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UKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers. In UKCTOCS, 202638 postmenopausal women, aged 50–74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978; ClinicalTrials.gov -NCT00058032. 1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early-stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms. Our findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial. [Display omitted] • High alert ovarian cancer symptoms based on reports by clinically diagnosed women are associated with poorer outcomes. • In UKCTOCS, we explore prospectively preclinical symptoms in women detected by screening earlier in the natural history. • In high grade serous ovarian cancer, the symptom profile was different between women with preclinical and clinical disease. • Women with preclinical early stage high grade serous ovarian cancer reported more gastrointestinal and systemic symptoms. • Key symptoms were change in bowel habits, dyspepsia and tiredness. [ABSTRACT FROM AUTHOR]

Background Ovarian and tubal cancers are lethal gynaecological cancers, with over 50% of the patients diagnosed at advanced stage. Trial design Randomised controlled trial involving 27 primary care trusts adjacent to 13 trial centres based at NHS Trusts in England, Wales and Northern Ireland. Methods Participants Postmenopausal average-risk women, aged 50–74, with intact ovaries and no previous ovarian or current non-ovarian cancer. Interventions One of two annual screening strategies: (1) multimodal screening (MMS) using a longitudinal CA125 algorithm with repeat CA125 testing and transvaginal scan (TVS) as second line test (2) ultrasound screening (USS) using TVS alone with repeat scan to confirm any abnormality. The control (C) group had no screening. Follow-up was through linkage to national registries, postal follow-up questionnaires and direct communication with trial centres and participants. Objective To assess comprehensively risks and benefits of ovarian cancer screening in the general population. Outcome Primary outcome was death due to ovarian or tubal cancer as assigned by an independent outcomes review committee. Secondary outcomes included incidence and stage at diagnosis of ovarian and tubal cancer, compliance, performance characteristics, harms and cost-effectiveness of the two screening strategies and a bioresource for future research. Randomisation The trial management system confirmed eligibility and randomly allocated participants using computer-generated random numbers to MMS, USS and C groups in a 1:1:2 ratio. Blinding Investigators and participants were unblinded and outcomes review committee was masked to randomisation group. Analyses Primary analyses were by intention to screen, comparing separately MMS and USS with C using the Versatile test. Results Recruitment 1,243,282 women were invited and 205,090 attended for recruitment between April 2001 and September 2005. Randomised 202,638 women: 50,640 MMS, 50,639 USS and 101,359 C group. Numbers analysed for primary outcome 202,562 (>99.9%): 50,625 (>99.9%) MMS, 50,623 (>99.9%) USS, and 101,314 (>99.9%) C group. Outcome Women in MMS and USS groups underwent 345,570 and 327,775 annual screens between randomisation and 31 December 2011. At median follow-up of 16.3 (IQR 15.1–17.3) years, 2055 women developed ovarian or tubal cancer: 522 (1.0% of 50,625) MMS, 517 (1.0% of 50,623) USS, and 1016 (1.0% of 101314) in C group. Compared to the C group, in the MMS group, the incidence of Stage I/II disease was 39.2% (95% CI 16.1 to 66.9) higher and stage III/IV 10.2% (95% CI –21.3 to 2.4) lower. There was no difference in stage in the USS group. 1206 women died of the disease: 296 (0.6%) MMS, 291 (0.6%) USS, and 619 (0.6%) C group. There was no significant reduction in ovarian and tubal cancer deaths in either MMS (p = 0.580) or USS (p = 0.360) groups compared to the C group. Overall compliance with annual screening episode was 80.8% (345,570/420,047) in the MMS and 78.0% (327,775/420,047) in the USS group. For ovarian and tubal cancers diagnosed within one year of the last test in a screening episode, in the MMS group, the sensitivity, specificity and positive predictive values were 83.8% (95% CI 78.7 to 88.1), 99.8% (95% CI 99.8 to 99.9), and 28.8% (95% CI 25.5 to 32.2) and in the USS group, 72.2% (95% CI 65.9 to 78.0), 99.5% (95% CI 99.5 to 99.5), and 9.1% (95% CI 7.8 to 10.5) respectively. The final within-trial cost-effectiveness analysis was not undertaken as there was no mortality reduction. A bioresource (UKCTOCS Longitudinal Women’s Cohort) of longitudinal outcome data and over 0.5 million serum samples including serial annual samples in women in the MMS group was established and to date has been used in many new studies, mainly focused on early detection of cancer. Harms Both screening tests (venepuncture and TVS) were associated with minor complications with low (8.6/100,000 screens MMS; 18.6/100,000 screens USS) complication rates. Screening itself did not cause anxiety unless more intense repeat testing was required following abnormal screens. In the MMS group, for each screen-detected ovarian or tubal cancer, an additional 2.3 (489 false positives; 212 cancers) women in the MMS group had unnecessary false-positive (benign adnexal pathology or normal adnexa) surgery. Overall, 14 (489/345,572 annual screens) underwent unnecessary surgery per 10,000 screens. In the USS group, for each screen-detected ovarian or tubal cancer, an additional 10 (1630 false positives; 164 cancers) underwent unnecessary false-positive surgery. Overall, 50 (1630/327,775 annual screens) women underwent unnecessary surgery per 10,000 screens. Conclusions Population screening for ovarian and tubal cancer for average-risk women using these strategies should not be undertaken. Decreased incidence of Stage III/IV cancers during multimodal screening did not translate to mortality reduction. Researchers should be cautious about using early stage as a surrogate outcome in screening trials. Meanwhile the bioresource provides a unique opportunity to evaluate early cancer detection tests. Funding Long-term follow-up UKCTOCS (2015–2020) – National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001–2014) – Medical Research Council (MRC) (G9901012/G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. Researchers at UCL were supported by the NIHR UCL Hospitals Biomedical Research Centre and by MRC Clinical Trials Unit at UCL core funding (MR_UU_12023). Plain language summary What was the question? Most women with ovarian cancer are diagnosed after the disease has spread widely (advanced stage – III and IV) and more than half die within 5 years. We wanted to find out if testing women without symptoms could pick up ovarian cancer at an earlier stage before it has spread beyond the ovaries and tubes and reduce deaths. We also wanted to assess the risks and benefits of such screening. What did we do? We invited over 1.2 million women living near 13 centres in England, Wales and Northern Ireland. Of them, 202,638 joined the trial. All women were between 50 and 74 and were no longer having periods. They had never been diagnosed with ovarian cancer or were not having treatment for any other cancer. They did not have many relatives with ovarian or breast cancer. The volunteers were placed into one of three groups at random: The blood test group contained 50,640 women who had yearly CA125 blood tests. If these showed a moderate or high chance of ovarian cancer, they had repeat CA125 tests and a scan. The scan group contained 50,639 women who had yearly internal scans of their ovaries and tubes which were repeated if they showed an abnormality. The no-screening group contained 101,359 women. Those in the blood and scan groups had screening every year until December 2011. We sent all women health questionnaires and also, with their permission, received information about them from the national cancer and death registries till mid-2020. What did we find? Women in the screened groups had an average of eight years of screening. We followed them for approximately 16 years after they had joined the trial. During this period, 2055 women were diagnosed with ovarian and tubal cancer. It was about 1 in 100 women (1%) in all three groups: 522 of 50,625 in the blood group 517 of 50,623 in the scan group 1016 of 101,314 in the no-screening group More women were diagnosed with early-stage cancer and fewer were diagnosed with advanced cancer in the blood group compared to the no-screening group. There was no difference in the number diagnosed with early or advanced disease between the scan and no-screening group. Despite this difference, the number of women in each group who died from ovarian and tubal cancer was similar in all three groups: 296 of 50,625 (0.6%) in the blood group, 291 of 50,623 (0.6%) in the scan group and 619 of 101,314 (0.6%) in the no-screening group. Other results showed: Overall, 81% women in the blood group and 78% in the scan group attended all of their annual screening appointments. In the blood group, screening detected 84% of ovarian and tubal cancers diagnosed within one year of the test and correctly classified as normal 99.8% of women who did not have ovarian and tubal cancer. In the scan group, screening detected 72% of ovarian and tubal cancers diagnosed within one year of the last test and correctly classified 99.5% of those who did not have ovarian and tubal cancer. Both screening tests were associated with minor complications. While screening did not increase anxiety, there was slightly increased worry in women who were asked to return for more intense repeat testing. Both screening methods picked up changes that were in fact not ovarian cancer. This meant that women had unnecessary surgery together with the worry and risk of complications that go with it. ◦In the blood group 14 women had unnecessary surgery for every 10,000 women screened annually. This means that for each woman found to have ovarian cancer, an additional 2 women had unnecessary surgery. ◦In the scan group 50 women had unnecessary surgery for every 10,000 women screened annually. This means that for each woman found to have ovarian cancer, an additional 10 women had unnecessary surgery. A biobank with all the donated data and over 0.5 million serum samples, including yearly samples from women in the blood group, was built and continues to be used in many new studies, mainly focused on early detection of cancer. What does this mean? Screening using the CA125 blood test or transvaginal ultrasound scan to test for ovarian cancer did not save lives. Additionally, it was associated with some harm. Therefore, an ovarian cancer screening programme for most women cannot be currently recommended. The trial also showed for the first time that ovarian cancer can be detected earlier through screening. However, for screening to save lives, the test needs to pick up many more women earlier in the course of the disease so that available treatments are effective. The biobank provides an opportunity for scientists to see if newer tests for cancer can detect the disease earlier.

