Hum Reprod Update. 2010 Oct 19. [Epub ahead of print]

The role of mast cells and their mediators in reproduction, pregnancy and labour.

Menzies FM, Shepherd MC, Nibbs RJ, Nelson SM.

Centre for Population and Health Science, College of Medicine , Veterinary and Life Sciences University of Glasgow, McGregor Building, Floor 2, Western Infirmary, Glasgow, UK.

BACKGROUND Mast cells (MCs) are the classical mediators of allergy, however, their importance in the development of innate and adaptive immune responses is increasingly being recognized. Herein, the present MC literature is summarized, with particular focus on studies of MCs in the endometrium and myometrium, and their involvement in fertility, implantation, pregnancy and labour. METHODS Recent developments in MC biology were identified by systematic searches of PubMed, Medline and Google Scholar from 2000 to November 2009. To specifically examine the role of MCs in fertility and pregnancy, we then performed a systematic review of English literature cited in the PubMed, Medline and Google Scholar databases, but extended the search period, from 1980 to January 2010 RESULTS MCs can respond to immunoglobulin E-independent innate immune stimuli and are present within the endometrium, with activation and release of mediators occurring prior to menstruation and in association with endometriosis. With respect to pregnancy, MCs are redundant during blastocyst implantation and although their mediators can induce myometrial contractility, there is no epidemiological link of preterm birth with allergy, suggesting a non-essential role or robust regulation. In males, MCs are present in the testes and are increased in oligo- and azoospermia, with MC mediators directly suppressing sperm motility in a potentially reversible manner. CONCLUSIONS MCs are prevalent in the female and male reproductive tract. However, whether MCs are absolutely required for a successful pregnancy or are fundamental to reproductive pathology, and thereby a therapeutic target, remains to be determined.

Genome Med. 2010 Oct 14;2(10):75. [Epub ahead of print]

Advances in the genetics of endometriosis.

Dun EC, Taylor RN, Wieser F.

Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, USA.

Endometriosis is a gynecological disease characterized by implantation of endometrial tissue outside of the uterus. Early familial aggregation and twin studies noted a higher risk of endometriosis among relatives. Studies on the roles of the environment, genetics and aberrant regulation in the endometrium and endometriotic lesions of women with endometriosis suggest that endometriosis arises from the interplay between genetic variants and environmental factors. Elucidating the hereditary component has proven difficult because multiple genes seem to produce a susceptibility to developing endometriosis. Molecular techniques, including linkage and genome-wide analysis, have identified candidate genes located near known loci related to development and regulation of the female reproductive tract. As new candidate genes are discovered and hereditary pathways identified using technologies such as genome-wide analysis, the possibility of prevention and treatment becomes more tangible for millions of women affected by endometriosis. Here, we discuss the advances of genetic research in endometriosis and describe technologies that have contributed to the current understanding of the genetic variability in endometriosis, variability that includes regulatory polymorphisms in key genes.

Colorectal Dis. 2010 Oct 19. doi: 10.1111/j.1463-1318.2010.02457.x. [Epub ahead of print]

Is routine histopathological examination of appendectomy specimens useful? A systematic review of the literature.

Swank H, Eshuis E, Ubbink D, Bemelman W.

Department of Surgery, Academic Medical Centre, Amsterdam . Department of Clinical Epidemiology & Biostatistics and Surgery, Academic Medical Centre, Amsterdam.

Aim  Histopathological examination of the appendix after appendectomy is routinely performed. The object of this systematic review is to determine whether routine histopathological examination of the appendix is justified on grounds of cost. Method  PubMed, EMBASE, Web of Science and the Cochrane library were searched without language restriction up to October 1 2009. All articles that reported on the incidence of histopathologically proven aberrant appendiceal pathology were included. Results  19 case series reported the incidence of a benign neoplasm (0.5%, weighted mean (WM)), malignant neoplasm (0.2%, WM) and other pathology (0-14%). Nine articles reported the sensitivity of the intraoperative findings to detect aberrant diagnoses. Parasitic infection was detected in 0-19%, endometriosis in 0% and granulomatosis in 0-11% of cases. Five articles addressed the consequences of aberrant pathology. Most patients with parasite infection, granulomatosis and malignant neoplasms underwent additional investigation or treatment, in contrast to patients with a benign neoplasm. Conclusion  The incidence of unexpected findings in appendectomy specimens is low and the intraoperative diagnosis alone appears insufficient for identifying unexpected disease. The benefit of histopathology is studied inadequately. From the present available evidence routine histopathology cannot be judged as useless.

Copyright © 2010 The Association of Coloproctology of Great Britain and Ireland.

Hum Reprod. 2010 Oct 17. [Epub ahead of print]

SB203580, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis by down-regulating proinflammatory cytokines and proteolytic factors in a mouse model.

Zhou WD, Yang HM, Wang Q, Su DY, Liu FA, Zhao M, Chen QH, Chen QX.

Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, China.

