BACKGROUND:The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; 2001-2020) showed no reduction in disease mortality in its primary intervention arm using multimodal screening (MMS) with longitudinal Cancer Antigen 125 (CA125) and transvaginal ultrasound. Whether this null result reflects the stop-screen design, screening performance, or ovarian cancer natural history remains unclear. METHODS:Using individual-level screening and diagnosis data from the MMS arm, we estimated ovarian cancer natural history, focusing on high-grade serous ovarian cancer (HGSC), the most common and lethal subtype. We then simulated trial outcomes under (1) continued screening beyond the trial screening interval and (2) high sensitivity for early-stage detection over an extended time period. RESULTS:The estimated window for detecting early-stage HGSC under MMS was <6 months. Continued screening yielded at most a 15% relative mortality reduction. Achieving a ≥20% mortality reduction required extending the detectable early-stage window to 1 year and attaining ≥70% sensitivity during this period. CONCLUSION:Current screening modalities offer a very limited opportunity to intercept HGSC at an early stage. Clinically effective ovarian cancer screening will require first- and second-line tests capable of detecting HGSC substantially earlier in its natural history.

Table S2 shows predictive fit and preclinical detectable phase estimates for the best-fitting models, alongside key parameter estimates.

BACKGROUND:The UK Collaborative Trial of Ovarian Cancer Screening did not detect a reduction in ovarian cancer mortality with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) compared with no screening. The trial data provide an invaluable resource to quantify the opportunity for interception in ovarian cancer. METHODS:We used Bayesian inference to estimate ovarian cancer natural history based on individual screening and cancer diagnosis records from the UK Collaborative Trial of Ovarian Cancer Screening, a randomized controlled ovarian cancer screening trial conducted in England, Wales, and Northern Ireland. The trial included 202,638 women ages 50 to 74 years with no family history of ovarian cancer, randomized in a 1:1:2 ratio to annual MMS (serum CA125 interpreted using the risk of ovarian cancer algorithm), annual USS, or no screening. The current analysis included 199,499 women, with 674,806 screens and 2,025 cancer diagnoses. RESULTS:Among high-grade serous cancers (HGSC), the estimated preclinical detectable phase was 1.7 years (95% credible interval, 1.3-2.2), compared with 7.8 years (95% credible interval, 5.7-10.6) for non-HGSCs. The preclinical detectable phase depended on screening modality: for HGSCs, it was longer in the MMS arm (2.2 years) compared with the USS arm (0.8 years), whereas for non-HGSCs, it was shorter in the MMS arm (2.7 years) compared with the USS arm (8.2 years). CONCLUSIONS:The interception opportunity for ovarian cancer strongly depends on histologic subtype and screening modality. IMPACT:Achieving a clinically significant benefit of ovarian cancer early detection will require prolonging the interception window through judicious combination of first- and second-line tests.

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 16/46/01, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1186/s13063-021-05125-8 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. 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. 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. 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. This publication was funded by the Health Technology Assessment programme as a part of award number 16/46/01. This article reports on one component of the research award Long term impact of screening on ovarian cancer mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/16/46/01] https://doi.org/10.1186/s13063-021-05125-8

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. OCfree 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 fi ndings 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. Copyright (c) 2025 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Table S3 shows natural history estimates from a model with MMS episode-specific sensitivity.

Figure S2 shows posterior predictive checks for the primary analysis across all cancers and trial arms, comparing observed data with model predictions for clinical and screen-detected cancers.

Figure S3 shows posterior predictive checks for the primary analysis among HGSC cancers across all trial arms, comparing observed data with model predictions for clinical and screen-detected cancers.

Figure S1 shows predictive model fits from approximate leave-one-out cross-validation for the full dataset and for cancer cases only, highlighting model selection steps and the final chosen model.