Background: The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)., Methods: In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement., Findings: Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months., Interpretation: We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset., Funding: NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding., Competing Interests: Declaration of interests UM had stock ownership, awarded by University College London (UCL) until October, 2021, in Abcodia, which holds the licence for risk of ovarian cancer algorithm (ROCA). UM and MKBP have received grants and AG-M, AR, and MB have been funded by grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. UM and AG-M have also received grants from the Australian National Health and Medical Research Council (NHMRC), MRC Proximity to Discovery Industrial Connectivity Award, and Innovate UK Grant. UM and AG-M report research collaboration contracts with iLOF (intelligent Lab on Fiber), Micronoma, Imperial College London, Dana Farber Cancer Institute (DFCI), QIMR Berghofer Medical Research Institute, Mercy Bioanalytics, and University of Innsbruck. UM additionally reports research collaboration contracts with RNA Guardian and DFCI. UM holds patent number EP10178345.4 for Breast Cancer Diagnostics. UM received an honorarium for a lecture from the New York Obstetrical Society (USA), and was reimbursed for travel and accommodations by New York Obstetrical Society. UM has also been a member of Tina's Wish Scientific Advisory Board (USA) and Research Advisory Panel, Yorkshire Cancer Research (UK). She has been a member of International Alliance for Cancer Early Detection (ACED); data monitoring committee for the mixed COVID-19 vaccines study in India; Trial Steering Committee, NOVEL; Trial Steering Committee, PROTECTOR. AG-M is a member of ACED Gynaecological Cancer Working Group and is ACED codirector Research Domain Trials. MKBP was an Associate Member of the EME funding committee while the project was active. SJS co-developed ROCA in 1995, which was patented by Massachusetts General Hospital, MA, USA, and Queen Mary University of London, London, UK, and is owned by these universities (the patent has expired). Massachusetts General Hospital and Queen Mary University of London granted a licence for the ROCA to Abcodia in 2014. SJS reports stock options from SISCAPA Assay Technologies for participation on a board. SJS received grants and JSB has been funded from the US National Cancer Institute. SJS additionally reports funding from Concord (MA) Detect Ovarian Cancer Early Fund and Mercy Bioanalytics. SJS participated in clinical and scientific advisory boards for Mercy BioAnalytics, SISCAPA Assay Technologies, and Guardant Health (for which he was paid consulting fees). IJJ reports grants from Eve Appeal Charity, MRC, Cancer Research UK, and NIHR during the conduct of the study. IJJ co-developed the ROCA in 1995. Massachusetts General Hospital and Queen Mary University of London granted a licence for the ROCA to Abcodia in 2014. IJJ was non-executive director, shareholder, and consultant to Abcodia and has rights to royalties from sales of the ROCA. IJJ founded (in 1985), was a trustee of (2012–14), and is now an Emeritus trustee (2015–present) of The Eve Appeal, one of the funding agencies for UKCTOCS. LF reports MRC funding for the psychosocial group of the UKCTOCS study 2001–13, paid to University of Sussex. AJM was a member of NIHR Health Technology Assessment and Efficacy and Mechanism Evaluation editorial board (2012–22). RM reports funding from The Eve Appeal, Rosetrees Charity, Barts Charity, Yorkshire Cancer Research, Ovacure, British Gynaecological Cancer Society, AstraZeneca, North East London Cancer Alliance, and GSK. RM reports consulting fees from Everything Genetics Limited. NS received honoraria from AstraZeneca–MSD and GSK for participation in advisory boards. All other authors declare no competing interests., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract Background During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model. Methods We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001–2020) using the Cox model (2014), (B) new data (2015–2020) only and (C) all data (2001–2020) using a test that allows for delayed effects. Results Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years. Conclusions The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials. Trial registration ISRCTN22488978 . Registered on 6 April 2000.

