The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: To assess the within-trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. METHODS: Within-trial economic evaluation of no screening (C) vs either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second-line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. RESULTS: Using a CA125-ROCA cost of £20, the within-trial results show USS to be strictly dominated by MMS, with the MMS vs C comparison returning an incremental cost-effectiveness ratio (ICER) of £91 452 per life year gained (LYG). If the CA125-ROCA unit cost is reduced to £15, the ICER becomes £77 818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30 033 per LYG, while Markov modelling produces an ICER of £46 922 per QALY. CONCLUSION: Analysis suggests that, after accounting for the lead time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared with the within-trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort.

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence of moderate to severe OHSS ranges from 0.6% to 5% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intravascular compartment to the third space, resulting in profound intravascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH METHODS: For the update of this review, we searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE (PubMed), CINHAL, PsycINFO, Embase, Google, and clinicaltrials.gov to 6 July 2016. SELECTION CRITERIA: We included only randomized controlled trials (RCTs) in which coasting was used to prevent OHSS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. They resolved disagreements by discussion. They contacted study authors to request additional information or missing data. The intervention comparisons were coasting versus no coasting, coasting versus early unilateral follicular aspiration (EUFA), coasting versus gonadotrophin releasing hormone antagonist (antagonist), coasting versus follicle stimulating hormone administration at the time of hCG trigger (FSH co-trigger), and coasting versus cabergoline. We performed statistical analysis in accordance with Cochrane guidelines. Our primary outcomes were moderate or severe OHSS and live birth. MAIN RESULTS: We included eight RCTs (702 women at high risk of developing OHSS). The quality of evidence was low or very low. The main limitations were failure to report live birth, risk of bias due to lack of information about study methods, and imprecision due to low event rates and lack of data. Four of the studies were published only as abstracts, and provided limited data. Coasting versus no coastingRates of OHSS were lower in the coasting group (OR 0.11, 95% CI 0.05 to 0.24; I² = 0%, two RCTs; 207 women; low-quality evidence), suggesting that if 45% of women developed moderate or severe OHSS without coasting, between 4% and 17% of women would develop it with coasting. There were too few data to determine whether there was a difference between the groups in rates of live birth (OR 0.48, 95% CI 0.14 to 1.62; one RCT; 68 women; very low-quality evidence), clinical pregnancy (OR 0.82, 95% CI 0.46 to 1.44; I² = 0%; two RCTs; 207 women; low-quality evidence), multiple pregnancy (OR 0.31, 95% CI 0.12 to 0.81; one RCT; 139 women; low-quality evidence), or miscarriage (OR 0.85, 95% CI 0.25 to 2.86; I² = 0%; two RCTs; 207 women; very low-quality evidence). Coasting versus EUFAThere were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 0.98, 95% CI 0.34 to 2.85; I² = 0%; 2 RCTs; 83 women; very low-quality evidence), or clinical pregnancy (OR 0.67, 95% CI 0.25 to 1.79; I² = 0%; 2 RCTs; 83 women; very low-quality evidence); no studies reported live birth, multiple pregnancy, or miscarriage. Coasting versus antagonistOne RCT (190 women) reported this comparison, and no events of OHSS occurred in either arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.74, 95% CI 0.42 to 1.31; one RCT; 190 women; low-quality evidence), or multiple pregnancy rates (OR 1.00, 95% CI 0.43 to 2.32; one RCT; 98 women; very low-quality evidence); the study did not report live birth or miscarriage. Coasting versus FSH co-triggerRates of OHSS were higher in the coasting group (OR 43.74, 95% CI 2.54 to 754.58; one RCT; 102 women; very low-quality evidence), with 15 events in the coasting arm and none in the FSH co-trigger arm. There were too few data to determine whether there was a difference between the groups in clinical pregnancy rates (OR 0.92, 95% CI 0.43 to 2.10; one RCT; 102 women; low-quality evidence). This study did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage, but stated that there was no significant difference between the groups. Coasting versus cabergolineThere were too few data to determine whether there was a difference between the groups in rates of OHSS (OR 1.98, 95% CI 0.09 to 5.68; P = 0.20; I² = 72%; two RCTs; 120 women; very low-quality evidence), with 11 events in the coasting arm and six in the cabergoline arm. The evidence suggested that coasting was associated with lower rates of clinical pregnancy (OR 0.38, 95% CI 0.16 to 0.88; P = 0.02; I² =0%; two RCTs; 120 women; very low-quality evidence), but there were only 33 events altogether. These studies did not report data suitable for analysis on live birth, multiple pregnancy, or miscarriage. AUTHORS' CONCLUSIONS: There was low-quality evidence to suggest that coasting reduced rates of moderate or severe OHSS more than no coasting. There was no evidence to suggest that coasting was more beneficial than other interventions, except that there was very low-quality evidence from a single small study to suggest that using FSH co-trigger at the time of HCG administration may be better at reducing the risk of OHSS than coasting. There were too few data to determine clearly whether there was a difference between the groups for any other outcomes.

