Transcranial direct current stimulation to reduce chronic pelvic pain in endometriosis: phase II randomized controlled clinical trial.

BACKGROUND: It is known that various chronic pain conditions lead to maladaptive changes in the central nervous system. Endometriosis is frequently associated with chronic pelvic pain (CPP). Its sufficient treatment remains a clinical challenge. Transcranial direct current stimulation (tDCS) has been shown to be a powerful method to reduce chronic pain. Therefore, this study aimed to investigate pain reduction via anodal tDCS in patients with endometriosis and CPP. METHODS: This clinical phase II, placebo-controlled, randomized, parallel-design study included 36 patients with endometriosis and CPP. All patients had CPP, defined as a score of ≥3/10 on the visual analog scale for ≥3 months in the prior 6 months. Anodal or placebo tDCS (18 patients per arm) was applied over the primary motor cortex for 10 days. The primary outcome measure was the pressure pain threshold (objective pain measure), and secondary outcomes were the numerical rating scale score (subjective pain measure), Von Frey monofilaments, and disease- and pain-related questionnaires. Data were collected at baseline, after the 10-day stimulation, and at a follow-up session, which took place 1 week after the tDCS had ended. Statistical analyses were performed with analyses of variance and t tests. RESULTS: Significant decreased pain perception in both pain measurements (pressure pain threshold and numerical rating scale score) was found for the active tDCS group compared with the placebo group. This proof-of-concept study shows that tDCS is a helpful supporting pain therapy for patients with endometriosis and CPP. Moreover, further analyses revealed that 1 week after the stimulation had ended, pain reduction as indexed by pressure pain threshold remained significantly decreased, which indicates possible long-term analgesic effects. CONCLUSION: The present study provides evidence that tDCS is an effective therapy for pain reduction in endometriosis-associated CPP. The results support the notion that CPP is developed and maintained in the central nervous system, making a multimodal pain therapy necessary. TRIAL REGISTRATION: www.ClinicalTrials.gov ID: NCT05231239.

Mechanisms of peripheral sensitization in endometriosis patients with peritoneal lesions and acyclical pain.

PURPOSE: Endometriosis (EM) is one of the most frequent differential diagnoses concerning chronic pelvic pain. Women under hormonal therapy (HT) often benefit from it but sometimes suffer a setback and develop acyclical pelvic pain. Due to the assumption that mechanisms of neurogenic inflammation are involved in the generation of chronic pelvic pain, we aimed to investigate the expression of sensory nerve markers in EM-associated nerve fibers of patients with/without HT. METHODS: Laparoscopically excised peritoneal samples from 45 EM and 10 control women were immunohistochemically stained for: PGP9.5, Substance P (SP), NK1R, NGFp75, TRPV-1, and TrkA. Demographics and severity of pain were documented. RESULTS: EM patients showed a higher nerve fiber density (PGP9.5 and SP) and increased expression of NGFp75, TRPV1, TrkA, and NK1R in blood vessels and immune cells compared with controls. Patients with HT have cycle-dependent pelvic pain but suffer from acyclical pelvic pain. Interestingly, reducing NK1R expression in blood vessels under HT was observed. A correlation between dyspareunia severity and nerve fibers density and between NGFRp75 expression in blood vessels and cycle-dependent pelvic pain severity was observed. CONCLUSION: Patients under HT have no ovulation and no (menstrual) bleeding, which correlate with inflammation and cyclical pain. However, acyclical pain seems to be due to peripheral sensitization once it is present under treatment. Neurotransmitters, like SP and their receptors, are involved in mechanisms of neurogenic inflammation, which are relevant for pain initiation. These findings indicate that in both groups (EM with/without HT), neurogenic inflammation is present and responsible for acyclical pain.

Pelvic floor hypertension: possible factors for pelvic floor tenderness in endometriosis patients-a pilot study.

