Martin Healey

Surgical treatment of endometriosis: a prospective randomized double-blinded trial comparing excision and ablation

OBJECTIVE To compare reduction of pain following laparoscopy after ablation or excision of endometriosis. DESIGN A prospective, randomized, double-blind study. SETTING Endometriosis and pelvic pain clinic at a university teaching hospital. PATIENT(S) Women of reproductive age presenting with pelvic pain and visually proved endometriosis. INTERVENTION(S) Subjects completed a questionnaire rating their various pains using visual analogue scales (VASs). After visual identification subjects were assigned randomly to treatment with ablation or excision by supervised training gynecologists as primary surgeon. Follow-up questionnaires at 3, 6, 9, and 12 months documented pain levels. MAIN OUTCOME MEASURE(S) Change in overall pain VAS score at 12 months after operation. RESULT(S) There was no significant difference in reduction in overall pain VAS scores at 12 months when comparing ablation and excision. CONCLUSION(S) This study has not been able to demonstrate a significant difference in pain reduction between ablation and excisional treatments. Nonsignificant trends suggest that a larger study may find a difference in outcomes looking at dyspareunia or dyschezia.

Rectal Surgery for Endometriosis—Should We Be Aggressive?

STUDY OBJECTIVE To assess the outcome of aggressive but conservative laparoscopic surgery in the treatment of severe endometriosis involving the rectum. DESIGN Retrospective study (Canadian Task Force classification III). SETTING Endosurgery unit of a tertiary referral center. PATIENTS One hundred sixty-nine women. INTERVENTION Laparoscopy or laparotomy. MEASUREMENTS AND MAIN RESULTS The procedure was completed successfully laparoscopically in 145 (86%) and by laparotomy in 24 women (14%). The rate of preoperative symptoms was higher in 25 women who underwent bowel resection compared with those who had other bowel surgery. In addition to bowel surgery, excision of uterosacral ligaments, adhesiolysis, excision of endometrioma, and oophorectomy were the four most commonly performed procedures. At 35-month follow-up 61 patients (36%) required further surgery for pain. The average time between primary and repeat surgery was 16 months. This second operation was performed by laparoscopy in over three-fourths of the women. Overall recurrent endometriosis was found in 26 patients (15%). Overall morbidity associated with all surgery was 12.4%. CONCLUSION Surgery for endometriosis of the cul-de-sac and bowel involves some of the most difficult dissections encountered, but it can be accomplished successfully with the low postoperative morbidity typical of laparoscopy.

Ten-year review of hysterectomy morbidity and mortality: can we change direction?

Summary: The medical records of all women who underwent hysterectomy for benign disease performed between 1986 and 1995 were reviewed to ascertain the incidence of morbidity and mortality of abdominal, vaginal, and laparoscopically assisted vaginal hysterectomy at a university teaching hospital. A total of 1940 hysterectomies were performed during this period; 74% of hysterectomies were performed abdominally, 24% vaginally and 2% were laparoscopically assisted. In 80% of the patients uterine leiomyomas, adenomyosis, dysfunctional uterine bleeding or uterine prolapse were the indications for hysterectomy. The overall complication rate was 44% for abdominal hysterectomy (AH) and 27.3% for vaginal hysterectomy (VH). An unintended major surgical procedure was required in 3% and 1% of women undergoing AH and VH respectively. The rate of return to the operating room for haemostasis was 0.6% for AH and 0.2% for VH. The AH group was four times more likely than the VH group to require surgical intervention (36% versus 9%) at readmission. Vaginal hysterectomy was associated with a lower febrile morbidity and minor complication rate. Prophylactic antibiotics reduced the febrile morbidity for VH and AH by 50% (Students t‐test, p = 0.02) and 40% (Students t‐test, p < 0.001) respectively The overall mortality rate was 1.5 per 1000.

Histology of lichen sclerosus varies according to site and proximity to carcinoma

To investigate why vulvar but not extragenital lichen sclerosus is associated with squamous cell carcinoma, we performed a histologic study of extragenital lichen sclerosus, vulvar lichen sclerosus without carcinoma, and vulvar lichen sclerosus with carcinoma adjacent to and distant from the carcinoma. We compared epidermal thickness, rete ridge length, mitotic activity, atypia, dermal collagen change, dermal inflammation, and presence of other dermatoses in 30 women in each group. Extragenital lichen sclerosus showed thinner epidermis (mean thickness of 0.13 mm versus 0.41 mm;P < 0.0005), shorter rete ridges (P = 0.0001), more dermal edema (P = 0.16), and absence of associated dermatoses of spongiotic dermatitis and lichen planus (P < 0.005) compared with vulvar lichen sclerosus. The epidermal thickening seen in vulvar lichen sclerosus was indistinguishable from lichen simplex chronicus. Vulvar lichen sclerosus without carcinoma was generally similar to that distant from carcinoma. Vulvar lichen sclerosus adjacent to carcinoma showed increased epidermal thickness (0.61 mm versus 0.26 mm;P < 0.005), more dermal fibrosis (P < 0.0005), more inflammation (P < 0.0005), and more simplex (differentiated) vulvar intraepithelial neoplasia (18 cases versus 1 case;P < 0.0005) compared with that distant from carcinoma. We concluded that (1) the classic histologic features of lichen sclerosus are seen in both vulvar and extragenital sites; (2) vulvar lichen sclerosus without associated carcinoma has a mean epidermal thickness more than three times that of extragenital lichen sclerosus; (3) the epidermal thickening is histologically indistinguishable from lichen simplex chronicus; (4) there is a tendency for vulvar lichen sclerosus to have a more sclerotic and inflamed dermis; (5) lichen sclerosus 10 mm from cancer is more similar to vulvar lichen sclerosus without carcinoma than lichen sclerosus 1 mm from carcinoma; and (6) lichen sclerosus adjacent to carcinoma tends to show exaggerated epidermis thickness, basal atypia, and loss of the edematous-hyaline layer.

