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Women diagnosed with early-stage (FIGO 1) endometrial cancer, grade 1 and 2 can have a good prognosis. Most of these women can be treated successfully with a hysterectomy and bilateral salpingo-oophorectomy and without the additional adjuvant treatment that is accompanied by more risks for complications. However, when recurrence does occur, the consequences can be dire. Accurate decisions must therefore be made by surgeons to avoid either under- or over-treatment. Risk and patient stratification for tailoring treatment still need further improvement. Both histopathology and genetic variants could be integrated into the decision process if relevant factors were identified. Morphological features and the presence of selected genetic mutations in isolated malignant endometrial epithelial cells from these tumors were analyzed in a strictly defined cohort of FIGO 1, grade 1 and 2 low-risk endometrial cancer. Their presence in this cohort, their relation to recurrence, and the association between histopathological features and mutations were determined. This analysis was performed using archival formalin-fixed paraffin-embedded tissue, complete re-evaluation of histopathological features, laser capture microdissection of epithelial cells, and a polymerase chain reaction-based mutational screening assay. Twenty-one women with recurrence, after initial identification as low-risk endometrial cancer, were compared with 20 matched control women. The histological marker of lymphovascular invasion was significantly associated with recurrence. There was also a very high prevalence of mutations in CTNNB1 gene, occurring in 50% of this cohort. PTEN mutations were also observed in 27.8% of cases and PIK3CA mutations in 22.2%; none of these mutations were significantly related to recurrence. This study supports the importance of lymphovascular space invasion to identify women with significant risk for recurrence in initially low-risk, early-stage endometrial cancer. It also identifies CTNNB1 as a significant mutation in early-stage disease, and although it may not represent a marker for recurrence its high prevalence in early stage disease could have relevance for both pathogenesis and early treatment.

IntroductionIn 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system.Materials and methodsWe classified molecularly a cohort of 604 women diagnosed with endometrial cancer using immunohistochemistry for TP53 and MMR proteins on a tissue microarray, as well as Sanger sequencing for POLE mutations. These results, combined with clinicopathologic data, allowed the patients to be risk grouped using both the new 2021 molecular/clinicopathologic parameters and the prior 2016 clinicopathologic system. In addition, clinical treatment and outcome data were collected from medical records.ResultsThe application of the 2021 molecular markers shows Kaplan-Meier curves with a significant difference between the groups for all survival. Molecular classification under the 2021 guidelines revealed a total of 39 patients (39/594, 7%) with a change in risk group in relation to the 2016 classification system: the shift was alone due to either P53abn or POLEmut molecular marker. In order to ensure correct 2021 molecular risk classification, not all patients with endometrial cancer need a molecular diagnostic: 386 (65.0%) cases would need to be analyzed by TP53 IHC, only 44 (7.4%) by MMR IHC and 109 (18.4%) POLE sequencing reactions.ConclusionApplication of the 2021 molecular risk groups is feasible and shows significant differences in survival. IHC for TP53 and MMR and applying POLE sequencing is only needed in selected cases and leads to shifting risk groups both upward and downward for a sizeable number of patients.

Objective To evaluate the ability of demographic and sonographic variables and the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE) classification to predict preoperatively tumor recurrence or progression in women with endometrial cancer. Methods The study included 339 women with histologically confirmed endometrial cancer who underwent expert transvaginal ultrasound in a single center before surgery as part of the prospective International Endometrial Tumor Analysis 4 study or who were evaluated using the same protocol. The tumors were classified according to histotype, FIGO (International Federation of Gynecology and Obstetrics) grade and FIGO stage. In addition, molecular analysis was performed for classification into the four ProMisE subtypes: polymerase‐ϵ exonuclease domain mutations (POLE EDM), mismatch repair proteins deficiency (MMR‐D), protein 53 wild type (p53 wt) and protein 53 abnormal (p53 abn). Demographic and preoperative sonographic characteristics, tumor recurrence or progression and survival were compared between the ProMisE subgroups. Cox regression analysis was used to identify prognostic factors associated with recurrence or progression, using univariable models to study crude associations and multivariable models to study adjusted associations. Logistic regression and receiver‐operating‐characteristics (ROC)‐curve analysis were used to assess the predictive ability of the preoperative prognostic factors regarding recurrence or progression of cancer within 3 years after surgery, and to compare their predictive ability to that of the European Society for Medical Oncology (ESMO) preoperative (based on depth of myometrial invasion, histotype and grade) and postoperative (based on histotype, grade, surgical stage and lymphovascular space invasion) risk classifications. In a separate subanalysis, cases were stratified according to ProMisE p53 abn status (present vs absent) and sonographic tumor size (anteroposterior (AP) diameter

