Cancer Epidemiol Biomarkers Prev. 2016 May;25(5):780-90.
Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.
Usset JL1, Raghavan R1, Tyrer JP2, McGuire V3, Sieh W3, Webb P4, Chang-Claude J5, Rudolph A5, Anton-Culver H6, Berchuck A7, Brinton L8, Cunningham JM9, DeFazio A10, Doherty JA11, Edwards RP12, Gayther SA13, Gentry-Maharaj A14, Goodman MT13, Høgdall E15, Jensen A16, Johnatty SE17, Kiemeney LA18, Kjaer SK19, Larson MC20, Lurie G21, Massuger L22, Menon U14, Modugno F23, Moysich KB24, Ness RB25, Pike MC26, Ramus SJ27, Rossing MA28, Rothstein J3, Song H2, Thompson PJ13, van den Berg DJ27, Vierkant RA20, Wang-Gohrke S29, Wentzensen N8, Whittemore AS3, Wilkens LR21, Wu AH27, Yang H8, Pearce CL30, Schildkraut JM31, Pharoah P32, Goode EL20, Fridley BL33; Ovarian Cancer Association Consortium and the Australian Cancer Study.
Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women.
We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed.
SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)).
We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions.
Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.
J Clin Endocrinol Metab. 2016 Apr;101(4):1552-61.
Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis.
Our study suggested that the Hippo/YAP-signaling play a critical role in the pathogenesis of endometriosis and may present a novel therapeutic method against endometriosis.
Hum Fertil (Camb). 2016 Apr;19(1):3-8.
When helping hurts: the effect of surgical interventions on ovarian reserve.
This commentary reviews some of the major papers that have been published on the effect of ovarian reserve after surgical interventions. At the end, the authors outline a summary on the effect of these interventions, in terms of future fertility and menopause.
Ceska Gynekol. 2016 Jan;81(1):31-7.
Functional morphology of recently discovered telocytes inside the female reproductive system.
Discovery of telocytes has become an important and key challenge in past few years. These cells are interstitial cells extending very long cytoplasmic processes named telopodes, by which they create functional networks in the interstitium of different organs. Telocytes are considered to be connective tissue elements that create contacts among each other, but they also function as intercellular structures, functionally connected with cells of the immune system, neurons and smooth muscle cells. Telocytes can be found also in the different parts of female reproductive system with functions and purpose, which is summarized in our overview. Telocytes regulate for example peristaltic movements in fallopian tubes. The decrease of their number (due to inflammatory disease or endometriosis) causes impairment in transport through fallopian tubes which may result in sterility or tubal gravidity. In uterus they regulate contraction of myometrial smooth muscle (blood expulsion in menstrual phase, childbirth) as well as they contribute in immunological care during embryo implantation. Telocytes probably control also the involution of uterus after delivery. Their function in vagina has not been yet clearly defined; they probably take part in slow muscle contraction movement during sexual intercourse. In mammary glands some scientists suppose their function in control of cell proliferation and apoptosis, that is why, they may play a role in carcinogenesis. In placenta they probably monitor and regulate flow of blood in vessels of chorionic villi and they may be responsible also for etiopathogenesis of pre-eclampsy. All these mentioned functions of telocytes are only in the level of hypothesis and have been published recently. New research and studies will try to answer the questions whether telocytes play a key role in these processes. Our review we completed with some original microphotographs of telocytes in different organs of female reproductive system.
Int J Fertil Steril. 2016 Jan-Mar;9(4):483-9.
Performance of Circulating Placental Growth Factor as A Screening Marker for Diagnosis of Ovarian Endometriosis: A Pilot Study.
The aim of this study is to compare the circulating placental growth factor (PlGF) concentration in women with and without endometrioma to verify the performance of this marker to diagnose the disease.
MATERIALS AND METHODS:
In this case-control study, thirteen women with histological diagnosis of ovarian endometriosis were compared with women without endometriosis disease. PlGF plasma levels of endometriotic patients and controls were investigated using a fluorescence immunoassay technique.
PlGF showed a direct correlation with body mass index (BMI) only in the control group (P=0.013). After adjustment for BMI values, PlGF median value in endometriosis group (14.7 pg/mL) resulted higher than in control group (13.8 pg/ mL, P=0.004).
PlGF is a promising peripheral blood marker that can discriminate between patients with and without ovarian endometriosis.
Medicine (Baltimore). 2016 Mar;95(11):e3075
Chinese Herbal Products for Female Infertility in Taiwan: A Population-Based Cohort Study.
Female infertility and low birth rate are significant public health issues with profound social, psychological, and economic consequences. Some infertile women resort to conventional, complementary, or alternative therapies to conceive. The aim of this study was to identify the Chinese herbal products (CHPs) most commonly used for female infertility in Taiwan. The usage of traditional Chinese medicine (TCM) and the frequency of CHP prescriptions to infertile women were determined based on a nationwide 1-million randomly sampled cohort of National Health Insurance Research Database beneficiaries. Descriptive statistics and multiple logistic regression analysis were employed to estimate the adjusted odds ratio (aOR) for TCM usage and potential risk factors. In total, 8766 women with newly diagnosed infertility were included in this study. Of those, 8430 (96.17%) had sought TCM treatment in addition to visiting the gynecologist. We noted that female infertility patients with risk factors (e.g., endometriosis, uterine fibroids, or irregular menstrual cycle) were more likely to use TCM than those without TCM medication (aOR = 1.83, 1.87, and 1.79, respectively). The most commonly used formula and single CHP were Dang-Gui-Sha-Yao-San (17.25%) and Semen Cuscutae (27.40%), respectively. CHP formula combinations (e.g., Dang-Gui-Sha-Yao-San plus Wen-Jing-Tang 3.10%) or single Chinese herbal combinations (e.g., Semen Cuscutae plus Leonurus japonicus 6.31%) were also commonly used to treat female infertility. Further well-conducted, double-blind, randomized, placebo-controlled studies will be needed to evaluate the efficacy and safety of these CHP combinations for female infertility.
Cancer Invest. 2016;34(3):148-54.
Does the Presence of Endometriosis Affect Prognosis of Ovarian Cancer?
Ovarian cancers diagnosed between 2000 and 2013 were examined and cases with and without endometriosiscompared. Among 139 epithelial ovarian, there were 49 (35%) with endometriosis and 90 (65%) without endometriosis. Endometriosis associated ovarian cancers were more likely to be confined to the pelvis (54% vs. 9%, p < 0.0001) and lower grade (51% vs. 29%, p = 0.014). Younger age and earlier stage independently predicted the presence of endometriosis (p = 0.0011 and p < 0.0001, respectively). Ovarian cancer patients with endometriosis had improved PFS and OS [(HR = 0.20; 95% CI, 0.09-0.43), (HR = 0.18; 95% CI, 0.04-0.81)], compared to patients without endometriosis; however, endometriosis had no independent prognostic significance.
BMC Microbiol. 2016 Mar 18;16:45.
Prevalence of plasmid-bearing and plasmid-free Chlamydia trachomatis infection among women who visited obstetrics and gynecology clinics in Malaysia.
The 7.5 kb cryptic plasmid of Chlamydia trachomatis has been shown to be a virulence factor in animal models, but its significance in humans still remains unknown. The aim of this study was to investigate the prevalence and potential involvement of the C. trachomatis cryptic plasmid in causing various clinical manifestations; including infertility, reproductive tract disintegrity, menstrual disorder, and polycystic ovarian syndrome (PCOS) among genital C. trachomatis-infected patients.
A total of 180 female patients of child bearing age (mean 30.9 years old, IQR:27-35) with gynecological complications and subfertility issues, who visited Obstetrics and Gynecology clinics in Kuala Lumpur, Malaysia were recruited for the study. Prevalence of genital chlamydial infection among these patients was alarmingly high at 51.1% (92/180). Of the 92 chlamydia-infected patients, 93.5% (86/92) were infected with plasmid-bearing (+) C. trachomatis while the remaining 6.5% (6/92) were caused by the plasmid-free (-) variant. Our data showed that genital C. trachomatis infection was associated with infertility issues, inflammation in the reproductive tract (mucopurulent cervicitis or endometriosis), irregular menstrual cycles and polycystic ovarian syndrome (PCOS). However, no statistical significance was detected among patients with plasmid (+) versus plasmid (-) C. trachomatis infection. Interestingly, plasmid (+) C. trachomatis was detected in all patients with PCOS, and the plasmid copy numbers were significantly higher among PCOS patients, relative to non-PCOS patients.
Our findings show a high incidence of C. trachomatis infection among women with infertility or gynecological problems in Malaysia. However, due to the low number of plasmid (-) C. trachomatis cases, a significant role of the plasmid in causing virulence in human requires further investigation of a larger cohort.
Sci Rep. 2016 Mar 18;6
Genome-wide Long Non-coding RNA Analysis Identified Circulating LncRNAs as Novel Non-invasive Diagnostic Biomarkers for Gynecological Disease.
