Friedrich Wieser

Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis

OBJECTIVE To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis. DESIGN Experimental transplantation study using mice. SETTING Academic medical center. ANIMAL(S) C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice. INTERVENTION(S) Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection). MAIN OUTCOME MEASURE(S) Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages. RESULT(S) Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls. CONCLUSION(S) The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages.

Multiple Anticancer Activities of EF24, a Novel Curcumin Analog, on Human Ovarian Carcinoma Cells

Curcumin, a component of turmeric, has been reported to exhibit potential antitumor activities. This study assessed the effects of a novel synthetic curcumin analog, EF24, on proliferation, apoptosis, and vascular endothelial growth factor (VEGF) regulation in platinum-sensitive (IGROV1) and platinum-resistant (SK-OV-3) human ovarian cancer cells. EF24 time- and dose-dependently suppressed the growth of both cell lines and synergized with cisplatin to induce apoptosis. Although treatment with EF24 had no significant effect on VEGF messenger RNA (mRNA) expression,VEGF protein secretion into conditioned media was dose-dependently reduced with EF24 demonstrating ∼8-fold greater potency than curcumin (P < .05). EF24 significantly inhibited hydrogen peroxide (H2O2)-induced VEGF expression, as did the phenolic antioxidant tert-butylhydroquinone (t-BHQ). EF24 upregulated cellular antioxidant responses as observed by the suppression of reactive oxygen species (ROS) generation and activation of antioxidant response element (ARE)-dependent gene transcription. Given its high potency, EF24 is an excellent lead candidate for further development as an adjuvant therapeutic agent in preclinical models of ovarian cancer.

Analysis of follicular fluid retinoids in women undergoing in vitro fertilization: retinoic acid influences embryo quality and is reduced in women with endometriosis.

Retinol (ROL) and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. The objectives of this study were to quantify and compare peripheral plasma (PP) and follicular fluid (FF) retinoid levels, including ATRA in women undergoing in vitro fertilization (IVF) and to investigate the relationship between retinoid levels and embryo quality. Retinoid levels were evaluated in PP and FF from 79 women undergoing IVF at the time of oocyte retrieval and corresponding embryo quality assessed on a daily basis after retrieval for 3 days until uterine transfer. Analysis compared the retinoid levels with day 3 embryo grades and between endometriosis versus control patients. Results demonstrated distinctive levels of retinoid metabolites and isomers in FF versus PP. There was a significantly larger percentage of high-quality grade I embryos derived from the largest versus smallest follicles. An increase in follicle size also correlated with a >50% increase in FF ROL and ATRA concentrations. Independent of follicle size, FF yielding grade I versus nongrade I embryos showed higher mean levels of ATRA but not ROL. In a nested case–control analysis, control participants had 50% higher mean levels of ATRA in their FF and PP than women with endometriosis. These findings strongly support the proposition that ATRA plays a fundamental role in oocyte development and quality, and that reduced ATRA synthesis may contribute to decreased fecundity of participants with endometriosis.

Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas.

Tumor-associated macrophages (TAMs) are derived from monocytes and recruited to the tumor microenvironment, where they play an important role in the progression of cancer. There is strong evidence for an inverse relationship between TAM density and clinical prognosis in solid tumors of the breast, prostate, ovary, and cervix. However, the role of TAMs in endometrial cancer is not well described. The objectives of this study were to determine whether macrophage distribution or density differed among normal endometrial tissue, hyperplasia, Type I, and II endometrial adenocarcinomas. In addition, we looked for a correlation among TAM density, known histopathologic prognostic indicators, and endometrial cancer progression. The pathologic specimens of women who underwent hysterectomy for benign disorders, endometrial hyperplasia, Type I, or Type II cancers were sectioned and stained with anti-CD68 antibody. The density of CD68+ macrophages was quantified and stratified according to their epithelial or stromal location. Type I and II endometrial carcinomas had significantly higher macrophage density in both epithelial and stromal compartments than benign endometrium. In both benign and neoplastic specimens, the numbers of macrophages were significantly higher in the stroma compared with the epithelium. Although there were important trends in the density of TAMs with regard to several histopathologic prognostic indicators of endometrial cancer, none were statistically significant and the patients’ cancer progression did not correlate significantly with the number of TAMs.

