Prophylactic mesh to prevent incisional hernia in laparotomy for ovarian tumors.

OBJECTIVE: Incisional hernias are a common complication of midline laparotomies. The aim of this study was to determine the impact of prophylactic mesh placement after midline laparotomy for ovarian tumors on the incidence of incisional hernia. METHODS: We collected retrospective data from patients undergoing midline laparotomy for borderline or ovarian cancer with at least 12 months of follow-up, including those with and without mesh. Patient demographics, preoperative characteristics and risk factors for hernia were reported and grouped according to prophylactic mesh placement. A multivariate analysis was conducted to identify independent risk factors for incisional hernia. Kaplan-Meier curves illustrating the cumulative incidence of incisional hernia based on mesh placement were performed. RESULTS: A total of 139 consecutive patients with available data were included, 58 in the non-mesh group and 81 in the mesh group, with high body mass index (BMI) as the most common reason for mesh placement. The mean (SD)) age was 60 years (13.97). A total of 11 patients (7.9%) had borderline tumors while 128 (92.1%) had invasive cancer. After clinical and radiological examination, 18.7% (26/139) of patients developed incisional hernia at a median follow-up of 35.8 months (IQR) 43.8): 31% (18/58) were detected in the non-mesh group, and 9.9% (8/81) in the mesh group (p<0.002). Multivariate analysis showed no-mesh placement (OR) 10; 95% CI) 2.8 to 35.919; p<0.001) as a significant risk factor for incisional hernia. Age ≥70 (OR 4.3; 95% CI 1.24 to 15; p=0.02) and BMI ≥29 (OR 4.4; 95% CI 1.27 to 14.93; p=0.019) were also identified as independent risk factors for hernia development. According to Kaplan-Meier curves, the cumulative incidence of incisional hernia was higher in the non-mesh group (p=0.002). CONCLUSION: The incidence of incisional hernia was high in patients undergoing midline laparotomy for ovarian tumors. The addition of a prophylactic mesh may reduce this incidence, therefore there is a need to consider it as an option for high-risk patients, particularly those aged over 70 years or with a BMI ≥29 kg/m2.

Procalcitonin and C-reactive protein as early markers of anastomotic leakage in intestinal resections for advanced ovarian cancer (EDMOCS).

INTRODUCTION: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers. MATERIAL AND METHODS: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity). CONCLUSIONS: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings.

Preoperative CA125 Significantly Improves Risk Stratification in High-Grade Endometrial Cancer.

Patients with high-grade endometrial carcinoma (EC) have an increased risk of tumor spread and lymph node metastasis (LNM). Preoperative imaging and CA125 can be used in work-up. As data on cancer antigen 125 (CA125) in high-grade EC are limited, we aimed to study primarily the predictive value of CA125, and secondarily the contributive value of computed tomography (CT) for advanced stage and LNM. Patients with high-grade EC (n = 333) and available preoperative CA125 were included retrospectively. The association of CA125 and CT findings with LNM was analyzed by logistic regression. Elevated CA125 ((>35 U/mL), (35.2% (68/193)) was significantly associated with stage III-IV disease (60.3% (41/68)) compared with normal CA125 (20.8% (26/125), [p < 0.001]), and with reduced disease-specific-(DSS) (p < 0.001) and overall survival (OS) (p < 0.001). The overall accuracy of predicting LNM by CT resulted in an area under the curve (AUC) of 0.623 (p < 0.001) independent of CA125. Stratification by CA125 resulted in an AUC of 0.484 (normal), and 0.660 (elevated). In multivariate analysis elevated CA125, non-endometrioid histology, pathological deep myometrial invasion ≥50%, and cervical involvement were significant predictors of LNM, whereas suspected LNM on CT was not. This shows that elevated CA125 is a relevant independent predictor of advanced stage and outcome specifically in high-grade EC.

Protein Supplementation in a Prehabilitation Program in Patients Undergoing Surgery for Endometrial Cancer.