Increasing evidence indicates that long non-coding RNAs (lncRNAs) play important roles in human diseases. This study aimed to investigate the tissue and serum lncRNAs that are differentially expressed between patients with endometriosis, a gynecological disease, to evaluate the potential of these lncRNAs as non-invasive markers for the disease. The differentially expressed lncRNAs as competing endogenous RNAs (ceRNAs) were also analyzed to predict their functions in disease development. Genome-wide profiling of lncRNA expression patterns revealed that many lncRNAs were abnormally expressed between sera and tissuesof the patient samples. A set of aberrant differentially expressed lncRNAs were further validated in a validation cohort of 110 serum and 24 tissue samples. Functional analysis predicted that differentially expressed lncRNAs may participate in disease development through crosstalk between the ceRNAs of miRNAs and may be involved in a range of cellular pathways including steroid or hormone responses. We also found a unique set of lncRNAs that were associated with disease severity and progression, and their diagnostic values were also investigated. Our study demonstrated that lncRNAs could potentially serve as non-invasive biomarkers for the diagnosis of endometriosis and as important regulators in the progression of this disease.
Chirurgia (Bucur). 2016 Jan-Feb;111(1):54-7.
Ovarian Damage after Laparoscopic Cystectomy for Endometrioma.
Despite extensive research endometriosis is an area with important controversies. The European Society of Human Reproduction and Embriology issued in 2014 the last Guideline for endometriosis management including the statement that among 83 recommendations in 32 cases the best available evidence was only based on good clinical practice, further research being necessary to solve the lack of evidence in this pathology. The prevalence of endometriosis is unknown in Romania but in the medical literature estimates range from 2 to 10% of women of reproductive age, to 50% of infertile women, worldwide. Ovarian endometrioma prevalence goes up to 44%. A Cochrane review published in 2008 by Hart et al. concluded that excisional surgery of ovarian endometriosis results in a more favorable outcome compared to drainage and ablation with regard to recurrence, pain symptoms and subsequent spontaneous pregnancy in subfertilewomen- so the gold standard was set. But several authors revealed that ovarian tissue was inadvertently excised together with the cyst wall and endometrioma cystectomy is associated with a significant decrease in residual ovarian volume that may result in diminished ovarian reserve and function. The aim of our retrospective study was to evaluate whether or not ovarian parenchyma is inadvertently removed during laparoscopic surgery for endometrioma in a Romanian academic center.
MATERIAL AND METHOD:
We performed a retrospective study including women having undergone endometrioma excision, between January 2009 to June 2014 in the Department of Gynecology and Obstetrics of Targu-Mures University Hospital. Histological specimens of excised endometriomas were reviewed by different pathologists, who carried out serial microscopic sections according to pathology protocol for diagnosis of ovarian mass but not specific for the ovarian parenchyma removed with the cyst.
Among 202 endometriomas, drainage and ablation was done in 60 cases and excisional surgery in the remaining 152 cases. Ovarian parenchyma was found in 40% of cases of endometrioma cystectomy.
We observed that endometrioma cystectomy leads to ovarian tissue removal in an important number of cases. Furthermore, at the time of surgery the amount of ovarian parenchyma loss may increases proportionally with increases in cyst diameter and patient age. Considering that most of the woman in our series were infertile and because of data from series using plasma energy, a shift in the endometrioma treatment paradigm is likely to occur.
J Gynecol Obstet Biol Reprod (Paris). 2016 Mar 14.
Management of deep infiltrating endometriosis by laparoscopic route with robotic assistance: 3-year experience.
To assess the feasibility of deep endometriosis surgery using robotic assistance, benefits and limits of this approach.
Case-series study enrolling patients managed for deep infiltrating endometriosis (DIE) using robotic assistance in our department between September 2011 and March 2014 (NCT02294825). Self-questionnaires including pain and digestive symptoms were filled in preoperatively and 1 year after surgery.
Thirty-five patients were enrolled in the series. They represented 54% of patients managed for gynecological disease by laparoscopic route with robotic assistance during the study period, and 14% of patients managed for deep endometriosis in our department. Follow-up averaged 24±8 months, and no patient was lost to follow-up. Thirty-two patients had rectal involvement: rectal shaving was performed in 25 patients, disc excision in 3 and colorectal resection in 4. Three patients had bladder resection. Thirteen patients presented with deep endometriosis of the ureters: ureterolysis was performed in 11 of them, and resection of the ureter followed by reimplantation into the bladder in 2 patients. One major complication (Clavien IIIb) was recorded in a patient presenting with necrosis of the right ureter on postoperative day 5. Nine patients tried to conceive after surgery and 8 have already become pregnant (88.9%). One year after surgery, self-questionnaires revealed a significant decrease in pain symptoms and significant improvement in several item values of gastrointestinal standardized questionnaires.
Surgical management of DIE is feasible using robotic assistance. However, data available in the literature and our own experience do not definitively support the hypothesis of the superiority of robotic assistance in the management of DIE.
Int J Med Robot. 2017 Jun;13(2)
Robot-assisted laparoscopic myomectomy for deep intramural myomas.
To evaluate the efficacy of robot-assisted laparoscopic myomectomy for deep intramural myomas.
We have conducted a retrospective study for 170 patients who underwent robot-assisted laparoscopic myomectomy by a single operator of tertiary university hospital.
There were 100 cases of robot-assisted laparoscopic myomectomy for deep intramural myomas. The patients had 3.8±3.5 myomas on average, and the mean size of the largest myoma of each patient was 7.5±2.1 centimeters in diameter. Mean operative time was 276.4±97.1 minutes, and mean console time was 146.0±62.7 minutes. Thirty two patients had surgeries for other gynecologic conditions such as pelvic endometriosis or endometrial polyps along with myomectomy at the same time. All the patients recovered without any major complication. After the surgery, nine(75.0 %) of the 12 women pursuing a pregnancy became pregnant.
Robot-assisted laparoscopic myomectomy for deep intramural myomas could be a minimal invasive surgical option for women who wish preserve fertility. Copyright © 2016 John Wiley & Sons, Ltd.
Gene Ther. 2016 Jul;23(7):580-91.
Adenoviral vector encoding soluble Flt-1 engineered human endometrial mesenchymal stem cells effectively regress endometriotic lesions in NOD/SCID mice.
This study was undertaken to study the efficiency of Adsflt-1 engineered human eutopic mesenchymal stem cells (MSCs) secreting anti-angiogenic sFlt-1 as a targeted cell-based therapy for endometriosis (EM). Eutopic MSCs were transduced with Adsflt-1/AdV0 viral vectors and were evaluated for expression and secretion of sFlt-1. EM was created in NOD/SCID mice using subcutaneous implantation techniques. Four doses of 10(6) MSC-Adsflt-1/MSC-AdV0 were administered to the model and therapeutic anti-angiogenic ability was analyzed by lesion size measurement, microvessel density, immunohistochemistry and real-time reverse transcriptase-PCR analysis. Approximately 86% of transduced MSCs expressed and secreted sFlt-1. MSC-Adsflt-1-treated animals exhibited significant reduction (52.8±1.8%) in size of endometriotic lesions. We observed a 2.3-fold decrease in the number and a 10-fold decrease in the size of endometrial glands in MSC-Adsflt-1-treated animals. A two-fold decrease in stromal cell densities was also observed in MSC-Adsflt-1-treated animals compared with the MSC-AdV0 group. Specific positive immunostaining for MSC marker, CD146 and sFlt-1 in the lesion sites of the MSC-Adsflt-1 group suggests possible homing of transduced MSCs, their survival and secretion of sFlt-1 at the target sites. A marked reduction in size of microvessels and microvessel density within endometriotic lesions and surrounding host subcutaneous layers was observed in MSC-Adsflt-1 group along with significantly downregulated expression of transcripts for vascular endothelial growth factor, fetal liver kinase 1 and matrix metalloproteinases (2 and 9). Our findings indicate the efficacy of a novel eutopic MSC-Adsflt-1 therapy in EM study models. Evaluating long-term effects of genetically modified MSCs in vivo is essential in translating MSC-Adsflt-1 therapy to the clinics.
Insights Imaging. 2016 Jun;7(3):311-27.
Non-neoplastic diseases of the fallopian tube: MR imaging with emphasis on diffusion-weighted imaging.
We illustrate the magnetic resonance imaging (MRI) features of non-neoplastic tubaric conditions.
A variety of pathologic non-neoplastic conditions may affect the fallopian tubes. Knowledge of their imaging appearance is important for correct diagnosis. With recent advances in MRI, along with conventional MR sequences, diffusion-weighted imaging (DWI) sequences are available and may improve lesion characterization by discriminating the nature of the content of the dilated tube. Tubal fluid with low signal intensity on T1-weighted images, high signal intensity on T2-weighted images and no restricted diffusion on DWI is indicative of hydrosalpinx. Content with high signal intensity on T1-weighted images and restricted diffusion on DWI is suggestive of hematosalpinx associated with endometriosis or tubal pregnancy. A dilated tube with variable or heterogeneous signal intensity content on conventional MR sequences and restricted diffusion on DWI may suggest a pyosalpinx or tubo-ovarian abscess. We describe morphological characteristics, MR signal intensity features, enhancement behaviour and possible differential diagnosis of each lesion.
