Protocol for the Endometriosis Research Queensland Study (ERQS): an integrated cohort study approach to improve diagnosis and stratify treatment.

INTRODUCTION: Endometriosis is a common gynaecological disease associated with pelvic pain and subfertility. There are no non-invasive diagnostic tests, medical management requires suppression of oestrogens and surgical removal is associated with risk. Endometriosis is a complex genetic disease with variants in at least 27 genetic regions associated with susceptibility. Previous research has implicated a variety of biological mechanisms in multiple cell types. Endometrial and endometriotic epithelial cells acquire somatic mutations at frequency higher than expected in normal tissue. Stromal cells have altered adhesive capacity and immune cells show altered cytotoxicity. Understanding the functional consequences of these genetic variants on each cell type requires the collection of patient symptoms, clinical and genetic data and disease-relevant tissue in an integrated program. METHODS AND ANALYSIS: The aims of this study are to collect tissue associated with endometriosis, chart the genetic architecture related to endometriosis in this tissue, isolate and propagate patient-specific cellular models, understand the functional consequence of these genetic variants and how they interact with environmental factors in pathogenesis and treatment response.We will collect patient information from online questionnaires prior to surgery and at 6 and 12 months postsurgery. Treating physicians will document detailed surgical data. During surgery, we will collect blood, peritoneal fluid, endometrium and endometriotic tissue. Tissue will be used to isolate and propagate in vitro models of individual cells. Genome wide genotyping and gene expression data will be generated. Somatic mutations will be identified via whole genome sequencing. ETHICS AND DISSEMINATION: The study has been approved and will be monitored by the Metro North Human Research Ethics committee (HREC) and research activities at the University of Queensland (UQ) will be overseen by the UQ HREC with annual reports submitted. Research results will be published in peer-reviewed journals and presented at conferences were appropriate. This study involves human participants and was approved by RBWH Human Research Ethics Committee; HREC/2019/QRBW/56763.The University of Queensland; 2017002744. Participants gave informed consent to participate in the study before taking part.

When is it too late? Ovarian preservation and duration of symptoms in ovarian torsion.

This 10-year retrospective study between 2008 and 2018, aims to investigate the duration of symptoms of ovarian torsion and the subsequent rate of ovarian preservation. Eighty-six women with surgically confirmed ovarian torsion were included. The median duration from the onset of pain symptoms to presentation (26.0 vs 6.0 h, p < .001) and from presentation to surgery (11.0 vs 5.5 h, p = .010) were significantly longer in women who required an oophorectomy compared to women who had conservative surgery. There was no significant difference in symptoms, signs or investigations except ultrasound finding of an enlarged ovary (94.9% vs 76.9%, p = .026). Awareness of the condition among the community and healthcare is crucial and routine investigations should not delay management as positive Doppler flow on ultrasound does not exclude an ovarian torsion.Impact StatementWhat is already known on this subject? Ovarian torsion is a gynaecological emergency and may lead to ovarian necrosis, infection and peritonitis. Early recognition is essential in preserving the ovary, particularly in patients with future fertility aspirations. Currently there is no consensus regarding the time period of ovarian viability after the onset of symptoms.What do the results of this study add? We have demonstrated a significant difference in the duration from the onset of symptoms to surgery. Furthermore, the duration from the onset of symptoms to presentation (26.0 vs 6.0 h, p<.001) and from presentation to surgery (11.0 vs 5.5 h, p=.010) were significantly longer in women who required an oophorectomy compared to women who had conservative surgery. There was no significant difference in symptoms, signs or investigations except ultrasound finding of an enlarged ovary.What are the implications of these findings for clinical practice and/or further research? Women with known ovarian cysts in particular should be educated of the risk of ovarian torsion. Routine investigations should not delay management as it does not exclude an ovarian torsion. Although our study suggests that early presentation and management would reduce the risk of oophorectomy, prospective studies are required to confirm the findings.

Impact of early surgical management on tubo-ovarian abscesses.

