The Impact of Intra-Uterine Manipulators on Outcome and Recurrence Patterns of Endometrial Cancer Patients Undergoing Minimally Invasive Surgery

The Impact of Intra-Uterine Manipulators on Outcome and Recurrence Patterns of Endometrial Cancer Patients Undergoing Minimally Invasive Surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Impact of Intra-Uterine Manipulators on Outcome and Recurrence Patterns of Endometrial Cancer Patients Undergoing Minimally Invasive Surgery Ido Laskov, Nadav Michaan, Liron Kogan, Xing Zeng, Shannon Salvador, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-538902/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To evaluate the use of an intrauterine manipulator on the oncologic outcome of women who had minimally invasive surgery for endometrial cancer. Methods Retrospective analysis of consecutive patients who were operated with or without the use of an intrauterine manipulator. Univariate and multivariate analysis were used to adjust for possible confounders. Results 699 patients were included, of whom 220 (32.8%) were operated with an intrauterine manipulator. The median follow-up was 44 months (range, 29-67). Disease-free survival was similar between groups. 19 (8.8%) patients had positive cytology in the manipulator group vs. 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). Sub-group analysis of 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 (HR, 1.28; 95% CI, 0.7-2.1, p=0.3) and for the sub-group 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 during surgery for endometrial cancer increases the risk of positive cytology as well as vaginal vault recurrences, but it does not reduce the disease-free and overall survival of patients. Obstetrics & Gynecology endometrial cancer uterine manipulator hysterectomy recurrence Figures Figure 1 Figure 2 Introduction Currently, the gold standard treatment for patients diagnosed with endometrial cancer is based primarily on staging surgery followed by adjuvant treatment if indicated [ 1 ]. After the primary surgery, patients are divided into risk groups (low, intermediate, and high) that will guide physicians as to the recommended adjuvant treatment if needed. The division into the different risk groups is based on multiple factors including patients' age, histologic subtype, tumor grade, staging of disease and presence of lympho-vascular space invasion [ 1 – 3 ]. Approximately 6–13% of all patients with endometrial cancer will develop recurrent disease, the majority during the first 3 years after a primary diagnosis with primary location in the vaginal vault [ 4 ]. Two minimally invasive (MIS) approaches are used for endometrial cancer staging surgery, total laparoscopic hysterectomy (TLH) and robotically assisted total laparoscopic hysterectomy (RH) [ 5 ]. Compared to laparotomy, the benefits of minimal invasive approach hysterectomy for endometrial cancer, include reduced blood loss, shorter recuperation time, lower cost, less use of pain medication, faster recovery, similar or fewer post-operative adverse events, and better quality of life up to 6 months after surgery [ 6 ]. In addition, no significant difference exists in cancer recurrence or outcome between MIS and laparotomy cases, indicating comparable oncologic safety of MIS [ 7 ]. For proper uterine manipulation during minimal invasive hysterectomy, various uterine manipulators are used with or without an intrauterine segment (usually a screw, a rod or a balloon) [ 8 ]. The intra-uterine component is inserted into the uterine cavity in order to allow surgeons manipulation of the uterus for better exposure. In addition to the intrauterine component, some of the uterine manipulators have a colpotomizer (cervical cap) that assists in identifying the anatomic landmarks such as the vaginal fornices and allow to increase the distance between the ureter and the vaginal vault [ 9 ]. Nevertheless, some surgeons are avoiding the use of the intrauterine component in cases of endometrial cancer, for concern of iatrogenic spillage, uterine perforation, and the potential risk of retrograde dissemination of cancer cells into the peritoneal cavity or the lymphatic spaces. In order to avoid this potential spread, some surgeons choose either not to use a uterine manipulator at all or to use an uterine manipulator with a colpotomizer but without an intrauterine segment [ 10 ]. The aim of this study was to evaluate the effect of the use of an intrauterine manipulator on the recurrence rate and outcome of patients undergoing minimal invasive staging surgery for endometrial cancer. Methods Study population and setting A retrospective cohort study, identifying all consecutive patients who underwent a minimal invasive hysterectomy for endometrial cancer at the McGill university tertiary-care hospitals during the years 2008–2016. All surgeries were performed by laparoscopic or robotic approach by 6 gynecologic oncology surgeons. MIS for staging of endometrial cancer included peritoneal cytology, total hysterectomy and salpingo-oophorectomy, with or without pelvic and/or para-aortic lymph node dissection (LND) or sentinel lymph node detection (SLND). In cases where the pre-operative histology was papillary serous or clear cell, surgical staging also included omentectomy, examination of the entire abdomino-pelvic cavity and retroperitoneal spaces. During the study period, routine coagulation of the fallopian tubes at the beginning of the procedure to avoid possible intraperitoneal spread of disease was not performed. Patients who had uterine perforation, morcellation, or conversion to laparotomy were excluded from the study. Uterine manipulators During the study, uterine manipulators that were used were either a Clermont Ferrand manipulator (Karl Storz, Tuttlingen, Germany), RUMI uterine manipulator with a Koh colpotomizer system (Cooper Surgical, Trumbull, CT, USA) or a ZUMI uterine manipulator (Cooper Surgical, Trumbull, CT, USA). In other cases, either a uterine manipulator was not used or an adjustment was made to the Hohl uterine manipulator (Storz, El Segundo, CA) so that it included only the handle with its colpotomizer without its intra-uterine component as described previously by our group [ 10 ]. The decision as to the type of intrauterine manipulator or lack of it was left to the discretion of the surgeon. Clinical information Data was collected from the department’s digital records, including operative reports, pathology reports, chemotherapy records, radiation oncology reports, laboratory results, and radiology reports were reviewed to determine baseline and perioperative characteristics until the end of follow-up period or death for each patient. Baseline characteristics included age, body mass index and medical comorbidities. Perioperative data included the surgical procedure with the type of uterine manipulator or colpotomizer used, stage of malignancy based on the 2009 FIGO for endometrial carcinoma [ 11 ], grade, histology, depth of myometrial invasion, lymph-vascular space invasion, fallopian tube and ovarian involvement, lower uterine segment and cervix involvement, lymph node involvement with total count, uterine size, tumor size and classification of pelvic cytology. Pelvic cytology was routinely obtained as follows: the suction irrigator was used to infuse saline into the pelvis following placement of the uterine manipulator. The manipulator was used to displace the uterus anteriorly while the saline was retrieved using the suction irrigator device; volume was not standardized. Because the risk of tumor dissemination may be related to tumor size and volume, measurements provided in the gross and microscopic sections of pathology reports were used to determine the maximum diameter of tumor and to calculate tumor volume if three-dimensional measurements were provided. Post-operative complications were collected in real time. For those patients who had recurrence, disease free survival (DFS) was defined as time from last treatment to the diagnosis of recurrence. Overall survival (OS) was defined as time from diagnosis to time of last follow-up or death. Recurrences were diagnosed clinically or radiologically. All vaginal recurrences were biopsy proven. During the surveillance period, routine follow-up examinations were performed at intervals of 4 months during the first two years, followed by every 6 months for up to 5 years, and then yearly until the end of the follow-up period or death. To assess the effect of different uterine manipulator types on LVSI, positive cytology and patient’s outcome, patients were divided into two groups. The first group (Intrauterine manipulator group) included patients who were operated using a uterine manipulator that necessitates a cervical os dilation prior to the placement of the intrauterine rod (Clermont Ferrand, RUMI or ZUMI) and a second group (No intrauterine manipulator group) of patients that were operated either without a uterine manipulator or using the intravaginal part of a Hohl uterine manipulator without the intrauterine manipulator, as previously published (10). Statistical analysis Statistical analysis was done using SPSS software (IBM, SPSS statistics, Version 25, 2017. IBM® corp. Armonk, NY, USA). All statistical analyses were 2 sided and P < 0.05 was considered significant. Continuous variables were compared using either one-way ANOVA or Kruskal- Wallis and Mann-Whitney tests according to distribution of variables. Chi squared test or Fishers' exact test were used to compare categorical variables. Disease free survival and overall survival were calculated using Kaplan Meier estimator and compared with log rank test with reverse censoring method. Univariate as well as multivariate cox regression analysis was used to evaluate the association between each of the predictors and disease-free survival and overall survival. Results During the study period we identified 782 patients who underwent minimal invasive hysterectomy for endometrial intraepithelial neoplasia (EIN) and newly diagnosed endometrial cancer. Eighty three patients (10.6%) were excluded from the study: 54 patients with EIN, 22 patients required conversion to laparotomy (2.8%), most of those required a simple mini-laparotomy at the end of the procedure in order to remove the uterus that could not be removed intact via the vagina (utero-vaginal disproportion) and 9 patients had a large uterus that was morcellated within an endobag placed via the vagina (1.1%). After exclusion, six-hundred and sixty-nine patients were included in the analysis and the clinicopathologic characteristics are presented in Table 1 . The mean patient age was 64 years (SD 11), and the mean body mass index (BMI) was 31.7 kg/m 2 (SD 8.6). Six hundred and thirteen patients (88%) underwent robotic assisted hysterectomy and 86 patients (12%) underwent laparoscopic hysterectomy. In four hundred and eighty-four patients (69%) the procedure included pelvic lymph node dissection (PLND) and for 203 patients (29%), para aortic lymph node dissection was performed in addition to PLND. The most common uterine manipulator used was the Hohl retractor (60%) without intrauterine component, followed by the Clermont Ferrand manipulator (19%). Table 1 Patient characteristics and surgical outcomes (n = 699). Characteristics Total (n = 