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Objectives: To compare surgical outcomes of patients with endometrial cancer who underwent robotic surgery across different BMI categories., Methods: A retrospective study including all consecutive patients with endometrial cancer who underwent robotic surgery at a tertiary cancer center between December 2007 and December 2022. The study analyzed outcome measures, including blood loss, surgical times, length of hospitalization, perioperative complications, and conversion rates with the Kruskal-Wallis test for BMI group differences and the Chi-squared test for associations between categorical variables., Results: A total of 1329 patients with endometrial cancer were included in the study. Patients were stratified by BMI: <30.0 (n = 576; 43.3%), 30.0-39.9 (n = 449; 33.8%), and ≥ 40.0 (n = 304; 22.9%). There were no significant differences in post-anesthesia care unit (PACU) stay (p = 0.105) and hospital stay (p = 0.497) between the groups. The rate of post-op complications was similar across the groups, ranging from 8.0% to 9.5% (p = 0.761). The rate of conversion to laparotomy was also similar across the groups, ranging from 0.7% to 1.0% (p = 0.885). Women with a BMI ≥40.0 had a non-clinically relevant but greater median estimated blood loss (30 mL vs. 20 mL; p < 0.001) and longer median operating room (OR) time (288 min vs. 270 min; p < 0.001). Within the OR time, the median set-up time was longer for those with a higher BMI (58 min vs. 50 min; p < 0.001). However, skin-to-skin time (209 min vs. 203 min; p = 0.202) and post-op time (14 min vs. 13 min; p = 0.094) were comparable between groups., Conclusion: BMI does not affect the peri-operative outcome of patients undergoing robotic staging procedures for endometrial cancer., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning., Methods: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python 'sklearn' library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models., Results: Of the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%-88%) and a low sensitivity (23%-51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646., Conclusions: Even using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology., (© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objective: To evaluate the use of manipulators on the outcome of women who had minimally invasive surgery for endometrial cancer. Methods: Retrospective analysis of patients operated with or without an intrauterine manipulator. Results: Six hundred ninety-nine patients were included. The median follow-up was 44 months (range, 29-67). Nineteen (8.8%) patients had positive cytology in the manipulator group versus 21 (4.4%) in the comparison group ( p  = 0.02). Total recurrence rate was similar between the groups (12.3% vs. 11.9%; p  = 0.8). Vaginal vault recurrence was the most common site of recurrence with higher incidence in the manipulator group (4.5% vs. 1.3%; p  = 0.007). Subgroup analysis of low-risk patients who did not receive adjuvant treatment showed higher recurrence rate (8.3% vs. 3%; p  = 0.023) and worse disease-free survival ( p  = 0.01) for the manipulator group. After controlling for other variables, the use of a manipulator did not affect the risk of recurrence for the whole cohort (hazard ratio [HR], 1.28; confidence interval [95% CI], 0.7-2.1, p  = 0.3) and for the low-risk subgroup of patients who did not receive adjuvant treatment (HR, 2.47; 95% CI, 0.8-7, p  = 0.08). Conclusion: The use of a manipulator increases the risk of positive cytology as well as vaginal vault recurrences, but it does not reduce the overall survival of patients.

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated with outcomes within the NSMP ECs that might be used to stratify prognosis and direct treatment. Clinicopathologic, immunohistochemical, and genetic features of a large series of NSMP EC were used to identify parameters that could identify the subset associated with a very favorable outcome (disease-specific death rate <5% at 5 years, termed low-risk NSMP). A total of 1110 NSMP ECs were profiled. In a univariate analysis, stage, grade, lymphovascular invasion, estrogen receptor (ER) and progesterone receptor (PR) expression, L1CAM overexpression, and mutations in PIK3CA were associated with disease-specific survival. Two critical features, grade and ER expression, identified a low-risk NSMP subset (grade 1-2, ER-positive [>1%], 84% of cases), which showed a 5-year disease-specific death rate of 1.6% across all stages and 1.4% within stage I. The remaining cases (high-risk NSMPs, grade 3, and/or ER-negative status) were responsible for most of the disease-specific deaths (disease-specific death rate at 5 years, 22.9%; hazard ratio compared with that of low-risk NSMPs: 16.3; 95% CI, 8.4-31.7). Within NSMP EC, the low-risk and high-risk categories were of prognostic significance independent of the stage on a multivariate analysis. Low-grade and ER-positive NSMP ECs are a homogeneous low-risk group associated with an exceptionally favorable prognosis in which de-escalation and/or endocrine therapy strategies can be applied. Grade 3 and/or ER-negative status identifies a high-risk NSMP subset, including rare high-grade histotypes (eg, clear cell, dedifferentiated, and mesonephric-like), responsible for most NSMP-related deaths. Subclassification of NSMPs allows for the category of low-risk EC molecular subtypes to be dramatically expanded because it now includes both POLEmut and the much more common low-risk NSMP EC., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy., Methods: Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021., Results: One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with >50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading >50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy., Conclusions: Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Objective: To develop machine-learning models to predict recurrence and time-to-recurrence in high-grade endometrial cancer (HGEC) following surgery and tailored adjuvant treatment., Methods: Data were retrospectively collected across eight Canadian centers including 1237 patients. Four models were trained to predict recurrence: random forests, boosted trees, and two neural networks. Receiver operating characteristic curves were used to select the best model based on the highest area under the curve (AUC). For time to recurrence, we compared random forests and Least Absolute Shrinkage and Selection Operator (LASSO) model to Cox proportional hazards., Results: The random forest was the best model to predict recurrence in HGEC; the AUCs were 85.2%, 74.1%, and 71.8% in the training, validation, and test sets, respectively. The top five predictors were: stage, uterus height, specimen weight, adjuvant chemotherapy, and preoperative histology. Performance increased to 77% and 80% when stratified by Stage III and IV, respectively. For time to recurrence, there was no difference between the LASSO and Cox proportional hazards models (c-index 71%). The random forest had a c-index of 60.5%., Conclusions: A bootstrap random forest model may be a more accurate technique to predict recurrence in HGEC using multiple clinicopathologic factors. For time to recurrence, machine-learning methods performed similarly to the Cox proportional hazards model., (© 2022 Wiley Periodicals LLC.)

Competing Interests: Competing interests: None declared.