Background Breast cancer is a leading cause of cancer-related death in women worldwide. Despite extensive studies in all areas of basic, clinical and applied research, accurate prognosis remains elusive, thus leading to overtreatment of many patients. Diagnosis could be improved by introducing multigene molecular scores in standard clinical practice. Several tests that work with formalin-fixed tissue have become routine. Molecular scores usually include several genes representing processes, response to oestrogens, progestogens and human epidermal growth factor receptor 2 (Her2), respectively, which are combined additively in single values. These multi-gene scores have the advantage of being more robust and reproducible than single-gene scores. Their utility may be further enhanced by combining them with classical diagnostic parameters. Here, we present an exploratory study comparing the RISK and research versions of Oncotype DX recurrence score (RS), Prosigna Risk of Recurrence (ROR) and EndoPredict (EP) with respect to their prognostic potential for ipsilateral recurrence and/or distant relapse in brain, and we compared the scores to the intrinsic subtypes based on PAM50. Methods RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue cores of primary tumours, local recurrences and brain metastases. Gene expression was measured on a NanoString nCounter Analysis System. Intrinsic subtypes and molecular scores were computed according to published literature and RISK, RS, ROR and EP were compared against each other and to the intrinsic subtypes Luminal A (lumA), Luminal B (lumB), Her2-enriched (Her2↑), Basal-like (basal), and Normal-like (normal) of PAM50. Local recurrences and brain metastases were compared to their corresponding primary tumours. Results All four molecular scores were highly correlated. Highest correlations were observed among genes related to proliferation while lower correlations were found among oestrogen-related genes. The scores were significantly higher in primary tumours progressing to brain metastases as compared to recurrence-free primary tumours and primary tumours that relapsed as local recurrences. Conclusions RISK and ROR-P are prognostic for primary tumours metastasizing to the brain. All four scores, RISK, RS, EP and ROR-P failed to discriminate between primary tumours that remained recurrence-free and primary tumours relapsing as local recurrences. Electronic supplementary material The online version of this article (10.1186/s12885-019-5752-8) contains supplementary material, which is available to authorized users.

Background and Purpose: In endometrial cancer, staging is performed surgically. Controversy about the required extent of lymph node removal is ongoing. In low-risk endometrial cancer (FIGO Stage 1, endometrioid histology, Grades 1 and 2), the risk of lymph-node involvement is 4–17%. Since the introduction of near-infrared optics and the use of indocyanine green, the role of sentinel lymph node removal is increasing and could offer an appropriate balance between the morbidity of a complete lymph-node dissection and the risk of missing lymph-node involvement. Methods In this retrospective comparative study on low-risk endometrial cancer, the extent of surgical lymph-node assessment (no lymphadenectomy vs removal vs lymphadenectomy) in two European institutions was compared and analyzed on the basis of perioperative data and oncological outcome. Results The study included 279 patients from: 103 (36.9%) had no lymphadenectomy, 118 (42.3%) underwent SLN removal and 58 (20.8%) underwent pelvic and/or para-aortic lymphadenectomy. There were significant differences among the groups in blood loss (p = 0.000), operation time (p = 0.000), and severity of postoperative complications (p = 0.063). In comparing only sentinel lymph-node removal vs no lymphadenectomy, there were no significant differences. No significant difference was seen between the extent of lymphadenectomy removal and the risk of recurrence. Age and Lymphovascular space invasion positivity were significant risk factors for recurrence (p = 0.004 and p = 0.019). Conclusions In early-stage, endometrial cancer, Grade 1 and 2, sentinel lymph node removal offers a convincing balance between oncological safety and perioperative morbidity. Especially in LVSI-positive cases, lymph-node evaluation in any form is crucial.