PURPOSE: Chronic pelvic pain (CPP) is one of the main problems of endometriosis, leading to a significant impairment of quality of life. Understanding the pain mechanisms and the pelvic floor muscles (PFM) changes in these patients is essential to integrate additional therapeutic strategies. We hypothesize that endometriosis patients have changes in PFM and that targeted vaginal electrostimulation can be a treatment option for CPP in this disease. METHODS: Fifteen patients with endometriosis and chronic acyclical pelvic pain were included. PFM electromyography with the Multiple Array Probe Leiden (MAPLe) was performed. Mapping of PFM was utilized and targeted electrostimulation of the hypertensive muscles was conducted. Control electromyography was performed afterward to evaluate the electrostimulation therapeutic effect. RESULTS: In 12/15 (80%) patients, the myofascial trigger point could be localized by digital examination. The most frequently affected muscle was the puborectalis (10/15-66.7%). Most of the patients showed serious changes in the average resting tone (aRT) of PFM. aRT was significantly increased in all patients and decreased after stimulation, whereby the difference prior to and after stimulation was not significant (p = 0.064). The detailed separated analysis of the hypertensive muscles showed a significant (p = 0.026) reduction in their resting tone (hRT), after targeted stimulation. CONCLUSION: Vaginal electrostimulation is a promising and feasible complementary treatment option for CPP in endometriosis patients. Targeted treatment of pelvic floor dysfunction should be included in clinical trials.

[Holistic treatment of endometriosis]. / Ganzheitliche Behandlung der Endometriose.

BACKGROUND: The pain phenomena caused by endometriosis are manifold. In addition to nociceptive pain there is also a nociplastic reaction with central sensitization. Atypical symptoms, such as acyclic lower abdominal pain, radiating pain, nonspecific bladder and intestinal complaints or even depression increasingly occur in addition to the classical cyclic complaints, such as severe dysmenorrhea, cyclic lower abdominal pain, dyspareunia, dysuria and dyschezia. Due to the diffuse range of symptoms, affected patients often consult not just gynecologists but also specialists from other disciplines (internal medicine, gastroenterology, orthopedics, pain therapy, psychology etc.). OBJECTIVE: The complexity of endometriosis is presented. The resulting approaches to multimodal interdisciplinary holistic treatment are described. RESULTS: Interdisciplinary concepts should be involved in the optimal treatment of endometriosis patients along with hormonal and surgical treatment, mostly under the supervision of a gynecologist and pain management, dietary changes, psychological support and physiotherapeutic management should also be included. This article provides an overview of possible treatment strategies for chronic symptomatic endometriosis. CONCLUSION: Based on multimodal treatment strategies and regarding the complex pathophysiological alterations of this disease, the complex complaints that significantly impair the quality of life of endometriosis patients can be greatly improved.

Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6-10% of women of reproductive age, with 30-50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain.

Functional changes of immune cells: signal of immune tolerance of the ectopic lesions in endometriosis?

RESEARCH QUESTION: What is the potential role of immune cells and their inflammatory cytokines in the pathogenesis, development and establishment of endometriosis? DESIGN: Peritoneal fluid from 59 women (43 with endometriosis and 16 controls) who had undergone laparoscopic surgery was analysed. Changes in the population of innate and adaptive immune cells, cytokines, chemokines and growth factor expression were measured by flow cytometry, Luminex Technology and enzyme-linked immunosorbent assay. RESULTS: No differences were found in the frequencies of the innate and adaptive immune cells between women with and without endometriosis. In the peritoneal fluid of women with endometriosis, IL-1ß, IL-1RN, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-17α, FGF2, G-CSF, MCP-1, MIP-1α and TNF-α were significantly increased compared with controls. A correlation between IL-2, MCP-1, MIP-1α, TNF-α and the severity of endometriosis was observed. The concentration of neopterin, a possible biomarker for this disease, was increased in women with endometriosis compared with controls. CONCLUSIONS: The functional activity of immune cells seemed to be reduced despite their numbers remaining unchanged. The data indicate that a shift of TH cytokine profile occurs, which increases the TH1-TH2 ratio. This is driven by the increased levels of the cytokines (TNF-α and IL-2) in women with severe endometriosis.