The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies.

STUDY QUESTION: What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? SUMMARY ANSWER: The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. WHAT IS KNOWN ALREADY: Accurate diagnosis of congenital anomalies still remains a clinical challenge because of the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. STUDY DESIGN, SIZE, DURATION: The ESHRE/ESGE CONgenital UTerine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. PARTICIPANTS/MATERIALS, SETTING, METHODS: The consensus is developed based on: (i) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy by performing a systematic review of evidence and (ii) consensus for the definition of where and how to measure uterine wall thickness and the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. MAIN RESULTS AND THE ROLE OF CHANCE: Uterine wall thickness is defined as the distance between the interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional (3D) US is recommended for the diagnosis of female genital anomalies in 'symptomatic' patients belonging to high risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine evaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the subgroup of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopically. LIMITATIONS, REASONS FOR CAUTION: The various diagnostic methods should always be used in the proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. WIDER IMPLICATIONS OF THE FINDINGS: The role of a combined US examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity. STUDY FUNDING/COMPETING INTERESTS: None.

Neonatal desensitization allows long-term survival of neural xenotransplants without immunosuppression.

Preclinical development of human cells for potential therapeutic application in neurodegenerative diseases requires that their long-term survival, stability and functional efficacy be studied in animal models of human disease. Here we describe a strategy for long-term immune protection of human fetal and stem cell-derived neural cells transplanted into the adult rat brain, by desensitizing the host rat to similar cells in the neonatal period, without the need for additional immunosuppression.

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort.