Enhanced recovery after surgery (ERAS) and prehabilitation programs are multidisciplinary care pathways to reduce stress response and improve perioperative outcomes, which also include nutritional interventions. The aim of this study is to assess the impact of protein supplementation with 20 mg per day before surgery in a prehabilitation program in postoperative serum albumin, prealbumin, and total proteins in endometrial cancer patients undergoing laparoscopic surgery. METHODS: A prospective study including patients who underwent laparoscopy for endometrial cancer was conducted. Three groups were identified according to ERAS and prehabilitation implementation (preERAS, ERAS, and Prehab). The primary outcome was levels of serum albumin, prealbumin, and total protein 24-48 h after surgery. RESULTS: A total of 185 patients were included: 57 in the preERAS group, 60 in the ERAS group, and 68 in the Prehab group. There were no basal differences in serum albumin, prealbumin, or total protein between the three groups. After surgery, regardless of the nutritional intervention, the decrease in the values was also similar. Moreover, values in the Prehab group just before surgery were lower than the initial ones, despite the protein supplementation. CONCLUSIONS: Supplementation with 20 mg of protein per day does not impact serum protein levels in a prehabilitation program. Supplementations with higher quantities should be studied.

Prehabilitation in an ERAS program for endometrial cancer patients: impact on post-operative recovery.

OBJECTIVES: Enhanced recovery after surgery (ERAS) and prehabilitation programs are multidisciplinary care pathways that aim to reduce stress response and improve perioperative outcomes. However, literature is limited regarding the impact of ERAS and prehabilitation in gynecologic oncology surgery. The aim of this study was to assess the impact of implementing an ERAS and prehabilitation program on post-operative outcomes of endometrial cancer patients undergoing laparoscopic surgery. METHODS: We evaluated consecutive patients undergoing laparoscopy for endometrial cancer that followed ERAS and the prehabilitation program at a single center. A pre-intervention cohort that followed the ERAS program alone was identified. The primary outcome was length of stay, and secondary outcomes were normal oral diet restart, post-operative complications and readmissions. RESULTS: A total of 128 patients were included: 60 patients in the ERAS group and 68 patients in the prehabilitation group. The prehabilitation group had a shorter length of hospital stay of 1 day (p<0.001) and earlier normal oral diet restart of 3.6 hours (p=0.005) in comparison with the ERAS group. The rate of post-operative complications (5% in the ERAS group and 7.4% in the prehabilitation group, p=0.58) and readmissions (1.7% in the ERAS group and 2.9% in the prehabilitation group, p=0.63) were similar between groups. CONCLUSIONS: The integration of ERAS and a prehabilitation program in endometrial cancer patients undergoing laparoscopy significantly reduced hospital stay and time to first oral diet as compared with ERAS alone, without increasing overall complications or the readmissions rate.

Impact of prehabilitation during neoadjuvant chemotherapy and interval cytoreductive surgery on ovarian cancer patients: a pilot study.

