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Background:The introduction of two-view mammography at incident (subsequent) screens in the National Health Service Breast Screening Programme (NHSBSP) has led to an increased number of cancers detected at screen. However, the effect of two-view mammography on interval cancer rates has yet to be assessed.Methods:Routine screening and interval cancer data were collated from all screening programmes in the United Kingdom for women aged 50-64, screened between 1 April 2003 and 31 March 2005. Interval cancer rates were compared based on whether two-view mammography was in use at the last routine screen.Results:The reduction in interval cancers following screening using two-view mammography compared with one view was 0.68 per 1 000 women screened. Overall, this suggests the introduction of two-view mammography at incident screen was accompanied by a 15-20% reduction in interval cancer rates in the NHSBSP.Conclusion:The introduction of two-view mammography at incident screens is associated with a reduction in incidence of interval cancers. This is consistent with previous publications on a contemporaneous increase in screen-detected cancers. The results provide further evidence of the benefit of the use of two-view mammography at incident screens. [ABSTRACT FROM AUTHOR]

Background: We provide a comprehensive view of the impact of alcohol consumption, tobacco smoking, excess body weight, and human papillomavirus (HPV) infection on cancer mortality and years of life lost (YLLs) in Brazil, Russia, India, China, South Africa, the United Kingdom (UK), and United States (US)., Methods: We collected population attributable fractions of the four risk factors from global population-based studies and applied these to estimates of cancer deaths in 2020 to obtain potentially preventable cancer deaths and their 95% confidence intervals (CIs). Using life tables, we calculated the number and age-standardised rates of YLLs (ASYR)., Findings: In Brazil, Russia, India, China, South Africa, the UK, and the US in 2020, an estimated 5.9 million (3.3 million-8.6 million) YLLs from cancer were attributable to alcohol consumption, 20.8 million (17.0 million-24.6 million) YLLs to tobacco smoking, 3.1 million (2.4 million-3.8 million) YLLs to excess body weight, and 4.0 million (3.9 million-4.2 million) YLLs to HPV infection. The ASYR from cancer due to alcohol consumption was highest in China (351.4 YLLs per 100,000 population [95% CI 194.5-519.2]) and lowest in the US (113.5 [69.6-157.1]) and India (115.4 [49.7-172.7). For tobacco smoking, China (1159.9 [950.6-1361.8]) had the highest ASYR followed by Russia (996.8 [831.0-1154.5). For excess body weight, Russia and the US had the highest ASYRs (385.1 [280.6-481.2] and 369.4 [299.6-433.6], respectively). The highest ASYR due to HPV infection was in South Africa (457.1 [453.3-462.6]). ASYRs for alcohol consumption and tobacco smoking were higher among men than women, whereas women had higher ASYRs for excess body weight and HPV infection., Interpretation: Our findings demonstrate the importance of cancer control efforts to reduce the burden of cancer death and YLLs due to modifiable cancer risk factors and promote the use of YLLs to summarise disease burden., Funding: Cancer Research UK., Competing Interests: The authors have no conflicts of interest to declare. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization., (© 2023 Published by Elsevier Ltd.)

Background: There has been growing interest in the UK and internationally of risk-stratified breast screening whereby individualised risk assessment may inform screening frequency, starting age, screening instrument used, or even decisions not to screen. This study evaluates the cost-effectiveness of eight proposals for risk-stratified screening regimens compared to both the current UK screening programme and no national screening., Methods: A person-level microsimulation model was developed to estimate health-related quality of life, cancer survival and NHS costs over the lifetime of the female population eligible for screening in the UK., Results: Compared with both the current screening programme and no screening, risk-stratified regimens generated additional costs and QALYs, and had a larger net health benefit. The likelihood of the current screening programme being the optimal scenario was less than 1%. No screening amongst the lowest risk group, and triannual, biennial and annual screening amongst the three higher risk groups was the optimal screening strategy from those evaluated., Conclusions: We found that risk-stratified breast cancer screening has the potential to be beneficial for women at the population level, but the net health benefit will depend on the particular risk-based strategy., (© 2023. The Author(s).)

Background: We investigated the application of years of life lost (YLL) in routine cancer statistics using cancer mortality data from 1988 to 2017., Methods: Cancer mortality data for 17 cancers and all cancers in the UK from 1988 to 2017 were provided by the UK Association of Cancer Registries by sex, 5-year age group, and year. YLL, age-standardised YLL rate (ASYR) and age-standardised mortality rate (ASMR) were estimated., Results: The annual average YLL due to cancer, in the time periods 1988-1992 and 2013-2017, were about 2.2 and 2.3 million years, corresponding to 4510 and 3823 ASYR per 100,000 years, respectively. During 2013-2017, the largest number of YLL occurred in lung, bowel and breast cancer. YLL by age groups for all cancers showed a peak between 60-64 and 75-79. The relative contributions to incidence, mortality, and YLL differ between cancers. For instance, pancreas (in women and men) made up a smaller proportion of incidence (3%) but bigger proportion of mortality (6 and 5%) and YLL (5 and 6%), whereas prostate cancer (26% of incidence) contributed 13% mortality and 9% YLL., Conclusion: YLL is a useful measure of the impact different cancers have on society and puts a higher weight on cancer deaths in younger individuals., (© 2023. The Author(s).)