Abstract Background There is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Methods Of the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard). Results Outcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7–86.2%) and 94.0% (1679/1786; 95% CI 93.2–94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4–91.2%) and 96.7% (1482/1533, 95% CI 95.8–97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4–92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9–95.5%). Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered. Conclusion Follow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses. Trial registration ISRCTN: ISRCTN22488978 . Registered on 6 April 2000

Objective: To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. Design: Prospective cohort study. Setting: Thirteen NHS Trusts in England, Wales and Northern Ireland. Population: A total of 202 506 postmenopausal women recruited between 2001 and 2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. Methods: Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. Main outcome measures: Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. Results: Hysterectomy with conservation of one or both adnexa was reported in 41 912 (20.7%; 41 912/202 506) women. Median follow up was 11.1 years (interquartile range 9.96–12.04), totalling >2.17 million woman‐years. Among women who had undergone hysterectomy, 0.55% (231/41 912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160 594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (hazard ratio 0.98, 95% CI 0.85–1.13, P = 0.765). Conclusions: This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. These data are important both for clinical counselling and for refining risk prediction models. Hysterectomy does not alter risk of invasive epithelial ovarian and tubal cancer. Hysterectomy does not alter risk of invasive epithelial ovarian and tubal cancer. Linked article This article is commented on by LF Wilson and SJ Jordan, p. 119 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471-0528.16952. [ABSTRACT FROM AUTHOR]

Background: During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model.Methods: We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001-2020) using the Cox model (2014), (B) new data (2015-2020) only and (C) all data (2001-2020) using a test that allows for delayed effects.Results: Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years.Conclusions: The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials.Trial Registration: ISRCTN22488978 . Registered on 6 April 2000. [ABSTRACT FROM AUTHOR]