BACKGROUND: Cytoreductive surgery followed by systemic chemotherapy is the standard of treatment in advanced ovarian cancer where feasible. Neoadjuvant chemotherapy (NACT) followed by surgery is applicable where upfront cytoreductive surgery is not feasible because of few certain reasons. Nevertheless, surgical interventions and the chemotherapy itself may be associated with postoperative complications usually entailing slow postoperative recovery. Prehabilitation programs consist of the patient's preparation before surgery to improve the patient's functional capacity. The aim of this study was to evaluate the impact of a prehabilitation program during neoadjuvant treatment and interval cytoreductive surgery for ovarian cancer patients. METHODS: A retrospective observational pilot study of patients with advanced ovarian cancer treated with NACT and interval cytoreductive surgery was conducted. The prehabilitation group received a structured intervention based on physical exercise, nutritional counseling, and psychological support. Nutritional parameters were assessed preoperatively and postoperatively, and functional parameters and perioperative and postoperative complications were also recorded. RESULTS: A total of 29 patients were included in the study: 14 in the prehabilitation group and 15 in the control group. The patients in the prehabilitation program showed higher mean total protein levels in both preoperative (7.4 vs. 6.8, p = 0.004) and postoperative (4.9 vs. 4.3, p = 0.005) assessments. Up to 40% of controls showed intraoperative complications vs. 14.3% of patients in the prehabilitation group, and the requirement of intraoperative blood transfusion was significantly lower in the prehabilitation group (14.3% vs. 53.3%, p = 0.027). The day of the first ambulation, rate of postoperative complications, and length of hospital stay were similar between the groups. Finally, trends towards shorter time between diagnosis and interval cytoreductive surgery (p = 0.097) and earlier postoperative diet restart (p = 0.169) were observed in the prehabilitation group. CONCLUSION: Prehabilitation during NACT in women with ovarian cancer candidates to interval cytoreductive surgery may improve nutritional parameters and thereby increase postoperative recovery. Nevertheless, the results of this pilot study are preliminary, and further studies are needed to determine the clinical impact of prehabilitation programs.

Predictor factors for conservative management of cervical intraepithelial neoplasia grade 2: Cytology and HPV genotyping.

OBJECTIVE: The purpose of this study was to evaluate the role of HPV genotyping and previous cytology result to predict the evolution of CIN2 histological lesions managed conservatively. METHODS: A prospective observational study was conducted at Hospital del Mar in Barcelona from January 2012 to May 2017. Women with new diagnosis of CIN2 were invited to undergo conservative management for 24 months. Complete regression, partial regression, persistence and progression to CIN3 were defined as final outcomes. Univariate and multivariate analyses combining HPV genotyping and cytology were used to establish progression predictors of CIN2. RESULTS: A total of 300 patients were included in the study, and 291 patients completed the 24-months follow-up. Of them, 214 patients (73.5%) showed regression; 43 (14.8%) persistence to CIN2, and 34 (11.7%) progression to CIN3. In multivariable analysis, HPV-16 infection (odds ratio [OR] 1.97, [95% confidence interval {CI} 1.13-3.43]) and previous HSIL cytology (OR 3.46, [95% CI 1.99-6.02]) significantly increased the risk of persistence or progression (CIN2+) of CIN2 lesions. In contrast, all HPV-negative lesions regressed (p < 0.001). CONCLUSIONS: The regression rate of CIN2 lesions supports conservative management in selected patients regardless of their age. Patients with a CIN2 biopsy and negative HPV test had a high rate of regression and should be offered follow-up without excisional treatment. In contrast, patients with HPV-16 and HSIL cytology had an increased risk of CIN2+, their treatment should be individualized and excisional treatment should be considered. The age may not be considered a criterion to decide the best management. New markers may help in the future to select the best management of CIN2.

Influence of age on treatment and prognosis of invasive cervical cancer.

OBJECTIVE: Invasive cervical cancer is considered a young women's disease, however up to 20 % of cases develop cervical cancer at advanced ages. The aim was to characterize invasive cervical cancer in women aged 65 and older assessing age-specific survival differences. STUDY DESIGN: A retrospective study including cervical cancer patients was conducted at Hospital del Mar Barcelona from July-2007 to December-2016. Women were stratified: <65 or ≥65years. Clinical and pathological data were collected. Multivariate analysis was used to compare outcomes. Adjusted hazard ratios with 95 % confidence intervals for disease-free survival, and overall survival were estimated using Cox proportional hazards models. RESULTS: 124 patients with invasive cervical cancer (n = 87 < 65years and n = 37 ≥ 65years) were included. At diagnosis, 48.3 % of <65years patients were diagnosed at advanced stages, while 64.9 % in ≥65years (p = 0.018). Standard treatment was given to 83.9 % of patients in <65years group compared to 62.2 % in ≥65years (p = 0.015). Disease-free survival and overall survival showed no significant differences between groups. Age ≥65 did not predict worse disease-free survival (HR: 0.3 95 %CI, 0.04-3.1, p = 0.347) or overall survival (HR: 0.82 95 %CI, 0.3-2.3, p = 0.729). CONCLUSION: Invasive cervical cancer was diagnosed at advanced stages and was treated less frequently with radical intention in patients ≥65years; overall survival and disease-free survival were similar to those cervical cancer diagnosed at younger ages.

