Publications by authors named "Anne Dawnay"

37 Publications

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

Ann Clin Biochem 2021 Jul 4:45632211029327. Epub 2021 Jul 4.

Clinical Biochemistry, Barts Health NHS Trust, London, UK.

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 (<0.001), likely due to inclusion of lower amounts of underlying serum proteins (y = 0.97x-2.03, R=0.993). Quantitating IgA biclonal isotype matched ( = 58) using the Hevylite assay gave higher results ( = 0.002) than capillary zone electrophoresis (y = 1.48x-7.13, R=0.959). In contrast, single IgA paraprotein results ( = 48) did not differ between the two methods ( = 0.466; y = 1.24x-2.74, R=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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/00045632211029327DOI Listing
July 2021

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

Clin Endocrinol (Oxf) 2021 Oct 19;95(4):576-586. Epub 2021 Jun 19.

Department of Endocrinology, St Bartholomew's Hospital, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.14534DOI Listing
October 2021

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.

Lancet 2021 06 12;397(10290):2182-2193. Epub 2021 May 12.

MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)00731-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192829PMC
June 2021

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

Trials 2021 Mar 1;22(1):173. Epub 2021 Mar 1.

MRC CTU at UCL, Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, 2nd Floor, London, WC1V 6LJ, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-021-05125-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919310PMC
March 2021

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

J Clin Endocrinol Metab 2020 10;105(10)

Department of Endocrinology, St Bartholomew's Hospital, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa519DOI Listing
October 2020

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

Cancers (Basel) 2020 Jul 17;12(7). Epub 2020 Jul 17.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London WC1V 6LJ, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12071931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409061PMC
July 2020

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

Oncotarget 2018 Apr 3;9(25):17430-17442. Epub 2018 Apr 3.

Institute for Women's Health, University College London, London, WC1E 6BT, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915126PMC
April 2018

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.

BMC Nephrol 2017 04 11;18(1):131. Epub 2017 Apr 11.

Kidney Research UK, Peterborough, UK.

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 m and patients >65 years with an incoming eGFR <40 ml/min/1.73 m. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-017-0522-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387350PMC
April 2017

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

J Clin Oncol 2017 May 27;35(13):1411-1420. Epub 2017 Feb 27.

Adam N. Rosenthal, Lindsay S.M. Fraser, Susan Philpott, Ranjit Manchanda, Matthew Burnell, Philip Badman, Richard Hadwin, Ivana Rizzuto, Andy Ryan, Robert Liston, Jeremy Ford, Richard Gunu, Usha Menon, and Ian J. Jacobs, University College London Elizabeth Garrett Anderson Institute for Women's Health; Elizabeth Benjamin, University College London; Naveena Singh, Barts Health National Health Service Trust; Ranjit Manchanda, Barts Cancer Institute, Queen Mary University of London; Anne Dawnay, University College London Hospital; James Mackay, The University College London Cancer Institute, London; D. Gareth Evans, University of Manchester, St Mary's Hospital Manchester, Manchester; Diana M. Eccles, Southampton General Hospital, Southampton, United Kingdom; Steven J. Skates, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and Ian J. Jacobs, University of New South Wales Australia, Sydney, New South Wales, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.69.9330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455461PMC
May 2017

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

Nephron 2017 29;135(3):189-195. Epub 2016 Dec 29.

Department of Nephrology and Hypertension, Royal Free London NHS Foundation Trust, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000452928DOI Listing
March 2017

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

Nephron 2016 19;132 Suppl 1:195-236. Epub 2016 Apr 19.

Royal Wolverhampton NHS Trust, UK.

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 2.2–2.5 mmol/L. 57.4% of HD and 65.0% of PD patients had a serum PTH between 16–72 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000444823DOI Listing
January 2017

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).

Steroids 2016 06 16;110:62-69. Epub 2016 Apr 16.

Women's Cancer, Institute for Women's Health, University College London, London, UK. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.steroids.2016.04.003DOI Listing
June 2016

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

Lancet 2016 Mar 17;387(10022):945-956. Epub 2015 Dec 17.

Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(15)01224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779792PMC
March 2016

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

J Clin Oncol 2015 Jun 11;33(18):2062-71. Epub 2015 May 11.