BACKGROUND p38 mitogen-activated protein kinase (p38 MAPK), a regulator of inflammation, may play a role in the pathogenesis of endometriosis (EM). We studied the effect of SB203580, a p38 MAPK inhibitor, on the development of EM in a mouse model. METHODS EM was induced in BALB/c mice by peritoneal injection of endometrium-rich fragments. Mice (n = 15) were injected i.p. for 24 days with SB203580 and 15 mice served as positive controls (EM group). Sham-operated mice received carrier only. Peritoneal fluid (PF) cells were collected for protein/mRNA analysis. Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, matrix metalloproteinase-2 (MMP-2) and MMP-9 proteins were measured using enzyme-linked immunosorbent assay and mRNAs by RT-PCR. Phosphorylation of p38 MAPK was evaluated by western blotting. RESULTS SB203580 decreased the weight and size (P < 0.05 versus EM) of endometriotic lesions in BALB/c mice. IL-1β, TNF-α, MMP-2 and MMP-9 mRNA levels were decreased in peritoneal cells of the SB203580 versus EM group (P < 0.01, P < 0.05, P < 0.05 and P < 0.05, respectively). Concentrations of IL-1β, TNF-α, MMP-2 and MMP-9 proteins in PF were reduced in the SB203580 versus EM group (P < 0.05, P < 0.01, P < 0.05 and P < 0.05, respectively). Compared with the sham-operated group, phosphorylation of p38 MAPK in the EM group was increased, and this was down-regulated by SB203580 (P < 0.01). CONCLUSIONS SB203580 may suppress the development of EM by inhibiting expression of proinflammatory cytokines and proteolytic factors. p38 MAPK might play a key role in progression of EM.

J Minim Invasive Gynecol. 2010 Nov-Dec;17(6):749-53.

Fourteen-year experience with laparoscopic ventrosuspension in patients with retroverted and retroflected uterus and pelvic pain syndromes.

Ott J, Nouri K, Demmel M, Zafraani S, Greilberger U, Huber JC, Mayerhofer K.

Department of Gynaecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, Vienna, Austria.

BACKGROUND: In women with a retroverted uterus, who have dyspareunia, chronic pelvic pain, or dysmenorrhea, laparoscopic ventrosuspension of the uterus has been reported effective in achieving symptom relief.

STUDY OBJECTIVE: To critically review our experience with our method of laparoscopic ventrosuspension.

DESIGN: Cohort study (Canadian Task Force classification II-3).

SETTING: Tertiary care center.

PATIENTS: Sixty-three women who had undergone laparoscopic ventrosuspension for treatment of pain syndromes during 1995 through 2008.

INTERVENTIONS: Laparoscopic ventrosuspension, and a questionnaire about the long-term outcome of the operation.

MEASUREMENTS AND MAIN RESULTS: There were no adverse events except for 2 repeat operations within 3 postoperative days. Forty-nine women (77.8%) answered the questionnaire about long-term outcome, and in these patients, significant pain relief was achieved (p <.001). Pain levels decreased, based on a numeric rating scale, from a mean (SD) of 6.35 (1.92) to 0.97 (1.40) in patients without endometriosis, and from 6.93 (2.09) to 3.80 (2.08) in those with endometriosis. Of 34 patients without endometriosis, 1 (2.9%) stated that the operation had not led to symptom relief, compared with 4 of 15 (26.7%) with endometriosis (p = .03).

CONCLUSION: Laparoscopic ventrosuspension is clearly beneficial in women with a retroverted and retroflected uterus who have pelvic pain syndromes, even in the long term.

Copyright © 2010 AAGL. Published by Elsevier Inc. All rights reserved.

Reprod Toxicol. 2010 Oct 15. [Epub ahead of print]

Cigarette Smoke Inhibits Recruitment of Bone-Marrow-Derived Stem cells to The Uterus.

Zhou Y, Gan Y, Taylor HS.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine.

Cigarette smoking leads to female infertility and a decreased incidence of endometriosis. Bone marrow derived stem cells are recruited to uterine endometrium and endometriosis. The effect of cigarette smoking on stem cell recruitment to any organ is uncharacterized. We hypothesized that bone marrow-derived mesenchymal stem cell recruitment to the uterus and differentiation would be diminished by cigarette smoke. We used human mesenchymal stem cells (hMSC) in vitro and a mouse model of cigarette smoke exposure. After myeloablation female C57BL/6J received bone marrow cells from males. Mice were exposed to room air or smoke from unfiltered cigarettes. Immunofluorescence and Y-FISH was performed on uterine sections. In vitro hMSCs were treated with 8-Br-cAMP to induce endometrial cell differentiation with or without cigarette smoke extract (CSE) and decidualization assessed morphologically and by prolactin expression. After 4 weeks the total number of Y-chromosome cells in the uterus was reduced by 68% in the smoke exposed mice. Both leukocytes and bone marrow derived endometrial cells were reduced by 60% and 73%, respectively. Differentiation of bone marrow derived cell to endometrial epithelial cells was reduced by 84%. hMSC treated with CSE failed to show cytological characteristics of decidualization. mRNA levels of the decidualization marker prolactin were decreased by 90% in CSE treated cells. Smoking inhibits both recruitment of bone marrow derived stem cells to uterus and stem cell differentiation. Inhibition of stem cells recruitment may be a general mechanism by which smoking leads to long term organ damage through inability to repair or regenerate multiple tissues.