Abstract Background We investigated the association between self-reported skirt size (SS) and change in SS, and incidence of chronic liver disease (CLD) in a prospective cohort study of women recruited to the UKCTOCS trial. Methods Women recruited to UKCTOCS in England without documented CLD self-reported their current UK SS during trial participation and were asked to recall their SS when aged in 20s (via completion of a questionnaire 3–5 years after recruitment). Participants were followed up via electronic health record linkage and hazard ratios (HR) calculated for incident liver-related events (LRE). Results Three hundred twenty-two (0.3%) of 94,124 women experienced a first LRE. Compared to SS ≤ 16, rates of LRE were higher in the SS ≥ 18 groups (both when aged in 20s and at questionnaire completion). Event rates were higher if there was no change in SS or an increase in SS, compared to a decrease in SS. In the models adjusted for potential confounders, HRs for LRE were higher in the groups of women reporting SS ≥ 18 both when aged in 20s (HR = 1.39 (95% CI; 0.87–2.23)) and at questionnaire completion (HR = 1.37 (95% CI; 1.07–1.75)). Compared to a decrease in SS, HRs were higher in the no change (HR = 1.78 (95% CI; 0.95–3.34)) and increase (HR = 1.80 (95% CI; 1.01–3.21)) groups. Conclusion CLD is associated with high SS and an increase in SS over time. These data suggest SS can be used in simple public health messages about communicating the risk of liver disease. Trial Registration UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.

Background: There is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).Methods: Of the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard).Results: Outcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7-86.2%) and 94.0% (1679/1786; 95% CI 93.2-94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4-91.2%) and 96.7% (1482/1533, 95% CI 95.8-97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4-92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9-95.5%). Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered.Conclusion: Follow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses.Trial Registration: ISRCTN: ISRCTN22488978 . Registered on 6 April 2000. [ABSTRACT FROM AUTHOR]

There are widespread efforts to increase symptom awareness of 'pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency' in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iEOC) in the 'no screen' (control) UKCTOCS arm. Of 101,299 women in the control arm, 574 were confirmed on outcome review to have iEOC between randomisation (2001–2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. Women presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI1.16–1.89, p = 0.001) or the modified Goff Index (HR1·68, 95%CI1·32–2.13, p < 0.0001) had significantly worse survival than those who did not. Each additional presenting symptom decreased survival (HR1·20, 95%CI1·12–1·28, p < 0.0001). In multivariable analysis, in addition to advanced stage, increasing residual disease and inadequate primary treatment, abdominal pain and loss of appetite/feeling full were significantly associated with increased mortality. The ovarian cancer symptom indices identify postmenopausal women with a poorer prognosis. This study however cannot exclude the possibility of better outcomes in those who are aware and act on their symptoms. • This study explored the association of symptoms of ovarian cancer, interval and route to diagnosis with survival. • Focus on 'high alert' symptoms: pelvic/abdominal pain, increase abdominal size/bloating and difficulty eating/feeling full • The ovarian cancer 'high alert' symptom complexes identify postmenopausal women with a significantly poorer prognosis. • The study could not however exclude the possibility of better outcomes in those who are aware and acted on these symptoms. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a low-prevalence postmenopausal cancer with a high mortality rate and is the fifth most lethal cancer in women. The most common serous subtype with TP53 mutations spreads rapidly throughout the peritoneal cavity (stage III/IV) when 5-year survival is 10%. If diagnosed while confined to the ovary (stage I), the survival rate exceeds 90%. This is the rationale for screening. Annual transvaginal ultrasound (TVU) scans used as a primary screening modality or as a second-line test following primary screening with serum CA125 (multimodal) have been investigated in several trials. Only two large randomized controlled trials have provided mortality data. The US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial studied over 78 000 women (randomized to screening with either TVU or CA125, or control) over 6 years with 14 years follow-up and found no mortality benefit from screening and increased morbidity in the screened arm. The UK Collaborative Trial of Ovarian Cancer Screening studied over 202 000 women randomized to TVU, multimodal or control in a 1 : 1 : 2 ratio over 7-11 years with 11 years follow-up. CA125 was interpreted by the Risk of Ovarian Cancer algorithm which identifies a rise in the level rather than a fixed cut-off. There was a late reduction in mortality after 7 years in the screened arm (23% in the multimodal arm and 21% in the TVU arm), but the overall reduction was not significant. Further follow-up may reveal whether TVU has a primary or secondary role in ovarian cancer screening. [ABSTRACT FROM AUTHOR]

The article presents a study evaluating the self-reported visualization rate (VR) of ovaries by sonographers during transvaginal sonographic (TVS) examinations in an effort to develop software that would automatically measure VR. Using data from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), it found that sonographers may mistake other biological structures for normal ovaries and concludes that quality control (QC) metrics based on self-reports are unreliable.

Biomarkers for the early detection of pancreatic cancer are urgently needed. The aim of this pilot study was to evaluate changes in serum N-glycoproteins and their glycosylation status prior to clinical presentation of pancreatic cancer that may be potential biomarkers. Prediagnosis serum samples pooled according to five time-to-diagnosis groups and a non-cancer control pool were digested with trypsin, labelled with mass tags, and subjected to titanium dioxide capture, deglycosylation, and 2D-LC-MS/MS profiling. Unbound peptides were profiled in parallel. Across the sample groups, 703 proteins were quantified and 426 putative sites of N-glycosylation were identified with evidence of several novel sites. Altered proteins with biomarker potential were predominantly abundant inflammatory response, coagulation, and immune-related proteins. Whilst glycopeptide profiles largely paralleled those of their parent proteins, there was evidence of altered N-glycosylation site occupancy or sialic acid content prior to diagnosis for some proteins, most notably of immunoglobulin gamma chains. α-1-Antitrypsin was tested as a biomarker, but found not to complement carbohydrate antigen 19-9 (CA19-9) in early detection of cancer. In conclusion, we provide preliminary evidence of altered glycosylation of several serum proteins prior to pancreatic cancer diagnosis, warranting further investigation of these proteins as early biomarkers. These changes may be largely driven by inflammatory processes that occur in response to tumour formation and progression. [ABSTRACT FROM AUTHOR]