699) Age, mean (SD), y 64.5 (11) BMI, mean (SD), kg/m2 31.7 (8.6) Surgery mode, n (%) Robotic 613 (88) Laparoscopic 86 (12) Surgical procedure, n (%) TH + BSO 12 (1.7) TH + BSO + PLND 484 (69.3) TH + BSO + PLND + PaLND 203 (29) Manipulator type, n (%) Hohl 420 (60) KF 136 (19) ZUMI 62 (9) RUMI/Koh 22 (3) None 59 (9) Histology, n (%) Endometrioid 546 (78) Serous 91 (13) Clear 19 (3) Other 43 (6) Stage†, n (%) Ia 416 (59) Ib 113 (16) II 42 (6) III 116 (17) IV 12 (2) Tumor grade†, n (%) 1 301 (43) 2 193 (28) 3 205 (29) Myometrial invasion, n (%) No 62 (9) Less than half 582 (83) More than half 55 (8) Lymph vascular invasion, n (%) 206 (29) Lymph node retrieval number, mean (SD) 12.3 (8.8) Positive Lymph node metastasis, n (%) 84 (12) Positive cytology, n (%) 40 (5.7) Adjuvant therapy, n (%) None 369 (53) RTx only 124 (17) CTx only 26 (4) Combined RTx + CTx 180 (23) Follow up time, median (range), month 45 (29–67) SD, standard deviation; BMI, body mass index; TH, total hysterectomy; BSO, bilateral salpingo-oophorectomy; PLND, pelvic lymph node dissection; PaLND, para aortic lymph node dissection; CF, Clermont Ferrand; RTx, radiotherapy; CTx, chemotherapy. †Tumor stage is presented according to the 2009 International Federation of Gynecology and Obstetrics stage and histologically classified and graded according to the World Health Organization. The majority of patients had stage I disease (n = 528, 75%) and endometrioid histology (n = 546, 78%), whereas 205 patients (29%) had grade 3 disease. Three hundred and thirty patients (44%) with moderate to high risk factors received adjuvant treatment, either radiotherapy, chemotherapy or combination of the two. The median follow-up time was 44 (range 29–67) months. Out of the 699 eligible patients, 220 (31.4%) underwent surgery with the support of an intrauterine manipulator (Intrauterine manipulator group) and in 479 patients (68.6%) no intrauterine manipulator was used (No intrauterine manipulator group). The distribution is presented in Fig. 1 . There were no significant differences between the two groups with regard to age at surgery, BMI, histologic type, FIGO stage, LVSI, tumor size and lymph node retrieval number (Table 2 ). Women in the intrauterine manipulator group had significantly more grade 1 disease (50% vs. 39%, p = 0.01) and positive cytology (8.8% vs. 4.4%, p = 0.02) compared to women in the no intrauterine manipulator group. Eighty-seven patients (39.5%) in the intrauterine manipulator group compared to 243 (50.7%) in the no intrauterine manipulator were classified to be intermediate/high risk for recurrence and received adjuvant treatment (p = 0.006). 27 patients (12.3%) recurred in the intrauterine manipulator group, compared to 57 (11.9%) patients in the no intrauterine manipulator group (p = 0.88). Vaginal vault recurrence was the most common site of recurrence, occurring in 10 (4.5%) patients in the intrauterine manipulator group vs. 6 (1.3%) patients in the no intrauterine manipulator group (p = 0.007). Nine patients (4.1%) in the intrauterine manipulator group had pelvic recurrences vs. 9 pelvic recurrences (1.9%) in the no intrauterine manipulator group (p = 0.08). Lower limb lymphedema was the most prevalent post-operative complication, occurring in 16 (7.3%) patients of the manipulator group compared to 12 (2.5%) patients in the no manipulator group (p = 0.003). Less common complications were wound and urinary infections but did not show statistical difference between the groups. Median DFS and OS were not reached and were not statistically different between the two groups. Table 2 Patient characteristics and surgical outcomes with patterns of recurrence (n = 699) and subgroup analysis for patients who did not receive adjuvant treatment (n = 369). Characteristics Intra-uterine manipulator No intra-uterine manipulator P value Total Cohort n = 220 n = 479 Age, mean (SD), years 64.9 (11) 64.3 (11) 0.605 BMI, mean (SD), kg/m2 31.2 (8) 32.0 (9) 0.392 Histology, n (%) Endometrioid 179 (81.4) 367 (76.8) 0.156 Serous 26 (11.8) 65 (13.6) Clear 5 (2.3) 14 (2.9) Other 10(4.5) 32 (6.7) Stage†, n (%) Ia 144 (65.5) 271 (56.7) 0.071 Ib 24 (10.9) 89 (18.6) II 13 (5.9) 29 (6.1) III 39 (17.7) 77 (16.1) Tumor grade†, n (%) 1 111 (50.5) 189 (39.5) 0.01 2 54 (24.5) 139 (29.1) 3 55 (25.0) 150 (31.4) Lymph vascular invasion, n (%) 69 (31.4) 137 (28.7) 0.478 Lymph node retrieval number, mean (SD) 13.8 (10.8) 11.6 (7.6) 0.101 Positive Lymph node metastasis, n (%) 24 (11.0) 60 (12.7) 0.525 Positive cytology, n (%) 19 (8.8) 21 (4.4) 0.022 Tumor size, median (range), cm 3.2 (1.9) 3.3 (1.9) 0.199 Uterine size, median (range), cm 8.2 (1.9) 7.8 (2.2) 0.005 Adjuvant therapy, n (%) Total 87 (39.5) 243 (50.7) 0.006 RTx only 29 (13) 95 (20) 0.033 CTx only 11 (5) 15 (3) 0.226 Combined RTx + CTx 47 (21) 133 (28) 0.072 Recurrence, n (%) 27 (12.3) 57 (11.9) 0.888 Site, n (%) Vaginal vault 10 (4.5) 6 (1.3) 0.007 Pelvic 9 (4.1) 9 (1.9) 0.087 Abdominal 8 (3.6) 22 (4.6) 0.563 Retroperitoneal LN 8 (3.6) 20 (4.2) 0.736 Lung 4 (1.8) 19 (4.0) 0.139 Multiple site 11 (5.0) 22 (4.6) 0.814 Complications, n (%) Lymphedema 16 (7.3) 12 (2.5) 0.003 Wound infection 9 (4.1) 9 (1.9) 0.087 Urinary infection 5 (2.3) 10 (2.1) 0.875 Vaginal cuff 1 (0.5) 6 (1.3) 0.325 Death, n (%) 30 (13.6) 54 (11.3) 0.378 Subgroup Analysis n = 133 n = 236 Lymph vascular invasion, n (%) 10 (7.5) 13 (5.6) 0.504 Positive cytology, n (%) 6 (4.5) 3 (1.3) 0.077 Recurrence (%) 11 (8.3) 7 (3) 0.023 Vaginal vault recurrence, n (%) 7 (5.3) 2 (0.8) 0.012 SD, standard deviation; BMI, body mass index. †Tumor stage is presented according to the 2009 International Federation of Gynecology and Obstetrics stage and histologically classified and graded according to the World Health Organization. To further assess the effect of uterine manipulation on patient’s outcome we have performed a subgroup analysis of all patients who did not receive adjuvant treatment (Table 2 ). In the intrauterine manipulator group, 11 (8.3%) patients recurred as compared to 7 (3%) in the no intrauterine manipulator group (p = 0.02), with a 5.3% rate of vaginal vault recurrence compared to 0.8% (p = 0.01). Median DFS was not reached however, in a Kaplan-Meyer survival analysis, patients in whom no intrauterine manipulator was used had significantly better DFS (Fig. 2 B, p = 0.01). When all the patients were included, whether they received adjuvant treatment or not, no significant differences in DFS could be observed between the groups (Fig. 2 A). To better assess the association between the use of intrauterine manipulator and recurrence rate as well as outcome of patients, a multivariate analysis was performed (Table 3 ). Figo stage, grade, LVSI, positive cytology and adjuvant treatment were all independently associated with risk of disease recurrence and decreased OS. The use of a uterine manipulator was not associated with the risk of relapse of endometrial cancer (Hazard ratio, 1.28; 95% confidence interval, 0.7–2.1, p = 0.3). The use of a uterine manipulator did not reach statistical significance for risk of relapse on a second multivariate analysis performed on the subgroup of patients who did not receive adjuvant treatment (Hazard ratio, 2.47; 95% confidence interval, 0.87–7.01, p = 0.08) (Table 3 ). Table 3 Factors associated with patient outcome in multivariate analysis. Disease Free Survival Overall Survival Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value Total Cohort Age 1.05 (0.98–1.02) 0.62 1.06 (1.03–1.08) < 0.001 Stage 1A 1B 2 3 4 1 2.16 (0.9–4.7) 3.8 (1.6–9.3) 4.7 (2.2–10.1) 10.4 (3.4–31) 0.053 0.003 < 0.001 < 0.001 1 2.26 (0.94–5.42) 3.51 (1.36–9.04) 7.69 (3.35–17.6) 24.7 (8.1–75.3) 0.06 0.009 < 0.001 < 0.001 Grade 1 2 3 1 1.89 (0.8–4.45) 4.4 (1.78-11) 0.143 0.001 1 2.92 (1.01–8.46) 6.69 (2.25–19.91) 0.048 0.001 Cytology Negative Positive 1 2.19 (1.1–4.3) 0.022 1 1.98 (1.03–3.81) 0.039 LVSI Negative Positive 1 1.84 (1.05–3.2) 0.032 1 1.81 (1.01–3.24) 0.044 Manipulator Not used Used 1 1.28 (0.76–2.1) 0.344 1 1.36 (0.81–2.29) 0.234 Adjuvant treatment Not used Used 1 0.59 (0.29–1.2) 0.16 1 0.46 (0.24–0.87) 0.018 Subgroup Analysis Age 1.06 (0.9–1.08) 0.1 1.01 (0.9–1.05) 0.5 Stage 1A 1B 2 3 4 1 2.2 (0.6–8.6) 1.6 (0.15-18) 29 (3.9–225) 0 0.06 0.2 0.6 0.001 0.9 1 1 (0.2–4.5) 1.2 (0.05-27) 6.9 (0.6–73) 0 0.9 0.8 0.1 0.9 Grade 1 2 3 1 0.6 (0.1–2.9) 1.6 (0.3–7.5) 0.5 0.5 0.5 1 1.05 (0.3–3.6) 2.3 (0.3–17) 0.9 0.4 Cytology Negative Positive 1 0 0.9 1 1.98 (1.03-38) 0.8 LVSI Negative Positive 1 7.5 (2.1–26.2) 0.01 1 1.5 (0.2–8.7) 0.6 Manipulator Not used Used 1 2.47 (0.8-7) 0.08 1 1.1 (0.4-3) 0.8 CI, Confidence interval; LVSI, lymph vascular space invasion. Discussion Concerns remain that the introduction of a device into the endometrial cavity may cause disruption of endometrial cancer cells and affect patient’s outcome. Available data is limited and indicates that this type of disruption does not seem to have clinically observable adverse effects [ 12 – 15 ]. Data regarding the possible effect of the use of intrauterine manipulators on the long-term outcome of patients with endometrial cancer is scarce. As a result, debates still take place in the gynecologic oncology community raising concern about the use of these devices. Two previous studies have tried to analyse survival after laparoscopic surgery for endometrial cancer using a uterine manipulator. However, those were largely underpowered to investigate long-term outcomes (< 70 patients included in each group) [ 16 , 17 ]. In a multicenter study by the Italian society of gynecological endoscopy, authors reviewed data from 951 consecutive patients who underwent laparoscopic surgery for endometrial cancer with or without intrauterine manipulator. In this study, data regarding the effect of the manipulator on the rate of positive cytology and LVSI was not reported but results showed a non-significant difference in the recurrence rate (13.5% vs. 11.6%) between the manipulator and no manipulator groups [ 15 ]. Results of our study raise some safety concerns regarding the use of uterine manipulators during MIS for endometrial cancer. For the entire cohort, total recurrence rate was similar between the two comparison groups but with higher rates of local vaginal recurrence for patients in whom a uterine manipulator was used during surgery. After excluding patients who received adjuvant treatment, the rate of vaginal vault recurrence and total recurrence was significantly higher with a worse DFS in the intra-uterine manipulator group compared to the no manipulator group. However, the use of a uterine manipulator was not found to be a predictor of worse outcome on multivariate analysis that was performed for the entire cohort but was close to statistical significance when performed for the subgroup of patients who did not receive adjuvant treatment. A recent multicenter study by the Spanish society of gynecology and obstetrics, followed over 2000 women with uterus confined endometrial cancer who underwent minimally invasive surgery and found, in concordance with the results presented here, that patients that were operated using a uterine manipulator had worse oncological outcome [ 18 ]. A possible explanation might be that local recurrence may be salvageable by either surgery or radiotherapy, with good long term outcomes [ 19 ]. Following recurrence, most