 95% CI: 0.306 to 0.543) and progression-free survival (HR = 0.231, 95% CI: 0.117 to 0.456). POLE-mutated tumors were mostly endometrioid histology (84.480%; 95% CI: 77.237 to 90.548), although not significantly more than wild type tumors (OR = 1.386; p = 0.073). The POLE mutant tumors significantly present (p<0.001) at Federation of International of Gynecologists and Obstetricians (FIGO) lower stages I-II (OR = 2.955, p<0.001) and highest grade III (OR = 1.717, P = 0.003). The tumors are significantly associated with invasion less than half (<50%) of the myometrium (OR = 1.765, p = 0.001), but not deeply invasive EC (MI>50%, OR = 0.83, p = 0.34). POLE mutations significantly protected against lymph node metastases (OR = 0.202, p = 0.001), and have no clear association with lymph-vascular space invasion (OR = 0.967, 95% 0.713-1.310, p = 0.826). The tumors are predominantly of low ESMO risk stratification distribution (40.356%; 95% CI: 27.577 to 53.838). CONCLUSIONS: POLE mutations serve as an important biomarker of favorable prognosis in EC. The tumors are characteristically high grade, early stage, and remain localized in the endometrium with reduced likelihood of lymph node metastasis for improved survival prospects and the lowest risk classification. These findings have implications for medical management of EC.