Objective: We aimed to evaluate the surgical and oncological outcomes of elderly patients with intermediate to high-risk endometrial cancer undergoing staging with sentinel lymph node (SLN) sampling and pelvic lymphadenectomy., Methods: We conducted a retrospective study of elderly (>65-year-old) patients diagnosed with endometrial cancer between December 2007 and August 2017. These patients had been treated at a single center in Montreal, Canada. We compared the surgical and oncological outcomes of three cohorts undergoing surgical staging in non-overlapping eras: 1) lymphadenectomy, 2) lymphadenectomy and SLN sampling, 3) SLN sampling alone. Using life tables, Kaplan-Meier survival curves and log-rank tests, we analyzed 2-year progression-free survival, overall survival, and disease-specific survival., Results: Our study included 278 patients with a median age of 73 years (range; 65-91): 84 (30.2%) underwent lymphadenectomy, 120 (43.2%) underwent SLN sampling with lymphadenectomy, and 74 (26.6%) had SLN sampling alone. The SLN sampling alone group had shorter operative times with a median duration of 199 minutes (range, 75-393) compared with 231 (range, 125-403) and 229 (range, 151-440) minutes in the SLN sampling with lymphadenectomy and lymphadenectomy cohorts; respectively (p<0.001). The SLN sampling alone group also had lower estimated blood loss with a median loss of 20 mL (range, 5-150) vs 25 mL (range, 5-800) and 40 mL (range, 5-400) in the SLN sampling with lymphadenectomy and lymphadenectomy cohorts, respectively (p=0.002). The 2 year overall survival and progression-free survival were not significantly different between the three groups (p=0.45, p=0.51, respectively). On multivariable analysis after adjusting for age, American Society of Anesthesiologists (ASA) score, stage, grade, and lymphovascular space invasion, adding SLN sampling was associated with better overall survival, (HR 0.2, CI [0.1 to 0.6], p=0.006) and progression-free survival (HR 0.5, CI [0.1 to 1.0], p=0.05)., Conclusion: Sentinel lymph node-based surgical staging is feasible and associated with better surgical outcomes and comparable oncological outcomes in elderly patients with intermediate and high - risk endometrial cancer., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Objectives: We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification., Methods: Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes., Results: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort)., Conclusion: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities., Competing Interests: Declaration of Competing Interest Dr. M McConechy, and R Aguirre- Hernandez are employees, and Dr. Huntsman is a founder and Chief Medical Officer of Canexia Health., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Objective: Although its use in endometrial cancer staging is relatively new, sentinel lymph node (SLN) sampling has been shown to be highly accurate and is associated with few complications. However, some studies report lower rates of detection with SLN sampling among patients with obesity. The aim of the current study is to evaluate the feasibility of SLN sampling in endometrial cancer for patients with obesity, and to determine whether omitting lymph node dissection (LND) in surgical staging using SLN sampling impacts oncologic outcomes., Methods: we conducted a retrospective study of patients with obesity (BMI ≥35 kg/m 2) , diagnosed with endometrial carcinoma between 2007 and 2017, that compared surgical and oncologic outcomes of 2 cohorts: patients who underwent LND and patients who underwent SLN without lymphadenectomy. The primary outcome was operative time. Secondary outcomes included intraoperative bleeding; lymph node assessment information; intraoperative and postoperative adverse events; and oncologic outcomes including progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS). PFS was defined as the time from surgery to the recurrence or death from any cause. OS was defined as time from diagnosis to death or the last date the patient was known to be alive, and DSS was defined as the time from the surgery to death from the disease., Results: Out of 223 patients with a median BMI of 40.6 kg/m 2 , 140 underwent LND and 83 underwent SLN alone. The median operative time for patients in the SLN group was shorter than that of patients in the LND group (190.5 [range 108-393] vs. 238 [131-440] min; P < 0.001), and the SLN group had lower median estimated blood loss than the LND group (30 [range 0-300] vs. 40 [range 0-800] mL; P = 0.03). At the 24-month follow-up cut-off, 98% of patients were alive and 95.5% were disease free, with no significant differences in OS, DSS, and PFS between the 2 groups (P = 0.7, P = 0.8, and P = 0.4, respectively)., Conclusions: In patients with obesity, omitting LND from surgical staging with SLN sampling was associated with shorter operative times and less bleeding and did not affect survival at 2 years., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. All rights reserved.)