Usha Menon, Andy Ryan, Jatinderpal Kalsi, Aleksandra Gentry-Maharaj, Mariam Habib, Sophia Apostolidou, Matthew Burnell, Susan Davies, Richard Gunu, Martin Widschwendter, Elizabeth Benjamin, Mahesh Parmar, and Ian Jacobs, University College London; Anne Dawnay and Tim Mould, University College London Hospital; Naveena Singh, Barts and the London School of Medicine and Dentistry; David Oram and Karina Reynolds, St Bartholomew's Hospital; Alistair McGuire, London School of Economics; Stuart Campbell, Create Health Clinic; Aarti Sharma, University Hospital of Wales; Nazar N. Amso, Cardiff University, Cardiff; Keith Godfrey, Queen Elizabeth Hospital, Gateshead; Alberto Lopes, Royal Cornwall Hospital, Truro; Jonathan Herod, Liverpool Women's Hospital, Liverpool; Karin Williamson, Nottingham City Hospital, Nottingham; Mourad W. Seif, St Mary's Hospital, Manchester; Howard Jenkins and Ian Scott, Royal Derby Hospital, Derby; Robert Woolas, Queen Alexandra Hospital, Portsmouth; John B. Murdoch, St Michael's Hospital, Bristol; Stephen Dobbs, Belfast City Hospital, Belfast; Simon Leeson, Llandudno Hospital, Ysbyty Gwynedd; Derek Cruickshank, James Cook University Hospital, Middlesbrough; Lesley Fallowfield, University of Sussex, Falmer, United Kingdom; Steven J. Skates, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and Ian Jacobs, UNSW Australia, Sydney, NSW, Australia.

Purpose: Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates.

Patients And Methods: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves.

Results: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869).

Conclusion: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.59.4945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463475PMC
June 2015

UK Renal Registry 17th Annual Report: Chapter 8 Biochemical Variables amongst UK Adult Dialysis Patients in 2013: National and Centre-specific Analyses.

Nephron 2015 22;129 Suppl 1:169-208. Epub 2015 Jan 22.

UK Renal Registry, Bristol, UK.

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 2013. The biochemical variables studied were phosphate, adjusted calcium, parathyroid hormone and bicarbonate.In addition, longitudinal analyses were performed (2002–2013) to show changes in achievement of clinical performance measures over time.

Results: Fifty-seven percent of HD and 62% of PD patients achieved a phosphate within the range recommended by the RA clinical practice guidelines. Seventy-eight percent of HD and of PD patients had adjusted calcium between 2.2–2.5 mmol/L. Fifty-seven percent of HD and 63% of PD patients had parathyroid hormone between 16–72 pmol/L. Fifty-nine percent of HD and 79% 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000370278DOI Listing
January 2016

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

Kidney Int 2015 Jan 15;87(1):62-73. Epub 2014 Oct 15.

Departments of Nephrology and Critical Care, Guy's & St Thomas' Hospital, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ki.2014.328DOI Listing
January 2015

Serum CA19-9 is significantly upregulated up to 2 years before diagnosis with pancreatic cancer: implications for early disease detection.

Clin Cancer Res 2015 Feb 17;21(3):622-31. Epub 2014 Jun 17.

Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.

Purpose: Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1, and REG3A are present before clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis.

Experimental Design: This nested case-control study within the UKCTOCS included 118 single and 143 serial serum samples from 154 postmenopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched noncancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1, and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times before diagnosis and for prognosis was evaluated.

Results: At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 years before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in approximately 20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20 to 23 months were estimated for test-positive cases. Prediagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR, 2.69 and 3.15, respectively).

Conclusions: CA19-9 and CA125 have encouraging sensitivity for detecting preclinical pancreatic cancer, and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is upregulated late in the course of pancreatic cancer development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-14-0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181906PMC
February 2015

Effect of remote ischaemic conditioning on contrast-induced nephropathy in patients undergoing elective coronary angiography (ERICCIN): rationale and study design of a randomised single-centre, double-blind placebo-controlled trial.

Clin Res Cardiol 2014 Mar 29;103(3):203-9. Epub 2013 Nov 29.

The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

Background: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is an important cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for an effective intervention. Remote ischaemic conditioning (RIC), where non-injurious ischaemia is applied to an arm prior to the administration of contrast, has shown promise in attenuating CIN but its effectiveness in preserving long-term renal function is unknown, which will be studied as part of the effect of remote ischaemic conditioning against contrast-induced nephropathy (ERICCIN) trial. ( http://Controlled-trials.com Identifier: ISRCTN49645414.)

Methods: The ERICCIN trial is a single-centre, randomised double-blinded placebo-controlled trial which plans to recruit 362 patients who are at risk of CIN, defined by pre-existent renal impairment (estimated glomerular filtration rate <60 ml/min/1.73 m2), over a period of 2 years. Patients will be randomised to either control or RIC consisting of 4, 5 min 200 mmHg balloon-cuff inflation/deflations, to the upper arm. The primary endpoint will be the development of CIN (>25% of eGFR, or rise of creatinine of >44 μmol/l) at 48 h. A key secondary endpoint will be whether RIC impacts upon persistent renal impairment over the 3-month follow-up period. Additional secondary endpoints include the measurement of serum neutrophil gelatinase-associated lipocalin and urinary albumin at 6, 48 h and 3 months following administration of contrast.