Histopathology. 2010 Oct;57(4):597-606. doi: 10.1111/j.1365-2559.2010.03667.x.

Expression of aberrantly glycosylated Mucin-1 in ovarian cancer.

Van Elssen CH, Frings PW, Bot FJ, Van de Vijver KK, Huls MB, Meek B, Hupperets P, Germeraad WT, Bos GM.

Department of Internal Medicine, Division of Haematology, Maastricht University Medical Center, Maastricht, the Netherlands PharmaCell BV, Maastricht, the Netherlands Department of Pathology, Maastricht University Medical Center, Maastricht, the Netherlands Department of Internal Medicine, Division of Oncology, Maastricht University Medical Center, Maastricht, the Netherlands.

Van Elssen C H M J, Frings P W H, Bot F J, Van de Vijver K K, Huls M B, Meek B, Hupperets P, Germeraad W T V & Bos G M J
(2010) Histopathology57, 597-606
Expression of aberrantly glycosylated Mucin-1 in ovarian cancer Aims:  Mucin 1 (MUC1) is an important tumour-associated antigen (TAA), both overexpressed and aberrantly glycosylated in adenocarcinomas. The aim of this study was to examine the MUC1-glycosylation status of primary ovarian adenocarcinomas and metastatic lesions. Methods and results:  Paraffin-embedded tissue sections of 37 primary ovarian adenocarcinomas representing all histotypes (22 serous, five mucinous, two clear-cell, eight endometrioid), four serous borderline tumours with intraepithelial carcinoma, seven sections of ovarian endometriosis and 13 metastatic lesions were analysed by immunohistochemistry. Non-neoplastic ovarian surface epithelium and serous cystadenomas were used as controls. All epithelia expressed MUC1 protein. Of primary tumours, 76% expressed the differentiation-dependent glycoform and 84% the cancer-associated glycoform (Tn/Sialyl-Tn-epitopes). In metastatic lesions this was 77% and 85%, respectively. Notably, in 57% of ovarian endometriosis and 75% of intraepithelial lesions, the cancer-associated MUC1 epitopes were expressed, whereas normal ovarian surface epithelium and serous cystadenomas did not express these epitopes. Conclusions:  The underglycosylated MUC1 epitopes are expressed by all histotypes of primary ovarian adenocarcinomas, by the vast majority of metastatic lesions and by possible ovarian cancer precursor lesions, but not by normal ovarian tissue. These results indicate that MUC1-associated Tn/STn-epitopes are important targets for immunotherapy and diagnostic imaging in ovarian cancer patients.

Histopathology. 2010 Oct;57(4):587-96. doi: 10.1111/j.1365-2559.2010.03673.x.

Endocervical-like (Müllerian) mucinous borderline tumours of the ovary are frequently associated with the KRAS mutation.

Kim KR, Choi J, Hwang JE, Baik YA, Shim JY, Kim YM, Robboy SJ.

Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center Seoul Graduate School, University of Ulsan Department of Pathology, Pochon Cha University Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center Seoul, Seoul, Korea Department of Pathology, Duke University Medical Center, Durham, NC, USA.

Kim K-R, Choi J, Hwang J-E, Baik Y-A, Shim J Y, Kim Y M & Robboy S J
(2010) Histopathology57, 587-596
Endocervical-like (Müllerian) mucinous borderline tumours of the ovary are frequently associated with the KRAS mutation Aims:  Clinicopathological aspects of the endocervical-like mucinous borderline tumour of the ovary (EMBT), including higher frequencies of bilaterality, endometriosis and hormone receptor reactivity, and often admixtures of various Müllerian-type epithelia, closely resembles endometrioid tumour more than mucinous borderline tumour of the intestinal type (IMBT). Thus, the aims of this study were to determine whether EMBT is really a subtype of mucinous borderline tumours, as shown in the current classification system, and to determine the best classification for EMBT. Methods and results:  The clinicopathological and immunohistochemical features of 17 EMBTs were analysed, including oestrogen receptor (ER), progesterone receptor (PR), PTEN, cytokeratins (CK) 7 and 20, and β-catenin. Additionally, mutational analyses of the KRAS (exon 1) and PTEN genes (all nine exons) were performed in all cases, and the results were compared with literature findings for IMBT and endometrioid tumours. Twelve patients (71%) were confirmed histologically to have endometriosis in one or both ovaries. In seven cases, gradual transitions from endometriotic foci to the EMBT were identified. Immunohistochemically, all cases were reactive for ER and PR, with no nuclear expression of β-catenin. CK7 positivity was strong in all patients, whereas there was no reactivity for CK20. PTEN reactivity was diffuse in the nuclei of epithelial and underlying stromal cells. Sixty-nine per cent showed KRAS mutations in exon 1 and codon 12, but no PTEN mutation was identified in any of the nine exons. Conclusion:  Our study suggests that EMBT has features of both mucinous and endometrioid tumours and is an additional tumour type arising in endometriosis. While clinicopathological features of EMBTs are closer to endometrioid tumours, they still have molecular characteristics closer to IMBTs.