BACKGROUND: The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. METHODS: We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. FINDINGS: 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5). INTERPRETATION: Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence varies from 1% to 10% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intra-vascular compartment to the third space resulting in profound intra-vascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH STRATEGY: For the update of this review we searched the Cochrane Menstrual Disorders and Subfertility Review Group Trials Register (July 2010), CENTRAL (inception to July 2010), MEDLINE (PubMed) (inception to July 2010), and EMBASE (inception to July 2010) for randomised controlled trials (RCTs) in which coasting was used to prevent OHSS. SELECTION CRITERIA: Only randomised controlled trials (RCTs) in which coasting was used to prevent OHSS were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Disagreements were resolved by discussion. Study authors were contacted to request additional information or missing data. The intervention comparisons were coasting versus early unilateral follicular aspiration (EUFA), no coasting or other interventions. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. MAIN RESULTS: This updated review identified 16 studies of which four met the inclusion criteria. There was no evidence of a difference in the incidence of moderate and severe OHSS (odds ratio (OR) 0.53, 95% CI 0.23 to 1.23), live birth (OR 0.48, 95% CI 0.14 to 1.62; P = 0.24) or in the clinical pregnancy rate (OR 0.69, 95% CI 0.44 to 1.08) between the groups. Significantly fewer oocytes were retrieved in coasting groups compared with GnRHa (OR -2.44, 95% CI -4.30 to -0.58; P = 0.01) or no coasting (OR -3.92, 95% CI -4.47 to -3.37; P < 0.0001). Data for coasting versus EUFA were not pooled for number of oocytes retrieved due to heterogeneity (I(2) = 87%). AUTHORS' CONCLUSIONS: There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence varies from 1% to 10% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intra-vascular compartment to the third space resulting in profound intra-vascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH STRATEGY: For the update of this review we searched the Cochrane Menstrual Disorders and Subfertility Review Group Trials Register (July 2010), CENTRAL (inception to July 2010), MEDLINE (PubMed) (inception to July 2010), and EMBASE (inception to July 2010) for randomised controlled trials (RCTs) in which coasting was used to prevent OHSS. SELECTION CRITERIA: Only randomised controlled trials (RCTs) in which coasting was used to prevent OHSS were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Disagreements were resolved by discussion. Study authors were contacted to request additional information or missing data. The intervention comparisons were coasting versus early unilateral follicular aspiration (EUFA), no coasting or other interventions. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. MAIN RESULTS: This updated review identified 16 studies of which four met the inclusion criteria. There was no evidence of a difference in the incidence of moderate and severe OHSS (odds ratio (OR) 0.53, 95% CI 0.23 to 1.23), live birth (OR 0.48, 95% CI 0.14 to 1.62; P = 0.24) or in the clinical pregnancy rate (OR 0.69, 95% CI 0.44 to 1.08) between the groups. Significantly fewer oocytes were retrieved in coasting groups compared with GnRHa (OR -2.44, 95% CI -4.30 to -0.58; P = 0.01) or no coasting (OR -3.92, 95% CI -4.47 to -3.37; P < 0.0001). Data for coasting versus EUFA were not pooled for number of oocytes retrieved due to heterogeneity (I(2) = 87%). AUTHORS' CONCLUSIONS: There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions.

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. METHODS: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. FINDINGS: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. INTERPRETATION: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

Fluorescein isothiocynate-dextran uptake by chinese hamster ovary cells in a 1.5 MHz ultrasonic standing wave in the presence of contrast agent.

Uptake of fluorescein isothiocynate-dextran (FITC-dextran) by Chinese hamster ovary cells was studied after exposure to ultrasonic standing wave (USW) in presence of Optison, an ultrasound contrast agent. Confluent Chinese hamster ovary cells were harvested and suspended in phosphate-buffered saline + 0.1% bovine serum albumin containing FITC-dextran (10, 40, and 500 kDa) at 10 microM final concentration. The suspension was seeded with contrast agent (75 microL/mL) and exposed to a 1.5 MHz USW system at acoustic pressures ranging from 0.98 to 4.2 MPa. Macromolecular uptake was assessed by fluorescent microscopy and quantified by flow cytometry 10 min after exposure. FITC-dextran positive cells, as assessed by flow cytometry, were 1 +/- 0.05% and 2.58 +/- 0.27% for acoustic pressures of 1.96 and 4.2 MPa, respectively (p = 0.006). Fluorescent microscopy indicated a degree of macromolecular loading at 0.98 MPa with 46% of peripherally FITC-dextran- and/or propidium iodide-stained cells coincident with the appearance of significant frequency (f0/2 and 2 f0) emission signals. At higher pressures, high macromolecular loading with 6% peripherally stained cells at 1.96 MPa was associated with lower order emission signals and white noise. The study conclusively demonstrates macromolecular loading in an USW, a significantly higher macromolecular loading at higher pressures and indicates potential of emission signals for a feedback loop to control the acoustic power outputs and fine-tune the biologic effects associated with sonoporation.

The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies.