Objective: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280)., Data Sources: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials., Study Eligibility Criteria: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data., Methods: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool., Results: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m 2 (range, 19.4-43.7 kg/m 2 ). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I 2 =59%) and 64% bilaterally (95% confidence interval, 53%-73%; I 2 =69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I 2 =44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I 2 =0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I 2 =0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I 2 =0%)., Conclusion: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Minimally invasive surgery (MIS) is a standard surgical approach for comprehensive surgical staging in women with endometrial cancer. As rates and complexity of MIS are steadily increasing, it is important to identify potential risk factors which may be associated with this approach. This study evaluates the impact of local factors on the risk of disease recurrence., Methods: A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) who underwent MIS between 2012 and 2016 at eight Canadian centers. Data was collected from medical records. The 75th percentile was calculated for estimated uterine volume and weight. All recurrences were categorized into two groups; intra-abdominal vs. extra-abdominal. To search for significant covariates associated with recurrence-free survival a Cox proportional hazard model was performed., Results: A total of 758 patients were included in the study. Intra-uterine manipulator was used in 497 (35.8%) of patients. Vaginal lacerations were documented in 9.1%. Median follow-up was 30.5 months (interquartile range 20-47). There were 157 who had disease recurrence (20.71%), including 92 (12.14%) intra-abdominal and 60 (7.92%) extra-abdominal only recurrences. In univariate analysis myometrial invasion, LVI, stage, uterine volume and weight > 75th percentile and chemotherapy were associated with increased risk of intra-abdominal recurrence. In multivariable analysis only stage, and specimen weight > 75th percentile (OR 2.207, CI 1.123-4.337) remained significant. Uterine volume, and weight were not associated with increased risk of extra-abdominal recurrences., Conclusion: For patients diagnosed with HGEC undergoing MIS, extracting a large uterus is associated with a significantly increased risk for intra-abdominal recurrence., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Study Objective: Surgical staging for apparent early-stage ovarian cancer includes systematic pelvic and para-aortic lymph node evaluation to detect occult stage III disease [1]. Although, lymphadenectomy procedure is associated with increased duration of surgery and a 13% risk of lymphocyst formation [2]. Sentinel lymph node (SLN) biopsy is still investigational, and no standardized approach has been studied. Recent mounting evidence has approved the applicability of SLN technique in early-stage ovarian cancer [3,4]. The objective of this video is to demonstrate a surgical technique for robotic performance of SLN biopsy in presumed early-stage ovarian cancer., Design: Stepwise demonstration of the robotic technique for SLN sampling in presumed early-stage ovarian cancer. This video report is part of an institutional, investigational review board-approved study., Setting: Academic tertiary referral center., Interventions: This video presents our team's robotic technique for SLN sampling in a 37-year-old woman who presented to our center with a 10-cm right complex adnexal mass, suspicious for malignancy. A 27-gauge spinal needle was inserted through the abdominal wall under direct visualization. We injected 0.5 mL of dilute indocyanine green solution (Novadaq Technologies, Mississauga, Ontario, Canada) (1.25 mg/mL) subperitoneally into the utero-ovarian ligament. The SLN was checked with the fluorescence-guided camera of the Xi DaVinci robotic system (Sunnyvale, CA). Eight to 10 minutes after the injection, a right para-aortic SLN was identified, and dissection was performed. After dissection, the node was extracted and sent to pathology for evaluation by ultra-staging. The final pathology revealed a stage IA low-grade serous ovarian cancer., Conclusion: SLN sampling appears to be feasible in presumed early-stage ovarian cancer and may allow the avoidance of systematic lymph node dissection in this set of patients., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate if the prognostic value of lymphovascular space invasion (LVSI) is different in endometrial cancer patients with negative lymph nodes following sentinel lymph node (SLN) mapping or lymph node dissection (LND) as staging procedure., Material and Methods: A retrospective study of 510 patients diagnosed with endometrial carcinoma in our institution between 2007 and 2014. We excluded patients that were diagnosed with positive nodes (Stage IIIc). We compared patients' characteristics and survival outcomes as function of their LVSI status (positive LVSI vs negative LVSI subgroups) in each cohort separately., Results: 413 patients met the inclusion criteria, out of whom 239 underwent SLN and 174 patients underwent LND only. In the SLN group, life table analysis showed 5-year OS and PFS of 80% and 72% in patients with LVSI compared to 96%, and 93% without LVSI. Same trend was observed among patients with LND with 5-year OS and PFS of 74% and 64% in patients with LVSI compared to 97%, and 90% without LVSI. On multivariable analysis, adjusted for age, FIGO stage, grade and maximal tumor size, the favorable survival of negative LVSI remained only in the LND cohort (SLN cohort: HR 1.2, CI [0.3-4.0], P = 0.8 and HR 1.7, CI [0.7-4.3], p = 0.2 for OS and PFS, respectively; LND cohort: HR 3.1, CI [1.4-6.5], p < 0.001 and HR 2.5, CI [1.2-4.9], p = 0.01 for OS and PFS, respectively)., Conclusions: The prognostic value of LVSI disappears when patients undergo staging with SLN and are found to have negative nodes in contrast to those who have undergone LND. Future studies should confirm our observation on patients with negative sentinel nodes, and plan on tailoring adjuvant treatment to this specific subgroup., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations. The aim of this meta-analysis is to evaluate the risk of endometrial cancer (EC) in BRCA1 or BRCA2 germline mutation carriers and to examine the justifiability of prophylactic hysterectomy at the time of RRSO., Data Sources: PubMed, Cochrane Central Register of Controlled Trials, BIOSIS, Medline (Ovid), Web of Science, ClinicalTrials.gov, and Google Scholar were searched. Eleven articles were selected and analyzed using the OpenMetaAnalyst 2012 software., Methods of Study Selection: Randomized controlled studies, cohort studies, and case-control studies evaluating the risk of EC and specifically uterine papillary serous carcinoma (UPSC) in germline BRCA1/2 mutation carriers were included. Articles were excluded if they did not meet the inclusion criteria, or if data were not reported and the authors did not respond to inquiries. We assessed the methodological quality of the included studies on the basis of the Newcastle-Ottawa scale. Dichotomous results from each of the studies eligible for the meta-analysis were expressed as the proportion of patients with EC or UPSC per total number of BRCA mutation carriers, with 95% confidence interval (CI). The Mantel-Haenszel statistical method was used., Tabulation, Integration, and Results: Eleven studies reported the outcome of interest and were included in the final meta-analysis. In total, 13 871 carriers of BRCA1 and BRCA2 mutations were identified. The pooled prevalence rates of EC and UPSC in BRCA1/2 mutation carriers were 82/13 827 (0.59%) and 19/11 582 (0.16%), respectively. The EC prevalence was 46/7429 (0.62%) in BRCA1 mutation carriers and 17/3546 (0.47%) in BRCA2 mutation carriers, with relative risk of 1.18 (95% CI, 0.7-2.0). For UPSC, the prevalence was 15/7429 (0.2%) and 3/3546 (0.08%) among BRCA1 and BRCA2 mutation carriers, respectively, (relative risk 1.39; 95% CI, 0.5-3.7)., Conclusion: Most studies in this meta-analysis suggest a slightly increased risk of EC in BRCA mutation carriers, mainly for BRCA1. The decision regarding concurrent hysterectomy should be tailored individually to each patient on the basis of the patient's age, type of mutation, future need for hormone replacement treatment, history of breast cancer, tamoxifen use, and personal operative risks., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: High grade cancers account for a disproportionate number of recurrences in patients with endometrial cancer. Accurately identifying these cases on endometrial biopsies allows for better surgical planning. This study evaluates the diagnostic accuracy of general pathologists (GP) compared to gynecological pathologists (GYNP) in interpreting preoperative biopsies., Methods: A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) between 2012 and 2016 at eight Canadian cancer centres. Data was collected from medical records. Pre-operative biopsies were categorized into groups; biopsies read by GP, GYNP and GP reviewed by GYNP. Rates of HGEC on pre-operative biopsy were calculated. Fisher exact test was used to compare differences between the groups. Univariate logistic regression analysis was conducted for HGEC prediction., Results: Of 1237 patients diagnosed with HGEC, 245 (19.8%) did not have a preoperative diagnosis of high-grade disease. Discordancy was identified in 91/287 (31.71%) of biopsies reported by GP, and in 114/910 (12.53%) of biopsies reported by a GYNP (p < 0.0001). Compared to GP, GYNP were 3.24 (CI 2.36-4.45) times more likely to identify high grade disease on preoperative biopsy. Patients whose biopsy was reported by a GYNP were more likely to have a comprehensive staging procedure (OR 1.77 CI 1.33-2.38) and less likely to receive adjuvant therapy (OR 0.71 CI 0.52-0.96)., Conclusion: GYNP are more likely to identify HGEC on pre-operative biopsies. Due to high rates of overall discordancy, it is possible that surgical staging procedures should not be based solely on preoperative biopsy. Further strategies to improve pre-operative biopsies' accuracy are needed., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To evaluate the impact of surgical wait times on outcome of patients with grade 3 endometrial cancer., Methods: All consecutive patients surgically treated for grade 3 endometrial cancer between 2007 and 2015 were included. Patients were divided into two groups based on the time interval between endometrial biopsy and surgery: wait time from biopsy to surgery ≤12 weeks (84 days) vs more than 12 weeks. Survival analyses were conducted using log-rank tests and Cox proportional hazards models., Results: A total of 136 patients with grade 3 endometrial cancer were followed for a median of 5.6 years. Fifty-one women (37.5%) waited more than 12 weeks for surgery. Prolonged surgical wait times were not associated with advanced stage at surgery, positive lymph nodes, increased lymphovascular space invasion, and tumor size (P = .8, P = 1.0, P = .2, P = .9, respectively). In multivariable analysis adjusted for clinical and pathological factors, wait times did not significantly affect disease-specific survival (adjusted hazard ratio [HR]: 1.2, 95% confidence interval [CI], 0.6-2.5, P = .6), overall survival (HR: 1.1, 95% CI, 0.6-2.1, P = .7), or progression-free survival (HR: 0.9, 95% CI, 0.5-1.7, P = .8)., Conclusion: Prolonged surgical wait time for poorly differentiated endometrial cancer seemed to have a limited impact on clinical outcomes compared to biological factors., (© 2020 Wiley Periodicals, Inc.)