Objectives: The negative publicity about menopausal hormone therapy (MHT) has led to increased use of complementary and alternative medicines (CAM) and non-pharmacological interventions (NPI) for menopausal symptom relief. We report on the prevalence and predictors of CAM/NPI among UK postmenopausal women.Method: Postmenopausal women aged 50-74 years were invited to participate in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). A total of 202 638 women were recruited and completed a baseline questionnaire. Of these, 136 020 were sent a postal follow-up-questionnaire between September 2006 and May 2009 which included ever-use of CAM/NPI for menopausal symptom relief. Both questionnaires included MHT use.Results: A total of 88 430 (65.0%) women returned a completed follow-up-questionnaire; 22 206 (25.1%) reported ever-use of one or more CAM/NPI. Highest use was reported for herbal therapies (43.8%; 9725/22 206), vitamins (42.6%; 9458/22 206), lifestyle approaches (32.1%; 7137/22 206) and phytoestrogens (21.6%; 4802/22 206). Older women reported less ever-use of herbal therapies, vitamins and phytoestrogens. Lifestyle approaches, aromatherapy/reflexology/acupuncture and homeopathy were similar across age groups. Higher education, Black ethnicity, MHT or previous oral contraceptive pill use were associated with higher CAM/NPI use. Women assessed as being less hopeful about their future were less likely to use CAM/NPI.Conclusion: One in four postmenopausal women reported ever-use of CAM therapies/NPI for menopausal symptom relief, with lower use reported by older women. Higher levels of education and previous MHT use were positive predictors of CAM/NPI use. UKCTOCS Trial registration: ISRCTN22488978. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) has the highest mortality of all gynaecological cancers. Early diagnosis offers an approach to achieving better outcomes. We conducted a blinded-evaluation of prospectively collected preclinical serum from participants in the multimodal group of the United Kingdom Collaborative Trial of Ovarian Cancer Screening. Using isobaric tags (iTRAQ) we identified 90 proteins differentially expressed between OC cases and controls. A second targeted mass spectrometry analysis of twenty of these candidates identified Protein Z as a potential early detection biomarker for OC. This was further validated by ELISA analysis in 482 serial serum samples, from 80 individuals, 49 OC cases and 31 controls, spanning up to 7 years prior to diagnosis. Protein Z was significantly down-regulated up to 2 years pre-diagnosis ( p = 0.000000411) in 8 of 19 Type I patients whilst in 5 Type II individuals, it was significantly up-regulated up to 4 years before diagnosis ( p = 0.01). ROC curve analysis for CA-125 and CA-125 combined with Protein Z showed a statistically significant ( p= 0.00033) increase in the AUC from 77 to 81% for Type I and a statistically significant ( p= 0.00003) increase in the AUC from 76 to 82% for Type II. Protein Z is a novel independent early detection biomarker for Type I and Type II ovarian cancer; which can discriminate between both types. Protein Z also adds to CA-125 and potentially the Risk of Ovarian Cancer algorithm in the detection of both subtypes. [ABSTRACT FROM AUTHOR]

Objective: To describe the quality assurance (QA) processes and their impact on visualization of postmenopausal ovaries in the ultrasound arm of a multicenter screening trial for ovarian cancer.Methods: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 50 639 women aged 50-74 years were randomized to the ultrasound arm and underwent annual transvaginal ultrasound (TVS) examinations. QA processes were developed during the course of the trial and included regular monitoring of the visualization rate (VR) of the right ovary. Non-subjective factors identified previously as impacting on VR of the right ovary were included in a generalized estimating equation model for binary outcomes to enable comparison of observed vs adjusted VR between individual sonographers who had undertaken > 1000 scans during the trial and comparison between centers. Observed and adjusted VRs of sonographers and centers were ranked according to the highest VR. Analysis of annual VRs of sonographers and those of the included centers was undertaken.Results: Between June 2001 and December 2010, 48 230 of 50 639 women attended one of 13 centers for a total of 270 035 annual TVS scans. One or both ovaries were seen in 228 145 (84.5%) TVS scans. The right ovary was seen on 196 426 (72.7%) of the scans. For the 78 sonographers included in the model, the median difference between observed and adjusted VR was -0.7% (range, -7.9 to 5.9%) and the median change in VR rank after adjustment was 3 (range, 0-18). For the 13 centers, the median difference between observed and adjusted VR was -0.5% (range, -2.2 to 1%), with no change in ranking after adjustment. The median adjusted VR was 73% (interquartile range (IQR), 65-82%) for sonographers and 74.7% (IQR, 67.1-79.0%) for centers. Despite the increasing age of the women being scanned, there was a steady decrease in the number of sonographers with VR < 60% (21.4% in 2002 vs 2.0% in 2010) and an increase in sonographers with VR > 80% (14.3% in 2002 vs 40.8% in 2010). The median VR of the centers increased from 65.5% (range, 55.7-81.0%) in 2001 to 80.3% (range, 74.5-90.9%) in 2010.Conclusions: A robust QA program can improve visualization of postmenopausal ovaries and is an essential component of ultrasound-based ovarian cancer screening trials. While VR should be adjusted for non-subjective factors that impact on ovarian visualization, subjective factors are likely to be the largest contributors to differences in VR. [ABSTRACT FROM AUTHOR]