What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. Accurate diagnosis of congenital anomalies still remains a clinical challenge due to the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, with some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available, enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. The ESHRE/ESGE Congenital Uterine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. The consensus is developed based on (1) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy performing a systematic review of evidence and (2) consensus for (a) the definition of where and how to measure uterine wall thickness and (b) the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. Uterine wall thickness is defined as the distance between interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynaecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional ultrasound (3D US) is recommended for the diagnosis of female genital anomalies in "symptomatic" patients belonging to high-risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine avaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the sub-group of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopy. The various diagnostic methods should be used in a proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. The role of a combined ultrasound examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity.

The role and applications of ultrasound in ambulatory gynaecology.

Ultrasound has changed gynaecological practice and continues to do so. One of the earliest applications of abdominal scanning in gynaecology was for monitoring follicular development during fertility treatment with clomiphene citrate or gonadotrophins in the 1960s and 1970s. Subsequently, it was natural that with the introduction of in vitro fertilization, abdominal and transvaginal ultrasound played a key role in the development of oocyte retrieval techniques. These were truly the first interventional ultrasound-guided ambulatory procedures in gynaecology. In this chapter, the reader will be introduced to the roles that the various ultrasound modalities play in our current daily practice, and how they have changed the management of numerous gynaecological conditions in both diagnostic and therapeutic contexts. We will also outline the recent developments and the 'hot' research topics in this field.

Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening.

PURPOSE: Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. PATIENTS AND METHODS: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. RESULTS: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). CONCLUSION: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.

Value of the serum estradiol level for preventing ovarian hyperstimulation syndrome: a retrospective case control study.

OBJECTIVE: To assess the value of different serum E(2) cut-off levels for predicting women at risk for ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective case-control study of a cohort of women undergoing assisted reproduction treatment (ART) over 12 months. SETTING: Tertiary university hospital. PATIENT(S): The study group included women with OHSS who fulfilled the endocrine inclusion criteria (n = 40). The control group was a random sample (n = 40) from the cohort of women undergoing ART. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): To evaluate the sensitivity and specificity of different serum E(2) cut-off levels on day 11 of ovarian stimulation in preventing the establishment of OHSS. RESULT(S): Three hundred ninety-nine cycles (IVF and intracytoplasmic sperm injection) were undertaken between June 2000 and May 2001. The study group (n = 40) was compared with the control group (n = 40) undergoing ART during the same period of time. On day 8 of ovarian stimulation, the mean (SD) E(2) level in the study group was 8,517(5.3) pmol/L (2,320 pg/mL), and in the control group it was 2,540 (2.6) pmol/L (691 pg/mL). On day 11 of stimulation the mean (SD) E(2) level was 15,662 (4.2) pmol/L (4,266 pg/mL) and 5,804 (4.5) pmol/L (1,581 pg/mL), respectively. Twenty-four (60%) women who developed OHSS had E(2)levels >6,000 pmol/L (1,634 pg/mL) on day 8 and above 11,000 pmol/L (2,996 pg/mL) on day 11. Sixteen (40%) had E(2) levels <6,000 pmol/L (1,634 pg/mL) on day 8, but all had levels above 11,000 pmol/l (2,996 pg/mL) on day 11. CONCLUSION(S): A serum E(2) level of 12,315 pmol/L (3,354 pg/mL) on day 11 of ovarian stimulation gives a sensitivity and specificity of 85% for the detection of women at risk for OHSS.

Spontaneous expulsion of three large fibroids after uterine artery embolization.

OBJECTIVE: To report a case of uneventful expulsion of huge fibroids after uterine artery embolization. Case report. SETTING: The Department of Obstetrics and Gynaecology of a university hospital. PATIENT(S): A 45-year-old woman who underwent uterine artery embolization for fibroids. INTERVENTION(S): Transfemoral selective bilateral uterine artery catheterization and injection of 500-700 microm polyvinyl alcohol particles. RESULT(S): Recovery of the patient. The spontaneous expulsion of three fibroids on three different occasions over several months resulted in a significant reduction in menstrual loss and dysmenorrhea. CONCLUSION(S): Delivering fibroids or sections of fibroids may be a natural process after uterine artery embolization, therefore it is essential to warn women about the possible risk. Close follow-up is also essential. The size of the fibroids discharged did not require hysterectomy. Adequate antibiotic cover may be necessary to prevent sepsis.

