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.

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.

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.

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

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

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.

The definition of acute kidney injury and its use in practice.

Acute kidney injury (AKI) is a common syndrome that is independently associated with increased mortality. A standardized definition is important to facilitate clinical care and research. The definition of AKI has evolved rapidly since 2004, with the introduction of the Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) classifications. RIFLE was modified for pediatric use (pRIFLE). They were developed using both evidence and consensus. Small rises in serum creatinine are independently associated with increased mortality, and hence are incorporated into the current definition of AKI. The recent definition from the international KDIGO guideline merged RIFLE and AKIN. Systematic review has found that these definitions do not differ significantly in their performance. Health-care staff caring for children or adults should use standard criteria for AKI, such as the pRIFLE or KDIGO definitions, respectively. These efforts to standardize AKI definition are a substantial advance, although areas of uncertainty remain. The new definitions have enabled the use of electronic alerts to warn clinicians of possible AKI. Novel biomarkers may further refine the definition of AKI, but their use will need to produce tangible improvements in outcomes and cost effectiveness. Further developments in AKI definitions should be informed by research into their practical application across health-care providers. This review will discuss the definition of AKI and its use in practice for clinicians and laboratory scientists.

Cancer-associated autoantibodies to MUC1 and MUC4--a blinded case­control study of colorectal cancer in UK collaborative trial of ovarian cancer screening.

Recent reports suggest that autoantibodies directed to aberrantly glycosylated mucins, in particular MUC1 and MUC4, are found in patients with colorectal cancer. There is, however, limited information on the autoantibody levels before clinical diagnosis, and their utility in cancer screening in the general population. In our study, we have generated O-glycosylated synthetic MUC1 and MUC4 peptides in vitro, to mimic cancer-associated glycoforms, and displayed these on microarrays. The assay's performance was tested through an initial screening of serum samples taken from patients at the time of colorectal cancer diagnosis and healthy controls. Subsequently, the selected biomarkers were evaluated in a blinded nested case­control study using stored serum samples from among the 50,640 women randomized to the multimodal arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), where women gave annual blood samples for several years. Cases were 97 postmenopausal women who developed colorectal cancer after recruitment and were age-matched to 97 women without any history of cancer. MUC1-STn and MUC1-Core3 IgG autoantibodies identified cases with 8.2 and 13.4% sensitivity, respectively, at 95% specificity. IgA to MUC4 glycoforms were unable to discriminate between cases and controls in the UKCTOCS sera. Additional analysis was undertaken by combining the data of MUC1-STn and MUC1-Core3 with previously generated data on autoantibodies to p53 peptides, which increased the sensitivity to 32.0% at 95% specificity. These findings suggest that a combination of antibody signatures may have a role as part of a biomarker panel for the early detection of colorectal cancer.

Relation between serum N-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy.

AIMS: To determine the relation between serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognosis in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In total, 847 patients (53 ± 15 years; 67% male) with HCM (28% with left ventricular outflow tract obstruction ≥ 30 mmHg at rest) were followed for 3.5 years (IQR 2.5-4.5 years). The median NT-proBNP concentration was 78 pmol/L (range < 5-1817 pmol/L and IQR 31-183 pmol/L). Sixty-eight patients (8%) reached the primary endpoint of all-cause mortality or cardiac transplantation. NT-proBNP concentration predicted long-term survival from the primary endpoint [area under the receiver operating characteristic curve of 0.78 (95% confidence interval 0.73-0.84)]. A serum concentration of ≥ 135 pmol/L was associated with an annual event rate of 6.1% (95% CI 4.4-7.7). Three independent predictors of primary outcome were identified in a multivariable Cox model: New York Heart Association class III/IV (HR 2.10, 95% CI 1.21-3.65, P = 0.008), ejection fraction (HR 0.98, 95% CI 0.96-1.00, P = 0.035), log NT-proBNP (HR 2.04, 95% CI 1.56-2.66, P < 0.001). Log NT-proBNP was a significant predictor of heart failure (HF) and transplant-related deaths (n = 23; HR 3.03, 95% CI 1.99-4.60, P < 0.001) but not sudden death or appropriate implantable cardioverter defibrillator shock (n = 11; HR 1.54, 95% CI 0.91-2.60, P = 0.111). In patients with ejection fraction ≥ 50% (n = 673), log NT-proBNP remained an independent predictor of the primary outcome (HR 2.11, 95% CI 1.54-2.90, P < 0.001). CONCLUSION: In patients with HCM, elevated NT-proBNP concentration is a strong predictor of overall prognosis, particularly HF-related death and transplantation.