MRI is the method of choice to study adnexal pelvic masses. Qualitative and quantitative functional imaging with DWI can be of help in characterization of tubaric diseases, provided that findings are interpreted in conjunction with those obtained with conventional MRI sequences.
- Nondilated fallopian tubes are not usually seen on MR images. • MRI is the method of choice to characterize and localize utero-adnexal masses. • MRI allows characterization of lesions through evaluation of the fluid content’s signal intensity. • DWI in conjunction with conventional MRI sequences may improve tissue characterization. • Pelvic inflammatory disease is the most common tubal pathology.
Mol Cell Endocrinol. 2016 Jun 15;428:1-16.
Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosisthrough epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation.
Smooth muscle metaplasia (SMM) and fibrotic tissues are frequently seen in endometriotic lesions, yet the mechanisms underlying their formation are poorly understood. In this study, we investigated the roles of activated platelets in driving epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in endometriosis. Through in vitro experimentations, we found that activated platelets, through the release of TGF-β1 and the induction of TGF-β/Smad signaling pathway, promoted EMT and FMT in endometriosis, resulting in increased cell contractility, collagen production, and ultimately to fibrosis. TGF-β blockade reversed these processes. Prolonged exposure of endometriotic stromal cells to activated platelets induced increased expression of α-SMA as well as markers of differentiated smooth muscle cells. Consequently, endometriotic lesions and their microenvironment contain all the necessary molecular machinery to promote SMM and fibrogenesis. Our results suggest that endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.
Reprod Sci. 2016 Oct;23(10):1332-9
Laparoscopic Surgery: A New Technique to Induce Endometriosis in a Mouse Model.
This prospective pilot study was designed to induce endometriosis in a mouse model using laparoscopy, a less invasive and more precise approach than laparotomy. We aimed to achieve a peritoneal implant rate of at least 50% by varying both duration of anesthesia and intra-abdominal insufflation pressure.
Female BALB/cANnCrl mice in metestrus or diestrus were used as donors (n = 5) or recipients (n = 20) of uterine transplant tissue. Each recipient mouse was laparoscopically inoculated with 10 uterine pieces (range: 10-12) from donor mice into the abdominal cavity. Before starting the study, recipient mice were randomly assigned to 4 groups with variable duration of anesthesia (ketamine/xylazine or pentobarbital) and variable intra-abdominal pressure (5 or 15 mm Hg). One week after laparoscopy, endometriosis incidence and peritoneal implant take rate were documented visually during laparotomy. The retrieved lesions were histologically analyzed.
Laparoscopic inoculation of uterine pieces in recipient mice resulted in an endometriosis incidence of 100% (20/20 animals) and an individual peritoneal implant take rate of 60% (121/206), ranging from 17% (2/12) till 83% (10/12), without differences between the 4 subgroups, and with a histological confirmation rate of 92% (58/63).
To the best our knowledge, this is the first report showing that endometriosis can be induced by laparoscopic surgery in rodents, with a 100% incidence and a median peritoneal implant take rate of 60%. This laparoscopic model offers important advantages over traditional laparotomy models that are limited by surgery-associated trauma and/or adhesion formation.
Reprod Sci. 2016 Sep;23(9):1258-68.
Correlation Between the Clinical Parameters and Tissue Phenotype in Patients Affected by Deep-Infiltrating Endometriosis.
The current study aimed to identify and validate an applicable immunohistochemistry panel including Ki-67, c-MYC, estrogen receptor-α (ER-α), and progesterone receptor isoforms A/B (PR-A/B) in correlation with clinicopathological parameters in patients affected by deep infiltrating endometriosis. Tissue microarrays were prepared from a cohort of 113 patients. Phenotypic profile of the panel molecules was evaluated in glands and stroma in parallel with microvessels and stroma density measurements. Principal component analysis was performed on 8 immunohistochemical variables, 2 histological variables, and 8 subgroups of clinical parameters. The immunohistochemical profiling showed consistent Ki-67 immunostaining in 17.9% of the samples and c-MYC in 83.1%, while intense ER-α immunoreactivity was detected in 84% of the samples and PR-A/B isoforms in 24.1% of them. The combination of clinical parameters and tissue phenotype allowed a stratification of endometriosis-affected patients. Such novel phenotypical and clinical correlation could be helpful in the future studies for a better stratification of the disease aiming at a personalized patient care.
Ginekol Pol. 2015 Dec;86(12):896-901.
Rectovaginal endometriosis–analysis of 160 cases.
The aim of the study was a retrospective analysis of the medical records of patients who underwent surgery due to deep infiltrating rectovaginal endometriosis (mainly with the use of the ‘shaving’ technique).
MATERIAL AND METHODS:
We analysed 160 cases of patients who underwent surgery due to the deep infiltrating rectovaginal endometriosis in our ward between 2003-2014. Depending on lesion localization, disease severity and clinical characteristics, three possible ways of operation were proposed: laparoscopic, vaginal or a combined vagino-laparoscopic approach.
A total of 120 patients underwent laparoscopic removal of the endometrial lesions, whereas 17 were operated vaginally and 23 with the use of the combined approach. Nodule resection was successfully performed in all cases. The combined vagino-laparoscopic operations were characterized by the longest operating time. The rate of perioperative complications was low in the group of patients who underwent laparoscopic or combined operations. The necessity of bowel wall suturing occurred in 15 cases. This procedure was performed in order to strengthen the bowel wall (in cases when no perforation occurred) or due to bowel resection during surgery. Unexpected bowel perforation occurred in only 5 cases. Conclusions: Vaginal, laparoscopic and the combined vagino-laparoscopic surgeries can be safely performed in cases of deep rectovaginal endometriosis.
Ann Ital Chir. 2016 Mar 23;87(ePub)
Ileal endometriosis and Crohn’s disease: an unusual association causing acute bowel obstruction.
Endometriosis is a commun health disorder in women, which is defined as the presence of bowel endometrial-like tissue outside the uterus. Bowel endometriosis occurs in approximately10% pf all cases, with ileal localization as a very rare clinical intestinal occlusion:acute intestinal obstruction is possible presentation of this disease. We report a case of a patient with known history of Crohn’s treated with ileal resection for acute intestinal occlusion;histology showed the coexistence of IBD and endometriosis in the intestinal wall.
A 35 years old female patient, with previous diagnosis of Crohn’s disease confirmed by endoscopic biopsies, was admitted to our Institutions because oc acute intestinal obstruction. She previously suffered of dysmenorrhea and pelvic pain during menstration. A contrast enhanced CT abdominal scan was performed with evidence of diffuse small bowel fluid distension and thickening of terminal iileum wall, compatible with ilea stenosis in acute Crohn disease.
The patient underwent laparoscopic resection of distal ileus. Definitive histological examination showed ileal wall with multiple endometriosis foci and chronic follicular flogosis.
The case that we have described shows a rare co-existence of the two clinical entitle (Crohn’s disease and ileal deep endometriosis), histologically demonstrated, with acute presentation as intestinal obstruction, susseflully treated with laparoscopic ileal resection KEY WORDS Bowel obstruction, Crohn’s disease, Endometriosis.
Cochrane Database Syst Rev. 2016 Mar 22;3:
Dietary supplements for dysmenorrhoea.
Dysmenorrhoea refers to painful menstrual cramps and is a common gynaecological complaint. Conventional treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and oral contraceptive pills (OCPs), which both reduce myometrial activity (contractions of the uterus). A suggested alternative approach is dietary supplements. We used the term ‘dietary supplement’ to include herbs or other botanical, vitamins, minerals, enzymes, and amino acids. We excluded traditional Chinese medicines.
To determine the efficacy and safety of dietary supplements for treating dysmenorrhoea.
We searched sources including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, PsycINFO (all from inception to 23 March 2015), trial registries, and the reference lists of relevant articles.
We included randomised controlled trials (RCTs) of dietary supplements for moderate or severe primary or secondary dysmenorrhoea. We excluded studies of women with an intrauterine device. Eligible comparators were other dietary supplements, placebo, no treatment, or conventional analgesia.
DATA COLLECTION AND ANALYSIS:
Two review authors independently performed study selection, performed data extraction and assessed the risk of bias in the included trials. The primary outcomes were pain intensity and adverse effects. We used a fixed-effect model to calculate odds ratios (ORs) for dichotomous data, and mean differences (MDs) or standardised mean differences (SMDs) for continuous data, with 95% confidence intervals (CIs). We presented data that were unsuitable for analysis either descriptively or in additional tables. We assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods.