Background: Evidence is mounting that area-level socioeconomic indicators are important tools for predicting health outcomes. However, few studies have examined these alongside individual-level education. This nested cohort study within the control arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) assesses the association of mutually adjusted individual (education) and area-level (Index of Multiple Deprivation-IMD 2007) socioeconomic status indicators and all-cause female mortality. Methods: Participants resident in England who had completed both baseline (Wave 1) and follow up (Wave 2) questionnaires were included. Follow-up was through the Health and Social Care Information Centre with deaths censored on 31st December 2012. IMD, education and a range of covariates were explored. Cox regression models adjusted for all covariates were used. Sensitivity analysis using imputation was performed (1) including those with missing data and (2) on the entire cohort who had completed the baseline questionnaire. Results: Of the 54,539 women resident in England who completed both Wave 1 and Wave 2 questionnaires, 4,510 had missing data. The remaining 50,029 women were included in the primary analysis. Area-level IMD was positively associated with all-cause mortality for the most deprived group compared to the least deprived (HR=1.42, CI=1.14-1.78) after adjusting for all potential confounders. Sensitivity analyses showed similar results with stronger associations in the entire cohort (HR=1.90, CI=1.68-2.16). The less educated an individual, the higher the mortality risk (test for trend p=<0.001). However, the crude effect on mortality of having no formal education compared to college/university education disappeared when adjusted for IMD rank (HR=1.08, CI=0.93-1.26). Conclusion: Women living in more deprived areas continue to have higher mortality even in this less deprived cohort and after adjustment for a range of potential confounders. [ABSTRACT FROM AUTHOR]

Abstract: Evidence of a mortality benefit continues to elude ovarian cancer (OC) screening. Data from the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial which used a screening strategy incorporating CA125 cut-off and transvaginal ultrasound has not shown mortality benefit. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is using the Risk of Ovarian Cancer (ROC) time series algorithm to interpret CA125, which has shown an encouraging sensitivity and specificity however the mortality data will only be available in 2015. The article explores the impact of growing insights into disease aetiology and evolution and biomarker discovery on future screening strategies. A better understanding of the target lesion, improved design of biomarker discovery studies, a focus on detecting low volume disease using cancer specific markers, novel biospecimens such as cervical cytology and targeted imaging and use of time series algorithms for interpreting markers profile suggests that a new era in screening is underway. [Copyright &y& Elsevier]