PURPOSE The aim of this study was to compare technetium radiocolloid (Tc99(m)) + blue dye (BD) versus Indocyanine green (ICG) fluorescent dye in terms of the overall detection rate and bilateral sentinel lymph node (SLN) mapping in patients with endometrial carcinoma. METHODS Patients from five European centers with apparently confined clinical stage I endometrial cancer were reviewed. A comparison was made between women who received SLN mapping with pelvic and/or aortic lymphadenectomy (LND), and women who underwent SLN algorithm (SA), was also performed between the two groups. RESULTS Three hundred and forty-two (342) women were involved (147 in the Tc99(m) + BD group and 195 in the ICG group). The overall detection rate of SLN biopsy was 97.3% (143/147) for women in the Tc99(m) + BD group and 96.9% (189/195) for women in the ICG group (p = 0.547). The bilateral mapping rate for ICG was 84.1%-significantly higher with respect to the 73.5% obtained with Tc99(m) + BD (p = 0.007). No differences in overall sensitivity (OS) and overall false negative rate (FNR) were seen between LND and SA (p value = 0.311), whereas the negative predictive value (NPV) was in favor of SA group (p value = 0.030). CONCLUSIONS In this study, fluorescent mapping using ICG resulted equivalent to the standard combined radiocolloid and BD, but real-time SLN mapping achieves a higher bilateral detection rate. The added value that this fast emerging technology promises to give certainly warrants future studies to further consolidate the advantages there are over the standard technique.

PURPOSE The adoption of a sentinel lymph node (SLN) algorithm and the presence of high bilateral detection rates have been associated with increased accuracy of SLN mapping in cervical and endometrial cancer patients. In this context, the significance of the number of SLNs removed has not yet been investigated. The aim of this study was to evaluate (a) whether or not a higher SLN removal count is associated with a reduced false-negative rate and (b) which clinical factors correlate with the number of SLNs removed. METHODS Patients with cervical or endometrial cancer who underwent SLN mapping with bilateral SLN detection followed by lymphadenectomy were evaluated retrospectively. On the basis of the mean number of the SLNs removed, the patients were divided in two groups: Group 1 included patients with up to 3 SLNs removed and Group 2 included patients with more than 3 SLNs removed. Factors predicting a higher SLN count were evaluated using univariate and multivariate analysis. RESULTS Eighty-four patients met the inclusion criteria. The two groups consisted of 42 patients each and differed only by the median SLN count. Two endometrial cancer patients in Group 1 had false-negative pelvic SLNs and isolated para-aortic metastases; no false-negative SLNs were recorded in Group 2 (p = n.s.). The results of multivariate analysis indicted that the number of SLNs removed was influenced only in cases where the operating surgeon had performed more than 20 laparoscopic ICG SLN mappings. CONCLUSIONS A higher SLN count does not seem to increase the accuracy of SLN mapping in cervical and endometrial cancer patients.

INTRODUCTION AND HYPOTHESIS Mixed urinary incontinence (MUI), defined as mixed symptoms of stress urinary incontinence (SUI) and overactive bladder (OAB), is a difficult entity if conservative treatment has failed. Cure rates are low compared with SUI, particularly the OAB component, may deteriorate after sling insertion. Bulking agents pose an appealing alternative for the treatment of MUI. They have shown beneficial effect in small case studies, but larger series are lacking. The aim of this prospective study was an analysis of treatment efficacy and safety profile of the bulking agent, Bulkamid, in female patients with MUI. METHODS One hundred fifty-four women with MUI symptoms (components of SUI/OAB within the limits of 60-40% either way) received bulking therapy with polyacrylamide hydrogel (Bulkamid). Patients were followed-up 3 months postoperatively. Primary outcome was the domain Incontinence impact on the King's Health Questionnaire (KHQ). Secondary outcomes were the other KHQ domains, visual analog scale (VAS), and International Continence Society (ICS) standardized pad weight test as objective measurement of incontinence. RESULTS Statistically significant improvements were found for all KHQ domains, pad weight test, and the visual analog scale (VAS) before and after bulking. Overall complication rate was 13%. CONCLUSIONS This study has shown improvement in MUI after bulking therapy according to both subjective and objective outcomes. We can advocate bulking therapy for treating MUI, as it is simple and safe and shows both objective and subjective improvement and relief. Long-term results (up to 1 year) are awaited.

