A stepped wedge cluster randomized trial of graphical surveillance of kidney function data to reduce late presentation for kidney replacement therapy.

Late presentation for kidney replacement therapy (KRT) is an important cause of avoidable morbidity and mortality. Here, we evaluated the effect of a complex intervention of graphical estimated glomerular filtration rate (eGFR) surveillance across 15% of the United Kingdom population on the rate of late presentation using data routinely collected by the United Kingdom Renal Registry. A stepped wedge cluster randomized trial was established across 19 sites with eGFR graphs generated from all routine blood tests (community and hospital) across the population served by each site. Graphs were reviewed by trained laboratory or clinical staff and high-risk graphs reported to family doctors. Due to delays outside the control of clinicians and researchers few laboratories activated the intervention in their randomly assigned time period, so the trial was converted to a quasi-experimental design. We studied 6,100 kidney failure events at 20 laboratories served by 17 main kidney units. A total of 63,981 graphs were sent out. After adjustment for calendar time there was no significant reduction in the rate of presentation during the intervention period. Therefore, implementation of eGFR graph surveillance did not reduce the rate of late presentation for KRT after adjustment for secular trends. Thus, graphical surveillance is an intervention aimed at reducing late presentation, but more evidence is required before adoption of this strategy can be recommended.

Insights from UKCTOCS for design, conduct and analyses of large randomised controlled trials.

Abstract: 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.

Randomised controlled trials help us decide whether new health-care approaches are better than those in current use. To successfully complete these on time and within budget, there is a constant need to review and revise the procedures used for delivering various aspects such as invitation, enrolment, follow-up of participants, delivery of the new test, data collection, and analysis. We report on the processes used in the United Kingdom Collaborative Trial of Ovarian Cancer Screening, one of the largest such trials. The United Kingdom Collaborative Trial of Ovarian Cancer Screening enrolled over 202,000 women (2001­5), delivered over 670,000 yearly screens (2001­11) and followed all participants until 2020. Key to our successful completion were the involvement of senior investigators in day-to-day running of the trial, a pre-emptive approach to issues, a willingness to innovate, and the use of 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 always contact either their local or the central team for clarifications and rescheduling of appointments. To facilitate this, we shared participant contact details (with consent) with both teams. We built a comprehensive electronic system to manage all aspects of the trial. This included online forms that the teams completed in real time (resulting in an almost paperless trial) and systems to check and manage trial processes and track blood samples. We automated key steps such as checking whether participants were eligible, assigning correct action based on results of screening tests, scheduling appointments and printing letters. As a result, all participants were treated as set out in the trial plan. Our engagement with participants ensured that they continued participating and we had a low rate of complaints. We faced issues with regard to our initial trial design and the way we planned to analyse the data. We feel that our solutions are highly relevant, especially as there is a renewed focus on trials for early detection of cancer.

Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial.

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 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) 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=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). 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 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). 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.

Mortality impact, risks, and benefits of general population screening for ovarian cancer: the UKCTOCS randomised controlled trial.

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: 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: 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).

Text: 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. Text: 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. List: 1. 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. List: 2. 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. List: 3. The no-screening group contained 101,359 women. Text: 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. Text: 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. List: • 522 of 50,625 in the blood group. List: • 517 of 50,623 in the scan group. List: • 1016 of 101,314 in the no-screening group. Text: 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. List: • Overall, 81% women in the blood group and 78% in the scan group attended all of their annual screening appointments. List: • 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. List: • 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. List: • Both screening tests were associated with minor complications. List: • While screening did not increase anxiety, there was slightly increased worry in women who were asked to return for more intense repeat testing. List: • 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. List: ◦ 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. List: ◦ 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. List: • 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. Text: 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.

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

The effect of paraprotein polymerisation on quantitation by capillary zone electrophoresis and Hevylite®.