We included 27 RCTs (3101 women). Most included studies were conducted amongst cohorts of students with primary dysmenorrhoea in their late teens or early twenties. Twenty-two studies were conducted in Iran and the rest were performed in other middle-income countries. Only one study addressed secondary dysmenorrhoea. Interventions included 12 different herbal medicines (German chamomile (Matricaria chamomilla, M recutita, Chamomilla recutita), cinnamon (Cinnamomum zeylanicum, C. verum), Damask rose (Rosa damascena), dill (Anethum graveolens), fennel (Foeniculum vulgare), fenugreek (Trigonella foenum-graecum), ginger (Zingiber officinale), guava (Psidium guajava), rhubarb (Rheum emodi), uzara (Xysmalobium undulatum), valerian (Valeriana officinalis), and zataria (Zataria multiflora)) and five non-herbal supplements (fish oil, melatonin, vitamins B1 and E, and zinc sulphate) in a variety of formulations and doses. Comparators included other supplements, placebo, no treatment, and NSAIDs.We judged all the evidence to be of low or very low quality. The main limitations were imprecision due to very small sample sizes, failure to report study methods, and inconsistency. For most comparisons there was only one included study, and very few studies reported adverse effects. Effectiveness of supplements for primary dysmenorrhoea We have presented pain scores (all on a visual analogue scale (VAS) 0 to 10 point scale) or rates of pain relief, or both, at the first post-treatment follow-up. Supplements versus placebo or no treatmentThere was no evidence of effectiveness for vitamin E (MD 0.00 points, 95% CI -0.34 to 0.34; two RCTs, 135 women).There was no consistent evidence of effectiveness for dill (MD -1.15 points, 95% CI -2.22 to -0.08, one RCT, 46 women), guava (MD 0.59, 95% CI -0.13 to 1.31; one RCT, 151 women); one RCT, 73 women), or fennel (MD -0.34 points, 95% CI -0.74 to 0.06; one RCT, 43 women).There was very limited evidence of effectiveness for fenugreek (MD -1.71 points, 95% CI -2.35 to -1.07; one RCT, 101 women), fish oil (MD 1.11 points, 95% CI 0.45 to 1.77; one RCT, 120 women), fish oil plus vitamin B1 (MD -1.21 points, 95% CI -1.79 to -0.63; one RCT, 120 women), ginger (MD -1.55 points, 95% CI -2.43 to -0.68; three RCTs, 266 women; OR 5.44, 95% CI 1.80 to 16.46; one RCT, 69 women), valerian (MD -0.76 points, 95% CI -1.44 to -0.08; one RCT, 100 women), vitamin B1 alone (MD -2.70 points, 95% CI -3.32 to -2.08; one RCT, 120 women), zataria (OR 6.66, 95% CI 2.66 to 16.72; one RCT, 99 women), and zinc sulphate (MD -0.95 points, 95% CI -1.54 to -0.36; one RCT, 99 women).Data on chamomile and cinnamon versus placebo were unsuitable for analysis. Supplements versus NSAIDSThere was no evidence of any difference between NSAIDs and dill (MD 0.13 points, 95% CI -1.01 to 1.27; one RCT, 47 women), fennel (MD -0.70 points, 95% CI -1.81 to 0.41; one RCT, 59 women), guava (MD 1.19, 95% CI 0.42 to 1.96; one RCT, 155 women), rhubarb (MD -0.20 points, 95% CI -0.44 to 0.04; one RCT, 45 women), or valerian (MD points 0.62 , 95% CI 0.03 to 1.21; one RCT, 99 women),There was no consistent evidence of a difference between Damask rose and NSAIDs (MD -0.15 points, 95% CI -0.55 to 0.25; one RCT, 92 women).There was very limited evidence that chamomile was more effective than NSAIDs (MD -1.42 points, 95% CI -1.69 to -1.15; one RCT, 160 women). Supplements versus other supplementsThere was no evidence of a difference in effectiveness between ginger and zinc sulphate (MD 0.02 points, 95% CI -0.58 to 0.62; one RCT, 101 women). Vitamin B1 may be more effective than fish oil (MD -1.59 points, 95% CI -2.25 to -0.93; one RCT, 120 women). Effectiveness of supplements for secondary dysmenorrhoea There was no strong evidence of benefit for melatonin compared to placebo for dysmenorrhoea secondary to endometriosis (data were unsuitable for analysis). Safety of supplements Only four of the 27 included studies reported adverse effects in both treatment groups. There was no evidence of a difference between the groups but data were too scanty to reach any conclusions about safety.
There is no high quality evidence to support the effectiveness of any dietary supplement for dysmenorrhoea, and evidence of safety is lacking. However for several supplements there was some low quality evidence of effectiveness and more research is justified.
Curr Protein Pept Sci. 2016;18(2):108-119.
Plasticity in Uterine Innervation: State of the Art.
Early studies often claimed that autonomic nerves were unimportant for uterine function, since denervation of the uterus had little effects on reproductive success. In 1979, Thorbert wrote, “It seems unlikely that Nature has equipped the uterus with a complex innervation merely as a structural ornament. Our ignorance in this area may be rather due to defects in methods of study”. Investigations carried out over the last four decades proved that Thorbert’s words were correct, because it is now clear that autonomic and sensory nerves regulate many critical uterine functions. However, the most remarkable aspect of uterine innervation is its capacity to change in response to physiological fluctuations in levels of sex hormones, as those accompanying pregnancy, the sex cycle and puberty. The present review provides an overview about how sex hormones influence uterine innervation. Data are presented about how this physiological plasticity is mimicked by exogenous administration of sex hormones, particularly estrogen. We will review recent developments illustrating the complex multifactorial mechanisms regulating uterine neural plasticity and the nature of molecular signals involved. Finally, we will go through recent findings pointing to the relevance of uterine innervation in gynecological diseases leading to pain and infertility.
Minerva Ginecol. 2016 Dec;68(6):700-12.
Current trends and controversies in reproductive surgery.
Even in the context of the expansion of assisted reproductive technologies (ART), reproductive surgery continues to fulfill its deserved place in the arsenal of fertility treatments. Rather than being competitive, these two avenues of treatment can optimize fertility care when utilized as an adjunct to one another. Surgical indications and techniques in modern reproductive surgery continue to evolve based on new information about the effects of pelvic pathology on infertility and new technology. This review aims to disentangle some of the common clinical dilemmas facing reproductive specialists in regard to the effect of benign gynecologic pathology on fertility and the relevance of surgical intervention in enhancing or preserving fertility in women. To this end, we focus on the management of intramural myomata, adenomyosis, ovarian and peritoneal endometriosis and teratomas in women of reproductive age. In addition, we also review the role of recently developed techniques in the field of ovarian tissue preservation as well as uterine transplantation.
J Clin Endocrinol Metab. 2016 Apr;101(4):1562-70.
Female Reproductive Disorders, Diseases, and Costs of Exposure to Endocrine Disrupting Chemicals in the European Union.
We estimated the economic costs of female reproductive disorders attributable to endocrine disrupting chemical exposures. These may contribute substantially to fibroids and endometriosis, costing nearly €1.5 billion annually.
Andrology. 2016 Jul;4(4):565-72
Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis.
Trasande L1,2,3,4, Zoeller RT5, Hass U6, Kortenkamp A7, Grandjean P8,9, Myers JP10, DiGangi J11, Hunt PM12, Rudel R13, Sathyanarayana S14, Bellanger M15, Hauser R8, Legler J16, Skakkebaek NE17, Heindel JJ18.
A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.
Obstet Gynecol Sci. 2016 Mar;59(2):123-9.
Increased expression of nuclear factor kappa-B p65 subunit in adenomyosis.
Nuclear factor kappa-B (NF-κB) is a critical proinflammatory regulator that has been suggested to play a pivotal role in the pathogenesis and pathophysiology of endometriosis. In the present study, we aimed to evaluate whether the expression of NF-κB p65 subunit is increased in the eutopic endometrium and/or in the adenomyosis nodule of women with adenomyosis.
Thirty-three women with histologically confirmed adenomyosis after laparoscopic or transabdominal hysterectomy were recruited. Women with carcinoma in situ of uterine cervix without evidence of adenomyosis or endometriosis (n=32) served as controls. Formalin-fixed, paraffin-embedded archival tissues were sectioned and immunostained utilizing a monoclonal anti-human NF-κB p65 subunit antibody, and the immunoreactivity of NF-κB p65 subunit was compared between women with and without adenomyosis.
The immunoreactivities of both the nuclear and the cytoplasmic NF-κB p65 subunit were significantly increased in the stromal cells in the eutopic endometrium as well as in the adenomyosis nodule of women with adenomyosis compared with controls, respectively. The nuclear expression of NF-κB p65 subunit was significantly higher in the glandular cells in the eutopic endometrium as well as the adenomyosis nodule of women with adenomyosis compared with controls, respectively.
The expression of NF-κB p65 is increased in the eutopic endometrium and adenomyosis nodule of women with adenomyosis, which strongly suggest that NF-κB plays a critical role in the pathogenesis and/or pathophysiology of adenomyosis.
Reprod Sci. 2016 Sep;23(9):1269-74.
Analysis of Gene Expression in the Endocervical Epithelium of Women With Deep Endometriosis.
