Dawn Teare

Contemporary Occupational Carcinogen Exposure and Bladder Cancer: A Systematic Review and Meta-analysis

IMPORTANCE Bladder cancer (BC) is a common disease. Despite manufacturing and legislative changes to workplace hygiene, many BCs still arise through occupational carcinogen exposure. OBJECTIVE To profile contemporary risks of occupational BC. DATA SOURCES A systematic review using PubMed, Medline, Embase, and Web of Science was performed in October 2012 (initial review) and May 2014 (final review) and was updated in June 2015. STUDY SELECTION We identified 263 eligible articles. We excluded reports in which BC or occupation were not the main focus, and those with insufficient case, risk, or confidence interval data. We selected the most recent data from populations with multiple reports. DATA EXTRACTION AND SYNTHESIS Reports were selected by 2 of us independently. We combined odds ratios and risk ratios (RRs) to provide pooled RRs, using maximally adjusted RRs in a random effects model. Heterogeneity and publication bias were assessed using I2 and Begg and Egger tests. Risk estimates were annotated by occupational class using Nordisk Yrkesklassificering, or Nordic Occupational Classification, and International Standard Classifications of Occupations (NYK and ISCO-1958) Codes. MAIN OUTCOMES AND MEASURES Occupations were profiled by BC incidence and mortality risk over time. After data collection, we detected a sex difference in these profiles and recorded this as a secondary outcome. RESULTS Meta-analysis revealed increased BC incidence in 42 of 61 occupational classes and increased BC-specific mortality in 16 of 40 occupational classes. Reduced incidence and mortality were seen in 6 of 61 and 2 of 40 classes, respectively. Risk varied with sex and was greatest in men (standardized incidence ratio, 1.03 [95% CI, 1.02-1.03]; P < .001]). From the 1960s to the 1980s, there was a steady decline in standarized incidence ratio (SIR) for both sexes. This trend reversed from the 1980s, as in the decade 2000 to 2010 the SIR increased to 1.13 (95% CI, 1.07-1.19) for men and 1.27 (95% CI, 1.12-1.43) for women. In contrast, mortality risk declined for both sexes from the 1960s to the 1990s. The overall risk of BC mortality was also greater for men (standardized mortality ratio [SMR], 1.32 [95% CI, 1.18-1.48]) than for women (SMR, 1.14 [95% CI, 0.80-1.63]). Limitations include possible publication bias, that reports stratify workers mostly by job title not task, that not all studies adjusted for smoking, and that the population was mostly derived from Western nations. CONCLUSIONS AND RELEVANCE The profile of contemporary occupations with increased BC risk is broad and differs for incidence and mortality. Currently the incidence seems to be increasing, and this increase is occurring faster in women than men. Improved detection mechanisms and screening are possible reasons for this. Workers with aromatic amine exposure have the highest incidence, while those exposed to polycyclic aromatic hydrocarbons and heavy metals have the greatest mortality.

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

BackgroundThe presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types.MethodsThe original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded.ResultsThe search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods).ConclusionWe have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.

Detection of early sub-clinical lung disease in children with cystic fibrosis by lung ventilation imaging with hyperpolarized gas MRI

Hyperpolarised 3He ventilation-MRI, anatomical lung MRI, lung clearance index (LCI), low-dose CT and spirometry were performed on 19 children (6–16 years) with clinically stable mild cystic fibrosis (CF) (FEV1>−1.96), and 10 controls. All controls had normal spirometry, MRI and LCI. Ventilation-MRI was the most sensitive method of detecting abnormalities, present in 89% of patients with CF, compared with CT abnormalities in 68%, LCI 47% and conventional MRI 22%. Ventilation defects were present in the absence of CT abnormalities and in patients with normal physiology, including LCI. Ventilation-MRI is thus feasible in young children, highly sensitive and provides additional information about lung structure–function relationships.

Sample size requirements for pilot randomised controlled trials with continuous outcomes: a simulation study

Results The bias in the pooled SD estimate is negligible once the total pilot sample is 60 or above and the relative gain in precision (for each ten subjects added to the pilot) drops to below 10% once the total sample size is 70. When planning the full RCT for a continuous outcome, estimates generated by pilot samples of 70 will have the required power with close to 50% confidence when the true standardised effect size is above 0.2. Adjusting the required sample sizes for the full RCT to deliver the required power with 80% confidence can result in excessively large full planned RCTs. Conclusions We recommend that an external pilot study needs at least a total of 70 measured subjects (35 per group) to estimate the pooled SD for a continuous outcome.