© 2010 Blackwell Publishing Limited.

Ultrasound Obstet Gynecol. 2010 Oct 15. [Epub ahead of print]

Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis-a systematic review and meta-analysis.

Hudelist G, English J, Thomas A, Tinelli A, Singer CF, Keckstein J.

Endometriosis & Pelvic Pain Clinic, Dpt. Obstetrics & Gynaecology, Wilhelminen Hospital Vienna, Austria.

OBJECTIVES: The aim of this study was to critically analyze the diagnostic value of TVS for non-invasive, presurgical detection of bowel endometriosis.

METHODS: MEDLINE (1966-2010) and EMBASE (1980-2010) databases were searched for relevant studies investigating the diagnostic accuracy of TVS for diagnosing deep infiltrating endometriosis (DIE) involving the bowel. Diagnosis was established by laparoscopy and/or histopathological analysis. Likelihood ratios (LHR’s) were recalculated in addition to traditional measures of effectiveness.

RESULTS: Out of 188 papers, a total of 10 studies fulfilled predefined inclusion criteria involving 1106 patients with suspected endometriosis. The prevalence of bowel endometriosis varied from 14% to 73.3%. Positive LHR’s ranged from 4.8 to 48.56, negative LHR’s ranged from 0.02 to 0.75 with wide confidence intervals (CI’s). Pooled estimates of sensitivities and specificities were 91% and 98%; positive and negative LHR’s 30.36 and 0.09, PPV’s and NPV’s 98% and 95%, respectively. Three of the studies used bowel preparations to enhance the visibility of the rectal wall; one study directly compared the use of water contrast (RWC-TVS) versus no prior bowel enema (TVS). The negative LHR was 0.04 for RWC-TVS versus 0.47 for TVS.

CONCLUSIONS: TVS with or without the use of prior bowel preparation is an accurate test for non-invasive, presurgical detection of deep infiltrating endometriosis of the rectosigmoid. Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.

Ann Diagn Pathol. 2010 Oct 7. [Epub ahead of print]

Primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma.

Baughn MR, Plaxe SC, Weidner N.

Department of Pathology, University of California, San Diego, CA 92103, USA.

We present a 58-year-old woman with primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma. Noninvolved ovary showed no Brenner tumor, endometriosis, transitional carcinoma, endometrioid adenocarcinoma, or typical multigerm layer classic mature teratoma. Moreover, no other primary site was possible because there were no prior or concomitant squamous carcinomas, or history of cervical intraepithelial neoplasia. The tumor showed strong positivity for p63 and CK5/6, reactivity that also extended from the squamous carcinoma into the basal-cell lining of the mucinous cyst of a likely monodermal teratoma. This basal-cell pattern was absent in a series of conventional benign and borderline cystic mucinous cystadenomas of the ovary, but clearly present in the mucinous cysts part of mature teratomas. We present this as a unique case of squamous carcinoma likely arising from a monodermal cystic mucinous teratoma. Moreover, we submit that the p63 and CK5/6 staining pattern may help to differentiate monodermal cystic mucinous teratoma from conventional cystic mucinous tumors.

Copyright © 2010 Elsevier Inc. All rights reserved.

Fertil Steril. 2010 Oct 15. [Epub ahead of print]

Imaging of endometriosis with computerized tomography colonography.

Koutoukos I, Langebrekke A, Young V, Qvigstad E.

Oslo University Hospital, Ulleval, Oslo, Norway.

We demonstrate the use of computerized tomography colonography for the imaging of intestinal endometriosis to facilitate preoperative management in our hospital setting.

Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

J Thorac Cardiovasc Surg. 2010 Nov;140(5):1189-90.

Pericardial, pleural, and diaphragmatic endometriosis.

Ceccaroni M, Clarizia R, Placci A.

Gynecologic Oncology Division, International School of Surgical Anatomy, Sacred Heart Hospital, Negrar, Verona, Italy.

Int J Cancer. 2010 Oct 14. [Epub ahead of print]

Endometriosis as a prognostic factor for cancer survival.

Melin A, Lundholm C, Malki N, Swahn ML, Sparen P, Bergqvist A.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Studies have shown an increased risk of malignancies in women with endometriosis. Little is known about the impact of endometriosis on cancer survival. We investigated whether the survival after a diagnosis of a malignancy differs in women with a previously diagnosed endometriosis compared to other women.Women with a first time diagnosis of a malignancy in 1969 – 2005, were identified using the National Swedish Cancer Register (NSCR). By use of the National Swedish Patient Register (NSPR) we identified all women with a diagnosis of endometriosis during the same period and linked these patients with the data from the NSCR. The cohort comprised 4 278 women with endometriosis and a malignancy, and 41 831 randomly selected matched women without endometriosis. Cox regression was used for all calculations to obtain crude and adjusted cause specific mortality rates, measured as hazard ratios (HR) with 95% confidence intervals (CI).46 109 women entered the study. There was a statistically significant better survival for women with endometriosis for all malignancies combined (HR=0.92) and for breast cancer (HR=0.86) and ovarian cancer (HR=0.81) specifically. For breast cancer the survival enhancing effect in women with endometriosis decreased with increasing parity. There was poorer survival in malignant melanoma for women with endometriosis (HR=1.52).The survival in a malignancy is better in women with a previously diagnosed endometriosis compared to women without endometriosis especially for breast and ovarian cancers. The prognosis of malignant melanoma is poorer in women with endometriosis.