[Management of endometriosis pain : Stage-based treatment strategies and clinical experience]. / Endometrioseschmerz beherrschen : Stufenschema und klinische Erfahrungen.

BACKGROUND: Endometriosis is associated with various types of intense pain. In addition to nociceptive pain, there is also a nociplastic reaction with central sensitization. Atypical symptoms such as acyclic lower abdominal pain, radiating pain, non-specific bladder and intestinal complaints or even depression are frequent as are classic cyclical complaints such as severe dysmenorrhea, cyclical lower abdominal pain, dyspareunia, dysuria and dyschezia. In cases of a diverse range of symptoms, patients often consult not just gynecologists but specialists from other disciplines (e.g., internal medicine, gastroenterology, orthopedics, pain therapy, psychology). AIMS: Overview about the pathophysiology and complexity of the disease and the resulting treatment options. A multimodal interdisciplinary concept might be able to take into consideration all aspects of the complex disease. METHODS: Interdisciplinary concepts should be involved in the treatment of endometriosis patients along with hormonal and surgical therapy, which are generally under the supervision of a gynecologist. Pain management, dietary changes, psychological support, as well as physiotherapy should be included. The present article is intended to provide an overview of possible treatment strategies for chronic, symptomatic endometriosis. CONCLUSION: The use of multimodal treatment strategies regarding the complex pathophysiological aspects of this disease might be helpful in significantly improving the quality of life of endometriosis patients.

Neurogenic Inflammation in the Context of Endometriosis-What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Possible Role of the Posterior Compartment Peritonectomy, as a Part of the Complex Surgery, Regarding Recurrence Rate, Improvement of Symptoms and Fertility Rate in Patients with Endometriosis, Long-Term Follow-Up.

STUDY OBJECTIVE: Beside the pain, there are 2 further problems in the management of endometriosis: the high recurrence rate (10% per year) and the high rate of impaired fertility. The objective of this study was to investigate the pathogenesis of these 2 factors. DESIGN: This is a retrospective cohort study, and the aim is to evaluate the complete excision of endometriotic lesions, including the posterior compartment of the peritoneum, with regard to postoperative outcome, focusing on relieving pain, increasing fertility rate, and decreasing recurrence rate. SETTING: Charité-University Clinic, Department of Gynaecology, Endometriosis research Centre. PATIENTS: Fifty-four patients were enrolled in this study, with severe deep infiltrating endometriosis (scored by ENZIAN) and superficial endometriosis, as well as endometriomas (revised American Society for Reproductive Medicine [rASRM] I = 3; II = 15; III = 10; and IV = 26). INTERVENTIONS: Posterior compartment peritonectomy (visible endometriotic lesions and inflamed altered peritoneum) was performed in all patients as part of a complex surgery: complete excision of endometriosis. MEASUREMENTS AND MAIN RESULTS: Postoperative outcomes were evaluated, based on the postoperative follow-up (up to 5 years) of 54 investigated patients. In 36 women (66%) preoperative complaints were eliminated. Furthermore, of 28 women seeking improved fertility, pregnancy was reported in 13 cases (46%). In 7 (54%) cases pregnancy occurred spontaneously, and in the remainder with assisted fertilization. In addition, long-term follow-up demonstrated a recurrence rate in 1.8% of patients. CONCLUSION: Overall, the number of complaints was significantly reduced. Only in the case of reproductive-aged women with ongoing postoperative complaints was it important to preserve the uterus. Although this pilot study on systematic posterior peritonectomy showed improvement in recurrence and fertility rate, the main question remains: will this surgical technique achieve better results and outcomes in the future? This has to be addressed in a prospective randomized study.

Post-operative management and follow-up of surgical treatment in the case of rectovaginal and retrocervical endometriosis.