Implications: Findings from ERICCIN trial will potentially demonstrate that RIC attenuates contrast-induced acute and chronic kidney injury and influence future clinical practice guidelines in at-risk patients undergoing coronary angiographic procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00392-013-0637-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937541PMC
March 2014

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

Int J Cancer 2014 May;134(9):2180-88

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 case–control 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.28538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234004PMC
May 2014

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

Eur Heart J 2013 Aug 1;34(32):2529-37. Epub 2013 Mar 1.

Institute of Cardiovascular Science, The Heart Hospital, University College London, 16-18 Westmoreland Street, London W1G 8PH, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/eht070DOI Listing
August 2013

Microarray Glycoprofiling of CA125 improves differential diagnosis of ovarian cancer.

J Proteome Res 2013 Mar 19;12(3):1408-18. Epub 2013 Feb 19.

Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine and School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/pr3010474DOI Listing
March 2013

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

Nephron Clin Pract 2013 14;125(1-4):219-58. Epub 2014 Feb 14.

Royal Wolverhampton NHS Trust, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000360031DOI Listing
January 2015

Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with anderson-fabry disease.

Am J Cardiol 2013 Jan 4;111(1):111-7. Epub 2012 Oct 4.

Heart Hospital, University College London Hospitals, National Health Service Foundation Trust, London, United Kingdom.

Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT-proBNP was measured under at rest conditions in 117 patients with AFD (age 48 ± 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range <5 to 6,059). Of the 117 patients, 67 (57%) had elevated, age-corrected, NT-proBNP levels. In the 56 patients (48%) with normal echocardiographic findings, the NT-proBNP levels were greater than the age-predicted cutoffs in 10 of 25 patients with abnormal electrocardiographic findings and 3 of 31 patients with normal electrocardiographic findings (p <0.05). On multiple regression analysis, age, creatinine, left atrial volume index, E/Ea, and the presence of abnormal electrocardiographic findings were independently associated with log NT-proBNP (R(2) = 0.67, p <0.05). In conclusion, NT-proBNP concentrations were elevated in patients with AFD and early cardiac involvement, suggesting its measurement could assist in decisions regarding the timing of enzyme replacement therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2012.08.055DOI Listing
January 2013

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

Nephron Clin Pract 2012 1;120 Suppl 1:c175-210. Epub 2012 Sep 1.

UK Renal Registry, Bristol, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000342852DOI Listing
March 2013

Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women.

Endocr Relat Cancer 2012 Apr 10;19(2):137-47. Epub 2012 Apr 10.

Department of Gynecological Oncology, Institute for Women's Health, Gynecological Cancer Research Centre, University College London, London, UK.

Postmenopausal women with elevated serum sex steroids have an increased risk of breast cancer. Most of this risk is believed to be exerted through binding of the sex steroids to their receptors. For the first time, we investigate the association of estrogen receptor (ER) and androgen receptor (AR) serum bioactivity (SB) in addition to hormone levels in samples from women with breast cancer collected before diagnosis. Two hundred postmenopausal women participating in the UK Collaborative Trial of Ovarian Cancer Screening who developed ER-positive breast cancer 0.6-5 years after sample donation were identified and matched to 400 controls. ER and AR bioassays were used to measure ERα, ERβ, and AR SB. Androgen and estrogen levels were measured with immunoassays. Subjects were classified according to quintiles of the respective marker among controls and the associations between SB and hormones with breast cancer risk were determined by logistic regression analysis. ERα and ERβ SB were significantly higher before diagnosis compared with controls, while estrogens showed no difference. Women had a twofold increased breast cancer risk if ERα SB (odds ratio (OR), 2.114; 95% confidence interval (CI), 1.050-4.425; P=0.040) was in the top quintile >2 years before diagnosis or estrone (OR, 2.205; 95% CI, 1.104-4.586; P=0.029) was in the top quintile <2 years before diagnosis. AR showed no significant association with breast cancer while androstenedione (OR, 3.187; 95% CI, 1.738-6.044; P=0.0003) and testosterone (OR, 2.145; 95% CI, 1.256-3.712; P=0.006) were significantly higher compared with controls and showed a strong association with an almost threefold increased breast cancer risk independent of time to diagnosis. This study provides further evidence on the association of androgens and estrogens with breast cancer. In addition, it reports that high ER but not AR SB is associated with increased breast risk >2 years before diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-11-0310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322660PMC
April 2012

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.

Nephron Clin Pract 2011 26;119 Suppl 2:c179-214. Epub 2011 Aug 26.

UK Renal Registry, Southmead Hospital, Bristol, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000331778DOI Listing
June 2012

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.

Nephron Clin Pract 2010 31;115 Suppl 1:c187-237. Epub 2010 Mar 31.

University College London Hospitals, London, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000301233DOI Listing
January 2011
-->