Urologe A. 2010 Oct 15. [Epub ahead of print]

Cyst, endometriosis, borderline tumor, CUP : Diagnostic stations of a supposedly simple renal cyst.

[Article in German]

Elert A, Forst F, Ihling C, Schneider A.

Klinik für Urologie und Kinderurologie, Main-Kinzig-Kliniken gGmbH, Herzbachweg 14, 63571, Gelnhausen, Deutschland,

Symptomatic renal cysts are not uncommon and can be treated by puncture, sclerotherapy, or laparoscopic fenestration. We report the case of a female patient in whom the diagnosis of a supposedly simple symptomatic renal cyst changed over endometriosis and borderline malignancy to a CUP. This case shows that in spite of all diagnostic measures and care the final diagnosis can be a surprise.

Rev Bras Ginecol Obstet. 2010 Jun;32(6):298-307.

Current aspects on diagnosis and treatment of endometriosis.

[Article in Portuguese]

Nácul AP, Spritzer PM.

Faculdade de Medicina, da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.

Endometriosis is characterized by the presence of endometrial tissue, localized outside the uterine cavity, such as peritoneal surface, ovaries, and rectum-vaginal septum. The prevalence is about 6 to 10%. Concerning the etiopathogenesis, the retrograde menstruation theory is accepted, although disruption in endometrial molecular biology seems to be fundamental to the development of endometriosis ectopic focuses. Women with endometriosis may be asymptomatic or may present complaints of dysmenorrhea, dispareunia, chronic pelvic pain and/or infertility. Although the definitive diagnosis of endometriosis needs a surgical intervention, mainly by laparoscopy, many findings obtained by physicalexamination and imaging and laboratory tests can predict, with a high degree of reliability, that the patient has endometriosis. The most common current treatments include surgery, ovarian suppression therapy or both. Pharmacological treatments that do not inhibit ovarian function are under investigation.

Rev Bras Ginecol Obstet. 2010 Jun;32(6):279-85.

Serum markers of oxidative stress in infertile women with endometriosis.

[Article in Portuguese]

Andrade AZ, Rodrigues JK, Dib LA, Romão GS, Ferriani RA, Jordão Junior AA, Navarro PA.

Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, SP, Brasil.

PURPOSE: to compare serum markers of oxidative stress between infertile patients with and without endometriosis and to assess the association of these markers with disease staging.

METHODS: this was a prospective study conducted on 112 consecutive infertile, non-obese patients younger than 39 years, divided into two groups: Endometriosis (n=48, 26 with minimal and mild endometriosis – Stage I/II, and 22 with moderate and severe endometriosis – Stage III/IV) and Control (n=64, with tubal and/or male factor infertility). Blood samples were collected during the early follicular phase of the menstrual cycle for the analysis of serum malondialdehyde, glutathione and total hydroxyperoxide levels by spectrophotometry and of vitamin E by high performance liquid chromatography. The results were compared between the endometriosis and control groups, stage I/II endometriosis and control, stage III/IV endometriosis and control, and between the two endometriosis subgroups. The level of significance was set at 5% (p < 0.05) in all analyses.

RESULTS: vitamin E and glutathione levels were lower in the serum of infertile women with moderate/severe endometriosis (21.7 ± 6.0 mMol/L and 159.6 ± 77.2 nMol/g protein, respectively) compared to women with minimal and mild endometriosis (28.3 ± 14.4 mMol/L and 199.6 ± 56.1 nMol/g protein, respectively). Total hydroxyperoxide levels were significantly higher in the endometriosis group (8.9 ± 1.8 µMol/g protein) than in the Control Group (8.0 ± 2 µMol/g protein) and among patients with stage III/IV disease (9.7 ± 2.3 µMol/g protein) compared to patients with stage I/II disease (8.2 ± 1.0 µMol/g protein). No significant differences in serum malondialdehyde levels were observed between groups.

CONCLUSIONS: we demonstrated a positive association between infertility related to endometriosis, advanced disease stage and increased serum hydroxyperoxide levels, suggesting an increased production of reactive species in women with endometriosis. These data, taken together with the reduction of serum vitamin E and glutathione levels, suggest the occurrence of systemic oxidative stress in women with infertility associated with endometriosis. The reproductive and metabolic implications of oxidative stress should be assessed in future studies.

J Coll Physicians Surg Pak. 2010 Oct;20(10):649-52.

Laparoscopic evaluation of female factors in infertility.