Background and purposeIndividualized therapy in endometrial cancer, the most common gynaecologic cancer in the developed world, focuses on identifying specific molecular subtypes. Mutations in the exonuclease domain of the DNA polymerase epsilon (POLE) gene define one such subtype, which causes an ultra-mutated tumour phenotype. These tumours may have an improved progression-free survival and may be receptive to specific therapies. However, the clinical phenotype of these tumours is unknown. The objective of this study was to evaluate the clinical and genetic features of POLE-mutated tumours from a large cohort of women whose cases are characterized by: (1) the availability of detailed clinical and lifestyle data; (2) mutation analysis; and (3) long-term follow-up.MethodsA total of 604 patients with endometrial cancer were included in the study. Data from a detailed questionnaire, including lifestyle and family history information, provided extensive pertinent information on the patients. Sequencing of exons 9-14 of the POLE gene was performed. Follow-up data were gathered and analysed.ResultsHotspot pathogenic POLE mutations were identified in N = 38/599 patients (6.3%). Patients with a POLE-mutated tumour were significantly younger, were more often nulliparous, and had a history of smoking. POLE-mutated tumours were more frequently aneuploid. Prognosis for patients with hotspot POLE-mutated tumours was significantly better in comparison with patients with non-mutated tumours; however careful selection of pathogenic mutations is essential to the definition of this prognostically favourable group.ConclusionsThis study demonstrates that POLE-mutated endometrial cancer is significantly associated with previously unknown clinicopathologic characteristics. Outcome in POLE-mutated tumours was excellent in cases with hotspot mutations. Our results suggest that prediction of excellent outcome in cases of POLE-mutated EMCA should be restricted to cases of EMCA with hotspot mutations until further data are available on the rising number of mutations with unknown significance.

The aim of this study was to compare technetium radiocolloid (Tc99Patients from five European centers with apparently confined clinical stage I endometrial cancer were reviewed. A comparison was made between women who received SLN mapping with pelvic and/or aortic lymphadenectomy (LND), and women who underwent SLN algorithm (SA), was also performed between the two groups.Three hundred and forty-two (342) women were involved (147 in the Tc99In this study, fluorescent mapping using ICG resulted equivalent to the standard combined radiocolloid and BD, but real-time SLN mapping achieves a higher bilateral detection rate. The added value that this fast emerging technology promises to give certainly warrants future studies to further consolidate the advantages there are over the standard technique.

PURPOSE To compare two surgical strategies used to identify lymph node metastases in patients with preoperative diagnosis of complex atypical hyperplasia (CAH), grade 1 and 2 endometrial cancer (EC). METHODS Data on patients with preoperative diagnosis of CAH, grade 1 and 2 EC undergoing laparoscopic indocyanine green (ICG) sentinel lymph node (SLN) mapping followed by frozen section of the uterus were collected. When risk factors were identified at frozen section, patients were subjected to a systematic lymphadenectomy. False negative (FN) rates, negative predictive values (NPV), positive predictive values (PPV) and correlation with stage IIIC EC were calculated for the systematic lymphadenectomy based on frozen section of the uterus and for the SLN mapping. RESULTS Six (9.5%) out of 63 patients had lymph nodal metastases. Based on frozen section of the uterus, 22 (34.9%) and 15 (22.2%) patients underwent a pelvic and a pelvic and paraaortic lymphadenectomy, respectively. Five patients with stage IIIC disease were identified with a FN rate of 16.7% and a NPV and PPV of 97.6 and 27.3%, respectively. Overall and bilateral detection rates of ICG SLN mapping were 100 and 97.6%, respectively; no FN were recorded. The identification of patients with stage IIIC disease with ICG SLN mapping showed a NPV and PPV of 100%. Correlation between indication to lymphadenectomy and stage IIIC disease was poor (κ = 0.244) when based on frozen section of the uterus and excellent (κ = 1) when based on SLN mapping. CONCLUSIONS ICG SLN mapping reduces the number of unnecessary systematic lymphadenectomies and the risk of underdiagnosing patients with metastatic lymph nodes.

