High expression of ecto-nucleotidases CD39 and CD73 in human endometrial tumors

One of the strategies used by tumors to evade immunosurveillance is the accumulation of extracellular adenosine, which has immunosupressive and tumor promoting effects. The study of the mechanisms leading to adenosine formation at the tumor interstitium are therefore of great interest in oncology. The dominant pathway generating extracellular adenosine in tumors is the dephosphorylation of ATP by ecto-nucleotidases. Two of these enzymes acting sequentially, CD39 and CD73, efficiently hydrolyze extracellular ATP to adenosine. They have been found to play a crucial role in a variety of tumors, but there were no data concerning endometrial cancer, the most frequent of the invasive tumors of the female genital tract. The aim of the present work is to study the expression of CD39 and CD73 in human endometrial cancer. We have analyzed protein and gene expression, as well as enzyme activity, in type I endometrioid adenocarcinomas and type II serous adenocarcinomas and their nonpathological endometrial counterparts. High levels of both enzymes were found in tumor samples, with significantly increased expression of CD39 in type II serous tumors, which also coincided with the higher tumor grade. Our results reinforce the involvement of the adenosinergic system in cancer, emphasizing the relevance of ecto-nucleotidases as emerging therapeutic targets in oncology

Prophylactic incisional negative pressure wound therapy for gynaecologic malignancies

Wound complications are an important cause of postoperative morbidity among patients with gynaecologic malignancies. We evaluated whether the placement of closed-incisional negative pressure therapy (ciNPT) at the time of laparotomy for gynaecologic cancer surgery reduced wound complication rates. A retrospective cohort study with primary wound closure performed by a gynaecologic oncologist was carried out. We evaluated two cohorts of patients who underwent surgery in 2017 with standard closure and patients who underwent surgery in 2019 with the placement of prophylactic ciNPT. Postoperative outcomes were examined. A total of 143 patients were included, 85 (59.4%) vs 58 (40.6%) with standard closure and ciNPT, respectively. The total complication rate in our sample was 38.71%. The rate of surgical complications in patients treated with ciNPT was 6.9% compared with 31.8% (P = .000) in patients treated with standard closure. In the analysis of complications, a significant reduction in infections (17.1%), seromas (15.4%), and wound dehiscence (17.1%) were observed when ciNPT was applied. The median hospital stay was 8 vs 6 days in the standard closure vs ciNPT groups (P = .048). The use of the prophylactic ciNPT following a laparotomy may decrease wound complications and hospital stays in oncological patients. ciNPT could be considered as part of clinical practice in patients at high risk of wound complications, such as patients with gynaecological malignancies

Ecto-nucleotidases activities in the contents of ovarian endometriomas: potential biomarkers of endometriosis

Endometriosis, defined as the growth of endometrial tissue outside the uterus, is a common gynecologic condition affecting millions of women worldwide. It is an inflammatory, estrogen-dependent complex disorder, with broad symptomatic variability, pelvic pain, and infertility being the main characteristics. Ovarian endometriomas are frequently developed in women with endometriosis. Late diagnosis is one of the main problems of endometriosis; thus, it is important to identify biomarkers for early diagnosis. The aim of the present work is to evaluate the ecto-nucleotidases activities in the contents of endometriomas. These enzymes, through the regulation of extracellular ATP and adenosine levels, are key enzymes in inflammatory processes, and their expression has been previously characterized in human endometrium. To achieve our objective, the echo-guided aspirated fluids of endometriomas were analyzed by evaluating the ecto-nucleotidases activities and compared with simple cysts. Our results show that enzyme activities are quantifiable in the ovarian cysts aspirates and that endometriomas show significantly higher ecto-nucleotidases activities than simple cysts (5.5-fold increase for ATPase and 20-fold for ADPase), thus being possible candidates for new endometriosis biomarkers. Moreover, we demonstrate the presence of ecto-nucleotidases bearing exosomes in these fluids. These results add up to the knowledge of the physiopathologic mechanisms underlying endometriosis and, open up a promising new field of study

Recommendations for a standardised educational program in robot assisted gynaecological surgery: consensus from the Society of European Robotic Gynaecological Surgery (SERGS)