Objective: To evaluate long-term oncological outcomes and the added value of sentinel lymph node sampling (SLN) compared to pelvic lymph node dissection (LND) in patients with endometrial cancer (EC)., Methods: During the evaluation phase of SLN for EC, we performed LND and SLN and retrospectively compared the oncologic outcome with the immediate non-overlapping historical era during which patients underwent LND., Results: From 2007 to 2010, 193 patients underwent LND and from December 2010 to 2014, 250 patients had SLN mapping with completion LND. Both groups had similar clinical characteristics. During a median follow-up period of 6.9 years, addition of SLN was associated with more favorable oncological outcomes compared to LND with 6-year overall survival (OS) of 90% compared to 81% (p = 0.009), and progression free survival (PFS) of 85% compared to 75% (p = 0.01) respectively. SLN was associated with improved OS (HR 0.5, 95% CI 0.3-0.8, p = 0.004), and PFS (HR 0.6, 95% CI 0.4-0.9, p = 0.03) in a multivariable analysis, adjusted for age, ASA score, stage, grade, non-endometrioid histology, and LVSI. Patients who were staged with SLN were less likely to have a recurrence in the pelvis or lymph node basins compared to patients who underwent LND only (6-year recurrence-free survival 95% vs 90%, p = 0.04)., Conclusion: Addition of SLN to LND was ultimately associated with improved clinical outcomes compared to LND alone in patients with endometrial cancer undergoing surgical staging, suggesting that the data provided by the analysis of the SLN added relevant clinical information, and improved the decision on adjuvant therapy., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: To evaluate the proportion of endometrial cancers surgically managed in rural centers, and to compare the surgical management and perioperative morbidity of hysterectomies for endometrial cancer performed in rural settings with those performed in urban settings., Materials and Methods: We conducted a retrospective cohort study using the Nationwide Inpatient Sample (NIS) database from 2003 to 2010. We included all patients diagnosed with endometrial cancer who underwent a hysterectomy and compared surgical approaches, lymph node dissection rates, perioperative complication rates, and lengths of stay according to location of care provided (rural versus urban centers), using multivariate logistic regression models., Results: Of the 52,299 women who underwent surgery for endometrial cancer, 6% were performed in rural centers-a proportion that trended down over the study period. A disparity in surgical management was noted between rural versus urban settings, with rural centers having lower rates of laparoscopy and robotics (6.9% vs. 18.5%; OR 0.35, CI 0.30-0.40), and lower rates of lymph node dissection both overall (39.4% vs. 67.0%; OR 0.32, CI 0.30-0.35) and for early (37.2% vs. 66.2%; OR 0.30, 95%CI 0.28-0.33) and advanced (57.7% vs. 71.7%; OR 0.56, 95% CI 0.44-0.70) stage disease. Perioperative morbidity was comparable in both settings, with lower rates of transfusion, sepsis, wound infection, ileus, and prolonged hospitalization in rural settings., Conclusions: Although women obtaining care for endometrial cancer in rural centers receive differential surgical management than women cared for in urban centers, perioperative morbidity appears to be overall comparable., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: To assess risk factors for lymph node involvement in patients with endometrial cancer and a body-mass index (BMI) ≥30 kg/m 2 ., Materials and Methods: A retrospective analysis was performed of obese patients diagnosed with endometrial carcinoma between 2007 and 2015, treated in a single center in Montreal. Preoperative variables evaluated were age, BMI, parity, and preoperative ASA score, grade, CA-125 and histology. Odds ratios (OR) and hazard ratios (HR) and their respective 95% confidence intervals (95%CI) were calculated using multivariable logistic regression and Cox proportional hazard models., Results: The study included 230 women with BMI ≥30, 223 (97.0%) had complete staging. Pelvic lymph node involvement was detected in 26 patients (11.3%). Sentinel node detection and pelvic lymph node dissection decreased with increasing BMI (adjusted OR 0.86, 95%CI 0.76-0.97 and 0.76, 95%CI 0.59-0.96, respectively, per 1 kg/m 2 increment). Pelvic lymph node involvement was inversely correlated with BMI (adjusted OR 0.88, 95%CI 0.79-0.99) and present in 16/85 (18.8%), 6/56 (10.7%), and 4/82 (4.9%) of patients with a BMI of 30.0-34.9, 35.0-39.9, and ≥40.0 kg/m 2 , respectively. Preoperative CA-125 was associated with lymph node involvement (adjusted OR 2.77, 95%CI 1.62-4.73, per quartile increment)., Conclusion: Pelvic lymph node dissection might be omitted in selected cases of morbidly obese patients with failed sentinel nodes mapping and a low CA-125., (Copyright © 2019. Published by Elsevier Inc.)

Objective: Sentinel lymph node (SLN) mapping is increasingly being used in the treatment of apparent early-stage endometrial cancer. The aim of this study was to evaluate whether three tracers (blue dye, indocyanine green (ICG), and technetium-99 (Tc99)) performed better than two (ICG and Tc99)., Study Design: Prospective study of all consecutive patients (n=163) diagnosed with clinical early-stage endometrial cancer from 2015 to 2017. All patients were randomly assigned to receive a mixture of ICG and Tc99 with or without blue dye. Subgroup analysis for detection rates was performed for each group (double versus triple tracer)., Results: One hundred and fifty-seven patients met the inclusion criteria. Eighty patients received ICG and Tc99 with unilateral and bilateral SLN detection rates of 97.5% and 81.3%, respectively. Seventy-seven patients received all three tracers with unilateral and bilateral detection rates of 93.5% and 80.5%, respectively. Only one patient in the triple tracer group was detected by blue dye alone. No significant differences were noticed in unilateral or bilateral detection rates between the two groups, nor in the detection of lymph node metastasis., Conclusion: The addition of blue dye to ICG and Tc99 did not demonstrate any improvement in SLN detection., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study sought to evaluate the incidence, risk factors, and estimated cost associated with venous thromboembolism (VTE) following robotic surgery for endometrial cancer., Methods: The study included all consecutive patients with newly diagnosed endometrial cancer who underwent robotic surgery, excluding patients with a previous history of VTE (3%), those taking long-term warfarin (3%), and patients with conversions to laparotomy (3%). The incidence of postoperative symptomatic VTE within 90 days was analyzed. Direct and indirect medical costs were estimated using a linked billing database for standardized, inflation-adjusted costs., Results: A total of 558 cases were identified. Median BMI was 29 kg/m 2 (range, 17-85 kg/m 2 ), median operative time was 227 minutes (range, 75-419 minutes), and median blood loss was 30 mL (range, 3-400 mL). All patients received thromboprophylaxis with intraoperative subcutaneous heparin and sequential pneumatic compression devices. Extended postoperative prophylaxis for 28 days was administered to 88 (17.2%) patients with high-risk factors. A total of eight patients (1.6%) developed symptomatic VTE, and all eight were in the group that did not receive extended prophylaxis. The number needed to treat to prevent one VTE was 52.8, with an absolute risk reduction 1.89% (95% CI 0.59% to 3.19%). The average cost for treatment of a VTE was $7653 (range, $4396-$12 211), equivalent to the cost of treating 21 patients with extended prophylaxis ($356 per patient)., Conclusion: The incidence of VTE in patients with endometrial cancer who underwent robotic-assisted surgery was low (1.6%), and none of the VTEs occurred in the cohort of high-risk patients who received extended thromboprophylaxis., (Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Introduction: Appropriate extent of lymphadenectomy in clinically, early stage endometrial cancer remains controversial but sentinel lymph node (SLN) mapping has emerged as an alternative staging strategy, until the advent of molecular prognostic markers. We sought to perform a systematic review of the literature to determine pooled estimates for SLN detection rate and diagnostic accuracy, while exploring impact of the SLN on adjuvant therapy and oncologic outcomes., Evidence Acquisition: We performed a systematic search utilizing Medline, EMBASE, and Web of Science electronic databases for all studies published in the English language until October 31, 2017. Studies were included for review and potential aggregate analyses if they contained at least 30 endometrial cancer patients with undergoing SLN mapping and reported on detection rates (overall, bilateral or para-aortic) or diagnostic accuracy (sensitivity and negative predictive value [NPV]). Pooled estimates were calculated via meta-analyses utilizing a random-effects model. Studies reporting on the impact of SLN on adjuvant therapy, as well as studies comparing SLN mapping to completion lymphadenectomy were qualitatively reviewed and analyzed as well., Evidence Synthesis: We identified 48 eligible studies, which included 5348 patients for review and inclusion in the meta-analysis for SLN detection or diagnostic accuracy. The pooled SLN detection rates were were 87% (95% CI: 84-89%, 44 studies) for overall detection, 61% (95% CI: 56-66%, 36 studies) for bilateral detection, and 6% (95% CI: 3-9%, 31 studies) for para-aortic detection. Indocyanine green use improved overall (94%, 95% CI: 92-96%, 19 studies) SLN detection rates compared to blue tracer (86%, 95% CI: 83-89%, 31 studies) or technetium-99 (86%, 95% CI: 83-89%, 25 studies). This trend was similarly seen in terms of bilateral detection rates (74% vs. 59% vs. 57%, respectively). There was no difference in para-aortic SLN detection rate between each tracer. The pooled estimates for diagnostic accuracy for 34 studies were 94% (95% CI: 91-96%) for sensitivity and 100% (95% CI: 99 - 100%) for NPV. Diagnostic accuracy of SLN mapping was not negatively affected in patients with high-grade endometrial histology. Patients with SLN mapping are more likely to receive adjuvant therapy and do not have inferior survival or recurrence outcomes compared to those undergoing completion lymphadenectomy., Conclusions: SLN mapping is a feasible and accurate alternative to stage patients with endometrial cancer. Utilizing indocyanine green results in the highest SLN detection rates. Future studies should prospectively examine the impact of SLN mapping on progression-free and overall survival.