The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study.

There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1-2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.

Gynecologic cancer surveillance in the era of SARS-CoV-2 (COVID-19).

The SARS-CoV-2 (COVID-19) pandemic has significantly impacted the management of patients with gynecologic cancers. Many centers have reduced access to routine visits to avoid crowded waiting areas and specially to reduce the infection risk for oncologic patients. The goal of this review is to propose a surveillance algorithm for patients with gynecologic cancers during the COVID-19 pandemic based on existing evidence and established guidelines. It is time to consider strategies based on telemedicine and to adapt protocols in this new era. We hereby propose a strategy for routine surveillance both during and beyond the pandemic.

Preoperative risk stratification in endometrial cancer (ENDORISK) by a Bayesian network model: A development and validation study.

BACKGROUND: Bayesian networks (BNs) are machine-learning-based computational models that visualize causal relationships and provide insight into the processes underlying disease progression, closely resembling clinical decision-making. Preoperative identification of patients at risk for lymph node metastasis (LNM) is challenging in endometrial cancer, and although several biomarkers are related to LNM, none of them are incorporated in clinical practice. The aim of this study was to develop and externally validate a preoperative BN to predict LNM and outcome in endometrial cancer patients. METHODS AND FINDINGS: Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), we performed a retrospective multicenter cohort study including 763 patients, median age 65 years (interquartile range [IQR] 58-71), surgically treated for endometrial cancer between February 1995 and August 2013 at one of the 10 participating European hospitals. A BN was developed using score-based machine learning in addition to expert knowledge. Our main outcome measures were LNM and 5-year disease-specific survival (DSS). Preoperative clinical, histopathological, and molecular biomarkers were included in the network. External validation was performed using 2 prospective study cohorts: the Molecular Markers in Treatment in Endometrial Cancer (MoMaTEC) study cohort, including 446 Norwegian patients, median age 64 years (IQR 59-74), treated between May 2001 and 2010; and the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study cohort, including 384 Dutch patients, median age 66 years (IQR 60-73), treated between September 2011 and December 2013. A BN called ENDORISK (preoperative risk stratification in endometrial cancer) was developed including the following predictors: preoperative tumor grade; immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), p53, and L1 cell adhesion molecule (L1CAM); cancer antigen 125 serum level; thrombocyte count; imaging results on lymphadenopathy; and cervical cytology. In the MoMaTEC cohort, the area under the curve (AUC) was 0.82 (95% confidence interval [CI] 0.76-0.88) for LNM and 0.82 (95% CI 0.77-0.87) for 5-year DSS. In the PIPENDO cohort, the AUC for 5-year DSS was 0.84 (95% CI 0.78-0.90). The network was well-calibrated. In the MoMaTEC cohort, 249 patients (55.8%) were classified with <5% risk of LNM, with a false-negative rate of 1.6%. A limitation of the study is the use of imputation to correct for missing predictor variables in the development cohort and the retrospective study design. CONCLUSIONS: In this study, we illustrated how BNs can be used for individualizing clinical decision-making in oncology by incorporating easily accessible and multimodal biomarkers. The network shows the complex interactions underlying the carcinogenetic process of endometrial cancer by its graphical representation. A prospective feasibility study will be needed prior to implementation in the clinic.

Role and impact of multimodal prehabilitation for gynecologic oncology patients in an Enhanced Recovery After Surgery (ERAS) program.