Background: the Society of European Robotic Gynaecological Surgery (SERGS) aims at developing a European consensus on core components of a curriculum for training and assessment in robot assisted gynaecological surgery. Methods: a Delphi process was initiated among a panel of 12 experts in robot assisted surgery invited through the SERGS. An online questionnaire survey was based on a literature search for standards in education in gynaecological robot assisted surgery. The survey was performed in three consecutive rounds to reach optimal consensus. The results of this survey were discussed by the panel and led to consensus recommendations on 39 issues, adhering to general principles of medical education. Results: on review there appeared to be no accredited training programs in Europe, and few in the USA. Recommendations for requirements of training centres, educational tools and assessment of proficiency varied widely. Stepwise and structured training together with validated assessment based on competencies rather than on volume emerged as prerequisites for adequate and safe learning. An appropriate educational environment and tools for training were defined. Although certification should be competence based, the panel recommended additional volume based criteria for both accreditation of training centres and certification of individual surgeons. Conclusions: consensus was reached on minimum criteria for training in robot assisted gynaecological surgery. To transfer results into clinical practice, experts recommended a curriculum and guidelines that have now been endorsed by SERGS to be used to establish training programmes for robot assisted surgery

TGFβ controls ovarian cancer cell proliferation

There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these tumors, research to elucidate the signaling pathways involved is required. The Transforming Growth Factor (TGFβ) family controls different cellular responses in development and cell homeostasis. Disruption of TGFβ signaling has been implicated in many cancers, including ovarian cancer. This article considers the involvement of TGFβ in ovarian cancer progression, and reviews the various mechanisms that enable the TGFβ signaling pathway to control ovarian cancer cell proliferation. These mechanistic explanations support the therapeutic use of TGFβ inhibitors in ovarian cancer, which are currently in the early phases of development

Impaired expression of ectonucleotidases in ectopic and eutopic endometrial tissue is in favor of ATP accumulation in the tissue microenvironment in endometriosis

Endometriosis is a prevalent disease defined by the presence of endometrial tissue outside the uterus. Adenosine triphosphate (ATP), as a proinflammatory molecule, promotes and helps maintain the inflammatory state of endometriosis. Moreover, ATP has a direct influence on the two main symptoms of endometriosis: infertility and pain. Purinergic signaling, the group of biological responses to extracellular nucleotides such as ATP and nucleosides such as adenosine, is involved in the biology of reproduction and is impaired in pathologies with an inflammatory component such as endometriosis. We have previously demonstrated that ectonucleotidases, the enzymes regulating extracellular ATP levels, are active in non-pathological endometria, with hormone-dependent changes in expression throughout the cycle. In the present study we have focused on the expression of ectonucleotidases by means of immunohistochemistry and in situ activity in eutopic and ectopic endometrial tissue of women with endometriosis, and we compared the results with endometria of women without the disease. We have demonstrated that the axis CD39-CD73 is altered in endometriosis, with loss of CD39 and CD73 expression in deep infiltrating endometriosis, the most severe, and most recurring, endometriosis subtype. Our results indicate that this altered expression of ectonucleotidases in endometriosis boosts ATP accumulation in the tissue microenvironment. An important finding is the identification of the nucleotide pyrophophatase/phosphodiesterase 3 (NPP3) as a new histopathological marker of the disease since we have demonstrated its expression in the stroma only in endometriosis, in both eutopic and ectopic tissue. Therefore, targeting the proteins directly involved in ATP breakdown could be an appropriate approach to consider in the treatment of endometriosis

European Society of Gynaecological Oncology quality indicators for surgical treatment of cervical cancer

Background: optimizing and ensuring the quality of surgical care is essential to improve the management and outcome of patients with cervical cancer.To develop a list of quality indicators for surgical treatment of cervical cancer that can be used to audit and improve clinical practice. Methods: quality indicators were developed using a four-step evaluation process that included a systematic literature search to identify potential quality indicators, in-person meetings of an ad hoc group of international experts, an internal validation process, and external review by a large panel of European clinicians and patient representatives. Results: fifteen structural, process, and outcome indicators were selected. Using a structured format, each quality indicator has a description specifying what the indicator is measuring. Measurability specifications are also detailed to define how the indicator will be measured in practice. Each indicator has a target which gives practitioners and health administrators a quantitative basis for improving care and organizational processes. Discussion: implementation of institutional quality assurance programs can improve quality of care, even in high-volume centers. This set of quality indicators from the European Society of Gynaecological Cancer may be a major instrument to improve the quality of surgical treatment of cervical cancer