OBJECTIVES: Up to 3% of patients with monoclonal gammopathies have multiple serum paraproteins. This article investigates whether multiple isotype-matched paraproteins, as seen on capillary zone electrophoresis, are truly biclonal. METHODS: Serum samples containing multiple isotype-matched paraproteins were treated with the reducing agent dithiothreitol, and capillary zone electrophoresis was performed pre- and post-treatment. Band resolution and effect of resolution on quantitation of paraprotein burden were assessed. The Hevylite® turbidimetric assay was also evaluated for ability to quantify such paraproteins. RESULTS: Among patients with biclonal isotype-matched paraproteins, 23/24 (96%) IgA paraproteins resolved into a single band following treatment with dithiothreitol compared with only 1/12 (8%) IgG paraproteins. Daratumumab therapy accounted for the second band in 5/9 non-resolving IgGκ paraproteins. Where initially quantified as a single IgA 'complex' (multiple bands in close proximity), the single postdithiothreitol band averaged 2.8 g/L less (P<0.001), likely due to inclusion of lower amounts of underlying serum proteins (y = 0.97x-2.03, R2=0.993). Quantitating IgA biclonal isotype matched (n = 58) using the Hevylite® assay gave higher results (P = 0.002) than capillary zone electrophoresis (y = 1.48x-7.13, R2=0.959). In contrast, single IgA paraprotein results (n = 48) did not differ between the two methods (P = 0.466; y = 1.24x-2.74, R2=0.898), suggesting that polymerisation enhances Hevylite® quantitation. CONCLUSIONS: These results suggest that disulphide-mediated polymerisation of IgA paraproteins is more common than true biclonal gammopathy and support dithiothreitol treatment of samples with isotype-matched IgA bands before quantifying by capillary zone electrophoresis. The Hevylite® assay should be utilized with caution where polymerisation is likely. Where IgGκ biclonal isotype-matched paraproteins appear on capillary zone electrophoresis, daratumumab therapy should be considered.

Performance evaluation of scoring systems for predicting post-operative hypertension cure in primary aldosteronism.

OBJECTIVE: Hypertension cure following adrenalectomy in unilateral primary aldosteronism is not guaranteed. Its likelihood is associated with pre-operative parameters, which have been variably combined in six different predictive scoring systems. The relative performance of these systems is currently unknown. The objective of this work was to identify the best performing scoring system for predicting hypertension cure following adrenalectomy for primary aldosteronism. DESIGN: Retrospective analysis in a single tertiary referral centre. PATIENTS: Eighty-seven adult patients with unilateral primary aldosteronism who had undergone adrenalectomy between 2004 and 2018 for whom complete data sets were available to calculate all scoring systems. MEASUREMENTS: Prediction of hypertension cure by each of the six scoring systems. RESULTS: Hypertension cure was achieved in 36/87 (41.4%) patients within the first post-operative year, which fell to 18/71 (25.4%) patients at final follow-up (median 53 months, P = .002). Analysis of receiver operating characteristic area under the curves for the different scoring systems identified a difference in performance at early, but not late, follow-up. For all systems, the area under the curve was lower at early compared with late follow-up and compared to performance in the cohorts in which they were originally defined. CONCLUSIONS: No single scoring system performed significantly better than all others when applied in our cohort, although two did display particular advantages. It remains to be determined how best such scoring systems can be incorporated into the routine clinical care of patients with PA.

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

BACKGROUND: Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS. METHODS: In this randomised controlled trial, postmenopausal women aged 50-74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1-17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (-41·8 to -2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (-21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group. INTERPRETATION: The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended. FUNDING: National Institute for Health Research, Cancer Research UK, and The Eve Appeal.

UKCTOCS update: applying insights of delayed effects in cancer screening trials to the long-term follow-up mortality analysis.

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.

Low-grade Cortisol Cosecretion Has Limited Impact on ACTH-stimulated AVS Parameters in Primary Aldosteronism.

CONTEXT: In primary aldosteronism, cosecretion of cortisol may alter cortisol-derived adrenal venous sampling indices. OBJECTIVE: To identify whether cortisol cosecretion in primary aldosteronism alters adrenal venous sampling parameters and interpretation. DESIGN: Retrospective case-control study. SETTING: A tertiary referral center. PATIENTS: 144 adult patients with primary aldosteronism who had undergone both adrenocorticotropic hormone-stimulated adrenal venous sampling and dexamethasone suppression testing between 2004 and 2018. MAIN OUTCOME MEASURES: Adrenal venous sampling indices including adrenal vein aldosterone/cortisol ratios and the selectivity, lateralization, and contralateral suppression indices. RESULTS: 21 (14.6%) patients had evidence of cortisol cosecretion (defined as a failure to suppress cortisol to ≤50 nmol/L post dexamethasone). Patients with evidence of cortisol cosecretion had a higher inferior vena cava cortisol concentration (P = .01) than those without. No difference was observed between the groups in terms of selectivity index, lateralization index, lateralization of aldosterone excess, or adrenal vein cannulation rate. CONCLUSIONS: Cortisol cosecretion alters some parameters in adrenocorticotrophic hormone-stimulated adrenal venous sampling but does not result in alterations in patient management.

Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women.

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.

Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholangitis.

The non-invasive differentiation of malignant and benign biliary disease is a clinical challenge. Carbohydrate antigen 19-9 (CA19-9), leucine-rich α2-glycoprotein (LRG1), interleukin 6 (IL6), pyruvate kinase M2 (PKM2), cytokeratin 19 fragment (CYFRA21.1) and mucin 5AC (MUC5AC) have reported utility for differentiating cholangiocarcinoma (CCA) from benign biliary disease. Herein, serum levels of these markers were tested in 66 cases of CCA and 62 cases of primary sclerosing cholangitis (PSC) and compared with markers of liver function and inflammation. Markers panels were assessed for their ability to discriminate malignant and benign disease. Several of the markers were also assessed in pre-diagnosis biliary tract cancer (BTC) samples with performances evaluated at different times prior to diagnosis. We show that LRG1 and IL6 were unable to accurately distinguish CCA from PSC, whereas CA19-9, PKM2, CYFRA21.1 and MUC5AC were significantly elevated in malignancy. Area under the receiver operating characteristic curves for these individual markers ranged from 0.73-0.84, with the best single marker (PKM2) providing 61% sensitivity at 90% specificity. A panel combining PKM2, CYFRA21.1 and MUC5AC gave 76% sensitivity at 90% specificity, which increased to 82% sensitivity by adding gamma-glutamyltransferase (GGT). In the pre-diagnosis setting, LRG1, IL6 and PKM2 were poor predictors of BTC, whilst CA19-9 and C-reactive protein were elevated up to 2 years before diagnosis. In conclusion, LRG1, IL6 and PKM2 were not useful for early detection of BTC, whilst a model combining PKM2, CYFRA21.1, MUC5AC and GGT was beneficial in differentiating malignant from benign biliary disease, warranting validation in a prospective trial.

A programme to spread eGFR graph surveillance for the early identification, support and treatment of people with progressive chronic kidney disease (ASSIST-CKD): protocol for the stepped wedge implementation and evaluation of an intervention to reduce late presentation for renal replacement therapy.

BACKGROUND: Patients who start renal replacement therapy (RRT) for End-Stage Kidney Disease (ESKD) without having had timely access to specialist renal services have poor outcomes. At one NHS Trust in England, a community-wide CKD management system has led to a decline in the incident rate of RRT and the lowest percentage of patients presenting within 90 days of starting RRT in the UK. We describe the protocol for a quality improvement project to scale up and evaluate this innovation. METHODS: The intervention is based upon an off-line database that integrates laboratory results from blood samples taken in all settings stored under different identifying labels relating to the same patient. Graphs of estimated glomerular filtration rate (eGFR) over time are generated for patients <65 years with an incoming eGFR <50 ml/min/1.73 m2 and patients >65 years with an incoming eGFR <40 ml/min/1.73 m2. Graphs where kidney function is deteriorating are flagged by a laboratory scientist and details sent to the primary care doctor (GP) with a prompt that further action may be needed. We will evaluate the impact of implementing this intervention across a large population served by a number of UK renal centres using a mixed methods approach. We are following a stepped-wedge design. The order of implementation among participating centres will be randomly allocated. Implementation will proceed with unidirectional steps from control group to intervention group until all centres are generating graphs of eGFR over time. The primary outcome for the quantitative evaluation is the proportion of patients referred to specialist renal services within 90 days of commencing RRT, using data collected routinely by the UK Renal Registry. The qualitative evaluation will investigate facilitators and barriers to adoption and spread of the intervention. It will include: semi-structured interviews with laboratory staff, renal centre staff and service commissioners; an online survey of GPs receiving the intervention; and focus groups of primary care staff. DISCUSSION: Late presentation to nephrology for patients with ESKD is a source of potentially avoidable harm. This protocol describes a robust quantitative and qualitative evaluation of a quality improvement intervention to reduce late presentation and improve the outcomes for patients with ESKD.

Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study.

Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.

Implementation of an Automated Primary Care Acute Kidney Injury Warning System: A Quantitative and Qualitative Review of 2 Years of Experience.