Microarray Glycoprofiling of CA125 improves differential diagnosis of ovarian cancer.

The CA125 biomarker assay plays an important role in the diagnosis and management of primary invasive epithelial ovarian/tubal cancer (iEOC). However, a fundamental problem with CA125 is that it is not cancer-specific and may be elevated in benign gynecological conditions such as benign ovarian neoplasms and endometriosis. Aberrant O-glycosylation is an inherent and specific property of cancer cells and could potentially aid in differentiating cancer from these benign conditions, thereby improving specificity of the assay. We report on the development of a novel microarray-based platform for profiling specific aberrant glycoforms, such as Neu5Acα2,6GalNAc (STn) and GalNAc (Tn), present on CA125 (MUC16) and CA15-3 (MUC1). In a blinded cohort study of patients with an elevated CA125 levels (30-500 kU/L) and a pelvic mass from the UK Ovarian Cancer Population Study (UKOPS), we measured STn-CA125, ST-CA125 and STn-CA15-3. The combined glycoform profile was able to distinguish benign ovarian neoplasms from invasive epithelial ovarian/tubule cancer (iEOCs) with a specificity of 61.1% at 90% sensitivity. The findings suggest that microarray glycoprofiling could improve differential diagnosis and significantly reduce the number of patients elected for further testing. The approach warrants further investigation in other cancers.

UK Renal Registry 16th annual report: chapter 12 biochemical variables amongst UK adult dialysis patients in 2012: national and centre-specific analyses.

INTRODUCTION: The UK Renal Association clinical practice guidelines include clinical performance measures for biochemical variables in dialysis patients. The UK Renal Registry (UKRR) annually audits dialysis centre performance against these measures as part of its role in promoting continuous quality improvement. METHODS: Cross sectional performance analyses were undertaken to compare dialysis centre achievement of clinical audit measures for prevalent haemodialysis (HD) and peritoneal dialysis (PD) cohorts in 2012. The biochemical variables studied were phosphate, adjusted calcium, parathyroid hormone, bicarbonate and total cholesterol. In addition, longitudinal analyses were performed (2002-2012) to show changes in achievement of clinical performance measures over time. RESULTS: Fifty-six percent of HD and 61% of PD patients achieved a phosphate within the range recommended by the RA clinical practice guidelines. Seventy-seven percent of HD and 78% of PD patients had adjusted calcium between 2.2-2.5 mmol/L. Fifty-eight percent of HD and 65% of PD patients had parathyroid hormone between 16-72 pmol/L. Fifty-nine percent of HD and 80% of PD patients achieved the audit measure for bicarbonate. There was significant inter-centre variation for all variables studied. CONCLUSIONS: The UKRR consistently demonstrates significant inter-centre variation in achievement of biochemical clinical audit measures. Understanding the causes of this variation is an important part of improving the care of dialysis patients in the UK.

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.

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.

Chapter 9 Biochemical variables amongst UK adult dialysis patients in 2010: national and centre-specific analyses.

INTRODUCTION: The UK Renal Association clinical practice guidelines include clinical performance measures for biochemical variables in dialysis patients. The UK Renal Registry (UKRR) annually audits dialysis centre performance against these measures as part of its role in promoting continuous quality improvement. METHODS: Cross sectional performance analyses were undertaken to compare dialysis centre achievement of clinical audit measures for prevalent haemodialysis (HD) and peritoneal dialysis (PD) cohorts in 2010. The biochemical variables studied were phosphate, adjusted calcium, parathyroid hormone, bicarbonate and total cholesterol. In addition longitudinal analyses were performed (2000-2010) to show changes in achievement of clinical performance measures over time. RESULTS: Fifty-six percent of HD and 69% of PD patients achieved a phosphate within the range recommended by the RA clinical practice guidelines. Seventy-five percent of HD and 76% of PD patients had adjusted calcium between 2.2-2.5 mmol/L. Twenty-eight percent of HD and 31% of PD patients had parathyroid hormone between 16- 32 pmol/L. Sixty percent of HD and 80% of PD patients achieved the audit measure for bicarbonate. There was significant inter-centre variation for all variables studied. CONCLUSIONS: The UKRR consistently demonstrates significant inter-centre variation in achievement of biochemical clinical audit measures. Understanding the causes of this variation is an important part of improving the care of dialysis patients in the UK.