patients in our cohort were either operated or received radiotherapy with or without chemotherapy. This is also in accordance to the previously reported LAP2 study that found a potential increased risk of uterine cancer recurrence with manipulator assisted laparoscopic hysterectomies compared to hysterectomies via laparotomy but this risk was quantified and found to be small [ 7 ]. We can speculate that the effect of higher recurrence rates on long term outcome of patients in the manipulator group, was eventually diluted by additional treatment modalities and that the presence of a uterine manipulator during surgery did not negatively affect the outcome of endometrial cancer patients on multivariate analysis. Our results show that the use of an intra-uterine manipulator in MIS for endometrial cancer was not associated with an increase in rates of LVSI, however, we found higher incidence of positive cytology in patients for whom a uterine manipulator was used during surgery. Previously published studies regarding LVSI and positive peritoneal cytology are conflicting, with some suggesting that the use of manipulators does not affect positive peritoneal cytology and/or LVSI [ 20 – 24 ], while other studies show an association between uterine manipulator use and positive peritoneal cytology and/or LVSI [ 25 , 26 ]. LVSI was previously shown to be an independent adverse prognostic factor for extra-uterine disease, particularly pelvic lymph node metastasis [ 27 , 28 ], isolated para-aortic lymph node Metastasis [ 29 , 30 ], and distant hematogenous recurrences [ 31 ]. LVSI in the presence of a uterine manipulator may reflect true invasion, pseudo-invasion, or an artifact of manipulator use that resulted in cell displacement into the vessels via a closed pressure system [ 32 ]. In the current study, LVSI was found in 27% of patients, which is in agreement previously published data. According to our results, the use of intrauterine manipulator was not associated with a significant difference in the rate of LVSI. With regard to positive cytology, we found that the rate of positive cytology was significantly higher in the group of patients who had an intra-uterine manipulator. Positive cytology was an independent prognostic factor for both DFS and OS on univariate and multivariate analysis. Other reports showed similar results that peritoneal washings were significantly more likely to be positive in women in whom a uterine manipulator had been used [ 25 , 26 , 33 ]. To elucidate whether the use of intra-uterine manipulator increases the risk of positive cytology, its necessary to obtain cytology twice in the same individual, before and after the insertion of the intra-uterine manipulator and compare them. The current study offers several strengths; data was collected from a large cohort of patients who underwent surgery by a team of surgeons who share a joint surgical protocol and unified approach. This enhances the impact of the use of intrauterine manipulators and allows the current comparison. Moreover, in our study we were also able to perform a subgroup analysis that excludes the effect of adjuvant radiation treatment on the outcome measures. In addition, the follow up time in our study is relatively long and was previously shown to include over 90% of recurrences from initial treatment [ 34 ]. However, this study is not without limitations including the inherent limitations that results from its retrospective nature. In addition, we did not perform coagulation of the tubes at the beginning of the procedure and this might have an effect with regard to positive cytology. Finally, in the current study we deal with the long-term outcome of uterine manipulators in endometrial cancer, but can we extrapolate these results to cervical cancer? Could the data presented here provide some hints to explain the poorer results for cervical cancer patients undergoing minimal invasive surgery with a uterine manipulator. Several theories have been proposed to explain the unexpected results of the LACC trial that compared minimally invasive radical hysterectomy to open abdominal radical hysterectomy among women with early-stage cervical cancer. One theory suggests that the use of a uterine manipulator is a possible cause of the poorer oncological outcome after minimal invasive radical hysterectomy for cervical cancer [ 35 ]. The results presented here show higher recurrence rates, mainly at the vaginal vault and decreased disease-free survival in a subgroup of patients who were operated using an intra-uterine manipulator and did not receive adjuvant treatment. In contrast to cervical cancer, the rise in disease recurrence did not significantly affect OS. We can speculate that this could either be related to differences in the biology of squamous cell carcinomas of the cervix and endometrial cancers, and/or be due to the salvage potential of the treatment modalities for recurrent localized endometrial cancer. A recent international European observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer found that patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse and those without the use of a uterine manipulator had similar disease-free-survival to the open surgery group [ 36 ]. In conclusion, results of the current study show that the use of an intra uterine manipulator is associated with a minimal impact on the oncological outcomes of patient who undergo MIS and adjuvant treatment for endometrial cancer, but may have implications on outcome for low risk patients who do not receive adjuvant treatment. Declarations Consent to participate not applicable . Funding: not applicable . Conflicts of interest/Competing interests: The authors report no conflict of interest. Ethics approval: Ethical approval was waived by the local Ethics Committee of University A in view of the retrospective nature of the study and all the procedures being performed were part of the routine care. Acknowledgement: this work was supported by grants from the Israel Cancer Research Fund and the Gloria’s Girls. CRediT authorship contribution statement: Ido Laskov: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing - original draft, Writing - review & editing, Visualization, Supervision, Project administration. Nadav Michaan: Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Visualization. Liron Kogan: Conceptualization, Investigation, Data curation, Writing - review & editing. Xing Zeng: Resources, Investigation, Data curation, Writing - review & editing. Shannon Salvador: Resources, Investigation, Data curation, Writing - review & editing. Kris Jardon: Resources, Investigation, Data curation, Writing - review & editing. Susie Lau: Resources, Investigation, Data curation, Writing - review & editing. Lucy Gilbert: Resources, Investigation, Data curation, Writing - review & editing, Supervision. Walter H. Gotlieb: Conceptualization, Methodology, Investigation, Resources, Data curation, Writing - original draft, Writing - review & editing, Supervision. Roy Kessous: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Writing - review & editing, Visualization. References Creutzberg CL et al (2000) Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355(9213):1404–1411 Keys HM et al (2004) A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 92(3):744–751 Group AES et al (2009) Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 373(9658):137–146 Creutzberg CL et al (2011) Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys 81(4):e631–e638 Patel PR et al (2014) Disparities in use of laparoscopic hysterectomies: a nationwide analysis. J Minim Invasive Gynecol 21(2):223–227 Walker JL et al (2009) Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 27(32):5331–5336 Walker JL et al (2012) Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 30(7):695–700 van den Haak L et al (2015) Efficacy and safety of uterine manipulators in laparoscopic surgery: a review. Arch Gynecol Obstet 292(5):1003–1011 Nassif J, Wattiez A (2010) Clermont Ferrand uterine manipulator. Surg Technol Int 20:225–231 Peeters F et al (2010) Technical modifications in the robotic-assisted surgical approach for gynaecologic operations. Journal of Robotic Surgery 4(4):253–257 Benedet JL et al (2000) FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 70(2):209–262 Eltabbakh GH, Mount SL (2006) Laparoscopic surgery does not increase the positive peritoneal cytology among women with endometrial carcinoma. Gynecol Oncol 100(2):361–364 Polyzos NP et al (2010) Intraperitoneal dissemination of endometrial cancer cells after hysteroscopy: a systematic review and meta-analysis. Int J Gynecol Cancer 20(2):261–267 Shinohara S et al (2017) Risk of spilling cancer cells during total laparoscopic hysterectomy in low-risk endometrial cancer. Gynecol Minim Invasive Ther 6(3):113–115 Uccella S et al., The effect of a uterine manipulator on the recurrence and mortality of endometrial cancer: a multi-centric study by the Italian Society of Gynecological Endoscopy . Am J Obstet Gynecol, 2017. 216(6): p. 592 e1-592 e11 Marcos-Sanmartin J et al (2016) Does the Type of Surgical Approach and the Use of Uterine Manipulators Influence the Disease-Free Survival and Recurrence Rates in Early-Stage Endometrial Cancer? Int J Gynecol Cancer 26(9):1722–1726 Tinelli R et al (2016) Laparoscopic treatment of early-stage endometrial cancer with and without uterine manipulator: Our experience and review of literature. Surg Oncol 25(2):98–103 Padilla-Iserte P et al., Impact of uterine manipulator on oncological outcome in endometrial cancer surgery . Am J Obstet Gynecol, 2020 Hardarson HA et al (2015) Vaginal vault recurrences of endometrial cancer in non-irradiated patients - Radiotherapy or surgery. Gynecol Oncol Rep 11:26–30 Frimer M et al (2010) Micrometastasis of endometrial cancer to sentinel lymph nodes: is it an artifact of uterine manipulation? Gynecol Oncol 119(3):496–499 Lee M et al (2013) Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective randomized clinical trial. Int J Gynecol Cancer 23(2):372–379 Momeni M et al (2013) Does the type of surgery for early-stage endometrial cancer affect the rate of reported lymphovascular space invasion in final pathology specimens? Am J Obstet Gynecol 208(1):71 e1–e6 Machida H et al (2018) Intrauterine Manipulator Use During Minimally Invasive Hysterectomy and Risk of Lymphovascular Space Invasion in Endometrial Cancer. Int J Gynecol Cancer 28(2):208–219 Machida H et al (2016) Timing of Intrauterine Manipulator Insertion During Minimally Invasive Surgical Staging and Results of Pelvic Cytology in Endometrial Cancer. J Minim Invasive Gynecol 23(2):234–241 Delair D et al (2013) Tumoral displacement into fallopian tubes in patients undergoing robotically assisted hysterectomy for newly diagnosed endometrial cancer. Int J Gynecol Pathol 32(2):188–192 Krizova A et al (2011) Histologic artifacts in abdominal, vaginal, laparoscopic, and robotic hysterectomy specimens: a blinded, retrospective review. Am J Surg Pathol 35(1):115–126 Akbayir O et al (2012) The novel criteria for predicting pelvic lymph node metastasis in endometrioid adenocarcinoma of endometrium. Gynecol Oncol 125(2):400–403 Zhang C, Wang C, Feng W (2012) Clinicopathological risk factors for pelvic lymph node metastasis in clinical early-stage endometrioid