Aziz N.

Department of Obstetrics and Gynaecology, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro.

OBJECTIVE: To find out different causes of female infertility with diagnostic laparoscopy and their comparative frequency in primary and secondary infertility.

STUDY DESIGN: A case series.

PLACE AND DURATION OF STUDY: Department of Obstetric and Gynaecology, Liaquat University Hospital (LUH), Hyderabad, rom January 2006 to December 2007.

METHODOLOGY: All infertile women underwent diagnostic laparoscopy for primary and secondary infertility during the study period were included. Couples who had not lived together for at least 12 months, and those with male factor infertility were excluded. Data were collected on a proforma, and analysed on SPSS package for windows version 10. Frequencies were calculated for laparoscopic findings regarding primary and secondary infertility.

RESULTS: Fifty infertile women underwent laparoscopy during the study period, 32 (64%) had primary infertility while 18 (36%) secondary infertility. Eight (25.0%) patients with primary and 2 (11.1%) patients with secondary infertility had no visible abnormality. The common finding was tubal blockage in 7 (21.9%) and 6 (33.3%) cases of primary and secondary infertility respectively. Five (15.6%) cases of primary infertility were detected as polycystic ovaries (PCO) which was not found in cases of secondary infertility. Endometriosis was found in 4 (12.5%) cases with primary infertility and 2 (11.1%) cases with secondary infertility. Pelvic inflammatory disease (PID) was found in 1 (3.1%) and 2 (16.7%) cases of primary and secondary infertility respectively. Peritubal and periovarian adhesions were detected in 2 (6.3%) cases with primary infertility and 4 (22.2%) cases with secondary infertility. Fibriod was found in 2 (6.3%) and 1 (5.6%) cases of primary and secondary infertility respectively. Ovarian cyst detected in 2 (6.3%) cases with primary infertility while none was found in cases of secondary infertility.

CONCLUSION: Most common causes responsible for infertility were tubal occlusion, endometriosis, peritubal and periovarian adhesions. Ovarian causes were seen in primary infertility only.

N Engl J Med. 2010 Oct 14;363(16):1574-5.

The origin of ovarian cancer—is it getting clearer?

Birrer MJ.

Comment on:

N Engl J Med. 2010 Oct 14;363(16):1532-43.

ARID1A mutations in endometriosis-associated ovarian carcinomas.

Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IeM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG.

British Columbia Cancer Agency, Vancouver, Canada.

Comment in:

BACKGROUND: Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.

METHODS: We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas.

RESULTS: ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions.

CONCLUSIONS: These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).

Reprod Sci. 2010 Nov;17(11):1016-23.

Deregulation of LOXL1 and HTRA1 gene expression in endometriosis.

Blassioli Dentillo D, Meola J, Rosa E Silva JC, Giuliatti S, Araujo Silva W Jr, Ferriani RA, Martelli L.

Department of Genetics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes, Ribeirao Preto, Sao Paulo, Brazil.

Endometriosis is a gynecologic disease characterized by the presence of endometrial tissue outside the uterine cavity. Although 15% of the female population in reproductive age is affected by endometriosis, its pathogenesis remains unclear. According to the most accepted pathogenesis hypothesis, endometrial fragments from the menstrual phase are transported through the uterine tubes to the peritoneal cavity, where they undergo implantation and growth, invading adjacent tissues. However, the establishment of the disease requires that endometrial cells present molecular characteristics favoring the onset and progression of ectopic implantation. In this investigation, we analyzed the differential gene expression profiles of peritoneal and ovarian endometriotic lesions compared to the endometrial tissue of nonaffected women using rapid subtraction hybridization (RaSH). In our study, this method was applied to samples of endometriotic lesions from affected women and to biopsies of endometrium of healthy women without endometriosis, where we could identify 126 deregulated genes. To evaluate the expression of genes found by RaSH method, we measured LOXL1, HTRA1, and SPARC genes by real-time polymerase chain reaction. Significant different expression was obtained for HTRA1 and LOXL1, upregulated in the ectopic endometrium, suggesting that these genes are involved in the physiopathology of endometriosis and may favor the viability of endometrial cells at ectopic sites.

BMC Immunol. 2010 Oct 12;11(1):49. [Epub ahead of print]

Natural killer cells are crucial for the efficacy of Icon (factor VII/human IgG1 Fc) immunotherapy in human tongue cancer.

Hu Z, Li J.

BACKGROUND: Icon is a novel, dual neovascular- and cancer cell-targeting immunotherapeutic agent and has shown efficacy in the treatment of cancer, wet form macular degeneration and endometriosis. However, its underlying mechanism remains to be investigated. The objective of this study is to elucidate the mechanism of Icon immunotherapy in cancer using a squamous carcinoma human tongue cancer line TCA8113 in vitro and in vivo in severe combined immunodeficiency (SCID) mice.