Patients undergoing major surgery are predisposed to a decrease in functional capacity as a response to surgical stress that can delay post-operative recovery. A prehabilitation program consists of patient preparation strategies before surgery, and include pre-operative measures to improve functional capacity and enhance post-operative recovery. Multimodal prehabilitation may include exercise, nutritional counseling, psychological support, and optimization of underlying medical conditions, as well as cessation of unfavorable health behaviors such as smoking and drinking. Currently, there are no standardized guidelines for prehabilitation, and the existent studies are heterogeneous; however, multimodal approaches are likely to have a greater impact on functional outcomes than single management programs. We have reviewed the literature on prehabilitation in general, and in gynecologic surgery in particular, to identify tools to establish an optimal prehabilitation program within an Enhanced Recovery After Surgery (ERAS) protocol for gynecologic oncology patients. We suggest a safe, reproducible, functional, and easy-to-apply multimodal prehabilitation program for gynecologic oncology practice based on patient-tailored pre-operative medical optimization, physical training, nutritional counseling, and psychological support. The analysis of the prehabilitation program implementation in an ERAS protocol should undergo further research in order to test the efficacy on surgical outcome and recovery after surgery.

Role of Chlamydia trachomatis serology in conservative management of cervical intraepithelial neoplasia grade 2.

OBJECTIVE: To evaluate the spontaneous progression of cervical intraepithelial neoplasia grade 2 (CIN2) in accordance with Chlamydia trachomatis (chlamydia) serology. METHODS: A prospective observational study included women diagnosed with CIN2 by cervical biopsy and managed conservatively for 24 months at Hospital del Mar, Barcelona, between December 2011 and October 2013. Serum anti-chlamydia immunoglobulin G (IgG), previous cytology, and high-risk human papillomavirus (HPV) genotyping were recorded at baseline. The outcome was regression, persistence, or progression of CIN2. RESULTS: Overall, 93 women aged 18-56 years were enrolled. Spontaneous regression was observed for 61 (66%) women, and 21 (23%) progressed to CIN3. Eight (9%) women had chlamydia seropositivity at baseline. Multivariate analysis showed that anti-chlamydia IgG seropositivity (odds ratio [OR], 19.1; 95% confidence interval [CI], 1.9-189.7), previous high-grade squamous intraepithelial lesion cytology (OR, 5.0; 95% CI, 1.7-14.6), and HPV16 (OR, 4.8; 95% CI, 1.7-13.7) increased the risk of CIN2 persistence or progression. CONCLUSION: Women with CIN2 and chlamydia IgG seropositivity had increased risk of progression to CIN2+ and immediate treatment may be recommended for these women. Larger clinical studies are needed to confirm the results, but chlamydia serology might be introduced into CIN2 management to better individualize treatment.

Addition of IMP3 to L1CAM for discrimination between low- and high-grade endometrial carcinomas: a European Network for Individualised Treatment of Endometrial Cancer collaboration study.

Discrimination between low- and high-grade endometrial carcinomas (ECs) is clinically relevant but can be challenging for pathologists, with moderate interobserver agreement. Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is an oncofoetal protein that is associated with nonendometrioid endometrial carcinomas but has been limited studied in endometrioid carcinomas. The aim of this study is to investigate the diagnostic and prognostic value of IMP3 in the discrimination between low- and high-grade ECs and its added value to L1CAM. IMP3 and L1CAM expression was assessed in tumors from 378 patients treated for EC at 1 of 9 participating European Network for Individualised Treatment of Endometrial Cancer centers. IMP3 was expressed in 24.6% of the tumors. In general, IMP3 was more homogeneously expressed than L1CAM. IMP3 expression was significantly associated with advanced stage, nonendometrioid histology, grade 3 tumors, deep myometrial invasion, lymphovascular space invasion, distant recurrences, overall mortality, and disease-related mortality. Simultaneous absence of IMP3 and L1CAM expression showed the highest accuracy for identifying low-grade carcinomas (area under the curve 0.766), whereas simultaneous expression of IMP3 and L1CAM was strongly associated with high-grade carcinomas (odds ratio 19.7; 95% confidence interval 9.2-42.2). Even within endometrioid carcinomas, this combination remained superior to IMP3 and L1CAM alone (odds ratio 8.6; 95% confidence interval 3.4-21.9). In conclusion, IMP3 has good diagnostic value and together with L1CAM represents the optimal combination of diagnostic markers for discrimination between low- and high-grade ECs compared to IMP3 and L1CAM alone. Because of the homogenous expression of IMP3, this marker might be valuable in preoperative biopsies when compared to the more patchy L1CAM expression.