Cathepsin Protease Inhibition Reduces Endometriosis Lesion Establishment

Endometriosis is a gynecologic disease characterized by the ectopic presence of endometrial tissue on organs within the peritoneal cavity, causing debilitating abdominal pain and infertility. Current treatments alleviate moderate pain symptoms associated with the disorder but exhibit limited ability to prevent new or recurring lesion establishment and growth. Retrograde menstruation has been implicated for introducing endometrial tissue into the peritoneal cavity, but molecular mechanisms underlying attachment and invasion are not fully understood. We hypothesize that cysteine cathepsins, a group of powerful extracellular matrix proteases, facilitate endometrial tissue invasion and endometriosis lesion establishment in the peritoneal wall and inhibiting this activity would decrease endometriosis lesion implantation. To test this, we used an immunocompetent endometriosis mouse model and found that endometriotic lesions exhibited a greater than 5-fold increase in active cathepsins compared to tissue from peritoneal wall or eutopic endometrium, with cathepsins L and K specifically implicated. Human endometriosis lesions also exhibited greater cathepsin activity than adjacent peritoneum tissue, supporting the mouse results. Finally, we tested the hypothesis that inhibiting cathepsin activity could block endometriosis lesion attachment and implantation in vivo. Intraperitoneal injection of the broad cysteine cathepsin inhibitor, E-64, significantly reduced the number of attached endometriosis lesions in our murine model compared to vehicle-treated controls demonstrating that cathepsin proteases contribute to endometriosis lesion establishment, and their inhibition may provide a novel, nonhormonal therapy for endometriosis.

A rare case of primary extranodal marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix in the setting of endometriosis

Extranodal marginal zone B-cell lymphomas are uncommon. Most occur in the gastrointestinal tract. Marginal zone B-cell lymphomas of the female genital tract are rare, and few cases exist of marginal zone B-cell lymphomas of the uterus, cervix, and fallopian tubes. We report the first marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix arising in endometriosis.

Office visceral slide test compared with two perioperative tests for predicting periumbilical adhesions.

OBJECTIVE: To determine whether the office visceral slide test is an effective screening test for predicting obliterating periumbilical adhesions compared with two ultrasound tests performed in the operating room. METHODS: Women undergoing benign laparoscopic gynecologic surgery between July 2012 and August 2013 were invited to participate. All participants had an office-based ultrasound test at their preoperative visit (the office visceral slide test), two operating room ultrasound tests (the preoperative examination with visceral slide and the periumbilical ultrasound-guided saline infusion test), and then their scheduled laparoscopic procedure. We measured the ability of the three screening tests to detect obliterating periumbilical adhesions. RESULTS: Eighty-two women completed the study; 12 women were excluded because they had no history of surgery and 70 women with a history of abdominal and pelvic surgery were analyzed in the study group. The study group (n=70) had a median of two (range, 1–6) previous abdominal surgeries. The median number of previous laparotomies was 0 (range, 0–5). The median number of previous laparoscopies was 1 (range, 0–6). At laparoscopy, 6 of 70 women (8.6%) had periumbilical adhesions diagnosed; 18 of 70 women (25.7%) had any adhesions located in the abdomen or pelvis. The office visceral slide test had a sensitivity of 83.3%, specificity of 100%, positive predictive value of 100%, negative predictive value of 98.5% and diagnostic accuracy of 98.6%. CONCLUSION: The office visceral slide test is a simple and reliable test for detecting obliterating periumbilical adhesions in the outpatient setting. LEVEL OF EVIDENCE: II

Novel port placement and 5-mm instrumentation for robotic-assisted hysterectomy

Background and Objectives: The value of robotic surgery for gynecologic procedures has been critically evaluated over the past few years. Its drawbacks have been noted as larger port size, location of port placement, limited instrumentation, and cost. In this study, we describe a novel technique for robotic-assisted laparoscopic hysterectomy (RALH) with 3 important improvements: (1) more aesthetic triangular laparoscopic port configuration, (2) use of 5-mm robotic cannulas and instruments, and (3) improved access around the robotic arms for the bedside assistant with the use of pediatric-length laparoscopic instruments. Methods: We reviewed a series of 44 women who underwent a novel RALH technique and concomitant procedures for benign hysterectomy between January 2008 and September 2011. Results: The novel RALH technique and concomitant procedures were completed in all of the cases without conversion to larger ports, laparotomy, or video-assisted laparoscopy. Mean age was 49.9 years (SD 8.8, range 33–70), mean body mass index was 26.1 (SD 5.1, range 18.9–40.3), mean uterine weight was 168.2 g (SD 212.7, range 60–1405), mean estimated blood loss was 69.7 mL (SD 146.9, range 20–1000), and median length of stay was <1 day (SD 0.6, range 0–2.5). There were no major and 3 minor peri- and postoperative complications, including 2 urinary tract infections and 1 case of intravenous site thrombophlebitis. Mean follow-up time was 40.0 months (SD 13.6, range 15–59). Conclusion: Use of the triangular gynecology laparoscopic port placement and 5-mm robotic instruments for RALH is safe and feasible and does not impede the surgeons ability to perform the procedures or affect patient outcomes.