Contrast agent bubble and erythrocyte behavior in a 1.5-MHz standing ultrasound wave.

Human erythrocytes and Optison contrast agent have been exposed to ultrasound, both alone and in combination, in a single-half-wavelength chamber driven at its resonance frequency (fo) of 1.5 MHz. Cell movements were recorded by video microscopy at speeds up to 500 frames/s. The hypothesis that cells near a standing wave pressure node might be stressed by the microbubble products of sonicated contrast agent was examined. In the absence of contrast agent, cells moved rapidly to form an aggregate in the standing wave pressure node plane. First subharmonic and second harmonic emissions were detected from cell-contrast agent suspensions immediately on exposure to a threshold peak pressure amplitude of 0.98 MPa. Emissions at 3fo/2 occurred at 1.47 MPa, whereas white noise and lower-order subharmonic emissions coincided with the appearance of visible bubbles at a threshold of approximately 1.96 MPa. Cells exposed together with contrast agent at a pressure of 0.98 MPa precessed very rapidly about the pressure node plane. This behavior was discussed in the context of a recent analysis predicting that, in contrast to the situation for lower-pressure amplitudes, subresonant size bubbles translate about pressure node plane if the driving pressure amplitude is sufficiently high. Many precessing erythrocytes were clearly spiculated and this morphology persisted after the cells had left the area of precession. Hemoglobin release was significant under conditions inducing precession with first subharmonic and first harmonic emissions. Protein release increased discontinuously near the pressure thresholds, where more complex categories of frequency emission were detected. The potential of this system, which induces erythrocyte morphology changes and some protein release at the first emission threshold, to provide some control on the membrane-permeabilizing stress experienced by cells in a cavitation field is discussed.

Spontaneous multiple pregnancy after uterine artery embolization for uterine fibroid: case report.

Uterine artery embolization (UAE) is an effective non-surgical treatment for uterine myomas. Effects on fertility preservation are still under investigation. Various complications have been reported as well as few pregnancies. We report a case of spontaneous twins pregnancy following UAE in a woman who desired to preserve fertility.

Intraoperative imaging.

Intraoperative image is a rapidly expanding field encompassing many applications that use a multitude of technologies. Some of the these applications have been in use for many years and are firmly embedded in, and indispensable to, clinical practice (e.g. the use of X-ray to locate foreign bodies during surgery or oocyte retrieval under ultrasound guidance. In others, the application may have been in use in one discipline but not yet fully explored in another. Examples include the use of intraoperative ultrasound with or without contrast enhancement for the detection of hepatic metastases not identified preoperatively, and the effect of such additional information on the ultimate operative procedure. Intraoperative identification of sentinel lymph nodes has been explored in many specialties to a varying extent, with the aim of fine tuning and avoiding unnecessary surgery. In both these instances, we do not know the long-term effect of these interventions on patient survival or quality of life. In this chapter, we will explore the available evidence on these applications and current advances in the new technology in general, with a specific focus on gynaecology.

Cross layer design for optimised region of interest of ultrasound video data over mobile WiMAX.

The application of advanced error concealment techniques applied as a post-process to conceal lost video information in error-prone channels, such as the wireless channel, demand additional processing at the receiver. This increases the delivery delay and needs more computational power. However, in general, only a small region within medical video is of interest to the physician and thus if only this area is considered, the number of computations can be curtailed. In this paper we present a technique whereby the Region of Interest (ROI) specified by the physician is used to delimit the area where the more complex concealment techniques are applied. A cross layer design approach in mobile WiMAX wireless communication environment is adopted in this paper to provide an optimized Quality of Experience (QoE) in the region that matters most to the mobile physician while relaxing the requirements in the background, ensuring real-time delivery. Results show that a diagnostically acceptable Peak Signal-to-Noise-Ratio (PSNR) of about 36 dB can still be achieved within reasonable decoding time.