ABSTRACT Objective Transvaginal sonography ( TVS) is core to any ovarian cancer screening strategy. General-population screening involves older postmenopausal women in whom ovarian visualization is difficult because of decreasing ovarian size and lack of follicular activity. We report on factors affecting the visualization of postmenopausal ovaries in the multicenter United Kingdom Collaborative Trial of Ovarian Cancer Screening ( UKCTOCS). Methods The UKCTOCS is a randomized controlled trial of 202 638 postmenopausal women with 50 639 women in the ultrasound scan arm. TVS is the primary screening modality in the ultrasound scan arm. Age, education, ethnicity, body mass index ( BMI), previous pelvic surgery, lifestyle and reproductive factors, and a personal/family history of cancer were assessed for their effects on ovarian visualization at the initial TVS. Results Between 11 June 2001 and 18 August 2007, 43 867 women underwent TVS. The median age and BMI of the women were 60.6 (interquartile range ( IQR), 9.9) years and 25.7 ( IQR, 5.8), respectively. The right ovary was visualized in 29 297 (66.8%) and the left ovary was visualized in 28 726 (65.5%). Visualization of ovaries decreased with previous hysterectomy (odds ratio ( OR) = 0.534; 95% CI, 0.504-0.567), previous tubal ligation ( OR = 0.895; 95% CI, 0.852-0.940), increasing age ( OR = 0.953; 95% CI, 0.950-0.956), unilateral oophorectomy ( OR = 0.224; 95% CI, 0.186-0.269) and being overweight ( OR = 0.918; 95% CI, 0.876-0.962) or obese ( OR = 0.715; 95% CI, 0.677-0.755). Increased visualization was observed with a history of infertility ( OR = 1.134; 95% CI, 1.005-1.279) and increasing age (in years) at menopause ( OR = 1.005; 95% CI, 1.001-1.009). Conclusions Several factors affect the visualization of postmenopausal ovaries. Their impact needs to be taken into consideration when developing quality assurance for ovarian ultrasound scanning or comparing study results as their prevalence may differ between populations. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To assess pain and overall experience of transvaginal sonography ( TVS) in asymptomatic postmenopausal women. Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening ( UKCTOCS), 50 639 postmenopausal women were randomized to undergo annual TVS at 13 trial centers in England, Wales and Northern Ireland. Together with the appointment letter for their annual scan, a random sample of 150 women per center was sent a detailed 48-item postal questionnaire regarding the screening experience. It included a specific question about pain using a score of 0-5, where 5 was severe pain and 3 was discomfort. To assess factors that might affect a woman's reported pain experience, the pain score was regressed on age, hormone replacement therapy use, body mass index, a history of hysterectomy, prolonged scanning time, ovarian visualization, scan result, sonographer's visualization rates and opinion of the women regarding the sonographer who performed the scan. Results Between 7 July and 9 September 2009, 1950 randomly chosen women (150 per regional center) were sent the questionnaire. Of the 800 (41.0%) who returned the questionnaire, 651 could be linked to their TVS appointment. One-hundred and fifty-two (23.3%) women reported pain/discomfort (score 3-5) during TVS and 473 (72.7%) reported no discomfort (score 0-2). Only 23 (3.5%) women reported experiencing moderate/severe pain. Increasing discomfort/pain was independently associated with a history of hysterectomy and participant's reporting of prolonged scan time. Women who experienced pain on TVS were less compliant (odds ratio = 0.87) with the following year's scan compared with those who did not experience pain. Conclusions The majority of postmenopausal women found TVS acceptable. Pain influenced compliance and correlated with women's perception of increased scanning time and previous hysterectomy.Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. Methods This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. Results Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8-9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25 th-75 th centiles, 6.03-7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79-1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5-1.03%); and for Type II it was 0.34% (95% CI, 0.33-0.79%). In the subgroup ( n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08-6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9-4.6%) and for Type II it was 1.3% (95% CI, 0.6-2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. Conclusion Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Women's awareness of ovarian cancer (OC) risks, their attitudes towards and beliefs about screening, together with misunderstandings or gaps in knowledge, may influence screening uptake.Methods: In total, 21 715 post-menopausal women completed questionnaires before randomisation into the UK Collaborative Trial of Ovarian Cancer Screening.Results: In all, 42.3% correctly identified their lifetime risk of OC; 87.1% knew that a family history of OC increased risk, but only 26.7% appreciated the association with a family history of breast cancer. Although 38.2% acknowledged increased risk post-menopause, only 8.8% were aware that OC diagnoses are highest in women over 65 years. Few (13.7%) recognised the association between pregnancy and reduced OC risk or protective effects of breastfeeding (6.2%). There were common misconceptions; 37.2% thought that an abnormal cervical smear and 26.4% that oral contraception increased the likelihood of OC. Although 84.4% recognised that most ovarian masses are benign, 20.2% thought having had a benign cyst increased OC risk. Most (99.4%) believed that a high uptake of OC screening would reduce mortality and (96.2%) that screen-detected cancers would have an improved prognosis.Conclusions: The results show a need for improved public understanding about OC risks and provide important information for GPs and health educationalists about initiatives needed for future awareness, prevention and screening programmes. [ABSTRACT FROM AUTHOR]

Summary: Over 6000 cases of ovarian cancer are diagnosed in the UK every year. Most women present with advanced disease. The overall 5-year survival is 26%. Only 5–10% of cases are hereditary and genetic testing can be offered in high-risk families. Screening with CA125 and transvaginal ultrasonography in the general population is currently being investigated in the UKCTOCS study. The treatment of ovarian cancer depends on the stage of disease. Suspected cases should be managed by a multidisciplinary team. Optimal staging and cytoreductive surgery should be performed by a gynaecological oncologist. In advanced disease adjuvant chemotherapy with platinum and paclitaxel is the treatment of choice. New approaches to the treatment of ovarian cancer include fertility sparing surgery, neoadjuvant chemotherapy followed by debulking surgery, and intraperitoneal chemotherapy. [Copyright &y& Elsevier]

Circulating intercellular adhesion molecule-1 (ICAM-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been widely proposed as potential diagnostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). We report on serum protein levels prior to clinical presentation of pancreatic cancer. Serum ICAM-1 and TIMP-1 were measured by ELISA in two case–control sets: 1 ) samples from patients diagnosed with pancreatic cancer ( n = 40), chronic pancreatitis ( n = 20), benign jaundice due to gall stones ( n = 20) and healthy subjects ( n = 20); 2 ) a preclinical set from the UK Collaborative Trial of Ovarian Cancer Screening biobank of samples collected from 27 post-menopausal women 0–12 months prior to diagnosis of pancreatic cancer and controls matched for date of donation and centre. Levels of ICAM-1 and TIMP-1 were significantly elevated in set 1 in PDAC patients with jaundice compared to PDAC patients without jaundice and both proteins were elevated in patients with jaundice due to gall stones. Neither protein was elevated in samples taken 0–12 months prior to PDAC diagnosis compared to non-cancer control samples. In conclusion, evaluation in pre-diagnosis samples discounts ICAM-1 and TIMP-1 as biomarkers for earlier diagnosis of pancreatic cancer. Failure to account for obstructive jaundice may have contributed to the previous promise of these candidate biomarkers. Biological significance Pancreatic cancer is usually diagnosed when at an advanced stage which greatly limits therapeutic options. Biomarkers that could facilitate earlier diagnosis are urgently sought. [ABSTRACT FROM AUTHOR]