Mesothelioma is classified into three histological subtypes, epithelioid, sarcomatoid, and biphasic, according to the relative proportions of epithelioid and sarcomatoid tumor cells present. Current guidelines recommend that the sarcomatoid component of each mesothelioma is quantified, as a higher percentage of sarcomatoid pattern in biphasic mesothelioma shows poorer prognosis. In this work, we develop a dual-task graph neural network (GNN) architecture with ranking loss to learn a model capable of scoring regions of tissue down to cellular resolution. This allows quantitative profiling of a tumor sample according to the aggregate sarcomatoid association score. Tissue is represented by a cell graph with both cell-level morphological and regional features. We use an external multicentric test set from Mesobank, on which we demonstrate the predictive performance of our model. We additionally validate our model predictions through an analysis of the typical morphological features of cells according to their predicted score., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In his Comment [...].

Malignant Mesothelioma is a difficult to diagnose and highly lethal cancer usually associated with asbestos exposure. It can be broadly classified into three subtypes: Epithelioid, Sarcomatoid, and a hybrid Biphasic subtype in which significant components of both of the previous subtypes are present. Early diagnosis and identification of the subtype informs treatment and can help improve patient outcome. However, the subtyping of malignant mesothelioma, and specifically the recognition of transitional features from routine histology slides has a high level of inter-observer variability. In this work, we propose an end-to-end multiple instance learning (MIL) approach for malignant mesothelioma subtyping. This uses an adaptive instance-based sampling scheme for training deep convolutional neural networks on bags of image patches that allows learning on a wider range of relevant instances compared to max or top-N based MIL approaches. We also investigate augmenting the instance representation to include aggregate cellular morphology features from cell segmentation. The proposed MIL approach enables identification of malignant mesothelial subtypes of specific tissue regions. From this a continuous characterisation of a sample according to predominance of sarcomatoid vs epithelioid regions is possible, thus avoiding the arbitrary and highly subjective categorisation by currently used subtypes. Instance scoring also enables studying tumor heterogeneity and identifying patterns associated with different subtypes. We have evaluated the proposed method on a dataset of 234 tissue micro-array cores with an AUROC of 0.89±0.05 for this task. The dataset and developed methodology is available for the community at: https://github.com/measty/PINS., Competing Interests: Declaration of competing interest The authors have no known conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The Cytosponge is a cell-collection device, which, coupled with a test for trefoil factor 3 (TFF3), can be used to diagnose Barrett's oesophagus, a precursor condition to oesophageal adenocarcinoma. BEST3, a large pragmatic, randomised, controlled trial, investigated whether offering the Cytosponge-TFF3 test would increase detection of Barrett's. Overall, participants reported mostly positive experiences. This study reports the factors associated with the least positive experience., Methods: Patient experience was assessed using the Inventory to Assess Patient Satisfaction (IAPS), a 22-item questionnaire, completed 7-14 days after the Cytosponge test., Study Cohort: All BEST3 participants who answered ≥ 15 items of the IAPS (N = 1458)., Statistical Analysis: A mean IAPS score between 1 and 5 (5 indicates most negative experience) was calculated for each individual. 'Least positive' experience was defined according to the 90th percentile. 167 (11.4%) individuals with a mean IAPS score of ≥ 2.32 were included in the 'least positive' category and compared with the rest of the cohort. Eleven patient characteristics and one procedure-specific factor were assessed as potential predictors of the least positive experience. Multivariable logistic regression analysis using backwards selection was conducted to identify factors independently associated with the least positive experience and with failed swallow at first attempt, one of the strongest predictors of least positive experience., Results: The majority of responders had a positive experience, with an overall median IAPS score of 1.7 (IQR 1.5-2.1). High (OR = 3.01, 95% CI 2.03-4.46, p < 0.001) or very high (OR = 4.56, 95% CI 2.71-7.66, p < 0.001) anxiety (relative to low/normal anxiety) and a failed swallow at the first attempt (OR = 3.37, 95% CI 2.14-5.30, p < 0.001) were highly significant predictors of the least positive patient experience in multivariable analyses. Additionally, sex (p = 0.036), height (p = 0.032), alcohol intake (p = 0.011) and education level (p = 0.036) were identified as statistically significant predictors., Conclusion: We have identified factors which predict patient experience. Identifying anxiety ahead of the procedure and discussing particular concerns with patients or giving them tips to help with swallowing the capsule might help improve their experience. Trial registration ISRCTN68382401., (© 2023. The Author(s).)