Introduction: To evaluate the anatomical location of sentinel lymph nodes (SLN) following intra-operative cervical injection in endometrial cancer., Methods: All consecutive patients with endometrial cancer undergoing sentinel lymph node mapping were included in this prospective study following intra-operative cervical injection of tracers. Areas of SLN detection distribution were mapped., Results: Among 436 patients undergoing SLN mapping, there were 1095 SLNs removed, and 7.9% of these SLNs found in 13.1% of patients, were detected in areas not routinely harvested during a standard lymph node dissection. These included the internal iliac vein, parametrial, and pre-sacral areas. The SLN was the only positive node in 46.1% (15/36) of cases with successful mapping and completion lymphadenectomy, including 3 cases where the sentinel node in the atypical location was the only node with metastatic disease., Conclusion: SLN mapping using intra-operative cervical injection is capable to map out areas not typically included in a standard lymphadenectomy. The sentinel node is the most relevant lymph node to analyze and may enable to discover metastatic disease in unusual areas., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Pilot study to assess the value of weekly paclitaxel plus carboplatin every 3weeks (dose dense regimen, DD) compared to the standard 3-weekly protocol in the adjuvant setting for endometrial cancer., Methods: Retrospective cohort study comparing consecutive patients with high and intermediate-high risk endometrial cancer, undergoing DD protocol (from 2011 to 2015) to a non-overlapping historical cohort with similar characteristics who received treatment every three weeks (2008-2011)., Results: 122 patients with endometrial cancer were included in the study, of these, 61 patients received the dose dense protocol and 61 were treated with the standard 3-weekly protocol. After a median follow-up of 61.6months in the 3-weekly cohort, compared with 41.6months in the DD cohort, 40 progressions were recorded. 29 progressions were observed in women treated in the standard protocol, with a three years progression free survival (PFS) of 57.4%, compared to 11 progressions observed in patients in the DD schedule, with a three years PFS of 79.5% (P=0.03). Patients who were treated with the DD protocol were less likely to have progression events compared to the standard cohort with a hazard ratio of 0.4 on multivariate analysis (CI 95%, 0.2-0.8, P=0.01), had significantly less distant metastases (P=0.01), and had improved overall survival when diagnosed with advanced stage disease (P=0.02). Complaints of musculoskeletal pain were more frequent in the standard cohort (n=17, 27.9%) compared to the dose dense cohort (n=4, 6.6%), P=0.005., Conclusion: Preliminary data suggests that dose dense chemotherapy might be a reasonable and superior option for adjuvant treatment of endometrial cancer, compared to standard chemotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair., Methods: Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay., Results: Cells with mutated PTEN showed over-activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor., Conclusion: Targeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies.

The emphasis in contemporary medical oncology has been "precision" or "personalized" medicine, terms that imply a strategy to improve efficacy through targeted therapies. Similar attempts at precision are occurring in surgical oncology. Sentinel lymph node (SLN) mapping has recently been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy, yet obtain prognostic information from lymph node status. The Society of Gynecologic Oncology's (SGO) Clinical Practice Committee and SLN Working Group reviewed the current literature for preparation of this document. Literature-based recommendations for the inclusion of SLN assessment in the treatment of patients with endometrial cancer are presented. This article examines., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The incidence of endometrial cancer among young women is increasing. Some patients with low-grade endometrial cancer receive hormone therapy (HT) before surgery to preserve fertility. It is unclear whether this adversely affects survival., Methods: Patients with localized, low-grade endometrial cancer who were aged <45 years were selected from the Surveillance, Epidemiology, and End Results database between 1993 and 2012. Propensity score matching was used to select comparable groups receiving HT or primary surgery. Cancer-specific and overall survival were measured using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (95% CIs) were estimated using Cox models adjusted for age, period of diagnosis, marital status, race, tumor grade, morphology, and previous radiotherapy., Results: A total of 6339 women were included in the current study cohort, 161 of whom initially received HT and 6178 of whom received primary surgery. After 15 years of follow-up, all-cause mortality did not differ between the groups (HT group: 14.1% [95% CI, 6.7%-28.4%] and propensity score-matched primary surgery group: 9.3% [95% CI, 4.1%-20.5%]). Cancer-specific mortality appeared higher in patients treated with HT compared with those treated with primary surgery (9.2% [95% CI, 3.4%-24.0%] vs 2.1% [95% CI, 1.5%-2.8%]). However, this difference was driven by 3 late deaths in the HT group. Sensitivity analyses using a broader definition of cancer-specific mortality provided no statistical evidence of a survival difference between the treatment groups. The hazard ratio for the overall risk of death was 1.45 (95% CI, 0.44-4.74)., Conclusions: Based on this population-based cohort, young patients with low-grade endometrial cancer appear to have excellent survival, regardless of the primary therapy chosen (HT vs primary surgery). The current selection of patients for HT to preserve fertility, which is managed carefully by experienced clinicians, does not appear to significantly worsen clinical outcomes. Cancer 2017;123:1545-1554. © 2017 American Cancer Society., (© 2016 American Cancer Society.)