Diagnosis of interstitial cystitis/bladder pain syndrome in women with chronic pelvic pain: a prospective observational study

Introduction and hypothesisThis study assesses the prevalence of interstitial cystitis (IC)/bladder pain syndrome (BPS) in women with chronic pelvic pain (CPP).MethodsThis was a prospective study of 150 women undergoing laparoscopy as investigation for CPP in an Endometriosis and Pelvic Pain unit. Preoperative questionnaires [demographic details, pelvic pain symptoms, the Pelvic Pain and Urgency/Frequency (PUF) and O’Leary-Sant (OLS) Symptom and Problem Index scores] were completed, and concurrent standardized cystoscopy with hydrodistention performed at laparoscopy. The primary outcome measures the proportion of IC in this group, defined by presence of glomerulations with CPP and urinary symptoms (urinary frequency, nocturia, urgency). The secondary outcome measures the proportion of BPS [defined by the European Society of the Study of Interstitial Cystitis (ESSIC)].ResultsIC was diagnosed in 48/150 (32%) individuals, and 80/150 (53%) had BPS. There were no significant differences in symptomatology or questionnaire results between groups with and without IC. Women with BPS had higher PUF (17.2 vs 12.9, p < 0.001), OLS Symptom (8.2 vs 6.0, p = 0.001) and Problem (7.5 vs 4.2, p < 0.001) scores and more severe pain symptoms. Visually proven endometriosis was seen in 90/150 (60%), and 27/150 (18%) had both endometriosis and IC. Of the 80 women with BPS, 45/80 (60%) had endometriosis.ConclusionsThe prevalence of IC/BPS varies depending on the definition used. This study showed IC in 32% of women with CPP based on symptoms and presence of glomerulations. BPS as defined by ESSIC was diagnosed in 53%. History and questionnaires did not correlate with positive cystoscopic findings.

Classification of ovarian endometriotic cysts

Current literature describes 3 different pathogenetic types of ovarian endometriotic cysts. Cortical invagination cysts arise when surface ovarian endometriotic deposits adhere to another structure (such as the broad ligament), blocking the egress of menstrual fluid produced by cycling endometriosis, which then collects and causes the ovarian cortex to invaginate. Surface inclusion cyst-related endometriotic cysts develop when endometriotic tissue colonizes preexisting inclusion cysts. Physiological cyst-related endometriotic cysts occur when endometriosis gains access to a follicle, such as at the time of ovulation. To determine whether routine histological examination is of use in the classification of endometriotic cysts, and if so, whether such classification is of clinical relevance, we reviewed the histology of endometriotic cysts of 29 women under 35 years of age. Young women were chosen so that ovarian cortex surrounding the endometriotic lining in invagination cysts could be identified by the finding of oocytes. Ten women (34%) had cortical invagination endometriotic cysts, but no inclusion or physiological cyst-related endometriomas were found. The remaining 19 women (66%) had unclassified endometriotic cysts, of which 14 (48% of total) had a fibrous wall between the endometriotic lining and medulla and 5 had extensive destruction of ovarian tissue. We concluded that cortical invagination cysts were the only common diagnosable sort of the 3 types currently being investigated and that unclassified cysts required further study to determine their pathogenesis. Our study highlights the need for a prospective study using standardized pathological and clinical methods.

A prospective randomised double-blind placebo controlled trial to assess whether gas drains reduce shoulder pain following gynaecological laparoscopy

To assess the effects on patient discomfort of an intraabdominal passive gas drain left for four hours postoperatively following gynaecologic laparoscopic surgery.

Can anyone screen for deep infiltrating endometriosis with transvaginal ultrasound

Surgical treatment of deep infiltrating endometriosis (DIE) is complex, and preoperative diagnosis benefits both surgeon and patient. Studies in expert centres have reported high accuracy for transvaginal ultrasound (TVUS) diagnosis of DIE. External validation of these findings has been limited, and no information is available on how quickly these skills can be acquired. The aim of this study was to measure the learning curve of DIE‐TVUS and to identify the causes for inaccuracies in the diagnosis of bowel lesions and Pouch of Douglas (POD) obliteration.

Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339

Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54; 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.

Endometrial vezatin and its association with endometriosis risk

STUDY QUESTION Do endometriosis risk-associated single nucleotide polymorphisms (SNPs) found at the 12q22 locus have effects on vezatin ( ITALIC! VEZT) expression? SUMMARY ANSWER 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. TRIAL REGISTRATION NUMBER N/A.