UK Renal Registry 13th Annual Report (December 2010): Chapter 10: calcium, phosphate, parathyroid hormone, bicarbonate and total cholesterol concentrations amongst patients receiving haemodialysis or peritoneal dialysis in England, Wales and Northern Ireland in 2009: national and centre-specific analyses.

INTRODUCTION: The UK Renal Association Clinical Practice Guidelines include clinical performance measures for biochemical variables in dialysis patients [1]. The UK Renal Registry (UKRR) annually audits dialysis centre performance against these measures as part of its role in promoting continuous quality improvement. METHODS: Cross sectional performance analyses were undertaken to compare dialysis centre achievement of clinical audit measures for prevalent haemodialysis (HD) and peritoneal dialysis (PD) cohorts in 2009. The biochemical variables studied were phosphate, adjusted calcium, parathyroid hormone, bicarbonate and total cholesterol. In addition longitudinal analyses were performed (2000-2009) to show changes in achievement of clinical performance measures over time. RESULTS: Sixty-one percent of HD and 70% of PD patients had phosphate between 1.1-1.8 mmol/L. Seventy-four percent of HD and 75% of PD patients had adjusted calcium between 2.2-2.5 mmol/L. Twenty-eight percent of HD and 32% of PD patients had parathyroid hormone between 16-32 pmol/L. Seventy-two percent of HD and 83% of PD patients achieved the audit measure for bicarbonate. There was significant inter-centre variation for all variables studied. CONCLUSIONS: The UKRR consistently demonstrates significant inter-centre variation in achievement of biochemical clinical audit measures. Understanding the causes of this variation is an important part of improving the care of dialysis patients in the UK.

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.

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.

UK Renal Registry 12th Annual Report (December 2009): chapter 10: biochemistry profile of patients receiving dialysis in the UK in 2008: national and centre-specific analyses.

INTRODUCTION: The UK Renal Association Clinical Practice Guidelines include clinical performance measures for biochemical parameters in dialysis patients [1]. The UK Renal Registry (UKRR) annually audits dialysis centre performance against these measures as part of its role in promoting continuous quality improvement. METHODS: Cross sectional performance analyses were undertaken to compare dialysis centre achievement of clinical performance measures for prevalent haemodialysis (HD) and peritoneal dialysis (PD) cohorts in 2008. The biochemical variables studied were phosphate, adjusted calcium, calcium phosphate product, parathyroid hormone, bicarbonate, total cholesterol and HbA1c. In addition, longitudinal analyses were performed (2000-2008) to show changes in achievement of clinical performance measures over time. RESULTS: Serum phosphate was between 1.1 and 1.8 mmol/L in 55% of HD and 64% of PD patients, which was similar to 2007. There was a fall in overall mean phosphate concentration to 1.55 mmol/L. A revised adjusted serum calcium target of 2.2-2.5 mmol/L was achieved by 63% of HD and 65% of PD patients. For comparison, the previous target of 2.2-2.6 mmol/L was achieved by 74% and 78% respectively, a figure little changed since 2005. The downward trend in serum calcium results evident for the previous nine years appears to have halted. The calcium phosphate target of <4.8 mmol(2)/L(2) was achieved by 84% of HD and 87% of PD patients, continuing the steady improvement over the past nine years and reflecting the downward trend in phosphate results. As in previous years, a minority of patients achieved the PTH target range of 16-32 pmol/L and there was considerable heterogeneity between centres. Although analytical and biological variability may have contributed to this, centres achieving the standards relating to one mineral parameter tended to achieve the standards in others suggesting that treatment factors were also relevant. The audit measure for bicarbonate was achieved in 71% of HD and 82% of PD patients. Eighty-five percent of HD patients and 69% of PD patients achieved a value for total cholesterol <5 mmol/L. This was the first year that HbA1c has been audited. Overall, 43% of diabetic dialysis patients exceeded the target of 7.5% HbA1c and there was considerable variation between centres. CONCLUSION: There is wide variation between centres in attainment of biochemical performance measures. There is some evidence in bone mineral metabolism that centres performing well in one variable are more likely to also meet the other standards. The inter-centre variation may be explained in part by laboratory practices and case mix but probably also represents variation in practice and in effectiveness of processes of care. Apart from glycaemic control there are a number of analytical and clinical factors that affect HbA1c that would be worthy of further investigation as a cause of variability.

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

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