Background: Sentinel lymph node (SLN) mapping has emerged as a promising solution to the ongoing debate regarding lymphadenectomy in the initial surgical management of endometrial cancer. Currently, little is known about its possible impact on location of disease recurrence compared to systematic lymphadenectomy., Methods: In this retrospective study, 472 consecutive patients with endometrial cancer who underwent either SLN mapping (SLN cohort, n=275) or systematic lymphadenectomy (LND cohort, n=197) from sequential, non-overlapping historical time points were compared. Clinical characteristics were extracted from a prospectively gathered electronic database. Both overall and pelvic sidewall recurrence free survival (RFS) were evaluated at 48-month post-operative follow-up., Results: No significant difference in overall RFS could be identified between the cohorts at 48months (HR 0.74, 95% CI 0.43-1.28, p=0.29). However, the SLN cohort had improved pelvic sidewall RFS compared to the LND cohort (HR 0.32, 95% CI 0.14-0.74, p=0.007). The pelvic sidewall recurrences accounted for 30% of recurrences in the SLN cohort (8 out of 26 recurrences) compared to 71.4% in the LND cohort (20 out of 28 recurrences)., Conclusions: SLN mapping may enable more efficient detection of the LNs at greatest risk of metastasis and help to guide adjuvant therapy, which in turn seems to decrease the risk of pelvic sidewall recurrences., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Minimally invasive surgery (MIS) has been associated with diminished postoperative pain and analgesia requirements. The objective of the current study was to evaluate the use of analgesia in the post-operative period following robotic surgery for endometrial cancer., Methods: All consecutive patients who underwent robotic surgery for the treatment of endometrial cancer were included in this study. The timing, dose, and type of analgesics administered postoperatively were recorded from patients' electronic medical record. Data was compared to a matched historical cohort of patients who underwent laparotomy before the introduction of the robotic program., Results: Only eight patients (2.4%, 5 during the first 25 cases and 3 following mini-laparotomy) received patient-controlled analgesia (PCA) following robotic surgery. Most patients' pain was alleviated by over-the-counter analgesics (acetaminophen, non-steroidal anti-inflammatories). In comparison to laparotomy, patients who underwent robotic surgery required significantly less opioids (71mg vs. 12mg IV morphine, p<0.0001) and non-opioids (4810mg vs. 2151mg acetaminophen, 1892 vs. 377mg ibuprofen, and 1470mg vs. 393mg naproxen; all p<0.0001)., Conclusion: Patients require less analgesics (opioids and non-opioids) following robotic surgery in comparison to conventional laparotomy, including the elderly and the obese. The diminished pain medication use is associated with some cost savings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Epithelial-mesenchymal transition (EMT) is a critical process for cancer metastasis and recurrence. Metformin, an effective oral antidiabetic drug, has been associated with decreased cancer risk and mortality. In this pilot study, we started to evaluate the effect of metformin on EMT in vivo and in vitro in endometrial cancer (EC)., Methods: Endometrial cancer cell lines and freshly isolated EC tumor specimens were used to assess EMT after metformin treatment. Cell lines were subjected to wound healing and AlamarBlue assays to determine cell migration and cell proliferation; messenger RNA levels were measured by real-time reverse transcriptase (RT) quantitative polymerase chain reaction (PCR), and protein levels were measured by Western blots to detect EMT marker expression., Results: Protein expression and messenger RNA of E-cadherin was found to be increased (P = 0.02 and 0.04, respectively) in 30 EC tumor specimens of diabetic patients treated with metformin compared with 20 EC tumor specimens of diabetic patients treated with other antidiabetic agents. In vitro, metformin reduced cell migration at 5 mM for 48 hours, as determined by the wound healing assay in EC cell lines (Ishikawa, 45% reduction; HEC50, 40% reduction), whereas more than 90% of the cells remained viable on the AlamarBlue assay. Metformin reduced EMT in the cell lines and regulated the expression of the EMT-related epithelial markers, E-cadherin and Pan-keratin; the mesenchymal markers, N-cadherin, fibronectin, and vimentin; and the EMT drivers, Twist-1, snail-1, and ZEB-1., Conclusions: Tumors of patients on metformin have increased E-cadherin expression, and metformin decreases EMT in EC cell lines in vitro, suggesting clinical biological relevance of metformin in women with EC.

Objectives: Sentinel lymph node (SLN) procedure could be an attractive solution to the debate on lymphadenectomy in endometrial cancer; however challenges to interpreting the literature include marked heterogeneity across studies, a wide variety of injection techniques and a lack of uniformly accepted definitions for important outcomes. We aim to critically appraise the published literature and streamline terminology and methodology for future studies in this field., Methods: We conducted a PubMed search and included all original research of endometrial cancer patients having undergone SLN procedure with an n>30. Data collected included injection technique, unilateral, bilateral, and para-aortic detection rates, and ultrastaging results. When different definitions were used for reporting outcomes, we recalculated the original study results according to our proposed definitions. Data was analyzed using descriptive statistics., Results: Seventeen studies met our inclusion criteria. Injection sites were categorized into cervical versus corporeal. Overall detection rates ranged from 60 to 100%; studies with n>100 all had overall detection rates of >80%. Bilateral detection rates were higher with a combination of two injection agents. Para-aortic mapping was most frequent after corporeal injection techniques (39%), and was higher after deep vs. standard cervical injection (17% vs. 2%). The proportion of metastatic lymph nodes diagnosed through ultrastaging was high (around 40%) and ultrastaging of SLN upstaged approximately 5% of patients. Retrospectively applying a surgical algorithm revealed a sensitivity of 95%, a negative predictive value of 99%, and a false negative rate of 5% (with only 9 false negative cases remaining in total)., Conclusion: Results of SLN research for endometrial cancer are promising. We believe that in future studies, uniform reporting is needed to improve our understanding of the safety and feasibility of SLN in EC. We propose 2 strategies: a checklist of elements to include in future reports and the standardization of key definitions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate and compare robot-assisted surgical staging on clinical outcomes, including quality of life and survival, as a function of patient age., Methods: Evaluation and comparison of perioperative morbidity, survival, and postoperative quality of life after prospective accumulation of clinical information including outcome measures for patients with endometrial cancer during the first 5 years of a robotic program, based on the following 3 age categories: women older than 80 years, women between 70 and 80 years, and women younger than 70 years., Results: All consecutive patients with endometrial cancer undergoing robotic surgery (n = 303) were included, with 197 women younger than 70 years, 75 women between 70 and 80 years, and 31 women older than 80 years. There were significantly more patients with advanced stage (stage II to IV in 17%, 34%, and 35%, P = 0.02) and grade 3 disease (26%, 43%, and 58%, P = 0.002) with increasing age. The perioperative data showed similar grade I or II complications (Clavien-Dindo classification) between the groups, but significantly more grade III and IV complications for women older than 80 years compared with women 80 years or younger (10% vs 1%, P = 0.004). The time needed to resume chore activities was significantly shorter for patients 70 years or older than patients younger than 70 years [8.9 (8.7) vs 18.8 (25.5) days, P = 0.048]. Overall, all patients irrespective of age were highly satisfied with the procedure. There was no difference between young and elderly patients for disease-free survival (P = 0.99)., Conclusions: Patient's age did not influence minor postoperative morbidity or overall satisfaction after robotic assisted surgery for endometrial cancer. Elderly patients had more major postoperative morbidity but resumed activities quicker than younger patients.