INTRODUCTION: Deep infiltrating endometriosis (DIE) affects between 3.8% and 37% of all endometriosis patients, mostly affecting rectovaginal septum or retrocervical space and characterized by the severe endometriosis-related complaints. Nowadays, generally managed with surgery. However, this is associated with a risk of postoperative complications. To better evaluate intra- and postoperative complications and outcomes for rectovaginal (RVE) and retrocervical endometriosis (RCE), the preoperative management should be accurately described and compared. METHODOLOGY: This is a cohort retrospective study performed at the Endometriosis Centre of Charité-University Clinic, Berlin. 34 patients were investigated in their reproductive age, n = 19 with RVE and n = 15 RCE, operated between 2011 and 2015. The surgical approach was divergent in both groups. Single laparoscopy was performed in RCE patients (RCEP) and vaginal assisted laparoscopy in RVE patients (RVEP). Long-term postoperative outcome included complications, fertility rate and recurrence rate. RESULTS: The median follow-up time was three years (y). Symptom-free status was revealed in n = 12 RVEP and n = 9 RCEP. Postoperatively, endometriosis-related complaints were presented in n = 7 RVEP and n = 6 RCEP, but with significant pain relief. From n = 8 RVE patients seeking fertility, pregnancy occurred in n = 7 and from n = 9 RCEP pregnancy appeared in n = 5 patients in the meantime of 6 months. Postoperative complications were reported in n = 1 RVEP with early postoperative bleeding, after ureter leakage and n = 1 RCEP with postoperative anastomotic insufficiency. The postoperative recurrence rate was equivalent to zero. CONCLUSION: The appropriate surgical approach for each group, preserving anatomy and functionality of the organs, seems to be very essential and efficient.

Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFß1) in myofibroblastic metaplasia.

PURPOSE: Superficial peritoneal endometriotic (pEM) lesions are composed of endometrial glands and stroma, in addition to a third component-myofibroblasts and smooth muscles (SM)-like cells. The latter develops secondary to a metaplasia. In this study, we characterised the third component cells in pEM according to differentiation markers in different micro-compartments. Furthermore, a possible effect of TGFß1 on myofibroblastic metaplasia in endometriotic epithelial cells was studied. METHODS: Seventy-six premenopausal patients were included. Peritoneal biopsies were excised from EM patients (n = 23), unaffected peritoneum (peritoneum from EM patients but without EM components, n = 5/23) and non-EM patients (n = 10). All peritoneal biopsies were immunolabeled for ASMA, calponin, collagen I, desmin, TGFß receptor 1 (R1), R2 and R3 in addition to ultrastructure examination by transmission electron microscopy (TEM) (n = 1). TGFß1 level was measured in peritoneal fluid (PF) (EM, n = 19 and non-EM, n = 13) collected during laparoscopy. Furthermore, TGFß1 effect on myofibroblastic metaplasia was studied in vitro. RESULTS: At the centre of pEM lesions, calponin immunolabeling outweighs the collagen I while in the periphery the reverse occurs. SM-like cells expressing desmin predominate at the periphery, while ASMA immunolabeling was detectable in all micro-compartments. Both indicate an abundance of myofibroblasts at the centre of pEM lesions and SM-like cells in the periphery. Although activated TGFß1 in PF did not differ between EM and non-EM, it inhibited the cell proliferation of the endometriotic epithelial cells and induced an upregulation in ASMA and collagen IA2 expression as well. CONCLUSION: The abundance of the myofibroblasts and SM-like cells points to a myofibroblastic metaplasia in pEM. Both cells are differentially arranged in the different micro-compartments of pEM lesions, with increasing cell maturity towards the periphery of the lesion. Furthermore, TGFß1 may play a role in the myofibroblastic metaplasia of the endometriotic epithelial cells. These findings provide a better insight in the micro-milieu in EM lesions, where most of the disease dynamics occur.

Laparoscopic Neuronavigation for Deep Lateral Pelvic Endometriosis: Clinical and Surgical Implications.