BACKGROUND: Acute kidney injury (AKI) is often detected late, leading to worse clinical outcomes. In 2012, we pioneered an AKI-alerting system for primary care clinicians (PCCs). We retrospectively analysed the alerts and evaluated PCC satisfaction to assess the feasibility of the system. METHODS: The study used a 2-pronged approach. AKI alerts, generated by an algorithm designed by University College London Hospital biochemistry department between June 2012 and June 2014, were analysed to reveal the demographics and outcomes of each patient generating an alert. Second, a survey was sent to all PCCs assessing awareness and satisfaction with the service. Simple statistical methods were applied (mean, median, SD and interquartile range). RESULTS: One hundred forty-two alerts were generated, of which 101 were genuine. Generally, the patient demographics, AKI stratification and aetiology were in keeping with the inpatient AKI population. Forty-eight percent of cases were referred to the hospital with a median length of stay of 9.9 days. Three-month mortality was 12%. Among PCCs, there was good awareness of the system with most finding it valuable. The key complaints around the system were to do with lack of knowledge of its existence. CONCLUSIONS: Our evaluation has demonstrated that the implementation of AKI alerts in the community is technically feasible, does not result in excessive demand on hospital services, appears to influence PCC behaviour and was perceived overwhelmingly as a useful service by these clinicians. This experience should inform further developments including behavioural interventions (such as clinician alerts) to improve community AKI care.

UK Renal Registry 18th Annual Report: Chapter 9 Biochemical Variables amongst UK Adult Dialysis Patients in 2014: National and Centre-specific Analyses.

In 2014 57.5% of HD patients and 62.7% of PD patients achieved the audit measure for phosphate. 29.0% of HD and 30.3% of PD patients had a serum phosphate above the audit standard range. 79.1% of HD and 79.7% of PD patients had adjusted calcium between 2.2­2.5 mmol/L. 57.4% of HD and 65.0% of PD patients had a serum PTH between 16­72 pmol/L. 16.4% of HD and 12.0% of PD patients had a serum PTH .72 pmol/L. Simultaneous control of all three parameters within current audit standards was achieved by 50.3% of HD and 52.5% of PD patients. 60.4% of HD and 81.8% of PD patients achieved the audit measure for bicarbonate.

Sex hormone measurements using mass spectrometry and sensitive extraction radioimmunoassay and risk of estrogen receptor negative and positive breast cancer: Case control study in UK Collaborative Cancer Trial of Ovarian Cancer Screening (UKCTOCS).

INTRODUCTION: Associations of endogenous sex hormone levels and all as well as estrogen-receptor (ER)-positive breast cancers are well described. However, studies investigating their association with ER-negative tumours are limited and none use accurate assays such as mass spectrometry. METHODS: Within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a nested case-control study was undertaken of postmenopausal-women who developed ER-negative (n=92) or ER-positive (n=205) breast cancer after sample donation and 297 (1:1) age-matched controls. Androgens (testosterone and androstenedione) were measured using mass spectrometry and estradiol by extraction radioimmunoassay (RIA). Bioavailable estradiol and testosterone were calculated using the total hormone level and the sex hormone-binding globulin concentration. Subjects were classified according to the quartile range among controls. Logistic regression was used to estimate odds-ratio (OR) and 95% confidence-intervals (CI) of the associations between two factors and breast cancer risk. A separate analysis was done by stratifying the women based on whether they provided their samples less than or more than 2years before diagnosis. RESULTS: Estradiol and free estradiol were significantly higher prior to diagnosis of ER-negative breast cancer compared with controls while androgens and SHBG did not show any difference. Estradiol, free estradiol, free testosterone and SHBG were significantly higher before ER-positive breast cancer diagnosis compared with controls. Women had a twofold increased ER-negative breast cancer risk if estradiol and free estradiol were in the top quartile but not androgens (testosterone and androstenedione) or SHBG. These associations remained significant only when samples closer (median 1.1y before) to diagnosis were analyzed rather than farther from diagnosis (median 2.9y before). Women had a 2.34 (95% CI: 1.21-4.61, p=0.001), 2.21 (95% CI: 1.14-4.38, p=0.001), 2 (95% CI: 1.05-3.89, p=0.005) fold increased ER-positive breast cancer risk if estradiol, free estradiol and free testosterone respectively were in the top quartile. These associations remained significant regardless of whether the samples were collected less than or more than 2years prior to diagnosis. CONCLUSION: In postmenopausal women increased estrogens but not androgens are associated with ER-negative breast cancer. Previously reported associations of estradiol and free testosterone with ER-positive breast cancer are confirmed. The use of mass spectrometry and sensitive RIA add validity to these findings.