Randomised controlled trials are challenging to deliver. There is a constant need to review and refine recruitment and implementation strategies if they are to be completed on time and within budget. We present the strategies adopted in the United Kingdom Collaborative Trial of Ovarian Cancer Screening, one of the largest individually randomised controlled trials in the world. The trial recruited over 202,000 women (2001–5) and delivered over 670,000 annual screens (2001–11) and over 3 million women-years of follow-up (2001–20). Key to the successful completion were the involvement of senior investigators in the day-to-day running of the trial, proactive trial management and willingness to innovate and use technology. Our underlying ethos was that trial participants should always be at the centre of all our processes. We ensured that they were able to contact either the site or the coordinating centre teams for clarifications about their results, for follow-up and for rescheduling of appointments. To facilitate this, we shared personal identifiers (with consent) with both teams and had dedicated reception staff at both site and coordinating centre. Key aspects were a comprehensive online trial management system which included an electronic data capture system (resulting in an almost paperless trial), biobanking, monitoring and project management modules. The automation of algorithms (to ascertain eligibility and classify results and ensuing actions) and processes (scheduling of appointments, printing of letters, etc.) ensured the protocol was closely followed and timelines were met. Significant engagement with participants ensured retention and low rates of complaints. Our solutions to the design, conduct and analyses issues we faced are highly relevant, given the renewed focus on trials for early detection of cancer. Future work There is a pressing need to increase the evidence base to support decision making about all aspects of trial methodology. Trial registration ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/46/01. The long-term follow-up UKCTOCS (2015 20) was supported by National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001–14) was funded by the MRC (G9901012 and 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 the MRC Clinical Trials Unit at UCL core funding (MC_UU_00004/09, MC_UU_00004/08, MC_UU_00004/07). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health and Social Care.

Figure S4. Posterior predictive checks for the primary analysis (all three trial arms) among non-HGSC cancers.

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 16/46/01, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.3390/cancers13040858 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. This publication was funded by the Health Technology Assessment programme as a part of award number 16/46/01. This article reports on one component of the research award Long term impact of screening on ovarian cancer mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/16/46/01] https://doi.org/10.3390/cancers13040858

Table S1 summarizes the model-based estimates of the empirical test sensitivity at the first (prevalence), second, and third screens.

Figure S7 shows posterior predictive checks for an analysis with episode-specific MMS sensitivities, comparing observed data with model predictions for clinical and screen-detected cancers across all trial arms.

Experiments on ASDEX Upgrade (AUG) in 2021 and 2022 have addressed a number of critical issues for ITER and EU DEMO. A major objective of the AUG programme is to shed light on the underlying physics of confinement, stability, and plasma exhaust in order to allow reliable extrapolation of results obtained on present day machines to these reactor-grade devices. Concerning pedestal physics, the mitigation of edge localised modes (ELMs) using resonant magnetic perturbations (RMPs) was found to be consistent with a reduction of the linear peeling-ballooning stability threshold due to the helical deformation of the plasma. Conversely, ELM suppression by RMPs is ascribed to an increased pedestal transport that keeps the plasma away from this boundary. Candidates for this increased transport are locally enhanced turbulence and a locked magnetic island in the pedestal. The enhanced D-alpha (EDA) and quasi-continuous exhaust (QCE) regimes have been established as promising ELM-free scenarios. Here, the pressure gradient at the foot of the H-mode pedestal is reduced by a quasi-coherent mode, consistent with violation of the high-n ballooning mode stability limit there. This is suggestive that the EDA and QCE regimes have a common underlying physics origin. In the area of transport physics, full radius models for both L- and H-modes have been developed. These models predict energy confinement in AUG better than the commonly used global scaling laws, representing a large step towards the goal of predictive capability. A new momentum transport analysis framework has been developed that provides access to the intrinsic torque in the plasma core. In the field of exhaust, the X-Point Radiator (XPR), a cold and dense plasma region on closed flux surfaces close to the X-point, was described by an analytical model that provides an understanding of its formation as well as its stability, i.e., the conditions under which it transitions into a deleterious MARFE with the potential to result in a disruptive termination. With the XPR close to the divertor target, a new detached divertor concept, the compact radiative divertor, was developed. Here, the exhaust power is radiated before reaching the target, allowing close proximity of the X-point to the target. No limitations by the shallow field line angle due to the large flux expansion were observed, and sufficient compression of neutral density was demonstrated. With respect to the pumping of non-recycling impurities, the divertor enrichment was found to mainly depend on the ionisation energy of the impurity under consideration. In the area of MHD physics, analysis of the hot plasma core motion in sawtooth crashes showed good agreement with nonlinear 2-fluid simulations. This indicates that the fast reconnection observed in these events is adequately described including the pressure gradient and the electron inertia in the parallel Ohm’s law. Concerning disruption physics, a shattered pellet injection system was installed in collaboration with the ITER International Organisation. Thanks to the ability to vary the shard size distribution independently of the injection velocity, as well as its impurity admixture, it was possible to tailor the current quench rate, which is an important requirement for future large devices such as ITER. Progress was also made modelling the force reduction of VDEs induced by massive gas injection on AUG. The H-mode density limit was characterised in terms of safe operational space with a newly developed active feedback control method that allowed the stability boundary to be probed several times within a single discharge without inducing a disruptive termination. Regarding integrated operation scenarios, the role of density peaking in the confinement of the ITER baseline scenario (high plasma current) was clarified. The usual energy confinement scaling ITER98( p,y ) does not capture this effect, but the more recent H20 scaling does, highlighting again the importance of developing adequate physics based models. Advanced tokamak scenarios, aiming at large non-inductive current fraction due to non-standard profiles of the safety factor in combination with high normalised plasma pressure were studied with a focus on their access conditions. A method to guide the approach of the targeted safety factor profiles was developed, and the conditions for achieving good confinement were clarified. Based on this, two types of advanced scenarios (‘hybrid’ and ‘elevated’ q -profile) were established on AUG and characterised concerning their plasma performance.