What is an ROC curve

The paper by Body et al is concerned with the evaluation of decision aids, which can be used to identify potential acute coronary syndromes (ACS) in the ED. The authors previously developed the Manchester Acute Coronary Syndromes model (MACS) decision aid, which uses several clinical variables and two biomarkers to ‘rule in’ and ‘rule out’ ACS. However, one of the two biomarkers (heart-type fatty acid bindingprotein, H-FABP) is not widely used so a revised decision aid has been developed (Troponin-only Manchester Acute Coronary Syndromes, T-MACS), which include a single biomarker hs-cTnT. In this issue, the authors show how they derive a revised decision aid and describe its performance in a number of independent diagnostic cohort studies. Decision aids (as well as other types of ‘diagnostic tests’) are often evaluated in terms of diagnostic testing parameters such as the area under the receiver operating characteristic (ROC) curve, sensitivity and specificity. In this article, we explain how the ROC analysis is conducted and why it is an essential step towards developing a test with the desirable levels of sensitivity and specificity.

Repeat coronary angiography with previously normal arteries: A futile exercise?

Up to 20% of coronary angiograms reveal normal arteries. How long they stay normal is poorly understood. This study investigated the fate of normal coronary arteries and determined the rate of development of coronary artery disease.

Genome-Wide Analysis of Circulating Cell-Free DNA Copy Number Detects Active Melanoma and Predicts Survival

BACKGROUND A substantial number of melanoma patients develop local or metastatic recurrence, and early detection of these is vital to maximise benefit from new therapies such as inhibitors of BRAF and MEK, or immune checkpoints. This study explored the use of novel DNA copy-number profiles in circulating cell-free DNA (cfDNA) as a potential biomarker of active disease and survival. PATIENTS AND METHODS Melanoma patients were recruited from oncology and dermatology clinics in Sheffield, UK, and cfDNA was isolated from stored blood plasma. Using low-coverage whole-genome sequencing, we created copy-number profiles from cfDNA from 83 melanoma patients, 44 of whom had active disease. We used scoring algorithms to summarize copy-number aberrations and investigated their utility in multivariable logistic and Cox regression analyses. RESULTS The copy-number aberration score (CNAS) was a good discriminator of active disease (odds ratio, 3.1; 95% CI, 1.5-6.2; P = 0.002), and CNAS above or below the 75th percentile remained a significant discriminator in multivariable analysis for active disease (P = 0.019, with area under ROC curve of 0.90). Additionally, mortality was higher in those with CNASs above the 75th percentile than in those with lower scores (HR, 3.4; 95% CI, 1.5-7.9; P = 0.005), adjusting for stage of disease, disease status (active or resected), BRAF status, and cfDNA concentration. CONCLUSIONS This study demonstrates the potential of a de novo approach utilizing copy-number profiling of cfDNA as a biomarker of active disease and survival in melanoma. Longitudinal analysis of copy-number profiles as an early marker of relapsed disease is warranted.

Development and validation of a clinical risk score to predict mortality after percutaneous coronary intervention

Objective To develop and validate a contemporary clinical risk score to predict mortality after percutaneous coronary intervention (PCI). Methods Using data collected from patients undergoing PCI at the South Yorkshire Cardiothoracic Centre, Sheffield, UK, between January 2007 and September 2013, a risk score was developed to predict mortality. Logistic regression was used to evaluate the effect of each variable upon 30-day mortality. A backwards stepwise logistic regression model was then used to build a predictive model. The results were validated both internally and externally with data from Manchester Royal Infirmary, UK. 30-Day mortality status was determined from the UK Office of National Statistics. Results The development data set comprised 6522 patients from Sheffield. Five risk factors, including cardiogenic shock, procedural urgency, history of renal disease, diabetes mellitus and age, were statistically significant to predict 30-day mortality. The risk score was validated internally on a further 3290 patients from Sheffield and externally on 3230 patients from Manchester. The discrimination of the model was high in the development (C-statistic=0.82, 95% CI 0.79 to 0.85), internal (C-statistic=0.81, 95% CI 0.76 to 0.86) and external (C statistics=0.90, 95% CI 0.87 to 0.93) cohorts. There was no significant difference between observed and predicted mortality in any group. Conclusion This contemporary risk score reliably predicts 30-day mortality after PCI using a small number of clinical variables obtainable prior to the procedure, without knowledge of the coronary anatomy.