Endometriosis affects approximately 12% of reproductive-age women and is currently diagnosed using invasive laparoscopic surgery. Differences in gene expression in the eutopic endometrium between women with and without endometriosis have been reported, and determining the reproducibility of these genetic differences in the endocervical epithelium would represent an important step toward developing novel diagnostic strategies. In this study, we analyzed gene expression in the endocervical epithelium in women with and without moderate or severe endometriosis. Using RT2 Profiler PCR Arrays, we analyzed gene expression in endocervical epithelial cells from women with deep endometriosis (n = 4) and healthy women (n =6). Nine genes were identified as being upregulated: 5 cell cycle genes (cyclin B1 [CCNB1], cyclin G1 [CCNG1], cullin 1 [CUL1], general transcription factor IIH, polypeptide 1 [GTF2H1], and proliferating cell nuclear antigen [PCNA]), 3 cytokine genes (C3, chemokine (C-C motif) ligand 21 [CCL21], and chemokine (C-X-C motif) ligand 14 [CXCL14]) and 1 gene related to dendritic cell pathways (ICAM2), showing that differential gene expression is present in the endocervical epithelium of women with deep endometriosis.
Reprod Biol Endocrinol. 2016 Mar 23;14:12
Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study.
In-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger.
We conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015.
Significant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section.
Excessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.
Hum Reprod. 2016 May;31(5):999-1013.
Endometrial vezatin and its association with endometriosis risk.
Do endometriosis risk-associated single nucleotide polymorphisms (SNPs) found at the 12q22 locus have effects on vezatin ( ITALIC! VEZT) expression?
The original genome-wide association study (GWAS) SNP (rs10859871), and other newly identified association signals, demonstrate strong evidence for ITALIC! cis-expression quantitative trait loci (eQTL) effects on ITALIC! VEZT expression.
WHAT IS KNOWN ALREADY:
GWAS have identified several disease-risk loci (SNPs) associated with endometriosis. The SNP rs10859871 is located within the ITALIC! VEZT gene. ITALIC! VEZT expression is altered in the endometrium of endometriosis patients and is an excellent candidate for having a causal role in endometriosis. Most of the SNPs identified from GWAS are not located within the coding region of the genome. However, they are likely to have an effect on the regulation of gene expression. Genetic variants that affect levels of gene expression are called expression quantitative trait loci (eQTL).
STUDY DESIGN, SIZE, DURATION:
Samples for genotyping and ITALIC! VEZT variant screening were drawn from women recruited for genetic studies in Australia/New Zealand and women undergoing surgery in a tertiary care centre. Coding variants for ITALIC! VEZT were screened in blood from 100 unrelated individuals (endometriosis-dense families) from the QIMR Berghofer Medical Research Institute dataset. SNPs at the 12q22 locus were imputed and reanalysed for their association with endometriosis. Reanalysis of endometriosis risk-association was performed on a final combined Australian dataset of 2594 cases and 4496 controls. Gene expression was performed on 136 endometrial samples. eQTL analysis in whole blood was performed on 862 individuals from the Brisbane Systems Genetics Study. Endometrial tissue-specific eQTL analysis was performed on 122 samples (eutopic endometrium) collected following laparoscopic surgery. VEZT protein expression studies employed ITALIC! n = 56 (western blotting) and ITALIC! n = 42 (immunohistochemistry) endometrial samples.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
The women recruited for this study provided blood and/or endometrial tissue samples in a hospital setting. Genomic DNA was screened for common and coding variants. SNPs of interest in the 12q22 region were genotyped using Agena MassARRAY technology or Taqman SNP genotyping assay. Gene expression profiles from RNA extracted from blood and endometrial tissue samples were generated using Illumina whole-genome expression chips (Human HT-12 v4.0). Whole protein extracted from endometrium was used for VEZT western blots, and paraffin sections of endometrium were employed for VEZT immunohistochemistry semi-quantitative analysis.
MAIN RESULTS AND THE ROLE OF CHANCE:
A total of 11 coding variants of ITALIC! VEZT (including one novel variant) were identified from an endometriosis-dense cohort. Polymorphic coding and imputed SNPs were combined with previous GWAS data to reanalyse the endometriosis risk association of the 12q22 region. The disease association signal at 12q22 was due to coding variants in ITALIC! VEZT or ITALIC! FGD6 (FYVE, RhoGEF and PH domain-containing 6) and SNPs with the strongest signals were either intronic or intergenic. We found strong evidence for ITALIC! VEZT cis-eQTLs with the sentinel SNP (rs10859871) in blood and endometrium, where the endometriosis risk allele (C) was associated with an increase in ITALIC! VEZT expression. We could not demonstrate this genotype-specific effect on VEZT protein expression in endometrium. However, we did observe a menstrual cycle stage specific increase in VEZT protein expression in endometrial glands, specific to the secretory phase ( ITALIC! P = 2.0 × 10(-4)).
LIMITATIONS, REASONS FOR CAUTION:
In comparison to the blood sample datasets, the study numbers of endometrial tissues were substantially reduced. Protein studies failed to complement RNA results, also likely a reflection of the low study numbers in these experiments. ITALIC! In silico prediction tools used in this investigation are typically based on cell lines different to our tissues of interest, thus any functional annotations drawn from these approaches should be considered carefully. Therefore, functional studies on VEZT and related pathway components are still warranted to unequivocally implicate a causal role for VEZT in endometriosis pathophysiology.
WIDER IMPLICATIONS OF THE FINDINGS:
GWAS have proven to be very valuable tools for deciphering complex diseases. Endometriosis is a text-book example of a complex disease, involving genetic, lifestyle and environmental influences. Our focused investigation of the 12q22 region validates an association with increased endometriosis risk. Endometriosis risk SNPs (including rs10859871) located within this locus demonstrated evidence for ITALIC! cis-eQTLs on ITALIC! VEZT expression. By examining women who possess an enhanced genetic risk of developing endometriosis, we have identified an effect on ITALIC! VEZT expression and therefore a potential gene/gene pathway in endometriosis disease establishment and development.
STUDY FUNDING/COMPETING INTERESTS:
Funding for this work was provided by NHMRC Project Grants GNT1012245, GNT1026033, GNT1049472 and GNT1046880. G.W.M. is supported by the NHMRC Fellowship scheme (GNT1078399). S.J.H.-C. is supported by the J.N. Peters Bequest Fellowship. The authors declare no competing interests.
Hum Reprod. 2016 Jun;31(6):1224-35.
Endometriotic mesenchymal stem cells significantly promote fibrogenesis in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of TGF-β1 and Wnt1.
Are endometriotic mesenchymal stem cells (Ecto-MSCs) involved in the fibrosis of ovarian endometrioma?
Ecto-MSCs enhanced the fibrotic behavior of stromal cells in ovarian endometrioma through the Wnt/β-catenin pathway by paracrine production of transforming growth factor-β1 (TGF-β1) and Wnt1.
WHAT IS KNOWN ALREADY:
Endometriosis is characterized by ectopic outgrowth of endometrial stroma and glands surrounded by dense fibrous tissues. The pathogenesis of endometriosis, especially ovarian endometrioma-associated fibrosis, is still unknown.
STUDY DESIGN, SIZE, DURATION:
We analyzed endometrial samples from 15 patients of reproductive age with ovarian endometrioma and normal menstrual cycles. A total of 54 nude mice received a single injection of proliferative endometrial fragments from 14 individuals without endometriosis.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Conditioned medium (CM) was collected from endometrial mesenchymal stem cells (Euto-MSCs) and Ecto-MSCs. The effects of CM on cell proliferation, migration, invasion and collagen gel contraction of endometrial and endometriotic stromal cells (Euto- and Ecto-ESCs) in ovarian endometrioma were evaluated by cell counting kit-8, transwell and collagen gel contraction assays. Effects of CM on fibrotic markers’ expression [including α-smooth muscle actin, Type I collagen, connective tissue growth factor and fibronectin (FN)] in Euto- and Ecto-ESCs were determined by real-time reverse-transcription-polymerase chain reaction and western blotting. Additionally, fibrogenic effects of Ecto-MSC CM treatment on endometriotic implants were analyzed using a xenograft model of endometriosis in immunodeficient nude mice.
MAIN RESULTS AND THE ROLE OF CHANCE:
Our results demonstrated that Ecto-MSC CM significantly promoted cell proliferation, migration, invasion and collagen gel contraction of Euto- and Ecto-ESCs from patients with ovarian endometrioma compared with control and Euto-MSC CM. Expression levels of fibrotic markers in Euto- and Ecto-ESCs were dramatically elevated after treatment with Ecto-MSC CM. Ecto-MSCs secreted higher levels of TGF-β1 and Wnt1 compared with Euto-MSCs. Furthermore, both TGF-β1 and Wnt1 significantly increased expression of fibrotic markers in Euto- and Ecto-ESCs, which was reversed by an anti-TGF-β1 antibody or Wnt1 negative regulator, Dickkopf-related protein 1 (Dkk1). Mechanistic studies demonstrated that Wnt/β-catenin signaling pathways in stromal cells were activated by Ecto-MSC CM. Animal experiments showed that TGF-β1 and Wnt1 as well as Ecto-MSC CM markedly increased the expression of FN and collagen I, which enhanced the progression of fibrosis in endometriosis.