This 5-year retrospective study aimed to investigate whether early surgical management improves outcomes in patients presenting with a tubo-ovarian abscess (TOA). Patient characteristics, investigation results and treatment outcomes were compared. 50 women were diagnosed with a TOA during the study period. Nineteen (38.0%) were treated with antibiotics (medical group) and thirty one (62.0%) were treated surgically on admission (early surgical group). The early surgical group was associated with a high success rate of 96.8% and the lowest risk of readmission within 12 months (16.1%). There was no significant difference in the length of stay between the early surgical and the successful medical group.Impact StatementWhat is already known on this subject? Tubo-ovarian abscess (TOA) is an inflammatory mass that forms most commonly as a complication of untreated pelvic inflammatory disease (PID). Traditionally, TOAs are treated first with broad-spectrum intra-venous antibiotics, with surgical intervention considered after 72 h. It is not known whether early surgical intervention would be beneficial to patient outcomes compared to traditional management.What do the results of this study add? In this study, we have demonstrated a high success rate with early surgical management. Readmission rate was lowest in the early surgical group compared to the medical and late surgical group. This suggests that early surgical intervention may be beneficial, compared to the standard management of trialling antibiotics and then proceeding to surgery 72 h later.What are the implications of these findings for clinical practice and/or further research? Our study suggests that early surgery may be beneficial in the management of TOAs. Although we were unable to demonstrate statistical significance, our data suggest that it would be worthwhile to investigate white blood cell (WBC) and C-reactive protein (CRP) further as a potential predictor for failure of medical management. In the future, more studies comparing early surgical management with medical and late surgical management could inform clinicians of the best mode of treatment for these patients.

The role of the endocannabinoid system in aetiopathogenesis of endometriosis: A potential therapeutic target.

Endometriosis affects a large proportion of women during their reproductive years and is associated with pain and infertility, also affecting psychological wellbeing and quality of life. The pathogenesis of the disease remains unclear, although it is believed to be multifactorial. The endocannabinoid system (ECS) consists of a number of ligands, receptors and enzymes, and has gained interests in endometriosis research. This review aims to summarise all available evidence reporting the roles of the ECS in endometriosis. A literature search of the PubMed, EMBASE, and Web of Science electronic medical databases was performed. Original and review articles published in peer-reviewed journals were included. No publication date or publication status restrictions were imposed. Significant differences in the concentrations and expressions of the components of the ECS were reported in the eutopic and ectopic endometrium, and the systemic circulation of women with endometriosis compared to controls. Endometriosis appears to be associated with downregulation of CB1 receptors and upregulation of TRPV1 receptors. The role of CB1 and progesterone in anti-inflammatory action and the role of TRPV1 in inflammation and pain are of particular interests. Furthermore, the ECS has been reported to be involved in processes relevant to endometriosis, including cell migration, cell proliferation, apoptosis, inflammation, and interacts with sex steroid hormones. The ECS may play a role in disease establishment, progression, and pain in endometriosis. However, reports are based on studies of limited size and there are inconsistencies among the definition of their control groups. There are also conflicting reports regarding precise involvement of the ECS in endometriosis. Future research with larger numbers, strict inclusion and exclusion criteria and detailed clinical information is imperative.

Unilateral Ureteric Endometriosis at the Pelvic Brim Resulting in Complete Loss of Renal Function.

Deep infiltrating endometriosis of the urinary tract is rare but can result in ureteric obstruction, hydroureteronephrosis and renal failure. Ureteric endometriosis usually affects the distal third of the left ureter among women of reproductive age. Greater awareness of ureteric endometriosis and a multidisciplinary approach in the management is essential to achieve optimal outcomes. We present an atypical case of right ureteric obstruction due to endometriosis at the pelvic brim resulting in complete loss of renal function and necessitating nephroureterectomy.

Management of caesarean scar pregnancy with high dose intravenous methotrexate infusion therapy: 10-year experience at a single tertiary centre.

OBJECTIVE: Incidence of caesarean scar pregnancy (CSP) is increasing due to rising caesarean section rate and advanced imaging modalities. At present, there is no consensus to recommend any specific intervention. In our centre, we have adopted the high dose intravenous methotrexate therapy followed by folinic acid for the management of CSP. In this retrospective study, we report the success rate and safety of this regimen. STUDY DESIGN: This was a 10-year retrospective study of women with CSP who received high dose methotrexate therapy with folinic acid at a tertiary centre from 1 st January 2008 to 31 st December 2017. Treatment regimen consisted of a bolus dose of intravenous methotrexate followed by methotrexate infusion over 12 h. Oral folinic acid rescues were given post treatment. Successful treatment was confirmed with either resolution of serum beta-human chorionic gonadotropin or subsequent intrauterine pregnancy. RESULTS: Of 28 women with CSP who were treated with the regimen, 24 women (85.7%) were treated successfully with methotrexate alone. 3 women (10.7%) required suction evacuation following initial treatment with methotrexate and folinic acid. There was no serious side effect from methotrexate. Advanced gestational age, higher serum ß-hCG, larger gestational sac diameter and crown-rump length, and the presence of embryonic cardiac activity were associated with methotrexate failure or need for additional therapy. CONCLUSIONS: Our high dose intravenous methotrexate infusion therapy with folinic acid is effective and well tolerated. Caution is needed with factors associated with failure. Ensuring follow up ultrasound for live CSP and follow up ß-hCG for all women with CSP is essential.