63 Increased risk of acute st-segment myocardial?infarction in female smokers – a?contemporary demographic study

Background Studies have shown that smoking increases the risk of acute ST-segment elevation myocardial infarction (STEMI). However, the impact of gender on this risk is unknown. Methods This retrospective ecological cohort study examined all patients presenting with acute STEMI undergoing primary percutaneous coronary intervention at the South Yorkshire Cardiothoracic Centre (UK) between 2009–14. Index cases were compared to population data from the UK Office for National Statistics for smoking status, gender and age. Incidence rates of STEMI for current and non-smokers were calculated by gender and their associated 95% confidence intervals (CI) determined from the Poisson distribution. Age-standardised incidence rate ratios (IRR) comparing STEMI rates between smokers and non-smokers were calculated between genders in three age groups (18–49, 50–64,>65). Results There were 2,996 STEMI patients. 27.1% were female, who were significantly older than male patients (mean age: 66.3 vs 60.9, p=0.03). Risk factor prevalence was similar between genders, although hypertension was more common in females (44.9% vs 36.7%, p<0.001). In current smokers, the peak STEMI rate in females was in the 70–79 age range (233/100,000 pt/yrs) and the 50–59 (458/100,000 pt/yrs) in males. Across all ages, smokers had a significantly higher acute STEMI risk with an IRR of 5.11 (CI: 4.83–5.40). Compared to their non-smoking gender counterparts, females had a significantly higher IRR than males (6.62 (CI: 5.91–7.38) vs 4.46 (CI: 4.18–4.76)), and this difference was significant in all three age groups. The highest IRR was in female smokers in the 18–49 group at 12.67 (CI: 9.69–16.28), vs 8.47 (CI: 7.50–9.53) in males. The most striking difference between genders was in the 50–64 group (IRR 11.03 (CI: 9.33–12.96) vs 4.63 (CI: 4.21–5.08)). Conclusion Smoking status had a significantly differential effect between genders, with female smokers at increased risk of acute STEMI over male smokers by a factor of 1.48. Young female smokers (18-49) had the highest IRR and were over 12 times more likely to suffer an acute STEMI than their non-smoking peers. The largest IRR gender difference, by a factor of 2.38, was in the 50–64 age group.

Abstract 817: Mendelian randomization and mediation analysis of 5p15.33, telomere length and lung cancer risk

Background: Telomere length (TL) is a predictor of lung cancer risk, but the direction of this association differs between and prospective and case-control studies. This discrepancy may be attributed to reverse causation in the latter, due to disease-related changes in TL that is measured after diagnosis or treatment. To overcome these limitations and characterize the relationship between TL and lung cancer risk we carried out observational and mediation analyses, and a 2-stage Mendelian Randomization (MR) analysis, where we developed novel genetic instruments for TL and tested the association with lung cancer using 20 OncoArray studies in the Transdisciplinary Research in Cancer of the Lung group of the International Lung Cancer Consortium. Methods: The observational analysis examined TL measured using qPCR in 1128 cases and 928 controls. Odds ratios (OR) for TL were adjusted for age, sex and cigarette pack-years. Mediation analysis was used to estimate the% of the lung cancer association in 5p15 that operates through TL. To develop novel TL instruments, variants identified through deep sequencing of the 5p15 locus were genotyped in 900 controls. Variants that met MR criteria were combined into a single instrumental variable (IV), and its association with TL was estimated. We also used 6 previously identified TL predictors (p Results: The observational analysis suggested that longer TL is associated with decreased lung cancer risk (OR = 0.94, p = 0.04). This was more pronounced for squamous carcinoma (OR = 0.77, p = 1.1×10-4). We also showed that TL mediates up to 8% (p Conclusions: We developed novel genetic instruments for TL, and confirmed that genetically predicted longer TL is associated with increased lung cancer risk. These findings suggest that previously reported associations of long TL with decreased risk were likely due to residual confounding by smoking, age and/or reverse causation. Citation Format: Linda Kachuri, George Davey Smith, Geoffrey Liu, Maria Teresa Landi, David C. Christiani, Neil E. Caporaso, James D. McKay, Xifeng Wu, Melinda C. Aldrich, Gad Rennert, Dawn Teare, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, John K. Field, Lambertus A. Kiemeney, Adonina Tardon, Aage Haugen, Stephen Lam, Loic Le Marchand, Matthew B. Schabath, Angeline S. Andrew, Mattias Johansson, Jonas Manjer, Philip Lazarus, Susanne Arnold, Gordon Fehringer, Xuchen Zong, Paul Brennan, Stig E. Bojesen, Christopher I. Amos, Rayjean J. Hung. Mendelian randomization and mediation analysis of 5p15.33, telomere length and lung cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 817.