Simple Summary: The United Kingdom Collaborative Trial of Ovarian Cancer Screening was undertaken to assess whether screening postmenopausal women from the general population might result in detection of ovarian/tubal cancers at an earlier stage and thus save lives. One of the screening strategies tested was a yearly transvaginal ultrasound scan of the ovaries (USS). Following the initial screen, 44,799 of the 50,639 women in the USS group went on to have a further 280,534 annual scans during April 2002–December 2011. Abnormalities leading to surgery were detected in 960 women of whom 113 (80 invasive epithelial) had ovarian/tubal cancer. Ovarian/tubal cancer was missed in 52 (50 invasive epithelial) women. Of the screen-detected cancers, 37.5% and missed cancers 6% were early stage(I/II). The number (detection rate 61.5%; 80/130) and advanced stage of the missed invasive cancers suggests that a yearly ultrasound scan may not be suitable for screening average risk women for ovarian cancer. Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95% CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95% CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95% CI: 60.8–75.5), 99.7% (95% CI: 99.7–99.7), and 11.8% (95% CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95% CI: 52.6–69.9); 99.7% (95% CI: 99.7–99.7) and 8.3% (95% CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000. [ABSTRACT FROM AUTHOR]

There has been concern about current ovarian cancer screening strategies after the publication showing a lack of benefit from screening in the ovarian part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening involves 202,638 low-risk postmenopausal women. The performance characteristics on prevalence screen in sensitivity, specificity, and stage distribution have been encouraging. Screening differs from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the use of algorithms to interpret CA125 and ultrasound imaging and well-defined, centrally coordinated management of screen-detected abnormalities with protocols for intervention based on screening findings. There is a possibility that these essential differences may be sufficient to alter the natural history of ovarian cancer and ultimately lead to demonstration of a mortality benefit from screening when the trial reports in 2014/2015. [ABSTRACT FROM AUTHOR]

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2–5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871–0.952) and 90.5% (82.5–98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: We investigated the association between self-reported skirt size (SS) and change in SS, and incidence of chronic liver disease (CLD) in a prospective cohort study of women recruited to the UKCTOCS trial.Methods: Women recruited to UKCTOCS in England without documented CLD self-reported their current UK SS during trial participation and were asked to recall their SS when aged in 20s (via completion of a questionnaire 3-5 years after recruitment). Participants were followed up via electronic health record linkage and hazard ratios (HR) calculated for incident liver-related events (LRE).Results: Three hundred twenty-two (0.3%) of 94,124 women experienced a first LRE. Compared to SS ≤ 16, rates of LRE were higher in the SS ≥ 18 groups (both when aged in 20s and at questionnaire completion). Event rates were higher if there was no change in SS or an increase in SS, compared to a decrease in SS. In the models adjusted for potential confounders, HRs for LRE were higher in the groups of women reporting SS ≥ 18 both when aged in 20s (HR = 1.39 (95% CI; 0.87-2.23)) and at questionnaire completion (HR = 1.37 (95% CI; 1.07-1.75)). Compared to a decrease in SS, HRs were higher in the no change (HR = 1.78 (95% CI; 0.95-3.34)) and increase (HR = 1.80 (95% CI; 1.01-3.21)) groups.Conclusion: CLD is associated with high SS and an increase in SS over time. These data suggest SS can be used in simple public health messages about communicating the risk of liver disease.Trial Registration: UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Registered 06/04/2000. [ABSTRACT FROM AUTHOR]

Objective: There has been considerable interest in the impact of reproductive factors on health but there are little data on how these have varied over time. We explore trends in reproductive/lifestyle factors of postmenopausal British women by analysing self-reported data from participants of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)., Design: Prospective birth cohort analysis., Setting: Population cohort invited between 2001 and 2005 from age-sex registers of 27 Primary Care Trusts in England, Wales and Northern Ireland and recruited through 13 National Health Service Trusts., Participants: 202 638 postmenopausal women aged 50-74 years at randomisation to UKCTOCS between April 2001 and October 2005., Interventions: Women were stratified into the following six birth cohorts (1925-1929, 1930-1934, 1935-1939, 1940-1944, 1945-1949, 1950-1955) based on year of birth. Self-reported data on reproductive factors provided at recruitment were explored using tabular and graphical summaries to examine for differences between the birth cohorts., Outcome Measures: Trends in mean age at menarche and menopause, use of oral contraceptives, change in family size, infertility treatments, tubal ligation and hysterectomy rates., Results: Women born between 1935 and 1955 made up 86% of the cohort. Median age at menarche decreased from 13.4 for women born between 1925 and 1929 to 12.8 for women born between 1950 and 1955. Increased use of the oral contraceptives, infertility treatments and smaller family size was observed in the younger birth cohorts. Tubal ligation rates increased for those born between 1925 and 1945, but this increase did not persist in subsequent cohorts. Hysterectomy rates (17-20%) did not change over time., Conclusions: The trends seen in this large cohort are likely to reflect the reproductive history of the UK female postmenopausal population of similar age. Since these are risk factors for hormone-related cancers, these trends are important in understanding the changing incidence of these cancers., Trial Registration Number: International Standard Randomised Controlled Trial Number: 22488978., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)