endometrial adenocarcinoma. Int J Gynecol Cancer 22(8):1373–1377 Chang SJ et al (2011) Lymph-vascular space invasion as a significant risk factor for isolated para-aortic lymph node metastasis in endometrial cancer: a study of 203 consecutive patients. Ann Surg Oncol 18(1):58–64 Park JY et al (2010) The role of pelvic and/or para-aortic lymphadenectomy in surgical management of apparently early carcinosarcoma of uterus. Ann Surg Oncol 17(3):861–868 Gadducci A et al (2009) Lymph-vascular space involvement and outer one-third myometrial invasion are strong predictors of distant haematogeneous failures in patients with stage I-II endometrioid-type endometrial cancer. Anticancer Res 29(5):1715–1720 Logani S et al (2008) Vascular "pseudo invasion" in laparoscopic hysterectomy specimens: a diagnostic pitfall. Am J Surg Pathol 32(4):560–565 Zhang C et al (2014) Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: a single institution study of 458 patients. Gynecol Oncol 133(2):211–215 Sohaib SA et al (2007) Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis. Clin Radiol 62(1):28–34; discussion 35 – 6 Ramirez PT et al (2018) Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer. N Engl J Med 379(20):1895–1904 Chiva L et al (2020) SUCCOR study: an international European cohort observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer. Int J Gynecol Cancer 30(9):1269–1277 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-538902","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":34360878,"identity":"132408ca-a75d-4d5b-8c8d-9a31d9a3d568","order_by":0,"name":"Ido Laskov","email":"","orcid":"https://orcid.org/0000-0002-5061-0670","institution":"Tel Aviv Sourasky Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ido","middleName":"","lastName":"Laskov","suffix":""},{"id":34360879,"identity":"7e21704f-c6b5-4990-874f-5b583553e74f","order_by":1,"name":"Nadav Michaan","email":"","orcid":"https://orcid.org/0000-0001-7987-404X","institution":"Tel Aviv University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nadav","middleName":"","lastName":"Michaan","suffix":""},{"id":34360880,"identity":"f8faa90f-a1a4-429d-94cb-9e0d1bcdb57b","order_by":2,"name":"Liron Kogan","email":"","orcid":"","institution":"Tel Aviv Sourasky Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liron","middleName":"","lastName":"Kogan","suffix":""},{"id":34360881,"identity":"6c57fcbc-941e-4b74-b4b5-fa71138548ab","order_by":3,"name":"Xing Zeng","email":"","orcid":"","institution":"McGill University and McGill University Health Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xing","middleName":"","lastName":"Zeng","suffix":""},{"id":34360882,"identity":"c587f14a-a1ae-4874-9aaa-8ed86cd1830d","order_by":4,"name":"Shannon Salvador","email":"","orcid":"https://orcid.org/0000-0002-8061-375X","institution":"Tel Aviv Sourasky Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shannon","middleName":"","lastName":"Salvador","suffix":""},{"id":34360883,"identity":"4f401631-b740-473e-b0e7-5cbcc4135943","order_by":5,"name":"Kris Jardon","email":"","orcid":"","institution":"McGill University and McGill University Health Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kris","middleName":"","lastName":"Jardon","suffix":""},{"id":34360884,"identity":"a7c7f2c9-9b34-4b3c-820f-764f6a34d377","order_by":6,"name":"Susie Lau","email":"","orcid":"","institution":"Tel Aviv Sourasky Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Susie","middleName":"","lastName":"Lau","suffix":""},{"id":34360885,"identity":"f97f7722-2e8c-4042-b471-b89b94bb3257","order_by":7,"name":"Lucy Gilbert","email":"","orcid":"https://orcid.org/0000-0001-8605-5472","institution":"McGill University and McGill University Health Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lucy","middleName":"","lastName":"Gilbert","suffix":""},{"id":34360886,"identity":"28ee4e0f-a0b8-4028-9dc1-cfa4b48431cf","order_by":8,"name":"Walter H. Gotlieb","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIie3QvWrDMBAHcIlApxavzuRXcJdOqfwgXWwE3bx31BFQlhat8ZwXyJihwxlDvZhmNWSxl87O1kILkZyPdpHbsRD9B3GI+6E7EeLi8i8zEqcCqZjoggI2g4TC3lxQQ+7NjcD4r0Q3F309SMIynzXbZ8JUAIDb1frOUwvzCguspEoA5m+EZ5KKPKs26bxuDeHXwkJuMIHpJRIevuipruQmXfq5IXovG1m3MP08ki/5eiKRldT6FYKE9YRKTJce9CSxkahuIXtEPx7LRORPFde7mE8OObeRseLYveMk8kZF0X2sWKpU2TbdA7u1kUP8H2P4sT7C4f5+wO/Sw9/bXVxcXM4qO/6DcCVhcZY7AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-6227-6369","institution":"Tel Aviv Sourasky Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Walter","middleName":"H.","lastName":"Gotlieb","suffix":""},{"id":34360887,"identity":"ec52629b-3837-48d1-b765-c4f1118aa9d9","order_by":9,"name":"Roy Kessous","email":"","orcid":"","institution":"Tel Aviv Sourasky Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Roy","middleName":"","lastName":"Kessous","suffix":""}],"badges":[],"createdAt":"2021-05-19 13:14:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-538902/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-538902/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":10753096,"identity":"2b59fb60-ed9d-4336-80a8-8cd959d28714","added_by":"auto","created_at":"2021-06-24 20:32:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":282063,"visible":true,"origin":"","legend":"Distribution of patients eligible for analysis.","description":"","filename":"FIG1copy.jpg","url":"https://assets-eu.researchsquare.com/files/rs-538902/v1/709bdeb077a51bc1ea896d40.jpg"},{"id":10753094,"identity":"44815021-71c5-4c44-a581-23b0fc8e0194","added_by":"auto","created_at":"2021-06-24 20:32:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":320333,"visible":true,"origin":"","legend":"Disease-free survival, Kaplan-Meyer curves compare disease-free survival in the manipulator vs no manipulator groups, for patients who received adjuvant treatment (A) and patients that did not receive adjuvant treatment (B).","description":"","filename":"FIG2copy.jpg","url":"https://assets-eu.researchsquare.com/files/rs-538902/v1/9266b6a5812315adf70c0f29.jpg"},{"id":13700387,"identity":"33329ae6-5a11-4cb7-b528-b72356289b01","added_by":"auto","created_at":"2021-09-17 13:24:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":764500,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-538902/v1/f0224787-4842-4e77-86e8-d92853e8d26e.pdf"}],"financialInterests":"","formattedTitle":"The Impact of Intra-Uterine Manipulators on Outcome and Recurrence Patterns of Endometrial Cancer Patients Undergoing Minimally Invasive Surgery","fulltext":[{"header":"Introduction","content":" \u003cp\u003eCurrently, the gold standard treatment for patients diagnosed with endometrial cancer is based primarily on staging surgery followed by adjuvant treatment if indicated [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. After the primary surgery, patients are divided into risk groups (low, intermediate, and high) that will guide physicians as to the recommended adjuvant treatment if needed. The division into the different risk groups is based on multiple factors including patients' age, histologic subtype, tumor grade, staging of disease and presence of lympho-vascular space invasion [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Approximately 6\u0026ndash;13% of all patients with endometrial cancer will develop recurrent disease, the majority during the first 3 years after a primary diagnosis with primary location in the vaginal vault [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTwo minimally invasive (MIS) approaches are used for endometrial cancer staging surgery, total laparoscopic hysterectomy (TLH) and robotically assisted total laparoscopic hysterectomy (RH) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Compared to laparotomy, the benefits of minimal invasive approach hysterectomy for endometrial cancer, include reduced blood loss, shorter recuperation time, lower cost, less use of pain medication, faster recovery, similar or fewer post-operative adverse events, and better quality of life up to 6 months after surgery [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, no significant difference exists in cancer recurrence or outcome between MIS and laparotomy cases, indicating comparable oncologic safety of MIS [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor proper uterine manipulation during minimal invasive hysterectomy, various uterine manipulators are used with or without an intrauterine segment (usually a screw, a rod or a balloon) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The intra-uterine component is inserted into the uterine cavity in order to allow surgeons manipulation of the uterus for better exposure. In addition to the intrauterine component, some of the uterine manipulators have a colpotomizer (cervical cap) that assists in identifying the anatomic landmarks such as the vaginal fornices and allow to increase the distance between the ureter and the vaginal vault [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNevertheless, some surgeons are avoiding the use of the intrauterine component in cases of endometrial cancer, for concern of iatrogenic spillage, uterine perforation, and the potential risk of retrograde dissemination of cancer cells into the peritoneal cavity or the lymphatic spaces. In order to avoid this potential spread, some surgeons choose either not to use a uterine manipulator at all or to use an uterine manipulator with a colpotomizer but without an intrauterine segment [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the effect of the use of an intrauterine manipulator on the recurrence rate and outcome of patients undergoing minimal invasive staging surgery for endometrial cancer.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and setting\u003c/h2\u003e \u003cp\u003e A retrospective cohort study, identifying all consecutive patients who underwent a minimal invasive hysterectomy for endometrial cancer at the McGill university tertiary-care hospitals during the years 2008\u0026ndash;2016. All surgeries were performed by laparoscopic or robotic approach by 6 gynecologic oncology surgeons. MIS for staging of endometrial cancer included peritoneal cytology, total hysterectomy and salpingo-oophorectomy, with or without pelvic and/or para-aortic lymph node dissection (LND) or sentinel lymph node detection (SLND). In cases where the pre-operative histology was papillary serous or clear cell, surgical staging also included omentectomy, examination of the entire abdomino-pelvic cavity and retroperitoneal spaces. During the study period, routine coagulation of the fallopian tubes at the beginning of the procedure to avoid possible intraperitoneal spread of disease was not performed. Patients who had uterine perforation, morcellation, or conversion to laparotomy were excluded from the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eUterine manipulators\u003c/h2\u003e \u003cp\u003eDuring the study, uterine manipulators that were used were either a Clermont Ferrand manipulator (Karl Storz, Tuttlingen, Germany), RUMI uterine manipulator with a Koh colpotomizer system (Cooper Surgical, Trumbull, CT, USA) or a ZUMI uterine manipulator (Cooper Surgical, Trumbull, CT, USA). In other cases, either a uterine manipulator was not used or an adjustment was made to the Hohl uterine manipulator (Storz, El Segundo, CA) so that it included only the handle with its colpotomizer without its intra-uterine component as described previously by our group [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The decision as to the type of intrauterine manipulator or lack of it was left to the discretion of the surgeon.