STUDY OBJECTIVE: To evaluate the clinical presentation and surgical outcome in patients with deep lateral pelvic endometriosis (dLPE). DESIGN: A retrospective multicentric study (Canadian Task Force classification II-2). SETTING: University tertiary referral centers. PATIENTS: One hundred forty-eight women with deep infiltrating endometriosis (DIE). INTERVENTIONS: Laparoscopic excision of DIE. Disease distribution was classified as follows: central pelvic endometriosis (CPE) when DIE involved 1 of the following anatomic sites: cervix, vagina, uterosacral ligaments, rectum, bladder, or pelvic peritoneum; superficial lateral pelvic endometriosis when parametria, ureters, or hypogastric plexus were involved; and dLPE in the presence of sacral plexus and/or sciatic nerve infiltration. MEASUREMENTS AND MAIN RESULTS: All patients showed CPE. LPE was detected in 116 cases (78.4%); among these, we observed dLPE in 41 patients (35.3%). dLPE occurred in 40% of women with CPE and in 72.7% of patients with hypogastric plexus involvement. Thirty women with dLPE (73.2%) received gastrointestinal or urologic resection in addition to gynecologic procedures compared with 40 patients (57.1%) without dLPE (p = .001). No differences were observed in terms of perioperative complications according to the presence of dLPE. According to univariate/multivariate analysis, chronic pelvic pain was the only predictor of dLPE (odds ratio = 3.041, p = .003). The median preoperative visual analog scale for dysmenorrhea (median = 8, range, 0-10) and dyspareunia (median = 5; range, 0-10) dropped to 0 after surgery. The median follow-up was 36 months (range, 6-66 months) with a recurrence rate of 8.8%. CONCLUSIONS: dLPE is not a rare event in women with DIE. Complete laparoscopic removal of endometriosis seems to ensure benefit in terms of recurrence rate without increased surgical morbidities.

Abdominal Wall Endometriosis: Myofibroblasts as a Possible Evidence of Metaplasia: A Case Report.

In this study, we report about a patient with extra-uterine endometriosis (EM) in the abdominal wall muscle with evident metaplasia based on the abundant alpha smooth muscle actin (ASMA)-expressing myofibroblasts. Laparotomy excision of the abdominal wall EM was done following ultrasonographic evidence of a hypodense swelling in the right rectus abdominis, which was confirmed by MRI. Immunohistochemistry staining for ASMA and collagen I was done, with the results confirming that endometriotic stromal cells expressed both. Anterior abdominal wall endometriosis was suspected because of the patient's history of recurrent EM combined with the cyclic nature of symptoms. MRI is useful in determining the extent of the disease. In case of persisting symptoms even under hormonal treatment, surgical excision is mandatory. The expression of both ASMA and collagen I in and around EM lesions supports the notion of the metaplastic process in the course of disease development.

Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis.

Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor ß, with up to 20% being estrogen receptor α positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1-differentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brain-derived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key role for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder.

Localization of TrkB and p75 receptors in peritoneal and deep infiltrating endometriosis: an immunohistochemical study.

BACKGROUND: The roles of the neurotrophins NGF (Neurotrophic growth factor) and BDNF (brain-derived neurotrophic factor) in neuronal growth and development are already known. Meanwhile, the neurotrophin receptors TrkA (tropomyosin related kinase A), TrkB, and p75 are important for determining the fate of cells. In endometriosis, this complex system has not been fully elucidated yet. The aim of this study was to evaluate the expression and location of these neurotrophins and their receptors in peritoneal (PE) and deep infiltrating endometriotic (DIE) tissues and to measure and compare the density of nerve fibers in the disease subtypes. METHODS: PE lesions (n = 20) and DIE lesions (n = 22) were immunostained and analyzed on serial slides with anti-BDNF, -NGF, -TrkA, -TrkB, -p75,-protein gene product 9.5 (PGP9.5, intact nerve fibers) and -tyrosine hydroxylase (TH, sympathetic nerve fibers) antibodies. RESULT: There was an equally high percentage (greater than 75 %) of BDNF-positive immunostaining cells in both PE and DIE. TrkB (major BDNF receptor) and p75 showed a higher percentage of immunostaining cells in DIE compared to in PE in stroma only (p < 0.014, p < 0.027, respectively). Both gland and stroma of DIE lesions had a lower percentage of NGF-positive immunostaining cells compared to those in PE lesions (p < 0.01 and p < 0.01, respectively), but there was no significant reduction in immunostaining of TrkA in DIE lesions. There was no difference in the mean density of nerve fibers stained with PGP9.5 between PE (26.27 ± 17.32) and DIE (28.19 ± 33.15, p = 0.8). When we performed sub-group analysis, the density of nerves was significantly higher in the bowel DIE (mean 57.33 ± 43.9) than in PE (mean 26.27 ± 17.32, p < 0.01) and non-bowel DIE (mean 14.6. ± 8.6 p < 0.002). CONCLUSIONS: While the neurotrophin BDNF is equally present in PE and DIE, its receptors TrkB and p75 are more highly expressed in DIE and may have a potential role in the pathophysiology of DIE, especially in promotion of cell growth. BDNF has a stronger binding affinity than NGF to the p75 receptor, likely inducing sympathetic nerve axonal pruning in DIE, resulting in the lower nerve fiber density seen.

Laparoscopic En Bloc Right Diaphragmatic Peritonectomy for Diaphragmatic Endometriosis According to the Sugarbaker Technique.

STUDY OBJECTIVE: To evaluate the feasibility of a novel laparoscopic procedure for complete eradication of diaphragmatic endometriosis (DE). DESIGN: A retrospective multicenter study (Canadian Task Force Classification II-2). SETTING: University tertiary referral centre. PATIENTS: A consecutive series of 9 women with DE. INTERVENTIONS: Laparoscopic en bloc eradication using Sugarbaker's peritonectomy technique with or without diaphragmatic resection for DE. All surgical procedures were performed by the same surgeon in 2 tertiary referral centers (Charitè University, Berlin, Germany, and Catholic University of the Sacred Heart, Foundation John Paul II, Campobasso, Italy). MEASUREMENTS AND MAIN RESULTS: Rate of conversion to laparotomy, perioperative outcomes, intra- and postoperative complications, and recurrence rate. The procedures were successfully performed in all patients laparoscopically without conversion to laparotomy. All patients also presented with multiple endometriotic lesions in the Morison pouch, and in 3 cases a deep infiltration of the right diaphragm was observed that required partial diaphragmatic resection. In 2 women, pulmonary nodules were also detected, and lung laparoscopic resection was attempted to eradicate the disease. A chest drain was placed in 7 women and was removed after a median time of 6 days (range, 4-10 days). No intra- or postoperative complications were recorded. To complete the diaphragmatic peritonectomy, the median operative time required was 180 minutes (range, 90-240 minutes). The median estimated blood loss was 100 mL (range, 50-300 mL), and the median hospital stay was 10 days (range, 5-17 days). After a median follow-up of 6 months, we observed symptomatic relief for all study patients without major surgery-related morbidity. In 1 woman, laparoscopic adhesiolysis was performed after 18 months from surgery without signs of recurrent endometriosis. CONCLUSION: Laparoscopic en bloc eradication of DE with Sugarbaker's peritonectomy is highly effective in the management of symptomatic DE, with no major intra-/postoperative complications and very favorable perioperative outcomes.

Characterization of endometriosis-associated immune cell infiltrates (EMaICI).

OBJECTIVE: To identify and characterize endometriosis-associated immune cell infiltrates (EMaICI). Furthermore, to define occurrence and size of EMaICI in various types of endometriosis. METHODS: Immune cells were characterized in samples of 60 premenopausal women with histological proven endometriosis. Therefore, immunohistochemical staining with monoclonal antibodies for CD3, CD4, CD8, CD45RO, CD25, CD56, CD68, and CD20 on sections of paraffin-embedded endometriotic tissue was performed. RESULTS: EMaICI were observed in all the types of endometriosis, and characterized as T lymphocytes (CD3+), helper T lymphocytes (CD4+), cytotoxic T lymphocytes (CD8+), antigen-experienced T lymphocytes"memory cells" (CD45RO+), macrophages (CD68+), and B lymphocytes (CD20+). The maximum frequency of EMaICI and their distribution per endometriotic lesion (EML) was observed in peritoneal endometriosis (pEM) and in ovarian endometriosis (Ov. EM). In myometrium from adenomyosis (M/AM), EMaICI occurrence was lower and smaller in size in comparison with EMaICI seen in other forms of endometriosis. EMaICI were negative for regulatory T cells (CD25+ high, FoxP3+) and natural killer cells (NK cells, CD56+). CONCLUSION: Numerous and brisk EMaICI comprising several types of immune cells in all endometriosis forms suggest acute immunological reactions within the microenvironment of endometriosis lesions.

Laparoscopic sentinel lymph node detection after hysteroscopic injection of technetium-99 in patients with endometrial cancer.

BACKGROUND AND OBJECTIVES: Endometrial cancer (EC) has an increasing incidence worldwide. Despite the unequivocal prognostic importance of nodal status, systematic lymphadenectomy is associated to elevated morbidity. Sentinel lymph node (SLN) biopsy is designed to avoid extensive nodal dissection and provide crucial oncologic information. The goal of this prospective study was to determine the feasibility, safety, and accuracy of laparoscopic SLN biopsy in EC obtained through hysteroscopic injection of technetium-99 (Tc-99). METHODS: From January 2008 to December 2012, a total of 42 women with EC were included in the study. We injected 20 mBq of Tc-99 hysteroscopically underneath the tumor minutes before definitive surgery. Thereafter, laparoscopic SLN identification /biopsy followed by pelvic and para-aortic lymphadenectomy, hysterectomy, and bilateral salpingo-oophorectomy were executed. RESULTS: The total number of removed nodes was 970. The detection rate of the method was 73% (31/42). Among the 70 isolated SLNs, 35% (24) were exclusively identified in the para-aortic area. Fourteen patients (45%) had SLN only in the pelvic region, whereas 11 (35%) had SLN in both pelvic and para-aortic areas and 6 women (20%) had isolated para-aortic SNL. Nodal metastases were histologically confirmed in 9 patients (22%), and SLN was identified in 7 of 9 patients (78%). Although the obtained specificity was 100% and the negative predictive value was 89%, the sensitivity was only 58% (false-negative rate of 42%). CONCLUSIONS: We could demonstrate that endoscopic SLN biopsy obtained through hysteroscopic injection of Tc-99 is a feasible and safe method. Despite the restricted number of included patients in this series, the obtained sensitivity and false-negative rates raise some questions about the real accuracy of the procedure in EC. Larger validation trials requiring quality pelvic and para-aortic lymphadenectomy are essential to correctly evaluate the method.

Shedding Light on the Interaction Between Rif1 and Telomeres in Ovarian Cancer.

Ovarian cancer, more precisely high-grade serous ovarian cancer, is one of the most lethal age-independent gynecologic malignancies in women worldwide, regardless of age. There is mounting evidence that there is a link between telomeres and the RIF1 protein and the proliferation of cancer cells. Telomeres are hexameric (TTAGGG) tandem repeats at the tip of chromosomes that shorten as somatic cells divide, limiting cell proliferation and serving as an important barrier in preventing cancer. RIF1 (Replication Time Regulation Factor 1) plays, among other factors, an important role in the regulation of telomere length. Interestingly, RIF1 appears to influence the DNA double-strand break (DSB) repair pathway. However, detailed knowledge regarding the interplay between RIF1 and telomeres and their degree of engagement in epithelial ovarian cancer (EOC) is still elusive, despite the fact that such knowledge could be of relevance in clinical practice to find novel biomarkers. In this review, we provide an update of recent literature to elucidate the relation between telomere biology and the RIF1 protein during the development of ovarian cancer in women.