Outcomes of women diagnosed and treated for low-risk gestational trophoblastic neoplasia at the Queensland Trophoblast Centre (QTC).

BACKGROUND: Gestational trophoblastic neoplasia (GTN) is classified as a highly curable group of pregnancy-related malignancies; however, approximately 15% will be persistent and require chemotherapy. Up to 25% of these women will develop resistance and 2% will develop disease relapse after initial chemotherapy. Despite the need for further chemotherapy in these women, cure rates are high. OBJECTIVE: To evaluate the outcomes of women diagnosed with low-risk GTN, assessing the type of treatment, the number of chemotherapy cycles received, development of resistance or disease relapse, survival, and to assess the feasibility of changing to a new drug regimen. METHODS: From March 2012 until February 2015, a retrospective study was conducted and 38 cases with low-risk GTN were reviewed. The number of cycles, type of treatment received, duration of treatment, development of resistance and disease relapse, and adverse side effects were analysed. RESULTS: The median duration of follow-up was 12 months. Disease-free survival was 100% and primary complete remission rates were achieved in 85.3% of patients who were treated with actinomycin D and 25% patients who were treated with methotrexate (MTX). A change in chemotherapy was required for nine patients. One patient developed disease relapse. Nausea, fatigue and constipation were the most frequent adverse events reported with actinomycin D. All women were cured of their disease. CONCLUSION: All women were successfully treated and achieved complete remission. Changing from MTX to actinomycin D as first-line chemotherapy for women with low-risk GTN was feasible and safe.

Management of interstitial ectopic pregnancy with intravenous methotrexate: An extended study of a standardised regimen.

BACKGROUND: Interstitial ectopic pregnancy is a rare but potentially life threatening condition. Of the three management options for this condition (expectant, medical and surgical treatment) methotrexate therapy in several regimens has been reported to be effective and beneficial. AIM: To assess the safety and efficacy of intravenous bolus and infusion of methotrexate with folinic acid rescue for the treatment of interstitial ectopic pregnancy. MATERIALS AND METHODS: A retrospective cohort study of women with interstitial ectopic pregnancy treated with methotrexate at the Royal Brisbane and Women's Hospital from April 2000 to December 2012. The treatment regimen comprised of a bolus dose of methotrexate 100 mg followed by 200 mg of methotrexate infusion over 12 h. Four doses of 15 mg oral folinic acid rescue were given post-treatment. Success of methotrexate therapy was confirmed by either a negative serum beta-human chorionic gonadotropin (ß-hCG) level or subsequent uneventful pregnancy. RESULTS: Of 33 women with interstitial ectopic pregnancy who were treated with this regimen, 31 (93.9%) were treated successfully, including women with a high ß-hCG level up to 106 634 IU/L and the presence of fetal cardiac activity. Minor side effects were documented in three cases. CONCLUSIONS: Intravenous methotrexate therapy with folinic acid rescue is well tolerated and highly effective.

The wandering Mirena: laparoscopic retrieval.

Levonorgestrel-containing intrauterine contraceptive devices, marketed as Mirena (Bayer HealthCare Pharmaceuticals, Inc. Australia) are widely used in contemporary gynecology, primarily as an effective method for contraception and for control of menstrual disorders like menorrhagia and dysmenorrhea. In this article, the authors report 2 cases of Mirena migration following intrauterine insertion by general practitioners (family physicians). In the first case, the contraceptive device had moved to the patient's right iliac fossa just anterior to the cecum and, in the second, within the peritoneal cavity close to the left leaf of the diaphragm. Both patients underwent uneventful laparoscopic retrieval of the devices.

Persistence and malignant sequelae of gestational trophoblastic disease: Clinical presentation, diagnosis, treatment and outcome.