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical information\u003c/h2\u003e \u003cp\u003eData was collected from the department\u0026rsquo;s digital records, including operative reports, pathology reports, chemotherapy records, radiation oncology reports, laboratory results, and radiology reports were reviewed to determine baseline and perioperative characteristics until the end of follow-up period or death for each patient.\u003c/p\u003e \u003cp\u003eBaseline characteristics included age, body mass index and medical comorbidities. Perioperative data included the surgical procedure with the type of uterine manipulator or colpotomizer used, stage of malignancy based on the 2009 FIGO for endometrial carcinoma [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], grade, histology, depth of myometrial invasion, lymph-vascular space invasion, fallopian tube and ovarian involvement, lower uterine segment and cervix involvement, lymph node involvement with total count, uterine size, tumor size and classification of pelvic cytology. Pelvic cytology was routinely obtained as follows: the suction irrigator was used to infuse saline into the pelvis following placement of the uterine manipulator. The manipulator was used to displace the uterus anteriorly while the saline was retrieved using the suction irrigator device; volume was not standardized. Because the risk of tumor dissemination may be related to tumor size and volume, measurements provided in the gross and microscopic sections of pathology reports were used to determine the maximum diameter of tumor and to calculate tumor volume if three-dimensional measurements were provided. Post-operative complications were collected in real time.\u003c/p\u003e \u003cp\u003eFor those patients who had recurrence, disease free survival (DFS) was defined as time from last treatment to the diagnosis of recurrence. Overall survival (OS) was defined as time from diagnosis to time of last follow-up or death. Recurrences were diagnosed clinically or radiologically. All vaginal recurrences were biopsy proven. During the surveillance period, routine follow-up examinations were performed at intervals of 4 months during the first two years, followed by every 6 months for up to 5 years, and then yearly until the end of the follow-up period or death. To assess the effect of different uterine manipulator types on LVSI, positive cytology and patient\u0026rsquo;s outcome, patients were divided into two groups. The first group (Intrauterine manipulator group) included patients who were operated using a uterine manipulator that necessitates a cervical os dilation prior to the placement of the intrauterine rod (Clermont Ferrand, RUMI or ZUMI) and a second group (No intrauterine manipulator group) of patients that were operated either without a uterine manipulator or using the intravaginal part of a Hohl uterine manipulator without the intrauterine manipulator, as previously published (10).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was done using SPSS software (IBM, SPSS statistics, Version 25, 2017. IBM\u0026reg; corp. Armonk, NY, USA). All statistical analyses were 2 sided and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. Continuous variables were compared using either one-way ANOVA or Kruskal- Wallis and Mann-Whitney tests according to distribution of variables. Chi squared test or Fishers' exact test were used to compare categorical variables. Disease free survival and overall survival were calculated using Kaplan Meier estimator and compared with log rank test with reverse censoring method. Univariate as well as multivariate cox regression analysis was used to evaluate the association between each of the predictors and disease-free survival and overall survival.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cp\u003eDuring the study period we identified 782 patients who underwent minimal invasive hysterectomy for endometrial intraepithelial neoplasia (EIN) and newly diagnosed endometrial cancer. Eighty three patients (10.6%) were excluded from the study: 54 patients with EIN, 22 patients required conversion to laparotomy (2.8%), most of those required a simple mini-laparotomy at the end of the procedure in order to remove the uterus that could not be removed intact via the vagina (utero-vaginal disproportion) and 9 patients had a large uterus that was morcellated within an endobag placed via the vagina (1.1%). After exclusion, six-hundred and sixty-nine patients were included in the analysis and the clinicopathologic characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean patient age was 64 years (SD 11), and the mean body mass index (BMI) was 31.7 kg/m\u003csup\u003e2\u003c/sup\u003e (SD 8.6). Six hundred and thirteen patients (88%) underwent robotic assisted hysterectomy and 86 patients (12%) underwent laparoscopic hysterectomy. In four hundred and eighty-four patients (69%) the procedure included pelvic lymph node dissection (PLND) and for 203 patients (29%), para aortic lymph node dissection was performed in addition to PLND. The most common uterine manipulator used was the Hohl retractor (60%) without intrauterine component, followed by the Clermont Ferrand manipulator (19%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics and surgical outcomes (n\u0026thinsp;=\u0026thinsp;699).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;699)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, mean (SD), y\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.5 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI, mean (SD), kg/m2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.7 (8.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eSurgery mode, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRobotic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e613 (88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLaparoscopic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eSurgical procedure, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e484 (69.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTH\u0026thinsp;+\u0026thinsp;BSO\u0026thinsp;+\u0026thinsp;PLND\u0026thinsp;+\u0026thinsp;PaLND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e203 (29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003eManipulator type, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHohl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e420 (60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e136 (19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZUMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRUMI/Koh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eHistology, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e546 (78)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSerous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cb\u003eStage\u0026dagger;, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e416 (59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e113 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116 (17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eTumor grade\u0026dagger;, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e301 (43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e193 (28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e205 (29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eMyometrial invasion, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLess than half\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e582 (83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMore than half\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph vascular invasion, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e206 (29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph node retrieval number, mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.3 (8.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive Lymph node metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive cytology, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eAdjuvant therapy, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e369 (53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRTx only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124 (17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCTx only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombined RTx\u0026thinsp;+\u0026thinsp;CTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e180 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow up time, median (range), month\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (29\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eSD, standard deviation; BMI, body mass index; TH, total hysterectomy; BSO, bilateral salpingo-oophorectomy; PLND, pelvic lymph node dissection; PaLND, para aortic lymph node dissection; CF, Clermont Ferrand; RTx, radiotherapy; CTx, chemotherapy.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u0026dagger;Tumor stage is presented according to the 2009 International Federation of Gynecology and Obstetrics stage and histologically classified and graded according to the World Health Organization.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe majority of patients had stage I disease (n\u0026thinsp;=\u0026thinsp;528, 75%) and endometrioid histology (n\u0026thinsp;=\u0026thinsp;546, 78%), whereas 205 patients (29%) had grade 3 disease. Three hundred and thirty patients (44%) with moderate to high risk factors received adjuvant treatment, either radiotherapy, chemotherapy or combination of the two. The median follow-up time was 44 (range 29\u0026ndash;67) months.\u003c/p\u003e \u003cp\u003eOut of the 699 eligible patients, 220 (31.4%) underwent surgery with the support of an intrauterine manipulator (Intrauterine manipulator group) and in 479 patients (68.6%) no intrauterine manipulator was used (No intrauterine manipulator group). The distribution is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no significant differences between the two groups with regard to age at surgery, BMI, histologic type, FIGO stage, LVSI, tumor size and lymph node retrieval number (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Women in the intrauterine manipulator group had significantly more grade 1 disease (50% vs. 39%, p\u0026thinsp;=\u0026thinsp;0.01) and positive cytology (8.8% vs. 4.4%, p\u0026thinsp;=\u0026thinsp;0.02) compared to women in the no intrauterine manipulator group. Eighty-seven patients (39.5%) in the intrauterine manipulator group compared to 243 (50.7%) in the no intrauterine manipulator were classified to be intermediate/high risk for recurrence and received adjuvant treatment (p\u0026thinsp;=\u0026thinsp;0.006). 