BACKGROUND In patients with a diagnosis of occult cervical cancer made on a hysterectomy specimen after surgery for a benign indication, lymph node assessment is crucial to determine treatment. We aimed to compare sentinel lymph node (SLN) mapping between patients with postoperative diagnosis of occult cervical carcinoma and patients with cervical cancer and uterus in situ. METHODS A retrospective analysis of cervical cancer patients International Federation of Gynecology and Obstetrics (FIGO) stage IA-IIA disease undergoing laparoscopic SLN mapping was performed. Patients were divided into two groups: those with a diagnosis of occult cervical cancer made on a hysterectomy specimen (group 1) and those with a diagnosis of cervical cancer and uterus in situ (group 2). Tracers used for SLN mapping included technetium-99m ((99m)Tc), blue dye, and indocyanine green. After detection and excision, the SLN was sent for frozen section analysis, and the planned surgical procedure was aborted in case of metastatic disease in favor of a chemoradiotherapeutic treatment. RESULTS Groups 1 and 2 included 9 and 62 patients, respectively. Clinicopathologic characteristics were similar among the two groups. Overall and bilateral detection rates were 66.6 and 33.3 and 95.1 and 87 % in groups 1 and 2, respectively (p

BACKGROUND In endometrial cancer (EMCA), indocyanine green (ICG) sentinel lymph node (SLN) mapping has been reported, mainly in conjunction with robotic surgery. OBJECTIVE We aimed to evaluate detection rates, sensitivity, and false negative (FN) rate of laparoscopic ICG SLN mapping in EMCA, and to evaluate differences in surgical outcomes between patients subjected to SLN biopsy only versus lymphadenectomy. METHODS A retrospective analysis of EMCA patients undergoing ICG SLN mapping ± pelvic (PLND) and/or para-aortic lymphadenectomy (PALND) was performed. Detection rates were calculated for the entire cohort. Sensitivity and FN rates were calculated for patients undergoing lymphadenectomy after SLN mapping, and surgical outcome was compared among patients undergoing SLN mapping only versus lymphadenectomy. RESULTS Of 75 patients, 33 underwent SLN mapping and 42 underwent SLN mapping followed by PLND/PALND. Overall and bilateral detection rates were 96 % (72/75) and 88 % (66/75), respectively, and the median number of removed SLNs, pelvic non-SLNs (NSLN) and para-aortic NSLNs was 3, 27, and 19, respectively. With a FN rate of 8.3 %, only one patient had bilateral FN SLNs and a metastatic para-aortal NSLN. Estimated blood loss (EBL) and operative (OR) time were significantly lower in patients undergoing SLN mapping only. No differences in complication rates between patients undergoing SLN mapping only and patients undergoing lymphadenectomy were recorded. CONCLUSIONS Laparoscopic ICG SLN mapping has excellent overall and bilateral detection rates and a low FN rate. Compared with lymphadenectomy, SLN biopsy is associated with significantly lower EBL and shorter OR time.

OBJECTIVE Bladder outlet obstruction may occur after any incontinence surgery and may present as OAB, hesitancy and or the feeling of incomplete emptying. Aim of this study was to analyze the clinical and urodynamical outcome after urethrolysis in patients presenting with various clinical symptoms after Burch colposuspension for stress urinary incontinence. STUDY DESIGN Between January 2005 and December 2014, all patients who presented with symptoms and with bladder outlet obstruction were included. All patients had undergone Burch or Cowan colposuspension for stress urinary incontinence previously. Primary endpoint was the visual analogue scale (VAS) as measurement of patient perceived disease impact. Secondary endpoints were the various domains of the King's Health Questionnaire, urodynamic parameters as detrusor pressure at maximum flow, residual urine and sonographic bladder wall thickness before and six months after intervention. RESULTS Seventy-two female patients were included in this study whereof 42 suffered from urgency and urge incontinence, 20 from hesitancy and/or slow stream, seven from residual urine of more than 100ml and three from a combination of urgency and residual urine. VAS improved significantly (p