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      Pathogenesis Based Diagnosis and Treatment of Endometriosis

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          Abstract

          Understanding the pathophysiology of endometriosis is changing our diagnosis and treatment. Endometriosis lesions are clones of specific cells, with variable characteristics as aromatase activity and progesterone resistance. Therefore the GE theory postulates GE incidents to start endometriosis, which thus is different from implanted endometrium. The subsequent growth in the specific environment of the peritoneal cavity is associated with angiogenesis, inflammation, immunologic changes and bleeding in the lesions causing fibrosis. Fibrosis will stop the growth and lesions look burnt out. The pain caused by endometriosis lesions is variable: some lesions are not painful while other lesions cause neuroinflammation at distance up to 28 mm. Diagnosis of endometriosis is made by laparoscopy, following an experience guided clinical decision, based on history, symptoms, clinical exam and imaging. Biochemical markers are not useful. For deep endometriosis, imaging is important before surgery, notwithstanding rather poor predictive values when confidence limits, the prevalence of the disease and the absence of stratification of lesions by size, localization and depth of infiltration, are considered. Surgery of endometriosis is based on recognition and excision. Since the surrounding fibrosis belongs to the body with limited infiltration by endometriosis, a rim of fibrosis can be left without safety margins. For deep endometriosis, this results in a conservative excision eventually with discoid excision or short bowel resections. For cystic ovarian endometriosis superficial destruction, if complete, should be sufficient. Understanding pathophysiology is important for the discussion of early intervention during adolescence. Considering neuroinflammation at distance, the indication to explore large somatic nerves should be reconsidered. Also, medical therapy of endometriosis has to be reconsidered since the variability of lesions results in a variable response, some lesions not requiring estrogens for growth and some being progesterone resistant. If the onset of endometriosis is driven by oxidative stress from retrograde menstruation and the peritoneal microbiome, medical therapy could prevent new lesions and becomes indicated after surgery.

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          Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

          Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here, we review data and technologies that have revealed intra-tumor heterogeneity across cancer types and the dynamics, constraints, and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis and consider the role of the tumor microenvironment in engendering heterogeneity and drug resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immune-microenvironment while limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.
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            Endometriosis

            Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.
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              Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium

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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                25 November 2021
                2021
                : 12
                : 745548
                Affiliations
                [1] 1 Latifa Hospital , Dubai, United Arab Emirates
                [2] 2 Prof Emeritus Obstet Gynecol (OBGYN), Catholic University Leuven (KU) , Leuven, Belgium
                [3] 3 University of Oxford-Hon Consultant , Oxford, United Kingdom
                [4] 4 University Cattolica , Roma, Italy
                [5] 5 Moscow State University , Moscow, Russia
                [6] 6 Gruppo Italo Belga, Villa Del Rosario , Rome, Italy
                [7] 7 Instituto do Cancer do Estado de São Paulo, University of São Paulo , São Paulo, Brazil
                [8] 8 Dubai Fertility Centre of the Dubai Health Authority , Dubai, United Arab Emirates
                [9] 9 Prof Department of Obstetrics and Gynaecology, University of Strasbourg , Strasbourg, France
                Author notes

                Edited by: Richard Ivell, University of Nottingham, United Kingdom

                Reviewed by: Qingxue Zhang, Sun Yat-sen Memorial Hospital, China; Jing-Yan Song, Shandong University of Traditional Chinese Medicine, China

                *Correspondence: Philippe R. Koninckx, Pkoninckx@ 123456gmail.com

                This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2021.745548
                8656967
                34899597
                8e0015e9-786e-4856-adbe-73a95f9d9001
                Copyright © 2021 Koninckx, Fernandes, Ussia, Schindler, Wattiez, Al-Suwaidi, Amro, Al-Maamari, Hakim and Tahlak

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 July 2021
                : 26 October 2021
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 97, Pages: 13, Words: 6733
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                endometriosis,endometriosis natural history,endometriosis diagnosis,endometriosis prevention,endometriosis treatment,endometriosis surgery

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