Poor outcome in hypoxic endometrial carcinoma is related to vascular density.

BACKGROUND: Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. METHODS: Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan-Meier curves and Cox regression analysis. RESULTS: Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). CONCLUSIONS: This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients.

ALCAM shedding at the invasive front of the tumor is a marker of myometrial infiltration and promotes invasion in endometrioid endometrial cancer.

Endometrial cancer (EC) is the sixth deadliest cancer in women. The depth of myometrial invasion is one of the most important prognostic factors, being directly associated with tumor recurrence and mortality. In this study, ALCAM, a previously described marker of EC recurrence, was studied by immunohistochemistry at the superficial and the invasive tumor areas from 116 EC patients with different degree of myometrial invasion and related to a set of relevant epithelial and mesenchymal markers. ALCAM expression presented a heterogeneous functionality depending on its localization, it correlated with epithelial markers (E-cadherin/ß-catenin) at the superficial area, and with mesenchymal markers at the invasive front (COX-2, SNAIL, ETV5, and MMP-9). At the invasive front, ALCAM-negativity was an independent marker of myometrial invasion. This negativity, together with an increase of soluble ALCAM in uterine aspirates from patients with an invasive EC, and its positive correlation with MMP-9 levels, suggested that ALCAM shedding by MMP-9 occurs at the invasive front. In vivo and in vitro models of invasive EC were generated by ETV5-overexpression. In those, we demonstrated that ALCAM shedding was related to a more invasive pattern and that full-ALCAM recovery reverted most of the ETV5-cells mesenchymal abilities, partially through a p-ERK dependent-manner.

Added Value of Estrogen Receptor, Progesterone Receptor, and L1 Cell Adhesion Molecule Expression to Histology-Based Endometrial Carcinoma Recurrence Prediction Models: An ENITEC Collaboration Study.

OBJECTIVES: Endometrial carcinoma mortality is mainly caused by recurrent disease, and various immunohistochemical markers to predict recurrences have been studied. Loss of the estrogen receptor (ER) and progesterone receptor (PR) and the presence of the L1 cell adhesion molecule (L1CAM) are promising markers, but their combined value has not been studied. MATERIALS AND METHODS: Expression of ER, PR, and L1CAM was immunohistochemically determined in 293 endometrial carcinomas from 11 collaborating European Network for Individualized Treatment of Endometrial Cancer centers. Estrogen receptor, PR, or L1CAM staining was considered positive or negative when expressed by greater than or equal to 10% or less than 10% of the tumor cells, respectively. The association between these markers and clinicopathological markers, and their combined value in predicting survival were calculated, both in the entire cohort and in a selected groups of stage I endometrioid and low-risk stage I endometrioid carcinomas. RESULTS: Estrogen receptor and PR were negative in 19% and 28% of the cases, respectively, and L1CAM was positive in 18%. All 3 were associated with advanced stage, high-grade, nonendometrioid histology, lymphovascular space invasion (LVSI), and reduced disease-free survival. Only advanced stage, loss of PR, and LVSI were associated with reduced disease-free survival in multivariate analysis. A prognostic model including these 3 markers was superior to 1 including only the 3 immunohistochemical markers, which was superior to the traditional model. In both the stage I endometrioid and the low-risk stage I endometrioid groups, only loss of PR was associated with reduced disease-free survival. CONCLUSIONS: Loss of ER and PR, and the presence of L1CAM are associated with high risk characteristics, and loss of PR is the strongest predictor of recurrent disease. Although a combination of these 3 markers is slightly superior to the traditional histological markers, a prognostic model including stage, PR expression, and LVSI is the most promising model in the identification of high risk carcinomas. In the stage I endometrioid carcinomas, PR immunohistochemistry appears to be of additional value in predicting recurrences.