Objectives: To determine the relationship between BMI, age, and the physical, functional, and psychosocial areas of health-related quality of life (HRQoL) and patient satisfaction in women with endometrial cancer undergoing robotic-assisted surgery., Methods: During the first two years of the robotic surgery program, we prospectively collected data concerning patient demographics and surgical outcomes. At the first postoperative visit (21 to 28 days after surgery), all participants completed a HRQoL questionnaire. We examined the association between BMI and age, as well as the different areas of HRQoL, using chi-square and ANOVA., Results: Of 109 participants, 41 were 70 years of age or older, and 51 had a BMI of 30 kg/m(2) or more. Following surgery, the mean (±SD) duration of hospital stay was 1.9 ± 1.5 days, and reported pain level was highest on the second postoperative day, with a mean score of 3.4 ± 2.1 on a seven-point scale. Moreover, two thirds of women reported no pain by the first postoperative visit, and only 18.2% of women aged 70 years or older used any narcotic for pain control. These results indicated that there was little influence of the surgery on HRQoL, and women resumed typical activities within an average of 11 days after surgery. Lastly, participants' average rating of satisfaction was 6.7 on a seven-point scale., Conclusion: This pilot study has demonstrated the advantages for HRQoL of robotic-assisted surgery in the management of endometrial cancer. Women with endometrial cancer benefited from use of robotic surgery regardless of age or BMI.

Background: Metformin has been associated with reduced cancer risk. The mechanisms underlying this cancer protective effect remain unknown., Methods: "Window of opportunity" study of metformin in women with operable endometrial cancer (EC). Eleven newly diagnosed, untreated, non-diabetic patients with EC received metformin 500 mg tid from diagnostic biopsy to surgery. Fasting plasma insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 1 (IGFBP-1) and insulin-like growth factor binding protein 7 (IGFBP-7) measurements were taken before and after metformin treatment. Ki-67, pAMPK, and pS6 immunohistochemistry staining was performed on the endometrial cancer before and after metformin treatment and was compared to a control group of 10 women with EC who did not receive metformin., Results: Metformin was administered for a mean of 36.6 days. None of the patients suffered side effects requiring withdrawal from the study. The study group comprised 8 patients with endometrioid EC, and 3 non-endometrioid EC, with a mean follow-up time of 57 months. Mean plasma insulin (p=0.0005), IGF-1 (p=0.001), and IGFBP-7 (p=0.0098) were significantly reduced after metformin treatment. A clear reduction in ki-67 and pS6 expression was observed by both conventional light microscope analysis and digital image analysis with a significant mean reduction in percentage of cells staining for ki-67 (9.7%, P=0.02) and pS6 (31%, P=0.03). In the non-treated control group expression was similar between the biopsy and the surgical specimens., Conclusions: This pilot trial presents biological evidence consistent with anti-proliferative effects of metformin in women with EC in the clinical setting., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate the impact of introducing a robotics program on clinical outcome of elderly patients with endometrial cancer., Methods: Evaluation and comparison of peri-operative morbidity and disease-free interval in 163 consecutive elderly patients (≥70years) with endometrial cancer undergoing staging procedure with traditional open surgery compared to robotic surgery., Results: All consecutive patients ≥70years of age with endometrial cancer who underwent robotic surgery (n=113) were compared with all consecutive patients ≥70years of age (n=50) before the introduction of a robotic program in December 2007. Baseline patient characteristics were similar in both eras. Patients undergoing robotic surgery had longer mean operating times (244 compared with 217minutes, p=0.009) but fewer minor adverse events (17% compared with 60%, p<0.001). The robotics cohort had less estimated mean blood loss (75 vs 334mL, p<0.0001) and shorter mean hospital stay (3 vs 6days, p<0.0001). There was no difference in disease-free survival (p=0.61) during the mean follow-up time of 2years., Conclusion: Transitioning from open surgery to a robotics program for the treatment of endometrial cancer in the elderly has significant benefits, including lower minor complication rate, less operative blood loss and shorter hospitalization without compromising 2-year disease-free survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SLN) mapping using intra-operative cervical injection of filtered 99mTc-sulfur colloid (99mTc-SC) and patent blue in patients with endometrial cancer., Methods: Prospective evaluation of the first 100 endometrial cancer patients undergoing SLN mapping using cervical injection of patent blue combined with filtered 99mTc-SC in the operating room was done. Patients underwent robotic-assisted lymphatic mapping with frozen section, hysterectomy, BSO, and completion bilateral lymphadenectomy (including para-aortic nodes in grade 2 and 3 tumors)., Results: At least one SLN was detected in 92% of patients; in 66 of these (72%) bilateral SLN were detected, and in 15 cases the SLN was in the para-aortic area. Eleven percent of all patients had lymph node metastases, and 4 of which had pre-operative grade 1 tumor. The SLN was the only positive node in 44% of the cases with positive nodes. Sensitivity was 89% with 1 false negative result, yielding a negative predictive value of 99% (95% CI 93-100). Specificity was 100% (95% CI 94-100), and positive predictive value was 100% (95% CI 60-100). No complications or anaphylactic reactions were noted., Conclusions: Intra-operative SLN biopsy, using cervical injection of patent blue and filtered 99mTc-SC in endometrial cancer patients is feasible and yields adequate detection rates., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of introducing a robotic program on cost and patient outcome., Methods: This was a prospective evaluation of clinical outcome and cost after introducing a robotics program for the treatment of endometrial cancer and a retrospective comparison to the entire historical cohort., Results: Consecutive patients with endometrial cancer who underwent robotic surgery (n=143) were compared with all consecutive patients who underwent surgery (n=160) before robotics. The rate of minimally invasive surgery increased from 17% performed by laparoscopy to 98% performed by robotics in 2 years. The patient characteristics were comparable in both eras, except for a higher body mass index in the robotics era (median 29.8 compared with 27.6; P<.005). Patients undergoing robotics had longer operating times (233 compared with 206 minutes), but fewer adverse events (13% compared with 42%; P<.001), lower estimated median blood loss (50 compared with 200 mL; P<.001), and shorter median hospital stay (1 compared with 5 days; P<.001). The overall hospital costs were significantly lower for robotics compared with the historical group (Can$7,644 compared with Can$10,368 [Canadian dollars]; P<.001) even when acquisition and maintenance cost were included (Can$8,370 compared with Can$10,368; P=.001). Within 2 years after surgery, the short-term recurrence rate appeared lower in the robotics group compared with the historic cohort (11 recurrences compared with 19 recurrences; P<.001)., Conclusion: Introduction of robotics for endometrial cancer surgery increased the proportion of patients benefitting from minimally invasive surgery, improved short-term outcomes, and resulted in lower hospital costs., Level of Evidence: II.

Purpose: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting., Patients and Methods: Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles., Results: In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome., Conclusion: mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.