RESULTS: We showed that Icon, as a chimeric factor VII and human IgG1 Fc immunoconjugate, could separately induce natural killer (NK) cells and activate complement to kill TCA8113 cancer cells in vitro via antibody dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, Icon-NK ADCC had a significantly stronger effect than that of Icon-CDC. Moreover, Icon could completely eradicate established human tongue tumour xenografts in vivo in the CB-17 strain of SCID mice that have functional NK cells at a normal level, whereas it was less effective in SCID/Beige mice that do not have functional NK cells.

CONCLUSIONS: We conclude that NK cells are crucial for the efficacy of Icon immunotherapy in the treatment of cancer. The results also suggest that impaired NK level/activity could contribute to the resistance to therapeutic antibodies that are currently under investigation in preclinical and clinical studies.

Bol Asoc Med P R. 2010 Apr-Jun;102(2):58-61.

Intestinal endometriosis as a cause of rectal bleeding: a case report.

Vergelí Rojas JA, Pagán Rodríguez L, Santiago Muñoz C, Gutiérrez Rivera S.

Department of Internal Medicine, Saint Luke’s Memorial Hospital, Avenida Tito Castro 917, Ponce, Puerto Rico 00733-6810.

Endometriosis is the presence of endometrial glands and stroma outside the uterine cavity and musculature. The estimated prevalence of endometriosis in Puerto Rico is 4.0%. The exact prevalence of extra-pelvic endometriosis is unknown. It has been reported that affects the intestinal tract in 3-37% of all patients with pelvic endometriosis, with the sigmoid colon and rectum being the most commonly involved areas. It can mimic colorectal cancer by producing an invasive abdominal mass. We present the case of a 40 y/o female patient with rectal bleeding that presented a mass on a colonoscopy highly suggestive of cancer. After all the studies and an exploratory laparotomy, the diagnosis was intestinal endometriosis. Because of lack of published data about intestinal endometriosis in Puerto Rico, it is very important to show this condition in order to properly assess young women with rectal bleeding in light of a clinical suspicion of endometriosis.

Minerva Ginecol. 2010 Oct;62(5):447-65.

Management of chronic pelvic pain.

Benjamin-Pratt AR, Howard FM.

Division of Gynecologic Specialties, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA –

Chronic pelvic pain (CPP) is a common complaint of women presenting for gynecologic and primary care. Evaluation of CPP requires obtaining a careful history including not only obstetrical and gynecologic information but also screening for gastrointestinal, urologic, musculoskeletal, and neurological disorders. A detailed physical examination is also necessary. Management of CPP depends largely on the cause. Gynecologic causes include endometriosis, pelvic inflammatory disease, adhesive disease, pelvic congestion syndrome, ovarian retention syndrome, ovarian remnant syndrome, adenomyosis, and leiomyomas. Some non-gynecologic causes are interstitial cystitis/painful bladder syndrome, irritable bowel syndrome, pelvic floor tension myalgia, and abdominal myofascial pain syndrome. Treatments may be directed toward specific causes or may be targeted to general pain management. The most effective therapy may involve using both approaches. The diagnosis and treatment of each of the above disorders, and the management of CPP itself, is discussed.

Minerva Ginecol. 2010 Oct;62(5):415-32.

Medical treatments for endometriosis.

Kappou D, Matalliotakis M, Matalliotakis I.

Department of Obstetrics and Gynecology, University of Crete, Heraklion, Greece –

Despite the extensive research, endometriosis remains an enigmatic disease as up to now there is no consensus regarding the exact underlying mechanisms which could explain its development and progress. A local environment enriched in estrogens, progesterone resistance, local inflammatory response and multiple other molecular alterations appear to be pivotal events in the establishment and development of ectopic tissue. In the light of the evidence produced by molecular pathology research, in vivo and in vitro studies, modifications in current treatment options are anticipated. Current management of endometriosis is based on pharmacologic treatment and surgical intervention. In particular, combined oral contraceptives, danazol, gonadotropin-releasing hormone (GnRH) analogues and progestins have been extensively used in clinical practice. Novel agents that will hopefully improve the therapeutic potential include aromatase inhibitors, immunomodulators, anti-inflammatory agents, steroids receptor modulators and GnRH antagonists. It is still early for enthusiasm as there is limited knowledge about their short- and long-term side effects, their optimal administration route, their selectivity towards their target genes and the duration of treatment. Although there is a continual report of novel findings, the application of them in clinical practice is a long-lasting procedure requiring longitudinal clinical trials so as to achieve a balance between efficacy and safety.

Hum Reprod. 2010 Oct 11. [Epub ahead of print]

Expression and possible role of non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) in the human endometrium and endometriosis.

Seo SK, Nam A, Jeon YE, Cho S, Choi YS, Lee BS.

Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University, College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea.