27 patients (12.3%) recurred in the intrauterine manipulator group, compared to 57 (11.9%) patients in the no intrauterine manipulator group (p\u0026thinsp;=\u0026thinsp;0.88). Vaginal vault recurrence was the most common site of recurrence, occurring in 10 (4.5%) patients in the intrauterine manipulator group vs. 6 (1.3%) patients in the no intrauterine manipulator group (p\u0026thinsp;=\u0026thinsp;0.007). Nine patients (4.1%) in the intrauterine manipulator group had pelvic recurrences vs. 9 pelvic recurrences (1.9%) in the no intrauterine manipulator group (p\u0026thinsp;=\u0026thinsp;0.08). Lower limb lymphedema was the most prevalent post-operative complication, occurring in 16 (7.3%) patients of the manipulator group compared to 12 (2.5%) patients in the no manipulator group (p\u0026thinsp;=\u0026thinsp;0.003). Less common complications were wound and urinary infections but did not show statistical difference between the groups. Median DFS and OS were not reached and were not statistically different between the two groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics and surgical outcomes with patterns of recurrence (n\u0026thinsp;=\u0026thinsp;699) and subgroup analysis for patients who did not receive adjuvant treatment (n\u0026thinsp;=\u0026thinsp;369).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntra-uterine manipulator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo intra-uterine manipulator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal Cohort\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;220\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;479\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, mean (SD), years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.9 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64.3 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.605\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI, mean (SD), kg/m2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.2 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.0 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.392\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eHistology, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEndometrioid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179 (81.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e367 (76.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSerous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (11.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65 (13.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (2.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (6.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eStage\u0026dagger;, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e144 (65.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e271 (56.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89 (18.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (6.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (17.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (16.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eTumor grade\u0026dagger;, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111 (50.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e189 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54 (24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e139 (29.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e150 (31.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph vascular invasion, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (31.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e137 (28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.478\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph node retrieval number, mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.8 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.6 (7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive Lymph node metastasis, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.525\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive cytology, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size, median (range), cm\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.2 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.3 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUterine size, median (range), cm\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.2 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.8 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eAdjuvant therapy, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (39.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e243 (50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRTx only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.033\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCTx only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombined RTx\u0026thinsp;+\u0026thinsp;CTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRecurrence, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.888\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003e\u003cb\u003eSite, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaginal vault\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePelvic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbdominal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.563\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRetroperitoneal LN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.736\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultiple site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.814\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eComplications, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLymphedema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWound infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUrinary infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.875\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaginal cuff\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.325\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDeath, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.378\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSubgroup Analysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;133\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;236\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLymph vascular invasion, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive cytology, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRecurrence (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVaginal vault recurrence, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eSD, standard deviation; BMI, body mass index.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026dagger;Tumor stage is presented according to the 2009 International Federation of Gynecology and Obstetrics stage and histologically classified and graded according to the World Health Organization.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo further assess the effect of uterine manipulation on patient\u0026rsquo;s outcome we have performed a subgroup analysis of all patients who did not receive adjuvant treatment (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the intrauterine manipulator group, 11 (8.3%) patients recurred as compared to 7 (3%) in the no intrauterine manipulator group (p\u0026thinsp;=\u0026thinsp;0.02), with a 5.3% rate of vaginal vault recurrence compared to 0.8% (p\u0026thinsp;=\u0026thinsp;0.01). Median DFS was not reached however, in a Kaplan-Meyer survival analysis, patients in whom no intrauterine manipulator was used had significantly better DFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, p\u0026thinsp;=\u0026thinsp;0.01). When all the patients were included, whether they received adjuvant treatment or not, no significant differences in DFS could be observed between the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo better assess the association between the use of intrauterine manipulator and recurrence rate as well as outcome of patients, a multivariate analysis was performed (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Figo stage, grade, LVSI, positive cytology and adjuvant treatment were all independently associated with risk of disease recurrence and decreased OS. The use of a uterine manipulator was not associated with the risk of relapse of endometrial cancer (Hazard ratio, 1.28; 95% confidence interval, 0.7\u0026ndash;2.1, p\u0026thinsp;=\u0026thinsp;0.3). The use of a uterine manipulator did not reach statistical significance for risk of relapse on a second multivariate analysis performed on the subgroup of patients who did not receive adjuvant treatment (Hazard ratio, 2.47; 95% confidence interval, 0.87\u0026ndash;7.01, p\u0026thinsp;=\u0026thinsp;0.08) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFactors associated with patient outcome in multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eDisease Free Survival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eOverall Survival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eHazard ratio (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eHazard ratio (95% CI)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal Cohort\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.05 (0.98\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.06 (1.03\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e 1A\u003c/p\u003e \u003cp\u003e1B\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.16 (0.9\u0026ndash;4.7)\u003c/p\u003e \u003cp\u003e3.8 (1.6\u0026ndash;9.3)\u003c/p\u003e \u003cp\u003e4.7 (2.2\u0026ndash;10.1)\u003c/p\u003e \u003cp\u003e10.4 (3.4\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.26 (0.94\u0026ndash;5.42)\u003c/p\u003e \u003cp\u003e3.51 (1.36\u0026ndash;9.04)\u003c/p\u003e \u003cp\u003e7.69 (3.35\u0026ndash;17.6)\u003c/p\u003e \u003cp\u003e24.7 (8.1\u0026ndash;75.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade\u003c/b\u003e 1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.89 (0.8\u0026ndash;4.45)\u003c/p\u003e \u003cp\u003e4.4 (1.78-11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.143\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.92 (1.01\u0026ndash;8.46)\u003c/p\u003e \u003cp\u003e6.69 (2.25\u0026ndash;19.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.048\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCytology\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.19 (1.1\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.98 (1.03\u0026ndash;3.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.039\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVSI\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.84 (1.05\u0026ndash;3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.81 (1.01\u0026ndash;3.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.044\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eManipulator\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNot used\u003c/p\u003e \u003cp\u003eUsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.28 (0.76\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.36 (0.81\u0026ndash;2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdjuvant treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNot used\u003c/p\u003e \u003cp\u003eUsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.59 (0.29\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.46 (0.24\u0026ndash;0.