LIMITATIONS, REASONS FOR CAUTION:
To our knowledge, this is the first study to identify the role of Ecto-MSCs in the pathogenesis of fibrosis in ovarian endometrioma. However, numerous other growth factors and cell types may also be involved in the pathogenesis. Therefore, further studies are required to elucidate the paracrine effects of cells in ovarian endometrioma.
WIDER IMPLICATIONS OF THE FINDINGS:
Ecto-MSCs may be involved in the pathogenesis of fibrosis in ovarian endometrioma.
Cell Biol Int. 2016 Jun;40(6):619-20.
Dimethyloxalylglycine may be enhance the capacity of neural-like cells in treatment of Alzheimer disease.
Although using differentiated stem cells is the best proposed option for the treatment of Alzheimer disease (AD), an efficient differentiation and cell therapy require enhanced cell survival and homing and decreased apoptosis. It seems that hypoxia preconditioning via Dimethyloxalylglycine (DMOG) may increase the capacity of MSC to induce neural like stem cells (NSCs). Furthermore, it can likely improve the viability of NSCs when transplanted into the brain of AD rats.
Rev Assoc Med Bras (1992). 2016 Jan-Feb;62(1):72-7.
Estrogen signaling in the proliferative endometrium: implications in endometriosis.
Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.
Mol Hum Reprod. 2016 Jul;22(7):526-35.
17 β-Estradiol promotes vascular endothelial growth factor expression via the Wnt/β-catenin pathway during the pathogenesis of endometriosis.
Do estrogen and Wnt/β-catenin signaling promote vascular endothelial growth factor (VEGF) expression in endometriosis and how?
17β-Estradiol (E2)-drives β-catenin triggered up-regulation of VEGF in effector human primary endometrial stromal cells (ESCs) and thus enhances their ability to establish a new blood supply to the human exfoliated endometrium.
WHAT IS KNOWN ALREADY:
Implantation and survival of exfoliated endometrium is crucially dependent on neovascularization and Wnt/β-catenin signaling plays an important role in stimulating angiogenesis.
STUDY DESIGN, SAMPLES/MATERIALS, METHODS:
Expression levels of VEGF mRNA, estrogen receptor α (ERα) and β-catenin protein were measured in ovarian endometriosis, eutopic endometrium of endometriosispatients and normal endometrium with real-time RT-PCR and western blot. ESCs were treated with 10 nM E2 for different times in order to evaluate the effect of E2 on ERα, β-catenin and VEGF expression in these cells. Human endometrial stromal cells (T HESCs) were cultured for transfection with expression vectors and siRNA constructs and used in chromatin immunoprecipitation (ChIP) and luciferase assays, which were conducted to clarify the regulation mechanism of E2 on VEGF.
MAIN RESULTS AND THE ROLE OF CHANCE:
VEGF, ERα and β-catenin expression was increased in endometriotic lesions compared with normal endometrium. E2 could promote ERα, β-catenin and VEGF expression in ESCs. ChIP and luciferase assays revealed that E2 up-regulated β-catenin expression by binding to the estrogen response element site on the β-catenin promoter. β-Catenin stabilization could activate Wnt/β-catenin signaling, which has a direct transcriptional effect on VEGF gene expression.
LIMITATIONS, REASONS FOR CAUTION:
Endometriotic lesions were all from ovarian endometriosis and may differ from other type of endometriosis.
WIDER IMPLICATIONS OF THE FINDINGS:
These promising results improve the body of knowledge on endometriosis pathogenesis and could open up new therapeutic strategies for the treatment of endometriosis.
Indian J Surg. 2015 Dec;77(Suppl 3):1285-90.
Unexpected Histopathological Findings in Appendectomy Specimens: a Retrospective Study of 1627 Cases.
Pathologic evaluation of the appendix after appendectomy is routine and can occasionally identify unexpected findings. The aim of the present study was to determine the incidence and type of pathologic diagnoses found in appendectomy specimens at our institution. The clinicopathological data of 1627 patients who underwent appendectomies for presumed acute appendicitis from January 2008 to October 2014 were reviewed retrospectively. There were 986 men and 641 women (sex ratio M/F = 1.5) aged between 16 months and 90 years (mean = 30 years). All patients underwent appendectomy (either open or laparoscopic). Histological examination of the surgical specimen showed acute inflammation of the appendix in 1455 cases (89.42 %), fibrosed appendix in 37 cases (2.27 %), and Enterobius vermicularis (n = 23). In 101 cases (6.2 %), the appendix was histologically normal. Incidental unexpected pathological diagnoses were noted in 57 appendectomy specimens. They included pinworm (n = 23), mucinous neoplasms (n = 12), neuroendocrine tumors (NET) (n = 8), adenocarcinoma (n = 2), granulomatous inflammation (n = 5), tuberculosis (n = 2), hyperplastic polyp (n = 1), tubular adenoma (n = 1), diverticulitis (n = 1), endometriosis (n = 1), and actinomycosis (n = 1). The routine histopathological examination of the appendix is of value for identifying unsuspected conditions requiring further postoperative management. Gross examination alone does not appear to be a good indicator of an unexpected finding on microscopic exam. It is recommended that in order to avoid misdiagnoses, all appendices should be histopathologically examined.
Am J Pathol. 2016 Apr;186(4):733-47.
The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded.
Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner tumors. As in the previous model, type II tumors are composed, for the most part, of high-grade serous carcinomas that can be further subdivided into morphologic and molecular subtypes. Type I tumors develop from benign extraovarian lesions that implant on the ovary and which can subsequently undergo malignant transformation, whereas many type II carcinomas develop from intraepithelial carcinomas in the fallopian tube and, as a result, disseminate as carcinomas that involve the ovary and extraovarian sites, which probably accounts for their clinically aggressive behavior. The new molecular genetic data, especially those derived from next-generation sequencing, further underline the heterogeneity of ovarian cancer and identify actionable mutations. The dualistic model highlights these differences between type I and type II tumors which, it can be argued, describe entirely different groups of diseases.
Reproduction. 2016 Jun;151(6):683-92.
Increased expression of CYP1A1 and CYP1B1 in ovarian/peritoneal endometriotic lesions.
Endometriosis is an estrogen-dependent disease affecting up to 10% of all premenopausal women. There is evidence that different endometriosis sites show distinct local estrogen concentration, which, in turn, might be due to a unique local estrogen metabolism. We aimed to investigate whether there was a site-specific regulation of selected enzymes responsible for the oxidative metabolism of estrogens in biopsy samples and endometrial and endometriotic stromal cells. Cytochrome P450 (CYP) 1A1 and CYP1B1 mRNA and protein expressions in deep-infiltrating (rectal, retossigmoidal, and uterossacral) lesions, superficial (ovarian and peritoneal) lesions, and eutopic and healthy (control) endometrium were evaluated by real-time PCR and western blot. Using a cross-sectional study design with 58 premenopausal women who were not under hormonal treatment, we were able to identify an overall increased CYP1A1 and CYP1B1 mRNA expression in superficial lesions compared with the healthy endometrium. CYP1A1 mRNA expression in superficial lesions was also greater than in the eutopic endometrium. Interestingly, we found a similar pattern of CYP1A1 and CYP1B1 expression in in vitro stromal cells isolated from ovarian lesions (n=3) when compared with stromal cells isolated from either rectum lesions or eutopic endometrium. In contradiction, there was an increased half-life of estradiol (measured by HPLC-MS-MS) in ovarian endometriotic stromal cells compared with paired eutopic stromal endometrial cells. Our results indicate that there is a site-dependent regulation of CYP1A1 and CYP1B1 in ovarian/peritoneal lesions and ovarian endometriotic stromal cells, whereas a slower metabolism is taking place in these cells.
J Minim Invasive Gynecol. 2016 Jul-Aug;23(5):781-6.
Reproductive Outcome Is Favorable After Laparoscopic Resection of Bladder Endometriosis.
To assess the reproductive outcome (spontaneous and assisted conception rates) in women who underwent laparoscopic resection of bladder endometriosis.
This was a retrospective, observational study analyzing prospectively recorded data (Canadian Task Force classification II-2).
A tertiary referral center.
Over a 9-year period, we identified 69 consecutive women with symptomatic pelvic endometriosis who underwent laparoscopic resection of bladder endometriosis at our center.
Group A patients (n = 21) had full-thickness endometriotic invasion of the bladder and underwent laparoscopic partial cystectomy. Group B (n = 48) patients had partial endometriotic bladder penetration and underwent partial-thickness excision of the detrusor muscle. Most patients (over 70%) had additional, nonbladder endometriotic lesions, which were also removed during surgery.
MEASUREMENTS AND MAIN RESULTS:
Fertility outcomes were analyzed in patients who wished to conceive (n = 42), and improvements in symptoms were assessed for all patients. The minimum follow-up after surgery was 36 months. Of the 42 patients who wished to conceive, 35 patients (83.3%) conceived: 16 patients spontaneously and 18 patients after IVF treatment. No difference was observed in fertility outcome between group A (partial cystectomy) and group B (partial-thickness excision of the detrusor muscle). For all patients, long-term follow-up revealed that 80% of the patients (55 patients) had no urinary/endometrial symptoms after surgery.