The first experimental attempts at controlling edge localised modes (ELMs) via the application of resonant magnetic perturbations on the MAST Upgrade tokamak are reported. Using the linear MHD model MARS-F, the phase shift between the upper and lower coil rows Delta Phi was optimised for toroidal mode number n = 1 and n = 2 fields, to provide forward guidance to experiments. In low beta N discharges, the application of n = 1 3D fields caused the ELM frequency f ELM to increase by over a factor 20 relative to the reference, and also induced a locked mode, which did not cause a plasma termination nor an H-L back transition. However when beta N was raised, this induced locked mode caused plasma termination which precluded mitigation access. Initially, applying a numerically optimised n = 2 field had no effect. However applying a rigid toroidal shift to this field caused a locked mode disruption, demonstrating the presence of a substantial n = 2 error field. Coil current ramps were conducted with Delta Phi set at 6 different values, resulting in either locked mode disruptions or no effect, but mitigation with n = 2 fields was not established.

Objective. 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. Methods. 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. Results. 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. Conclusions. 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.(c) 2023 The Authors. Published by Elsevier Inc.

Background In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy.Methods UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to -screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032.Findings 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0 center dot 5%) of 50 625 participants in the multimodal screening group and 520 (0 center dot 5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0 center dot 0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0 center dot 0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0 center dot 0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0 center dot 0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0 center dot 69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9 center dot 51 years (IQR 6 center dot 04-13 center dot 00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6 center dot 9% (95% CI 0 center dot 4-13 center dot 0; p=0 center dot 042) at 18 years (21% [95% CI 15 center dot 6-26 center dot 2] vs 14% [95% CI 10 center dot 5-17 center dot 4]).Interpretation To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer.Funding National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Supplementary figures, tables and materials & methods Supplementary Figure 1. Schematic presentation of steps in immunoassay development, validation and studies for screening TP53 autoantibody in human serum samples. Supplementary Figure 2. Identifying a common cut-off value for TP53 autoantibody immunoassay. Supplementary Table 1. Characteristics of patients with invasive epithelial ovarian/tubal/peritoneal cancer in MDACC-NROSS set Supplementary Table 2. Characteristics of patients with invasive epithelial ovarian/tubal/peritoneal cancer in AOCS set Supplementary Table 3. Characteristics of patients with invasive epithelial ovarian/tubal/peritoneal cancer by stage and primary site in the UKCTOCS study Supplementary Figure 3. Examples of longitudinal analysis of CA125 and TP53 autoantibody titers in pre-diagnostic serial serum samples from ovarian cancer patients in the UKCTOCS Study. Supplementary Figure 4. ROC curve analysis for TP53 autoantibody and CA125 biomarkers in UKCTOCS trial. Supplementary Figure 5. Comparison of TP53 autoantibody titers between cancer cases with TP53 wild-type and mutant genes in the AOCS biobanking study. Supplementary Figure 6. The list of TP53 mutant protein candidates for preliminary screening of autoantibody against specific TP53 mutant proteins. Supplementary Table 4. Summary of specific TP53 mutant autoantibody titers of individual cancer patients with corresponding TP53 protein mutations in the AOCS biobanking study Supplementary Table 5. Summary of multiplex immunoassay results for screening TP53 mutant-specific autoantibody using samples from the AOCS biobanking study.

MAST Upgrade has just begun its third physics campaign in April of 2023. The set of magnetic probes used to diagnose the magnetic field and currents on MAST Upgrade are described, and their calibration procedures are outlined including calculation of uncertainties. The median uncertainty in the calibration factors of the flux loops and pickup coils are calculated as 1.7% and 6.3%. The arrays of installed instability diagnostics are described, and the detection and diagnosis of a specimen MHD mode are demonstrated. Plans for the improvement of the magnetics arrays are outlined.