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSubgroup Analysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06 (0.9\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01 (0.9\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e 1A\u003c/p\u003e \u003cp\u003e1B\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.2 (0.6\u0026ndash;8.6)\u003c/p\u003e \u003cp\u003e1.6 (0.15-18)\u003c/p\u003e \u003cp\u003e29 (3.9\u0026ndash;225)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003cp\u003e0.2\u003c/p\u003e \u003cp\u003e0.6\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1 (0.2\u0026ndash;4.5)\u003c/p\u003e \u003cp\u003e1.2 (0.05-27)\u003c/p\u003e \u003cp\u003e6.9 (0.6\u0026ndash;73)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003cp\u003e0.8\u003c/p\u003e \u003cp\u003e0.1\u003c/p\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade\u003c/b\u003e 1\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.6 (0.1\u0026ndash;2.9)\u003c/p\u003e \u003cp\u003e1.6 (0.3\u0026ndash;7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.05 (0.3\u0026ndash;3.6)\u003c/p\u003e \u003cp\u003e2.3 (0.3\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCytology\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.98 (1.03-38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLVSI\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e7.5 (2.1\u0026ndash;26.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.5 (0.2\u0026ndash;8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eManipulator\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNot used\u003c/p\u003e \u003cp\u003eUsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.47 (0.8-7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.1 (0.4-3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCI, Confidence interval; LVSI, lymph vascular space invasion.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eConcerns remain that the introduction of a device into the endometrial cavity may cause disruption of endometrial cancer cells and affect patient\u0026rsquo;s outcome. Available data is limited and indicates that this type of disruption does not seem to have clinically observable adverse effects [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Data regarding the possible effect of the use of intrauterine manipulators on the long-term outcome of patients with endometrial cancer is scarce. As a result, debates still take place in the gynecologic oncology community raising concern about the use of these devices. Two previous studies have tried to analyse survival after laparoscopic surgery for endometrial cancer using a uterine manipulator. However, those were largely underpowered to investigate long-term outcomes (\u0026lt;\u0026thinsp;70 patients included in each group) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In a multicenter study by the Italian society of gynecological endoscopy, authors reviewed data from 951 consecutive patients who underwent laparoscopic surgery for endometrial cancer with or without intrauterine manipulator. In this study, data regarding the effect of the manipulator on the rate of positive cytology and LVSI was not reported but results showed a non-significant difference in the recurrence rate (13.5% vs. 11.6%) between the manipulator and no manipulator groups [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Results of our study raise some safety concerns regarding the use of uterine manipulators during MIS for endometrial cancer. For the entire cohort, total recurrence rate was similar between the two comparison groups but with higher rates of local vaginal recurrence for patients in whom a uterine manipulator was used during surgery. After excluding patients who received adjuvant treatment, the rate of vaginal vault recurrence and total recurrence was significantly higher with a worse DFS in the intra-uterine manipulator group compared to the no manipulator group. However, the use of a uterine manipulator was not found to be a predictor of worse outcome on multivariate analysis that was performed for the entire cohort but was close to statistical significance when performed for the subgroup of patients who did not receive adjuvant treatment.\u003c/p\u003e \u003cp\u003eA recent multicenter study by the Spanish society of gynecology and obstetrics, followed over 2000 women with uterus confined endometrial cancer who underwent minimally invasive surgery and found, in concordance with the results presented here, that patients that were operated using a uterine manipulator had worse oncological outcome [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA possible explanation might be that local recurrence may be salvageable by either surgery or radiotherapy, with good long term outcomes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Following recurrence, most patients in our cohort were either operated or received radiotherapy with or without chemotherapy. This is also in accordance to the previously reported LAP2 study that found a potential increased risk of uterine cancer recurrence with manipulator assisted laparoscopic hysterectomies compared to hysterectomies via laparotomy but this risk was quantified and found to be small [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. We can speculate that the effect of higher recurrence rates on long term outcome of patients in the manipulator group, was eventually diluted by additional treatment modalities and that the presence of a uterine manipulator during surgery did not negatively affect the outcome of endometrial cancer patients on multivariate analysis.\u003c/p\u003e \u003cp\u003eOur results show that the use of an intra-uterine manipulator in MIS for endometrial cancer was not associated with an increase in rates of LVSI, however, we found higher incidence of positive cytology in patients for whom a uterine manipulator was used during surgery. Previously published studies regarding LVSI and positive peritoneal cytology are conflicting, with some suggesting that the use of manipulators does not affect positive peritoneal cytology and/or LVSI [\u003cspan additionalcitationids=\"CR21 CR22 CR23\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], while other studies show an association between uterine manipulator use and positive peritoneal cytology and/or LVSI [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. LVSI was previously shown to be an independent adverse prognostic factor for extra-uterine disease, particularly pelvic lymph node metastasis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], isolated para-aortic lymph node Metastasis [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and distant hematogenous recurrences [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. LVSI in the presence of a uterine manipulator may reflect true invasion, pseudo-invasion, or an artifact of manipulator use that resulted in cell displacement into the vessels via a closed pressure system [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In the current study, LVSI was found in 27% of patients, which is in agreement previously published data. According to our results, the use of intrauterine manipulator was not associated with a significant difference in the rate of LVSI.\u003c/p\u003e \u003cp\u003eWith regard to positive cytology, we found that the rate of positive cytology was significantly higher in the group of patients who had an intra-uterine manipulator. Positive cytology was an independent prognostic factor for both DFS and OS on univariate and multivariate analysis. Other reports showed similar results that peritoneal washings were significantly more likely to be positive in women in whom a uterine manipulator had been used [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. To elucidate whether the use of intra-uterine manipulator increases the risk of positive cytology, its necessary to obtain cytology twice in the same individual, before and after the insertion of the intra-uterine manipulator and compare them.\u003c/p\u003e \u003cp\u003eThe current study offers several strengths; data was collected from a large cohort of patients who underwent surgery by a team of surgeons who share a joint surgical protocol and unified approach. This enhances the impact of the use of intrauterine manipulators and allows the current comparison. Moreover, in our study we were also able to perform a subgroup analysis that excludes the effect of adjuvant radiation treatment on the outcome measures. In addition, the follow up time in our study is relatively long and was previously shown to include over 90% of recurrences from initial treatment [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, this study is not without limitations including the inherent limitations that results from its retrospective nature. In addition, we did not perform coagulation of the tubes at the beginning of the procedure and this might have an effect with regard to positive cytology.\u003c/p\u003e \u003cp\u003eFinally, in the current study we deal with the long-term outcome of uterine manipulators in endometrial cancer, but can we extrapolate these results to cervical cancer? Could the data presented here provide some hints to explain the poorer results for cervical cancer patients undergoing minimal invasive surgery with a uterine manipulator. Several theories have been proposed to explain the unexpected results of the LACC trial that compared minimally invasive radical hysterectomy to open abdominal radical hysterectomy among women with early-stage cervical cancer. One theory suggests that the use of a uterine manipulator is a possible cause of the poorer oncological outcome after minimal invasive radical hysterectomy for cervical cancer [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The results presented here show higher recurrence rates, mainly at the vaginal vault and decreased disease-free survival in a subgroup of patients who were operated using an intra-uterine manipulator and did not receive adjuvant treatment. In contrast to cervical cancer, the rise in disease recurrence did not significantly affect OS. We can speculate that this could either be related to differences in the biology of squamous cell carcinomas of the cervix and endometrial cancers, and/or be due to the salvage potential of the treatment modalities for recurrent localized endometrial cancer. A recent international European observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer found that patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse and those without the use of a uterine manipulator had similar disease-free-survival to the open surgery group [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, results of the current study show that the use of an intra uterine manipulator is associated with a minimal impact on the oncological outcomes of patient who undergo MIS and adjuvant treatment for endometrial cancer, but may have implications on outcome for low risk patients who do not receive adjuvant treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003enot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003enot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests:\u003c/strong\u003e The authors report no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e Ethical approval was waived by the local Ethics Committee of University A in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u003c/strong\u003e this work was supported by grants from the Israel Cancer Research Fund and the Gloria\u0026rsquo;s Girls. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIdo Laskov:\u003c/strong\u003e Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing - original draft, Writing - review \u0026amp; editing, Visualization, Supervision, Project administration. \u003cstrong\u003eNadav Michaan:\u003c/strong\u003e Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Visualization. \u003cstrong\u003eLiron Kogan:\u003c/strong\u003e Conceptualization, Investigation, Data curation, Writing - review \u0026amp; editing. \u003cstrong\u003eXing Zeng:\u003c/strong\u003e Resources, Investigation, Data curation, Writing - review \u0026amp; editing. \u003cstrong\u003eShannon Salvador:\u003c/strong\u003e Resources, Investigation, Data curation, Writing - review \u0026amp; editing. \u003cstrong\u003eKris Jardon:\u003c/strong\u003e Resources, Investigation, Data curation, Writing - review \u0026amp; editing. \u003cstrong\u003eSusie Lau:\u003c/strong\u003e Resources, Investigation, Data curation, Writing - review \u0026amp; editing. \u003cstrong\u003eLucy Gilbert:\u003c/strong\u003e Resources, Investigation, Data curation, Writing - review \u0026amp; editing, Supervision. \u003cstrong\u003eWalter H. Gotlieb:\u003c/strong\u003e Conceptualization, Methodology, Investigation, Resources, Data curation, Writing - original draft, Writing - review \u0026amp; editing, Supervision. \u003cstrong\u003eRoy Kessous:\u003c/strong\u003e Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing - original draft, Writing - review \u0026amp; editing, Visualization.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCreutzberg CL et al (2000) Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355(9213):1404\u0026ndash;1411\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKeys HM et al (2004) A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 92(3):744\u0026ndash;751\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGroup AES et al (2009) Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 373(9658):137\u0026ndash;146\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCreutzberg CL et al (2011) Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. 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Arch Gynecol Obstet 292(5):1003\u0026ndash;1011\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNassif J, Wattiez A (2010) Clermont Ferrand uterine manipulator. Surg Technol Int 20:225\u0026ndash;231\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeeters F et al (2010) Technical modifications in the robotic-assisted surgical approach for gynaecologic operations. Journal of Robotic Surgery 4(4):253\u0026ndash;257\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenedet JL et al (2000) FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 70(2):209\u0026ndash;262\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEltabbakh GH, Mount SL (2006) Laparoscopic surgery does not increase the positive peritoneal cytology among women with endometrial carcinoma. Gynecol Oncol 100(2):361\u0026ndash;364\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolyzos NP et al (2010) Intraperitoneal dissemination of endometrial cancer cells after hysteroscopy: a systematic review and meta-analysis. Int J Gynecol Cancer 20(2):261\u0026ndash;267\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShinohara S et al (2017) Risk of spilling cancer cells during total laparoscopic hysterectomy in low-risk endometrial cancer. Gynecol Minim Invasive Ther 6(3):113\u0026ndash;115\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUccella S et al., \u003cem\u003eThe effect of a uterine manipulator on the recurrence and mortality of endometrial cancer: a multi-centric study by the Italian Society of Gynecological Endoscopy\u003c/em\u003e. Am J Obstet Gynecol, 2017. 216(6): p. 592 e1-592 e11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarcos-Sanmartin J et al (2016) Does the Type of Surgical Approach and the Use of Uterine Manipulators Influence the Disease-Free Survival and Recurrence Rates in Early-Stage Endometrial Cancer? Int J Gynecol Cancer 26(9):1722\u0026ndash;1726\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTinelli R et al (2016) Laparoscopic treatment of early-stage endometrial cancer with and without uterine manipulator: Our experience and review of literature. Surg Oncol 25(2):98\u0026ndash;103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePadilla-Iserte P et al., \u003cem\u003eImpact of uterine manipulator on oncological outcome in endometrial cancer surgery\u003c/em\u003e. Am J Obstet Gynecol, 2020\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHardarson HA et al (2015) Vaginal vault recurrences of endometrial cancer in non-irradiated patients - Radiotherapy or surgery. Gynecol Oncol Rep 11:26\u0026ndash;30\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrimer M et al (2010) Micrometastasis of endometrial cancer to sentinel lymph nodes: is it an artifact of uterine manipulation? Gynecol Oncol 119(3):496\u0026ndash;499\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee M et al (2013) Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective randomized clinical trial. Int J Gynecol Cancer 23(2):372\u0026ndash;379\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMomeni M et al (2013) Does the type of surgery for early-stage endometrial cancer affect the rate of reported lymphovascular space invasion in final pathology specimens? Am J Obstet Gynecol 208(1):71 e1\u0026ndash;e6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMachida H et al (2018) Intrauterine Manipulator Use During Minimally Invasive Hysterectomy and Risk of Lymphovascular Space Invasion in Endometrial Cancer. Int J Gynecol Cancer 28(2):208\u0026ndash;219\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMachida H et al (2016) Timing of Intrauterine Manipulator Insertion During Minimally Invasive Surgical Staging and Results of Pelvic Cytology in Endometrial Cancer. J Minim Invasive Gynecol 23(2):234\u0026ndash;241\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelair D et al (2013) Tumoral displacement into fallopian tubes in patients undergoing robotically assisted hysterectomy for newly diagnosed endometrial cancer. Int J Gynecol Pathol 32(2):188\u0026ndash;192\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrizova A et al (2011) Histologic artifacts in abdominal, vaginal, laparoscopic, and robotic hysterectomy specimens: a blinded, retrospective review. Am J Surg Pathol 35(1):115\u0026ndash;126\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAkbayir O et al (2012) The novel criteria for predicting pelvic lymph node metastasis in endometrioid adenocarcinoma of endometrium. Gynecol Oncol 125(2):400\u0026ndash;403\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang C, Wang C, Feng W (2012) Clinicopathological risk factors for pelvic lymph node metastasis in clinical early-stage endometrioid endometrial adenocarcinoma. Int J Gynecol Cancer 22(8):1373\u0026ndash;1377\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChang SJ et al (2011) Lymph-vascular space invasion as a significant risk factor for isolated para-aortic lymph node metastasis in endometrial cancer: a study of 203 consecutive patients. Ann Surg Oncol 18(1):58\u0026ndash;64\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark JY et al (2010) The role of pelvic and/or para-aortic lymphadenectomy in surgical management of apparently early carcinosarcoma of uterus. Ann Surg Oncol 17(3):861\u0026ndash;868\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGadducci A et al (2009) Lymph-vascular space involvement and outer one-third myometrial invasion are strong predictors of distant haematogeneous failures in patients with stage I-II endometrioid-type endometrial cancer. Anticancer Res 29(5):1715\u0026ndash;1720\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLogani S et al (2008) Vascular \"pseudo invasion\" in laparoscopic hysterectomy specimens: a diagnostic pitfall. Am J Surg Pathol 32(4):560\u0026ndash;565\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang C et al (2014) Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: a single institution study of 458 patients. Gynecol Oncol 133(2):211\u0026ndash;215\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSohaib SA et al (2007) Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis. Clin Radiol 62(1):28\u0026ndash;34; discussion 35 \u0026ndash; 6\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamirez PT et al (2018) Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer. N Engl J Med 379(20):1895\u0026ndash;1904\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChiva L et al (2020) SUCCOR study: an international European cohort observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer. Int J Gynecol Cancer 30(9):1269\u0026ndash;1277\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"endometrial cancer, uterine manipulator, hysterectomy, recurrence","lastPublishedDoi":"10.21203/rs.3.rs-538902/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-538902/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose\u003c/p\u003e\u003cp\u003eTo evaluate the use of an intrauterine manipulator on the oncologic outcome of women who had minimally invasive surgery for endometrial cancer. \u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003eRetrospective analysis of consecutive patients who were operated with or without the use of an intrauterine manipulator. Univariate and multivariate analysis were used to adjust for possible confounders. \u003c/p\u003e\u003cp\u003eResults\u003c/p\u003e\u003cp\u003e699 patients were included, of whom 220 (32.8%) were operated with an intrauterine manipulator. The median follow-up was 44 months (range, 29-67). Disease-free survival was similar between groups. 19 (8.8%) patients had positive cytology in the manipulator group vs. 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). Sub-group analysis of 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 (HR, 1.28; 95% CI, 0.7-2.1, p=0.3) and for the sub-group of patients who did not receive adjuvant treatment (HR, 2.47; 95% CI, 0.8-7, p=0.08).\u003c/p\u003e\u003cp\u003eConclusion\u003c/p\u003e\u003cp\u003eThe use of a manipulator during surgery for endometrial cancer increases the risk of positive cytology as well as vaginal vault recurrences, but it does not reduce the disease-free and overall survival of patients.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"The Impact of Intra-Uterine Manipulators on Outcome and Recurrence Patterns of Endometrial Cancer Patients Undergoing Minimally Invasive Surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-06-24 20:32:48","doi":"10.21203/rs.3.rs-538902/v1","editorialEvents":[{"type":"communityComments","content":3}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fc76ce39-e059-4278-902e-3f17f8f6cf7d","owner":[],"postedDate":"June 24th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":5183311,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2021-09-10T16:02:45+00:00","versionOfRecord":[],"versionCreatedAt":"2021-06-24 20:32:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-538902","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-538902","identity":"rs-538902","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}