Pregnancy rates after laparoscopic surgery for bladder endometriosis by either partial cystectomy or deep excision of the detrusor muscle are favorable, both for spontaneous pregnancy and conception after IVF treatment. Additionally, urinary symptoms were improved for the majority of patients. Based on our findings, it seems warranted to offer laparoscopic surgical management to symptomatic infertile patients diagnosed with bladder endometriosis, even after IVF failure.
Arch Gynecol Obstet. 2016 Sep;294(3):525-31.
Surgical outcome and complications of total laparoscopic hysterectomy for very large myomatous uteri in relation to uterine weight: a prospective study in a continuous series of 461 procedures.
To analyze whether a large uterine size was associated with increased rate of intraoperative and postoperative surgical complications in patients who underwent total laparoscopic hysterectomy (TLH) for myomatous uteri.
We examined prospectively data from 461 consecutive TLHs performed by a single surgeon between August 2004 and August 2014 at the Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, and at the Department of Gynecologic Oncology, Businco Hospital, Cagliari, Italy. Demographic and surgical data were stratified by uterine weight (range 90-5500 g) into four groups: <300 g; from 300 to 500 g; from 500 to 800 g; and >800 g. Outcomes examined included blood loss, operative time, intraoperative and postoperative complications, and duration of hospital stay. A linear regression analysis was performed to identify whether uterine weight was an independent predictor affecting these outcomes. In addition, BMI, previous surgery with adhesiolysis, and endometriosis were tested as a predictor of surgical complications and outcomes.
No significant difference was found in intraoperative and postoperative complications, as well as hospital stay, by uterine weight. Increased uterine size was significantly associated with longer operative time and increased blood loss. Beside uterine weight, prior surgery was predictive of postoperative complications. In contrast, higher BMI was not associated with increased complication rate. Independent predictors of longer operative time included previous surgery, endometriosis, and BMI.
Our results showed that in experienced hands, TLH is feasible and safe also in presence of very large uteri. TLH results in a few complications and short hospital stay regardless of uterine weight.
Mol Endocrinol. 2016 May;30(5):518-32.
Endometrial Expression of Steroidogenic Factor 1 Promotes Cystic Glandular Morphogenesis.
Epigenetic silencing of steroidogenic factor 1 (SF1) is lost in endometriosis, potentially contributing to de novo local steroidogenesis favoring inflammation and growth of ectopic endometrial tissue. In this study, we examine the impact of SF1 expression in the eutopic uterus by a novel mouse model that conditionally expresses SF1 in endometrium. In vivo SF1 expression promoted the development of enlarged endometrial glands and attenuated estrogen and progesterone responsiveness. Endometriosis induction by autotransplantation of uterine tissue to the mesenteric membrane resulted in the increase in size of ectopic lesions from SF1-expressing mice. By integrating the SF1-dependent transcriptome with the whole genome binding profile of SF1, we identified uterine-specific SF1-regulated genes involved in Wingless and Progesterone receptor-Hedgehog-Chicken ovalbumin upstream promoter transcription factor II signaling for gland development and epithelium-stroma interaction, respectively. The present results indicate that SF1 directly contributes to the abnormal uterine gland morphogenesis, an inhibition of steroid hormone signaling and activation of an immune response, in addition to previously postulated estrogen production.
PLoS One. 2016 Mar 28;11(3):
Inhibition of Hyaluronic Acid Synthesis Suppresses Angiogenesis in Developing Endometriotic Lesions.
The development and long-term survival of endometriotic lesions is crucially dependent on an adequate vascularization. Hyaluronic acid (HA) through its receptor CD44 has been described to be involved in the process of angiogenesis.
To study the effect of HA synthesis inhibition using non-toxic doses of 4-methylumbelliferone (4-MU) on endometriosis-related angiogenesis.
MATERIALS AND METHODS:
The cytotoxicity of different in vitro doses of 4-MU on endothelial cells was firstly tested by means of a lactate dehydrogenase assay. The anti-angiogenic action of non-cytotoxic doses of 4-MU was then assessed by a rat aortic ring assay. In addition, endometriotic lesions were induced in dorsal skinfold chambers of female BALB/c mice, which were daily treated with an intraperitoneal injection of 0.9% NaCl (vehicle group; n = 6), 20 mg/kg 4-MU (n = 8) or 80 mg/kg 4-MU (n = 7) throughout an observation period of 14 days. The effect of 4-MU on their vascularization, survival and growth were studied by intravital fluorescence microscopy, histology and immunohistochemistry.
Non-cytotoxic doses of 4-MU effectively inhibited vascular sprout formation in the rat aortic ring assay. Endometriotic lesions in dorsal skinfold chambers of 4-MU-treated mice dose-dependently exhibited a significantly smaller vascularized area and lower functional microvessel density when compared to vehicle-treated controls. Histological analyses revealed a downregulation of HA expression in 4-MU-treated lesions. This was associated with a reduced density of CD31-positive microvessels within the lesions. In contrast, numbers of PCNA-positive proliferating and cleaved caspase-3-positive apoptotic cells did not differ between 4-MU-treated and control lesions.
The present study demonstrates for the first time that targeting the synthesis of HA suppresses angiogenesis in developing endometriotic lesions. Further studies have to clarify now whether in the future this anti-angiogenic effect can be used beneficially for the treatment of endometriosis.
Theriogenology. 2016 Jul 15;86(2):516-22
Inflammatory response in chronic degenerative endometritis mares treated with platelet-rich plasma.
Degenerative changes of the endometrium are directly related to age and fertility in mares. Chronic degenerative endometritis (CDE) is correlated with uterine fluid retention and reduced ability to clear uterine inflammation. Recent research in the areas of equine surgery and sports medicine has shown that platelet-rich plasma (PRP) treatment acts as an immunomodulator of the inflammatory response. Therefore, the aim of this study was to determine if the uterine infusion of PRP could modulate the local inflammatory response and modify the intrauterine NO concentrations after artificial insemination (AI) in both normal mares and those with CDE. Thirteen mares with endometrium classified as grade III on the histology (mares with CDE) and eight mares with endometrial histological classification I or II-a normal mares were selected to investigate the effect of PRP therapy. The mares were inseminated with fresh semen in two consecutive cycles in a crossover study design. Thereby, each mare served as its own control and the treatment was performed with intrauterine PRP infusion four hours after AI. The percentage of neutrophils in uterine cytology (CIT, %), uterine fluid accumulation observed on ultrasonography (FLU, mm) and nitric oxide concentration of uterine fluid (NO, μM) were analyzed before and 24 hours after AI. The results reported that mares with CDE (CIT, 68.3 ± 3.27, FLU, 10.7 ± 1.61) have a higher (P < 0.05) intrauterine inflammatory response after AI than normal mares (CIT, 24.4 ± 3.56, FLU, 0), but NO concentrations did not differ (P > 0.05) between categories of mares. In treated cycles with PRP, the intrauterine inflammatory response decrease (P < 0.05) in CDE mares (CDE: CIT, 31.4 ± 6.48, FLU, 5.5 ± 1.28; normal mares: CIT, 13.5 ± 4.31, FLU, 0) when compared with nontreated cycle (CDE: CIT, 68.3 ± 3.27, FLU, 10.7 ± 1.61; NM: CIT, 24.4 ± 3.56, FLU, 0), but did not modify NO concentrations in uterine fluid. Thus, we can conclude that PRP was effective in modulating the exacerbated uterine inflammatory response to semen in mares with CDE but did not reduce NO concentrations in intrauterine fluid.
Expert Opin Drug Metab Toxicol. 2016 May;12(5):581-8
Overview of elagolix for the treatment of endometriosis.
Suppression of sex-steroid secretion is required in a variety of gynecological conditions. This can be achieved using gonadotropin releasing hormone (GnRH) agonists that bind pituitary gonadotropin receptors and antagonize the link-receptor of endogenous GnRH, inhibiting the mechanism of GnRH pulsatility. On the other hand, GnRH antagonists immediately reduce gonadal steroid levels, avoiding the initial stimulatory phase of the agonists. Potential benefits of GnRH antagonists over GnRH agonists include a rapid onset and reversibility of action. Older GnRH antagonists are synthetic peptides, obtained by modifications of certain amino acids in the native GnRH sequence. They require subcutaneous injections, implantation of long-acting depots. The peptide structure is responsible for histamine-related adverse events and the tendency to elicit hypersensitivity reactions.
Research has worked towards the development of non-peptidic molecules exerting antagonist action on GnRH. They are available for oral administration and may have a more beneficial safety profile in comparison with peptide GnRH antagonists. This article focuses on the data of the literature about elagolix, a novel non-peptidic GnRHantagonist, in the treatment of endometriosis.
Elagolix demonstrated efficacy in the management of endometriosis-associated pain and had an acceptable safety and tolerability profile. However, further studies are necessary to evaluate its non-inferiority in comparison with other endometriosis’s treatments.
Rev Esp Enferm Dig. 2016 Aug;108(8):524-5.
Intestinal endometriosis. Our experience.
Intestinal endometriosis is defined as a bowel infiltration by ectopic endometrial tissue. The prevalence is 3-37% of all women affected by endometriosis. Rectosigmoid colon is the most frequent location (70-93%), followed to ileocecal region, appendix and other colon and small bowel segments. Intestinal endometriosis usually is asymptomatic. Often it is only diagnosed during surgery for other reasons. The symptoms frequently are nonspecific, although it may appear as an acute abdominal pain. Clinical history, physical examination and image techniques are necessary for the diagnosis. The choice of the operative technique depends on the clinical presentation and on the fertility wishes of the patient. Laparotomy and laparoscopy are equally effective, but laparoscopic approach is preferred. We present 17 cases of patients from our Hospital diagnosed with intestinal endometriosis, from 2006 to 2015.
J Endocrinol Invest. 2016 Aug;39(8):923-31.
Comparative, open-label prospective study on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain on 2 mg dienogest/30 µg ethinyl estradiol continuous or 21/7 regimen oral contraceptive.
To evaluate the effects of a continuous regimen combined oral contraceptive (COC) containing 2 mg dienogest and 30 µg ethinyl estradiol (DNG/EE) compared to a 21/7 regimen on the quality of life (QoL) and sexual function in women affected by endometriosis-associated pelvic pain.
Sixty-three women constituted the Study group treated with DNG/EE COC continuous regimen; 33 women were given DNG/EE COC in a 21/7 regimen. To define the endometriosis-associated pelvic pain, the Visual Analogic Scale was used. The Short Form-36, Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to assess QoL, sexual function and sexual distress, respectively. The study included two follow-ups.
At 3 and 6 months of treatment there was an improvement in pain of the Study group (p < 0.001). The Control group underwent pain improvement at the second follow-up (p < 0.05). At the first and the second follow-ups, the Study group reported QoL improvements in all categories (p < 0.001). The Control group reported QoL improvements in all categories at the second follow-up (p < 0.05). At the first and the second follow-ups of the Study group, the FSFI total score had risen (p < 0.001), and the FSDS score had dropped (p < 0.001). An improvement of the FSFI score and a reduction of the FSDS score of the Control group was observed at the second follow-up (p < 0.001), but not at the first follow-up (p = NS).
Women on DNG/EE COC continuous regimen reported a reduction of endometriosis-associated pelvic pain and there was an improvement of their sexual activity and their QoL that was better than the DNG/EE 21/7 conventional regimen.
Gynecol Obstet Invest. 2017;82(1):78-85.
Aberrant Methylation of the E-Cadherin Gene Promoter Region in Endometrium and Ovarian Endometriotic Cysts of Patients with Ovarian Endometriosis.
The loss of E-cadherin expression plays an important role in the development of endometriosis, but the molecular mechanism is not clear to date. It has been confirmed that the hypermethylation of the CpG island may be an important molecular mechanism in the transcriptional inactivation of E-cadherin gene (CDH1) in many cancers. The present study investigated the methylation status of CDH1 promoter region in ovarian endometriotic cysts and the endometrium of women with ovarian endometriosis. The results showed that the frequency of CDH1 promoter methylation in eutopic (26%), ectopic tissues (32%) of women with ovarian endometriosis was significantly higher than that of endometrium tissue of women without endometriosis (8%). Further, results of the study showed that the expression level of mRNA and protein of E-cadherin in methylation-positive tissues was significantly lower than that in methylation-negative tissues (p = 0.023 and 0.035, respectively). Pearson’s correlation coefficients analysis showed the level of CDH1 mRNA expression was closely related to the level of E-cadherin protein expression. The results implied that the aberrant methylation of the CDH1 promoter region in the endometrium of the women may contribute, at least in part, to the development of ovarian endometriosis.
Circ Cardiovasc Qual Outcomes. 2016 May;9(3):257-64.
Endometriosis and Risk of Coronary Heart Disease.
Endometriosis is a prevalent gynecologic disease associated with systemic chronic inflammation, heightened oxidative stress, and atherogenic lipid profile that may increase women’s risk for coronary heart disease (CHD).
METHODS AND RESULTS:
We examined the prospective association between laparoscopically confirmed endometriosis and subsequent CHD among 116 430 women in the Nurses’ Health Study II (1989-2009). Participants with a history of heart disease and stroke were excluded. When compared with women without endometriosis, women with laparoscopically confirmed endometriosis had a higher risk of myocardial infarction (relative risk, 1.52; 95% confidence interval, 1.17-1.98), angiographically confirmed angina (1.91; 1.59-2.29), coronary artery bypass graft surgery/coronary angioplasty procedure/stent (1.35; 1.08-1.69), or any of these CHD end points combined (1.62; 1.39-1.89), independent of potential demographic, anthropometric, family history, reproductive, and lifestyle confounders. Relative risk for the combined CHD end point was highest among women aged ≤40 years (3.08; 2.02-4.70) and decreased as age increased (40< age ≤50 years, 1.65; 1.35-2.02; 50< age ≤55 years, 1.44; 1.07-1.94; and age >55 years, 0.98; 0.56-1.72; P value, test for heterogeneity=0.001). Having had a hysterectomy/oophorectomy was associated with higher risk of combined CHD compared with not having had a hysterectomy/oophorectomy (1.51; 1.34-1.71). A percentage of 42 of the association between endometriosis and CHD could be explained by greater frequency of hysterectomy/oophorectomy and earlier age at surgery after endometriosis diagnosis.
In this large, prospective cohort, laparoscopically confirmed endometriosis was associated with increased risk of CHD. The association was strongest among young women. Hysterectomy/oophorectomy was associated with higher risk of CHD and could partially explain the association between endometriosis and CHD.
Oncotarget. 2016 May 10;7(19):27021-32.
The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo.
A phase 2 clinical trial investigating the efficacy and safety of AS602801, a newly developed JNK inhibitor, in the treatment of inflammatory endometriosis is complete. We are now examining whether AS602801 acts against human cancer cells in vitro and in vivo. In vitro, AS602801 exhibited cytotoxicity against both serum-cultured non-stem cancer cells and cancer stem cells derived from human pancreatic cancer, non-small cell lung cancer, ovarian cancer and glioblastoma at concentrations that did not decrease the viability of normal human fibroblasts. AS602801 also inhibited the self-renewal and tumor-initiating capacity of cancer stem cells surviving AS602801 treatment. Cancer stem cells in established xenograft tumors were reduced by systemic administration of AS602801 at a dose and schedule that did not adversely affect the health of the tumor-bearing mice. These findings suggest AS602801 is a promising anti-cancer stem cell agent, and further investigation of the utility of AS602801 in the treatment of cancer seems warranted.
Curr Med Res Opin. 2016 Jun;32(6):1073-82.
Analysis of subsequent surgery rates among endometriosis patients who underwent surgery with and without concomitant leuprolide acetate therapy.
Objective To compare subsequent endometriosis-related surgery following initial laparoscopy among women treated with leuprolide acetate (LA) or other endometriosis therapies versus women who received no pharmacotherapy. Research design and methods This retrospective cohort analysis utilized MarketScan Commercial claims data. Women with endometriosis aged 18-49 who underwent laparoscopy between 1 January 2005 and 31 December 2011 were identified using diagnosis and procedures codes and were categorized into four cohorts based on claims within 90 days of laparoscopy: surgery plus adherent LA, surgery plus non-adherent LA, surgery plus other therapy, and surgery alone. Patients with proportion of days covered ≥0.80 in the 6 months after laparoscopy were considered adherent to LA. Main outcome measures Subsequent endometriosis-related surgery (laparoscopy, laparotomy or other excision/ablation/fulguration of endometriosis lesions, oophorectomy, or hysterectomy) was measured in the 6 and 12 months following initial laparoscopy. Risk of subsequent surgery was compared using multivariable Cox proportional hazards modeling. Results Most women were treated with surgery only (n = 9865); fewer were treated with LA (adherent: n = 202; non-adherent: n = 490) or other therapies (n = 230). The proportion of patients with subsequent surgery ranged from 2.0% to 10.0% during the 6 month follow-up (12 month: 9.7% to 13.5%). Adherent LA use was associated with significantly lower risk of surgery compared to surgery alone (hazard ratio [HR] = 0.31, p = 0.020) while use of other therapies was associated with significantly higher risk (HR = 1.51, p = 0.045) over the 6 month follow-up. There was no significant difference between the surgery plus non-adherent LA and surgery only cohort over 6 months (p = 0.247). The association between adherent LA and subsequent surgery was not significant over the 12 month follow-up. Conclusion Therapy with LA after laparoscopy for endometriosis was associated with lower risk of subsequent surgery at 6 months among women who were adherent to LA. Key limitations include lack of ability to capture disease severity which may have resulted in uncontrolled confounding.