Objective: This is a prospective evaluation of the outcome of minimal invasive surgery using robotics in function of the body mass index (BMI) of patients., Methods: This is a prospective cohort study of consecutive women undergoing surgery for endometrial cancer at a tertiary care facility since the initiation of a robotic program in December 2007. Surgical and personal outcome variables as well as quality of life and postoperative recovery were assessed using a combination of objective and subjective/self-report questionnaires. Women were divided into 3 groups based on their BMI. Comparative analyses among nonobese (n = 52), obese (n = 33) and morbidly obese (n = 23) women were performed on the outcome measures after surgery., Results: The mean BMI and the range in each of the BMI categories was 25 kg/m² (18.7-29.4 kg/m²), 34 kg/m² (30.1-38.4 kg/m²), and 46 kg/m² (40.0-58.8 kg/m²). Women with higher BMI tended to be more frequently affected with comorbidities such as diabetes (15.4%, 26.0%, and 27.3%, respectively; P = 0.32) and hypertension (55.8%, 69.6%, and 69.7%, respectively; P = 0.19). Despite these differences, surgical console time (P = 0.20), major postoperative complications (P = 0.52), overall wound complications (P = 0.18), and median length of hospitalization in days (P = 0.17) were not statistically different among the 3 groups. Only 5.6% of women needed a mini laparotomy all of which were performed for the removal of their enlarged uterus, which could not be delivered safely via the vagina, at the end of the surgical procedure. There was no increased conversion to laparotomy due to increased BMI. Women in all 3 groups reported rapid resumption of hygiene regimens and chores, little need for narcotic analgesia, and high satisfaction with the procedure., Conclusions: Obese and morbidly obese patients with endometrial cancer are also good candidates for robotic surgery. These women benefit considerably from minimal invasive surgery and have little perioperative complications.

Background: Preserving reproductive function in young patients with early endometrial cancer is an accepted concept today. The safety and feasibility of long-term conservative treatment, allowing more than 1 pregnancy, remain to be ascertained., Methods: This study was a retrospective chart review of a 27 women with endometrioid adenocarcinoma of the endometrium, who were treated conservatively at 2 tertiary-care institutions. Treatment comprised oral high-dose progestins with or without a levonorgestrel-releasing intrauterine device. Endometrial biopsy was repeated every 2 to 3 months., Results: Over 7.8 to 412 months (median, 57.4 months), tumors regressed completely in 24 (89%) of 27 patients and partially in 2 patients, with 79% responding within 1 to 17 months. Of the complete responders, 15 (62%) of 24 had a recurrence; 4 underwent hysterectomy, and 11 underwent subsequent progestational treatment. All 11 responded, and 3 subsequently conceived. After 2 to 4 years, 5 patients again had a recurrence, of whom 3 underwent hysterectomy. Overall, 2 patients developed ovarian adenocarcinoma. All patients are currently disease-free. Conception occurred in 14 (51.8%) of 27 patients, in 5 more than once. There were 17 live births, and 2 patients are pregnant., Conclusions: According to our data, prolonged progestational therapy for early-stage endometrial adenocarcinoma, allowing women to conceive, is feasible and apparently does not alter clinical outcome. Patients should be advised of the high recurrence rate and possible concomitant ovarian malignancy.

Objective: Evaluation of surgical outcomes, including quality of life, in patients with endometrial cancer in the early phase of implementation of a robotic surgery program, comparing elderly with younger patients., Methods: Prospective evaluation of perioperative data and a postoperative quality-of-life survey of the first 100 robotic surgeries for endometrial cancer performed in the Division of Gynecologic Oncology at a tertiary cancer center. Women were divided in 2 groups based on age, allowing comparison of outcomes between the elderly (≥70 years) and younger groups (<70 years)., Results: Of the first 100 patients, 41 were elderly (mean age, 78 years). The elderly group had significantly higher number of comorbidities and more advanced disease when compared with the younger women. Despite this, elderly women had similar mean operative times (252 vs 243 minutes), mean console times (171 vs 175 minutes), and mean blood loss (83 vs 81 mL) as compared with the younger group. Conversion rate to minilaparotomy was 6%, all of which were performed at the end of surgery for the removal of enlarged uteri that could not be delivered vaginally. The overall perioperative complication rates were not statistically different between the age groups. Median hospital stay tended to be longer for the elderly women (2 vs 1 day) but was not statistically significant. The postoperative quality-of-life assessment revealed that patients young and old alike were highly satisfied with the procedure., Conclusions: Prospective evaluation indicates that even in the early phases of implementation of a robotic surgical program for endometrial cancer, the procedure seems safe and confers an excellent quality of life for elderly patients.

Uterine cancer is the fourth most common cancer in Canadian women, with an estimated 4200 new cases and 790 disease-related deaths in 2008. We investigated the domains that are important for further implementation of minimally invasive surgery for the management of endometrial cancer by performing a literature review to assess the available data on overall and disease-free survival in laparoscopic versus open surgery. We also investigated the influence of patient- related factors, surgical factors, quality of life, and cost implications. Among the 23 articles reviewed, five were randomized controlled trials (RCTs), four were prospective reviews, and 14 were retrospective reviews. The RCTs showed no difference in overall and disease-free survival for patients with endometrial cancer who had undergone laparoscopic hysterectomy compared with open surgery. Morbid obesity is a limiting factor for the feasibility of complete laparoscopic staging. Laparoscopy seems to decrease complications and decrease blood loss. It also shortens hospital stay, with improved short-term quality of life and cosmesis, while yielding similar lymph node counts. Overall, laparoscopy is cost-effective, because the increased operation cost of laparoscopy is offset by the shorter hospital stay and faster return to work. On the basis of currently available data, patients with endometrial cancer should be offered minimally invasive surgery as part of their treatment for endometrial cancer whenever possible.

Background: Uterine artery embolization has increasingly been used in the last decade as a conservative treatment approach for uterine fibroids. Rarely sarcomas have been diagnosed shortly after uterine artery embolization. It remains unclear whether a change in diagnostic work-up is required prior to uterine artery embolization in order to avoid missing sarcomas and delaying definitive treatment., Case: A 45 year old underwent uterine artery embolization for symptomatic uterine fibroids. Six months later, following progressive symptoms, she underwent surgery which revealed an endometrial stromal sarcoma. This manuscript raises the issue and reviews the existing literature concerning the need of tissue diagnosis prior to uterine artery embolization., Conclusion: Assessing the risk of malignancy by taking into account the clinical symptoms, physical exam, and imaging findings is essential prior to uterine artery embolization.

Objective: To evaluate the safety of fertility-sparing hormonal therapy for endometrial cancer in young patients., Methods: We reviewed the clinical and pathologic records of patients diagnosed with endometrial adenocarcinoma before the age of 40, who were treated and followed over a 30-year period in the Division of Gynecologic Oncology. All patients who underwent conservative management with progestins (n = 13) are the subjects of this study., Results: Follow-up was available for all 13 patients, with a mean follow-up of 82 months. All patients responded to treatment within a mean period of 3.5 months, with normal pathology on follow-up endometrial samplings. Six patients had a recurrence within a period extending between 19 and 358 months (median 40 months). Four patients were treated with a second course of progestins, and all had a histologic complete response. As of the time of preparation of this report, nine healthy infants had been born, and all the patients remained without evidence of disease., Conclusion: Conservative management of well-differentiated endometrial carcinoma in young patients, combined with assisted reproductive technologies, if needed, does not seem to worsen the prognosis. This approach also provides the possibility of conceiving and carrying a normal pregnancy.