Utility of Human Papillomavirus Genotyping in the Management of Low-Grade Squamous Intraepithelial Lesions.

OBJECTIVE: The aim of the study was to determine the usefulness of human papillomavirus (HPV) partial genotyping test in the triage of newly diagnosed low-grade squamous intraepithelial lesions (LSILs). MATERIALS AND METHODS: We analyzed 143 patients with LSIL diagnosed de novo. Lesions were classified as positive for HPV 16 or HPV 18, positive for HPV but not HPV 16 or HPV 18 (HPVno16no18) or no HPV detected (HPVneg). Patients were followed for a period of 2 years or until the lesion progressed. We calculated absolute and relative risks for progression and regression according to the HPV result. RESULTS: The mean (SD) age was 33.8 (11.1) years. A total of 19.6% were positive for HPV 16, 4.9% for HPV 18, and 63.6% for HPVno16no18. The absolute risk of HPV 16 for progression to cervical intraepithelial neoplasia grade 2 or more (CIN 2+) was 32.1%, 14.3% for HPV 18, and 5.8% for HPVno16no18. None of the HPVneg cases evolved to CIN 2+. The presence of HPV 16 conferred a 7.4 (95% CI = 2.7-20.3) times greater risk of developing CIN 2+ than its absence. The absolute risks for HPV 16, HPV 18, HPVno16no18, and HPVneg for regression were 53.6%, 57.1%, 75.4%, and 87.5%, respectively. Relative risks for regression were 0.7 (95% CI = 0.5-0.9) for HPV 16 and 1.3 (95% CI = 1.1-1.5) for HPVneg. CONCLUSIONS: The HPV 16 LSILs are more likely to progress to CIN 2+, so tight control and immediate colposcopy are crucial, whereas when HPV 16 is not present, follow-up could be less strict. Low-grade squamous intraepithelial lesions in which high-risk HPV is not detected do not progress to CIN 2+, so its control should be different from other LSIL, and conservative management could be an acceptable strategy.

Usefulness of p16INK4a staining for managing histological high-grade squamous intraepithelial cervical lesions.

p16INK4a (p16) tumor-suppressor protein is a biomarker of human papillomavirus (HPV) oncogenic activity that has revealed a high rate of positivity in histological high-gade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 2 (HSIL/CIN2) lesions. However, there is a paucity of data regarding p16 status as a surrogate marker of HSIL/CIN2 evolution. The aim of this study was to evaluate the outcome of HSIL/CIN2 patients followed up without treatment for 12 months according to p16 immunohistochemical staining. Patients diagnosed with HSIL/CIN2 colposcopy-directed biopsy, were recruited prospectively between December 2011 and October 2013. p16 staining was performed in all HSIL/CIN2 diagnostic biopsies. Follow-up was conducted every 4 months by cytology, colposcopy and biopsy if suspicion of progression and once the 12 months of follow-up completed. Complete regression, partial regression, persistence, and progression rates of HSIL/CIN2 were defined as a final outcome. A total of 96 patients were included in the analysis. The rate of spontaneous regression was 64%, while 28% had persistent disease, and 8% progressed at 12 months of follow-up. p16 was positive in 81 (84%) initial HSIL/CIN2 biopsies. Regression was observed in all 15 p16 negative cases and in 46 of 81 (57%) p16 positive cases (P=0.001). In conclusion, patients with p16 negative HSIL/CIN2 biopsy had a high rate of regression during first 12 months of follow-up. Status of p16 staining could be considered for HSIL/CIN2 management.

L1CAM expression in endometrial carcinomas: an ENITEC collaboration study.

BACKGROUND: Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas. METHODS: The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated. RESULTS: In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non-endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs. CONCLUSIONS: The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied.