Surgical Treatment of Patients with Endometriosis in the Certified Endometriosis Centers of the DACH Region - A Subanalysis of the Quality Assurance Study QS ENDO pilot.

Introduction After puberty, at least 10% of all women and girls suffer from endometriosis. Surgery is useful for both the diagnosis and therapy. To date, quality indicators for the surgical treatment of endometriosis are lacking. QS ENDO aims to record the quality of care provided in the DACH region and to introduce quality indicators for the diagnosis and treatment of endometriosis. In the first phase of the study, QS ENDO real, the reality of care was recorded using a questionnaire. The second phase, QS ENDO pilot, investigated the treatment of patients who underwent surgery in certified endometriosis centers in a defined time-period. Material and Methods The surgical data of 10 patients from each of the 44 endometriosis centers in the DACH region was recorded using an online tool. Collected data included the approach used, the endometriosis phenotype, a description of the surgical site, resection status, histological confirmation, the use of a classification, and any complications. All operations were carried out in October 2016 as the defined time-period. The surgical approaches used were compared with the recommendations in the current guidelines. Results The data of 435 patients with a median age of 34 years were evaluated. 315 (72.4%) were nulliparous. 120 patients had given birth to at least one child and 42.5% (51) of them had delivered their child by caesarean section. About 50% of all patients also had deep infiltrating endometriosis in addition to ovarian endometriosis, and the median NAS score was 7.5. With regards to the surgical treatment, endometriomas were completely resected in 81% (94) of patients. 87.3% of patients underwent resection of peritoneal endometriosis. Forty-one patients had a hysterectomy, with a total hysterectomy carried out in 26 (63.4%) and a supracervical hysterectomy in 15 (36.6%) patients. Of the 59 patients with bowel endometriosis, half had segmental resection and half had shaving of the anterior rectal wall. Complications requiring revision occurred in 0.9% of cases. Conclusion The surgical procedures carried out in the certified endometriosis centers of the DACH region are largely in line with the recommendations for appropriate surgical approaches in the current standard guidelines.

The Different Gene Expression Profile in the Eutopic and Ectopic Endometrium Sheds New Light on the Endometrial Seed in Endometriosis.

The changes in endometrial cells, both in the eutopic endometrium of patients with and without endometriosis and in lesions at ectopic sites, are frequently described and often compared to tumorigenesis. In tumorigenesis, the concept of "seed and soil" is well established. The seed refers to tumor cells with metastatic potential, and the soil is any organ or tissue that provides a suitable environment for the seed to grow. In this systematic review (PRISMA-S), we specifically compared the development of endometriosis with the "seed and soil" hypothesis. To determine changes in the endometrial seed, we re-analyzed the mRNA expression data of the eutopic and ectopic endometrium, paying special attention to the epithelial-mesenchymal transition (EMT). We found that the similarity between eutopic endometrium without and with endometriosis is extremely high (~99.1%). In contrast, the eutopic endometrium of patients with endometriosis has a similarity of only 95.3% with the ectopic endometrium. An analysis of EMT-associated genes revealed only minor differences in the mRNA expression levels of claudin family members without the loss of other cell-cell junctions that are critical for the epithelial phenotype. The array data suggest that the changes in the eutopic endometrium (=seed) are quite subtle at the beginning of the disease and that most of the differences occur after implantation into ectopic locations (=soil).

Prevention of peritoneal adhesions after gynecological surgery: a systematic review.

IMPORTANCE: The formation of adhesions after gynecological surgery not only has detrimental impacts on those affected, including pain, obstruction, and infertility, but also imposes a high economic burden on healthcare systems worldwide. OBJECTIVE: The aim of this review was to evaluate the adhesion prevention potential of all currently available adhesion barriers for gynecological surgery. EVIDENCE ACQUISITION: We systematically searched MEDLINE and CENTRAL databases for randomized controlled trials (RCTs) on the use of adhesion barriers as compared with peritoneal irrigation or no treatment in gynecological surgery. Only RCTs with second-look surgery to evaluate adhesions in the pelvic/abdominal (but not intrauterine) cavity were included. RESULTS: We included 45 RCTs with a total of 4,120 patients examining a total of 10 unique types of barriers in second-look gynecological surgery. While RCTs on oxidized regenerated cellulose (significant improvement in 6 of 14 trials), polyethylene glycol with/without other agents (4/10), hyaluronic acid and hyaluronate + carboxymethylcellulose (7/10), icodextrin (1/3), dextran (0/3), fibrin-containing agents (1/2), expanded polytetrafluoroethylene (1/1), N,O-carboxymethylchitosan (0/1), and modified starch (1/1) overall showed inconsistent findings, results for expanded polytetrafluoroethylene, hyaluronic acid, and modified starch yielded the greatest improvements regarding adhesion reduction at 75%, 0-67%, and 85%, respectively. CONCLUSIONS AND RELEVANCE: Best results for adhesion prevention were reported after applying Gore-Tex Surgical Membrane, hyaluronic acid, and 4DryField®. As Gore-Tex Surgical Membrane is nonabsorbable, it is associated with a greater risk of new adhesion formation due to second-look surgery to remove the product. 4DryField® yielded the greatest improvement in adhesion score compared to all other barrier agents (85%). For better comparability, future studies should use standardized scores and put more emphasis on patient-reported outcome measures, such as pain and infertility.

Long-Term Maintenance of Viable Human Endometrial Epithelial Cells to Analyze Estrogen and Progestin Effects.

There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the main reasons is the scarcity of protocols enabling prolonged epithelial cell culture. Even though it is possible to culture HPEECs in 3D over a longer period of time, it is technically demanding. In this study, we successfully established a highly pure, stable, and long-term viable human conditionally reprogrammed endometrial epithelial cell line, designated as eCRC560. These cells stained positive for epithelial markers, estrogen and progesterone receptors, and epithelial cell-cell contacts but negative for stromal and endothelial cell markers. Estradiol (ES) reduced the abundance of ZO-1 in a time- and dose-dependent manner, in contrast to the dose-dependent increase with the progestin dienogest (DNG) when co-cultured with HPESCs. Moreover, ES significantly increased cell viability, cell migration, and invasion of the eCRC560 cells; all these effects were inhibited by pretreatment with DNG. DNG withdrawal led to a significantly disrupted monolayer of eCRC560 cells in co-culture with HPESCs, yet it markedly increased the adhesion of eCRC560 to the human mesothelial MeT-5A cells. The long-term viable eCRC560 cells are suitable for in vitro analysis of HPEECs to study the epithelial compartment of the human endometrium and endometrial pathologies.

Predictors of significant distress in cervical cancer patients: a cross sectional study.

PURPOSE: This cross-sectional study aims to investigate parameters that predict relevant levels of distress in women in a perioperative setting undergoing treatment for cervical cancer. MATERIALS AND METHODS: Data from 495 patients with cervical cancer that were treated at the university hospital Aachen between 2010 and 2022 were analysed based on their respective National Comprehensive Cancer Network (NCCN) Distress Thermometer score (DT) and Problem List (PL) and their clinical history. 105 patients were enrolled in the study. 18 medical and demographic variables were analysed using multivariate logistic regression. RESULTS: Three variables contributed significantly to the prediction of a DT score ≥ 5. Significant distress was defined as a DT score of ≥ 5, which was observed in 70.5% of the participants (mean: 5.58 ± 2.892). Women who chose to receive psycho-oncological counselling were more likely to have a DT score ≥ 5 (Odds Ratio(OR) = 3.323; Confidence Interval (CI95%): 1.241-8.900; p-value: 0.017). In addition, women who did not receive chemoradiation had significantly higher DT scores (OR = 3.807; CI 95%:1.185-12.236; p-value: 0.025), as did women whose Distress Thermometer was assessed in the first month after their initial diagnosis (OR = 3.967; CI 95%:1.167-13.486; p-value: 0.027). CONCLUSION: Increased distress in women with cervical cancer is common especially in the first month after diagnosis, in patients who do not receive chemoradiation and in patients who seek psycho-oncological counselling. Surgical factors do not play a major role in patient distress.

Comparative study using indocyanine green and patent blue dye for sentinel lymph node biopsy in patients with early-stage cervical cancer.

BACKGROUND: Lymphatic involvement is the most important prognostic factor in early-stage cervical cancer. Sentinel lymph node biopsy is a viable alternative to systematic lymphadenectomy and may identify metastases more precisely. OBJECTIVE: To compare two tracers (indocyanine green and patent blue) to detect sentinel nodes. METHODS: A single-center, retrospective study of women treated due to early-stage cervical cancer (International Federation of Gynecology and Obstetrics 2009 IA1 with lymphovascular invasion, IA2, and IB1). Location and tracer of all detected sentinel nodes had been documented for a prospective, multicenter trial (SENTIX trial). All sentinel nodes were sent to frozen section and final analysis through ultrastaging using a standard protocol. RESULTS: Overall, 103 patients were included. Bilateral detection rate for indocyanine green (93.2%) was significantly higher than for blue dye (77.7%; p=0.004). Their combined use significantly increased the bilateral detection to 99.0% (p=0.031). While 97.4% of all sentinel nodes were located below the common iliac vessels, no para-aortic nodes were labeled. Simultaneous bilateral detection with both tracers was found in 71.8% of the cases, of which the sentinel nodes were identical in 91.9%. Nine positive nodes were detected among seven patients (6.8%), all marked with indocyanine green while patent blue labeled six. Frozen section failed to detect one of three macrometastases and three of four micrometastases (sensitivity 43%; negative prediction value 96%). CONCLUSION: Anatomical distribution and topographic localization of the sentinel nodes obtained with these tracers were not different. Indocyanine green provided a significantly higher bilateral detection rate and had superior sensitivity to detect positive nodes compared with patent blue. Combining indocyanine green and blue dye increased the bilateral detection rate significantly.

The effect of early skin-to-skin contact after cesarean section on breastfeeding duration and development of atopic-allergic diseases.

INTRODUCTION: Breastfeeding to strengthen the immune system suggests allergy prevention as a possible option. The connection between breastfeeding and the development of atopic-allergic diseases is being discussed. The primary aim of this work was to investigate an association of the first early skin-to-skin contact following cesarean section with the development of atopic diseases within the 1st year of life. METHODS: The present study was conducted as a bicentric prospective cohort study in central Germany with a 15-month recruitment period. Data collection was by telephone interviews with a follow-up of 12 months. The statistical evaluation procedure was based on a hierarchical test of the association of early skin-to-skin contact between mother and child with the two main outcome measures. The primary outcome is the duration of breastfeeding. The second outcome is the onset of atopic-allergic disease within the 1st year of life. RESULTS: Mothers breastfed longer if they had skin-to-skin contact within the first 30 minutes postpartum [χ²(df=5) = 19.020, p=0.002], if they breastfed their newborns early immediately after birth (p<0.001), and if the first skin-to-skin contact lasted more than one hour [χ²(df=4) = 19.617, p<0.001]. Regarding atopic-allergic diseases, no significant effects of skin-to-skin contact were found in relation to disease development. Regarding breastfeeding, no significant effects of atopic-allergic diseases could be detected either. CONCLUSIONS: The results of this study reflect the benefits of skin-to-skin contact in the context of breastfeeding and atopic disease. The current scientific knowledge regarding skin contact and the development of atopic-allergic diseases should be extended and deepened.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

Application of the #Enzian classification for endometriosis on MRI: prospective evaluation of inter- and intraobserver agreement.

Objectives: The purpose of this investigation was to evaluate the inter- and intraobserver variability of the updated #Enzian classification of endometriosis on MRI and to evaluate the influence of reader experience on interobserver concordance. Methods: This was a prospective single-center study. All patients were included who received an MRI of the pelvis for evaluation of endometriosis between March and July 2023 and who have provided written informed consent. Images were reviewed independently for endometriosis by three radiologists, utilizing the MRI-applicable categories of the #Enzian classification. Two radiologists had experience in pelvic MRI and endometriosis imaging. One radiologist had no specific experience in pelvic MRI and received a one-hour briefing beforehand. Results: Fifty consecutive patients (mean age, 34.9 years ±8.6 [standard deviation]) were prospectively evaluated. Interobserver agreement was excellent for diagnosis of deep infiltrating endometriosis (Fleiss' kappa: 0.89; 95% CI 0.73-1.00; p < 0.001) and endometriomas (Fleiss' kappa: 0.93; 95% CI 0.77-1.00; p < 0.001). For the experienced readers, interobserver agreement in the assessment of compartments A, B and C was excellent (κw ranging from 0.84; 95% CI 0.71-0.97; p < 0.001 to 0.89; 95% CI 0.82-0.97; p < 0.001). For the pairings of the experienced readers to the reader without specific experience in pelvic MRI, agreement was substantial to excellent (κw ranging from 0.64; 95% CI 0.44-0.85; p < 0.001 to 0.91; 95% CI 0.84-0.98; p < 0.001). Intraobserver variability was excellent for compartments A, B and C (κw ranging from 0.85; 95% CI 0.73-0.96; p < 0.001 to 0.95; 95% CI 0.89-1.00; p < 0.001). Conclusion: With sufficient experience, the #Enzian classification enables the achievement of excellent inter- and intraobserver agreement in MRI-based diagnosis of deep infiltrating endometriosis and endometriomas.

Analysis of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP, MMP14) in Eutopic and Ectopic Endometrium and in Serum and Endocervical Mucus of Endometriosis.

BACKGROUND: Membrane type-matrix metalloproteinases (MT-MMPs) are a subgroup of the matrix metalloproteinases (MMPs) family and are key molecules in the degradation of the extracellular matrix. Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP14) is often deregulated in different cancer tissues and body fluids of human cancer patients; however, MT1-MMP levels in endometriosis and adenomyosis patients are currently unknown. MATERIALS AND METHODS: Tissue samples from patients with and without endometriosis or adenomyosis were analyzed with immunohistochemistry for the localization of MT1-MMP. Serum and endocervical mucus samples from patients with and without endometriosis or adenomyosis were investigated with MT1-MMP ELISAs. RESULTS: MT1-MMP was localized preferentially in the glands of eutopic and ectopic endometrium. MT1-MMP protein levels are significantly reduced in ovarian endometriosis (HSCORE = 31) versus eutopic endometrium (HSCORE = 91) and adenomyosis (HSCORE = 149), but significantly increased in adenomyosis (HSCORE = 149) compared to eutopic endometrium (HSCORE = 91). Similarly, analysis of the levels of MT1-MMP using enzyme-linked immune assays (ELISAs) demonstrated a significant increase in the concentrations of MT1-MMP in the serum of endometriosis patients (1.3 ± 0.8) versus controls (0.7 ± 0.2), but not in the endocervical mucus. Furthermore, MT1-MMP levels in the endocervical mucus of patients with endometriosis were notably reduced in patients using contraception (3.2 ± 0.4) versus those without contraception (3.8 ± 0.2). CONCLUSIONS: Taken together, our findings showed an opposite regulation of MT1-MMP in the tissue of ovarian endometriosis and adenomyosis compared to eutopic endometrium without endometriosis but increased serum levels in patients with endometriosis.

Predictive Model for the Non-Invasive Diagnosis of Endometriosis Based on Clinical Parameters.

OBJECTIVES: Are other pain symptoms in addition to dysmenorrhea, dyspareunia, dyschezia, dysuria, and chronic pelvic pain correlated to endometriosis and suitable for a clinical prediction model? METHODS: We conducted a prospective study from 2016 to 2022, including a total of 269 women with numerous pain symptoms and other parameters. All women filled out two questionnaires and were examined by palpation and transvaginal ultrasound (TVUS). In cases of suspected deep endometriosis, magnetic resonance imaging (MRI) was performed. After the operation, endometriosis was diagnosed by histological examination. RESULTS: All in all, 30 significant parameters and 6 significant numeric rating scale (NRS) scores associated with endometriosis could be identified: 7 pain adjectives, 8 endometriosis-associated pain symptoms, 5 pain localizations, 6 parameters from the PainDETECT, consumption of analgesics, and allergies. Furthermore, longer pain duration (before, during, and after menstruation) was observed in women with endometriosis compared to women without endometriosis (34.0% vs. 12.3%, respectively). Although no specific pain for endometriosis could be identified for all women, a subgroup with endometriosis reported radiating pain to the thighs/legs in contrast to a lower number of women without endometriosis (33.9% vs. 15.2%, respectively). Furthermore, a subgroup of women with endometriosis suffered from dysuria compared to patients without endometriosis (32.2% vs. 4.3%, respectively). Remarkably, the numbers of significant parameters were significantly higher in women with endometriosis compared to women without endometriosis (14.10 ± 4.2 vs. 7.75 ± 5.8, respectively). A decision tree was developed, resulting in 0.904 sensitivity, 0.750 specificity, 0.874 positive predictive values (PPV), 0.802 negative predictive values (NPV), 28.235 odds ratio (OR), and 4.423 relative risks (RR). The PPV of 0.874 is comparable to the positive prediction of endometriosis by the clinicians of 0.86 (177/205). CONCLUSIONS: The presented predictive model will enable a non-invasive diagnosis of endometriosis and can also be used by both patients and clinicians for surveillance of the disease before and after surgery. In cases of positivety, as evaluated by the questionnaire, patients can then seek advice again. Similarly, patients without an operation but with medical therapy can be monitored with the questionnaire.

QS ENDO Pilot - A Study by the Stiftung Endometrioseforschung (SEF) on the Quality of Care Provided to Patients with Endometriosis in Certified Endometriosis Centers in the DACH Region.

Introduction Endometriosis significantly reduces patients' quality of life and is additionally a burden on healthcare and social security systems. There are currently no quality indicators for the treatment of endometriosis. The care of patients with endometriosis must be considered inadequate. QS ENDO aims to record the quality of care available in the DACH region and to introduce quality indicators for the diagnosis and treatment of endometriosis as part of providing quality assurance in endometriosis care. The first phase, QS ENDO Real, recorded the reality of current care using a questionnaire. The second phase, QS ENDO Pilot, investigated the treatment of 435 patients who underwent surgical treatment within a defined one month period in certified endometriosis centers. Material and Methods An online tool was used to gather information about 9 points which covered both prior patient history and the process of clinical diagnosis. Surgery reports were reviewed to obtain information about the surgical approach, the investigated sites, findings of any histological examinations, the use of classification systems, and information about resection status. Results 85.3% of patients were asked all 4 questions about their prior medical history. All 5 diagnostic steps were carried out in 34.5% of patients. The 3 areas needed to describe potential sites of disease were recorded in 67.1% of patients. Samples for histological examination were taken in 84.1% of patients. The endometriosis stage was classified in 94.7% of surgeries. A combination of the rASRM and the ENZIAN classifications, which is needed for complex cases, was used in 46.1% of patients. Complete resection was achieved in 81.6% of surgical procedures. Conclusion For the first time, the quality of care in certified endometriosis centers has been recorded using QS ENDO Pilot. Despite the high certification standards, a substantial number of required indicators were omitted.

Feasibility of periprocedural decision on the administration of intravenous contrast media in MRI for endometriosis.

PURPOSE: To assess the feasibility of a periprocedural decision on the administration of intravenous contrast media in MRI for endometriosis and to evaluate the frequency and reasons of contrast administrations, the corresponding MRI diagnoses, and outcome. METHODS: In this retrospective, descriptive cross-sectional single-center study all patients were included, who received a pelvic MRI for evaluation of endometriosis between April 2021 and February 2023. Frequency and reasons of optional intravenous administration of contrast media, corresponding MRI diagnoses and clinical outcome data were noted after re-review of all images, review of radiology reports and review of patients' medical records. The decision on the administration of intravenous contrast media had been made by experienced radiologists, depending on the findings of the non-contrast sequences and the presence of ancillary questions. RESULTS: 303 consecutive patients (mean age, 33.4 years +/- 8.3 [standard deviation]) were evaluated. Periprocedural decision on the administration of intravenous contrast media had been made in all cases. For 219/303 (72.3%) patients, it was decided after review of the non-contrast sequences and exclusion of ancillary questions that contrast administration was not required. 84/303 (27.7%) patients received contrast media, and the most frequent reasons were indeterminate ovarian lesion (41/84 cases, 48.8%) or suspicion of pelvic venous congestion syndrome (26/84 cases, 31.0%). No relevant differences in patient outcomes could be noted (non-contrast/contrast MRI). CONCLUSIONS: A periprocedural decision on the administration of contrast media in MRI for endometriosis is feasible with little effort. It allows the administration of contrast media to be avoided in most cases. If the administration of contrast media is deemed necessary, repeat examinations can be avoided.

Factors influencing surgical performance and learning progress in minimally invasive surgery - results of an interdisciplinary multicenter study.

BACKGROUND: Advancing surgical techniques require a high level of adaptation and learning skills on the part of surgeons. The authors need selection procedures and decision support systems for the recruitment of medical students and young surgeons. The authors aimed to investigate factors influencing the surgical performance and learning abilities of surgeons and medical students. MATERIALS AND METHODS: The training scores of persons attending 16 standardized training courses (at three training centers) of the German Working Group for Gynecological Endoscopy (AGE e.V.) from 2017 to 2020, individual characteristics, and the results of psychomotor tests of three-dimensional imagination and hand-eye coordination were correlated. Similar analyses were performed for medical students in their final clinical year from 2019 to 2020. The training concept was evaluated in a prospective, multicenter, interdisciplinary, multinational setting. RESULTS: In all, 180 of 206 physicians (response rate 87.4%) and 261 medical students (response rate 100%) completed the multistage training concept successfully. Of personal characteristics, the strongest correlation was noted for good surgical performance and learning success, and the absolute number of performed laparoscopic surgeries ( r =0.28-0.45, P <0.001/ r =0.1-0.28, P <0.05). A high score on the spatial visualization ability test was also correlated with good surgical performance ( r =0.18-0.27, P <0.01). Among medical students with no surgical experience, however, age was negatively correlated with surgical performance, that is the higher the age, the lower the surgical performance ( r =0.13/ r =0.22, P <0.05/ P <0.001). CONCLUSION: Individual factors (e.g. surgical experience, self-assessment, spatial visualization ability, eye-hand coordination, age) influence surgical performance and learning. Further research will be needed to create better decision support systems and selection procedures for prospective physicians. The possibilities of surgical training should be improved, promoted, and made accessible to a maximum number of surgical trainees because individual learning curves can be overcome even by less talented surgeons. Training options should be institutionalized for those attending medical school.

Deep Infiltrating Endometriosis: Diagnostic Accuracy of Preoperative Magnetic Resonance Imaging with Respect to Morphological Criteria.

Several current guidelines recommend imaging in the diagnostic work-up of deep infiltrating endometriosis (DIE). The purpose of this retrospective diagnostic test study was to evaluate the diagnostic accuracy of MRI compared to laparoscopy for the identification of pelvic DIE, considering lesion morphology using MRI. In all, 160 consecutive patients were included who received pelvic MRI for evaluation of endometriosis between October 2018 and December 2020 and underwent subsequent laparoscopy within 12 months of the MRI examination. MRI findings were categorized for suspected DIE using the Enzian classification and were additionally graded using a newly suggested deep infiltrating endometriosis morphology score (DEMS). Endometriosis was diagnosed in 108 patients (all types, i.e., purely superficial and DIE), of which 88 cases were diagnosed with DIE and 20 with solely superficial peritoneal endometriosis (i.e., not deep infiltrating endometriosis/DIE). The overall positive and negative predictive values of MRI for the diagnosis of DIE, including lesions with assumed low and medium certainty of DIE on MRI (DEMS 1-3), were 84.3% (95% CI: 75.3-90.4) and 67.8% (95% CI: 60.6-74.2), respectively, and 100.0% and 59.0% (95% CI: 54.6-63.3) when strict MRI diagnostic criteria were applied (DEMS 3). Overall sensitivity of MRI was 67.0% (95% CI: 56.2-76.7), specificity was 84.7% (95% CI: 74.3-92.1), accuracy was 75.0% (95% CI: 67.6-81.5), positive likelihood ratio (LR+) was 4.39 (95% CI: 2.50-7.71), negative likelihood ratio (LR-) was 0.39 (95% CI: 0.28-0.53), and Cohen's kappa was 0.51 (95% CI: 0.38-0.64). When strict reporting criteria are applied, MRI can serve as a method to confirm clinically suspected DIE.

Multiplex Immunofluorescence: A Powerful Tool in Cancer Immunotherapy.

Traditional immunohistochemistry (IHC) has already become an essential method of diagnosis and therapy in cancer management. However, this antibody-based technique is limited to detecting a single marker per tissue section. Since immunotherapy has revolutionized the antineoplastic therapy, developing new immunohistochemistry strategies to detect multiple markers simultaneously to better understand tumor environment and predict or assess response to immunotherapy is necessary and urgent. Multiplex immunohistochemistry (mIHC)/multiplex immunofluorescence (mIF), such as multiplex chromogenic IHC and multiplex fluorescent immunohistochemistry (mfIHC), is a new and emerging technology to label multiple biomarkers in a single pathological section. The mfIHC shows a higher performance in cancer immunotherapy. This review summarizes the technologies, which are applied for mfIHC, and discusses how they are employed for immunotherapy research.

Near Infrared Photoimmunotherapy: A Review of Recent Progress and Their Target Molecules for Cancer Therapy.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed molecular targeted cancer treatment, which selectively kills cancer cells or immune-regulatory cells and induces therapeutic host immune responses by administrating a cancer targeting moiety conjugated with IRdye700. The local exposure to near-infrared (NIR) light causes a photo-induced ligand release reaction, which causes damage to the target cell, resulting in immunogenic cell death (ICD) with little or no side effect to the surrounding normal cells. Moreover, NIR-PIT can generate an immune response in distant metastases and inhibit further cancer attack by combing cancer cells targeting NIR-PIT and immune regulatory cells targeting NIR-PIT or other cancer treatment modalities. Several recent improvements in NIR-PIT have been explored such as catheter-driven NIR light delivery, real-time monitoring of cancer, and the development of new target molecule, leading to NIR-PIT being considered as a promising cancer therapy. In this review, we discuss the progress of NIR-PIT, their mechanism and design strategies for cancer treatment. Furthermore, the overall possible targeting molecules for NIR-PIT with their application for cancer treatment are briefly summarised.

Activin A Modulates Betaglycan Shedding via the ALK4-SMAD3-Dependent Pathway in Endometriotic Cells.

The TGF-ß superfamily members, activins and inhibins, are mainly involved in cell proliferation, cell survival, invasion, immune surveillance, and lesion growth in endometriosis. Herein, we investigated the modulation of the TGF-ß type III receptor (betaglycan or BG) by activin A and inhibin A in endometriosis in vitro. Often, BG undergoes ectodomain shedding releasing soluble BG (sBG) which frequently antagonizes TGF-ß signaling. The effects of activin A on BG shedding and signaling pathways involved were evaluated with the inhibitors LY364947 and SIS3, siRNA knockdown in human endometrial cells (12Z, THESC, Ishikawa, and primary stromal cells) and were quantified with BG ELISAs. The effects of activin A and inhibin A on the secretion of MMP2 and MMP3 were analyzed using ELISAs. The effects of activin A on the BG expression were analyzed using RT-qPCR and western blot. The CCK-8 and BrdU assays were used to evaluate the effects of the recombinant BG on cell viability and proliferation. Activin A stimulation resulted in a significant time- and dose-dependent reduction in BG shedding, which was found to be activin A/ALK-4/SMAD3- but not SMAD2-dependent. Activin A increased the BG mRNA expression but had no effect on the protein expression. Likewise, inhibin A was found to block BG shedding. Activin A, but not inhibin A, significantly enhanced the secretion of MMP2 and MMP3. The recombinant BG had no effect on the viability and proliferation of endometriotic cells. Together, these observations support a novel role for activin A with BG in modulating the TGF-ß superfamily ligands in endometrial cells in vitro.

Claudin-10 Expression Is Increased in Endometriosis and Adenomyosis and Mislocalized in Ectopic Endometriosis.

Claudins, as the major components of tight junctions, are crucial for epithelial cell-to-cell contacts. Recently, we showed that in endometriosis, the endometrial epithelial phenotype is highly conserved, with only minor alterations. For example, claudin-11 is strongly expressed; however, its localization in the endometriotic epithelial cells was impaired. In order to better understand the role of claudins in endometrial cell-to-cell contacts, we analyzed the tissue expression and localization of claudin-10 by immunohistochemistry analysis and two scoring systems. We used human tissue samples (n = 151) from the endometrium, endometriosis, and adenomyosis. We found a high abundance of claudin-10 in nearly all the endometrial (98%), endometriotic (98−99%), and adenomyotic (90−97%) glands, but no cycle-specific differences and no differences in the claudin-10 positive endometrial glands between cases with and without endometriosis. A significantly higher expression of claudin-10 was evident in the ectopic endometrium of deep-infiltrating (p < 0.01) and ovarian endometriosis (p < 0.001) and in adenomyosis in the cases with endometriosis (p ≤ 0.05). Interestingly, we observed a shift in claudin-10 from a predominant apical localization in the eutopic endometrium to a more pronounced basal/cytoplasmic localization in the ectopic endometria of all three endometriotic entities but not in adenomyosis. Significantly, despite the impaired endometriotic localization of claudin-10, the epithelial phenotype was retained. The significant differences in claudin-10 localization between the three endometriotic entities and adenomyosis, in conjunction with endometriosis, suggest that most of the aberrations occur after implantation and not before. The high similarity between the claudin-10 patterns in the eutopic endometrial and adenomyotic glands supports our recent conclusions that the endometrium is the main source of endometriosis and adenomyosis.