Risk factors for recurrence after robot-assisted radical hysterectomy for early-stage cervical cancer: a multicenter retrospective study

This retrospective analysis aimed to assess the risk factors for recurrence in patients diagnosed with early-stage cervical cancer (≤IB1 or IIA1, FIGO 2009) undergoing robot-assisted radical hysterectomy in Spain and Portugal between 2009 and 2018. A second primary objective was to audit the oncological outcomes according to quality indicators (QI) proposed by the European Society of Gynecology Oncology (ESGO). The study population included 239 women. After a median follow-up of 51 months, recurrence occurred in 26 patients (10.9%). Independent factors for recurrence were clinical tumor size > 20 mm (hazard ratio (HR) 2.37), adenocarcinoma as histological type (HR 2.51), positive pelvic lymph nodes (HR 4.83), tumor grade 2 (HR 4.99), tumor grade 3 (HR 8.06), and having not performed sentinel lymph node biopsy (SLNB) (HR 4.08). All 5 QI selected were surpassed by our results. In patients with early-stage cervical cancer undergoing robotic radical hysterectomy, clinicians should be aware that tumor grade 2 and 3, tumor size > 20 mm, adenocarcinoma, positive pelvic nodes, and lack of performance of SLNB are risk factors for recurrence. Fulfillment of QI targets of the ESGO might be considered as an objective oncological outcome indicator supporting the minimally invasive approach for early-stage cervical cancer treatment. KEYWORDS: early-stage cervical cancer; oncological outcome; radical hysterectomy; recurrence; robotic surgery

Exosome-like vesicles in uterine aspirates: a comparison of ultracentrifugation-based isolation protocols

Background: Uterine aspirates are used in the diagnostic process of endometrial disorders, yet further applications could emerge if its complex milieu was simplified. Exosome-like vesicles isolated from uterine aspirates could become an attractive source of biomarkers, but there is a need to standardize isolation protocols. The objective of the study was to determine whether exosome-like vesicles exist in the fluid fraction of uterine aspirates and to compare protocols for their isolation, characterization, and analysis. Methods: We collected uterine aspirates from 39 pre-menopausal women suffering from benign gynecological diseases. The fluid fraction of 27 of those aspirates were pooled and split into equal volumes to evaluate three differential centrifugation-based procedures: (1) a standard protocol, (2) a filtration protocol, and (3) a sucrose cushion protocol. Characterization of isolated vesicles was assessed by electron microscopy, nanoparticle tracking analysis and immunoblot. Specifically for RNA material, we evaluate the effect of sonication and RNase A treatment at different steps of the protocol. We finally confirmed the efficiency of the selected methods in non-pooled samples. Results: All protocols were useful to isolate exosome-like vesicles. However, the Standard procedure was the best performing protocol to isolate exosome-like vesicles from uterine aspirates: nanoparticle tracking analysis revealed a higher concentration of vesicles with a mode of 135 +/- 5 nm, and immunoblot showed a higher expression of exosome-related markers (CD9, CD63, and CD81) thus verifying an enrichment in this type of vesicles. RNA contained in exosome-like vesicles was successfully extracted with no sonication treatment and exogenous nucleic acids digestion with RNaseA, allowing the analysis of the specific inner cargo by Real-Time qPCR. Conclusion: We confirmed the existence of exosome-like vesicles in the fluid fraction of uterine aspirates. They were successfully isolated by differential centrifugation giving sufficient proteomic and transcriptomic material for further analyses. The Standard protocol was the best performing procedure since the other two tested protocols did not ameliorate neither yield nor purity of exosome-like vesicles. This study contributes to establishing the basis for future comparative studies to foster the field of biomarker research in gynecology

Correction: Dueñas et al. Assessing effectiveness of colonic and gynecological risk reducing surgery in Lynch syndrome individuals. Cancers 2020, 12, 3419.

In the original article, there was a mistake in Figure 3 as published [1]. The image presented corresponded to endometrial cancer-specific mortality cumulative incidence, instead of the figure referred to in the title (all-cause mortality cumulative incidence)