BACKGROUND Non-steroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) is involved in cellular processes such as inflammation, apoptosis and tumorigenesis. However, little is known about the expression and function of NAG-1 in the endometrium. This study aimed to evaluate the expression of NAG-1 in the endometrium and in the absence or presence of endometriosis and to investigate the effect of celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, on NAG-1 mRNA levels and apoptosis in human endometrial stromal cells (HESCs). METHODS Eutopic endometrial samples were obtained during surgery from 40 patients with, and 40 patients without, endometriosis. Real-time PCR was used to quantify NAG-1 mRNA levels and immunohistochemistry was used to localize NAG-1 protein in the endometrium. To investigate the effects of celecoxib, HESCs were isolated and cultured with different concentrations of celecoxib or with 100 µM celecoxib at different times. Apoptosis was assessed by flow cytometry. RESULTS NAG-1 mRNA levels and immunoreactivity showed cyclical changes through the menstrual cycle, increasing during the late secretory and menstrual phases. NAG-1 mRNA and protein levels were significantly lower in patients with endometriosis, compared with the control group. Celecoxib induced NAG-1 mRNA levels and apoptosis in cultured HESCs, with the effects dependent on drug concentrations and duration of treatment. Celecoxib treatment had no effect on prostaglandin E(2) levels in the culture supernatants. CONCLUSIONS NAG-1 may be important in maintaining homeostasis in the normal endometrium and alterations in NAG-1 expression may be associated with the establishment of endometriosis. NAG-1 might be a therapeutic target for endometriosis.

J Gastrointest Surg. 2010 Oct 9. [Epub ahead of print]

Predictive Value of POSSUM and ACPGBI Scoring in Mortality and Morbidity of Colorectal Resection: A Case-Control Study.

Teeuwen PH, Bremers AJ, Groenewoud JM, van Laarhoven CJ, Bleichrodt RP.

Department of Surgery, Division of Gastro-Intestinal Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands,

BACKGROUND: Preoperative risk prediction to assess mortality and morbidity may be helpful to surgical decision making. The aim of this study was to compare mortality and morbidity of colorectal resections performed in a tertiary referral center with mortality and morbidity as predicted with physiological and operative score for enumeration of mortality and morbidity (POSSUM), Portsmouth POSSUM (P-POSSUM), and colorectal POSSUM (CR-POSSUM). The second aim of this study was to analyze the accuracy of different POSSUM scores in surgery performed for malignancy, inflammatory bowel diseases, and diverticulitis. POSSUM scoring was also evaluated in colorectal resection in acute vs. elective setting. In procedures performed for malignancy, the Association of Coloproctology of Great Britain and Ireland (ACPGBI) score was assessed in the same way for comparison.

METHODS: POSSUM, P-POSSUM, and CR-POSSUM predictor equations for mortality were applied in a retrospective case-control study to 734 patients who had undergone colorectal resection. The total group was assessed first. Second, the predictive value of outcome after surgery was assessed for malignancy (n = 386), inflammatory bowel diseases (n = 113), diverticulitis (n = 91), and other indications, e.g., trauma, endometriosis, volvulus, or ischemia (n = 144). Third, all subgroups were assessed in relation to the setting in which surgery was performed: acute or elective. In patients with malignancy, the ACPGBI score was calculated as well. In all groups, receiver operating characteristic (ROC) curves were constructed.

RESULTS: POSSUM, P-POSSUM, and CR-POSSUM have a significant predictive value for outcome after colorectal surgery. Within the total population as well as in all four subgroups, there is no difference in the area under the curve between the POSSUM, P-POSSUM, and CR-POSSUM scores. In the subgroup analysis, smallest areas under the ROC curve are seen in operations performed for malignancy, which is significantly worse than for diverticulitis and in operations performed for other indications. For elective procedures, P-POSSUM and CR-POSSUM predict outcome significantly worse in patients operated for carcinoma than in patients with diverticulitis. In acute surgical interventions, CR-POSSUM predicts mortality better in diverticulitis than in patients operated for other indications. The ACPGBI score has a larger area under the curve than any of the POSSUM scores. Morbidity as predicted by POSSUM is most accurate in procedures for diverticulitis and worst when the indication is malignancy.

CONCLUSION: The POSSUM scores predict outcome significantly better than can be expected by chance alone. Regarding the indication for surgery, each POSSUM score predicts outcome in patients operated for diverticulitis or other indications more accurately than for malignancy. The ACPGBI score is found to be superior to the various POSSUM scores in patients who have (elective) resection of colorectal malignancy.

Mol Hum Reprod. 2010 Oct 8. [Epub ahead of print]

Evaluation of polymorphisms in predicted target sites for micro-RNAs differentially expressed in endometriosis.

Zhao ZZ, Croft L, Nyholt DR, Chapman B, Treloar SA, Hull ML, Montgomery GW.

Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, Queensland 4029, Australia.

Previous microarray analyses identified 22 miRNAs differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and SNPs in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf-Hirschhorn syndrome candidate gene1 (WHSC1) 3’UTR(untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% Confidence Interval = 2.4 – 60.7, P = 9.03 × 10(-5)). SNP haplotype AGG in the solute carrier family 22 member 23 (SLC22A23) 3’UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, Ingenuity Pathways Analysis identified tumour necrosis factor (TNF) and cyclin-dependant kinase inhibitor (CDKN) as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility, and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on sub-phenotypes of this disease. Replication studies in independent large sample sets to confirm and characterise the involvement of the gene variation in the pathogenesis of endometriosis are needed.

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