BACKGROUND: The major concern in gestational trophoblastic disease is management of persistent disease and malignant sequelae. However, prediction of response to treatment is difficult and methods used controversial. AIM AND METHODS: To evaluate the usefulness of clinical presentation, methods of diagnosis and categorisation of risk in determining clinical outcomes, by analysis of a database of 705 registered patients collected over 30 years. RESULTS: From the database, there were 97 patients who developed persistent disease and malignant sequelae on the basis of defined criteria - 80.4% had molar pregnancy and 19.6% non-molar pregnancy. Vaginal bleeding was not a common presentation; 59.8% had no clinical symptoms. According to protocol, monitoring by serial human chorion gonadotrophin (HCG) levels followed by imaging screen was used in all patients; histology was also available in 41.2% from hysterectomy and curettage specimens. There were 16 of 76 patients with persisting disease who had metastases (21.1%), and 2 of 20 patients with choriocarcinoma who had an antecedent molar pregnancy (10.0%). Based on five risk factors, 25 patients were categorised as 'high risk' and assigned to receive multi-drug chemotherapy. There were two deaths (2.1% for all malignant sequelae); both were from molar pregnancies. One patient failed to respond and the other suffered a complication of intensive chemotherapy. CONCLUSION: Serial HCG levels remain the best monitor to determine therapeutic response. Categorisation of 'high risk' by five factors is useful in treatment. Albeit a small series, clinical outcome is favourable with a five-year survival of 89.7%.

The obstructed hemivagina, ipsilateral renal anomaly, uterus didelphys triad.

The triad of obstructed hemivagina, renal anomaly and uterus didelphys is an uncommon cause of abdominal pain and menstrual discomfort in adolescent girls. Accurate diagnosis and surgical treatment can be delayed for several months or even years. Adolescent girls presenting with these symptoms should have a baseline pelvic ultrasound scan to establish uterine anatomy. In those with ultrasound findings of Müllerian anomalies appropriate follow up would include a magnetic resonance imaging, preferably at a tertiary centre with expertise in interpretation of Müllerian anatomy, as well as early consultation and referral to a centre with experience in the management of these rare conditions. Appropriate surgery would be a single stage procedure to either excise or completely divide the obstructing septum. There is currently no consensus on concurrent laparoscopy. We present a case series of four patients with the triad of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis managed between 2005-2009 at a tertiary centre for paediatric and adolescent gynaecology.

Analysis of risk factors for persistent gestational trophoblastic disease.

SETTING: Persistent disease is a serious consequence of molar pregnancies. Its early detection is critical to effective chemotherapy. Therefore, determination of risk becomes an important clinical decision. OBJECTIVES: To determine the relative risk of persistent disease in a cohort of patients with partial and complete molar pregnancies by analysis of five factors derived from a database using multivariate analysis. RESULTS: Of 686 patients, 78 developed persistent disease which required treatment (rate of 11.3%). Risk was markedly increased when serum human chorionic gonadotrophin (HCG) failed to reach negative by 12 weeks after evacuation [hazard ratio (HR) = 120.78, P < 0.001]. Risk was markedly decreased when the interval from last pregnancy exceeded 12 months (HR = 0.24, P = 0.005). Other factors such as patient's age, stage of gestation and serum HCG level at presentation were not found to be strongly associated with risk of persistent disease. CONCLUSION: These findings support the application of the following two factors in risk prediction for molar pregnancies: > 12 weeks to become HCG negative and interval from last pregnancy < 12 months. They will contribute to a greater awareness of persistent disease and assist in early detection and effective chemotherapy.

A medical management of interstitial ectopic pregnancy: a 5-year clinical study.

BACKGROUND: Medical treatment of the rare interstitial ectopic pregnancy with methotrexate has been considered an alternative to surgical resection. AIM: To determine the treatment success rate with a single-dose intravenous methotrexate/folinic acid regimen and to identify predictors of treatment outcome. METHODS: A 5-year audit (April 2000-August 2005) was carried out, collecting clinical imaging data and serum beta-human chorionic gonadotrophin (beta-hCG). Time taken for complete beta-hCG resolution was recorded, and a negative beta-hCG result was used as an endpoint of successful outcome. RESULTS: Of the 13 cases, two required urgent surgery for rupture on presentation. In the remaining 11 cases, intravenous methotrexate (300 mg) was used, with oral folinic acid rescue (15 mg x 4 doses). There were no side-effects. Complete beta-hCG resolution was achieved in 10 of the 11 medically treated cases (91% success rate), requiring 21-129 days. Successful outcome was seen with initial beta-hCG level as high as 106 634 IU/L and gestation sac as large as 6 cm and a live fetus. CONCLUSION: The methotrexate/folinic acid regimen used as a one-dose treatment is safe and effective for unruptured interstitial pregnancy, with no side-effects and the advantage of avoiding invasive surgery. Subsequent tubal patency and reproductive function are yet to be ascertained.