Objectives: The BEST3 trial demonstrated the efficacy and safety of the Cytosponge-trefoil factor 3, a cell collection device coupled with the biomarker trefoil factor 3, as a tool for detecting Barrett's oesophagus, a precursor of oesophageal adenocarcinoma (OAC), in primary care. In this nested study, our aim was to understand patient experiences., Design: Mixed-methods using questionnaires (including Inventory to Assess Patient Satisfaction, Spielberger State-Trait Anxiety Inventory-6 and two-item perceived risk) and interviews., Outcome Measures: Participant satisfaction, anxiety and perceived risk of developing OAC., Setting: General practices in England., Participants: Patients with acid reflux enrolled in the intervention arm of the BEST3 trial and attending the Cytosponge appointment (N=1750)., Results: 1488 patients successfully swallowing the Cytosponge completed the follow-up questionnaires, while 30 were interviewed, including some with an unsuccessful swallow.Overall, participants were satisfied with the Cytosponge test. Several items showed positive ratings, in particular convenience and accessibility, staff's interpersonal skills and perceived technical competence. The most discomfort was reported during the Cytosponge removal, with more than 60% of participants experiencing gagging. Nevertheless, about 80% were willing to have the procedure again or to recommend it to friends; this was true even for participants experiencing discomfort, as confirmed in the interviews.Median anxiety scores were below the predefined level of clinically significant anxiety and slightly decreased between baseline and follow-up (p < 0.001). Interviews revealed concerns around the ability to swallow, participating in a clinical trial, and waiting for test results.The perceived risk of OAC increased following the Cytosponge appointment (p<0.001). Moreover, interviews suggested that some participants had trouble conceptualising risk and did not understand the relationships between test results, gastro-oesophageal reflux and risk of Barrett's oesophagus and OAC., Conclusions: When delivered during a trial in primary care, the Cytosponge is well accepted and causes little anxiety., Trial Registration Number: ISRCTN68382401., Competing Interests: Competing interests: RCF is named on patents related to the Cytosponge-trefoil factor 3 test. Covidien GI Solutions (now Medtronic) licensed the Cytosponge from the Medical Research Council, and the device has now received the CE mark and is cleared by the US Food and Drug Administration. RCF is a shareholder in Cyted, a company working on early detection technology. PS reports fees paid to his organisation from GRAIL, outside of the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Current guidelines recommend endoscopic surveillance for Barrett oesophagus (BE), but the value of surveillance is still debated. Using a combination of primary care, secondary care and cancer registry datasets, we examined the impact of a prior BE diagnosis, clinical and risk factors on survival from oesophageal cancer and adenocarcinoma., Methods: Retrospective cohort study of patients aged 50 and above diagnosed with malignant oesophageal cancer between 1993 and 2014 using Clinical Practice Research Datalink (CPRD). All prior BE diagnoses and endoscopies were identified from CPRD and Hospital Episode Statistics. Histology information was obtained from linked cancer registry data. We used flexible parametric models to estimate excess hazard ratios (EHRs) for relative survival. We simulated the potential impact of lead-time by adding random lead-times from a variety of distributions to all those with prior BE., Results: Among our oesophageal cancer (n = 7503) and adenocarcinoma (n = 1476) cohorts only small percentages, 3.4% and 5.3%, respectively, had a prior BE diagnosis. Two-year relative survival was better among patients with BE: 48.0% (95% CI 41.9-54.9) compared to 25.2% (24.3-26.2) without. Patients with BE had a better prognosis (EHR = 0.53, 0.41-0.68). Survival was higher even if patients with BE had fewer than two endoscopies (50.0%; 43.6-57.3). A survival benefit was still observed after lead-time adjustment, with a 20% absolute difference in 2-year survival using a 5 year mean sojourn time., Conclusions: Patients with a prior BE diagnosis had a survival advantage. This was not fully explained by surveillance endoscopies., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants., Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual., Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0)., Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings., Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer., Competing Interests: Declaration of interests HL holds patents on intact PSA assays and is named on a patent for a statistical method to detect prostate cancer licensed to Arctic Partners and commercialised by OPKO Health, and has stock in Arctic Partners and OPKO Health and receives royalties from sales of the 4Kscore test. RAE has received speaker honoraria from Genitourinary-American Society of Clinical Oncology, The University of Chicago, European Society for Medical Oncology (paid by Bayer and Ipsen), and The Royal Marsden NHS Foundation Trust (with support from Janssen), and is a member of the AstraZeneca UK Limited Prostate Dx Advisory Panel external expert committee. No organisation had any role in the decision to publish or in the writing of the manuscript. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management., Methods: This multicentre, pragmatic, randomised controlled trial was done in 109 socio-demographically diverse general practice clinics in England. Randomisation was done both at the general practice clinic level (cluster randomisation) and at the individual patient level, and the results for each type of randomisation were analysed separately before being combined. Patients were eligible if they were aged 50 years or older, had been taking acid-suppressants for symptoms of gastro-oesophageal reflux for more than 6 months, and had not undergone an endoscopy procedure within the past 5 years. General practice clinics were selected by the local clinical research network and invited to participate in the trial. For cluster randomisation, clinics were randomly assigned (1:1) by the trial statistician using a computer-generated randomisation sequence; for individual patient-level randomisation, patients were randomly assigned (1:1) by the general practice clinics using a centrally prepared computer-generated randomisation sequence. After randomisation, participants received either standard management of gastro-oesophageal reflux (usual care group), in which participants only received an endoscopy if required by their general practitioner, or usual care plus an offer of the Cytosponge-TFF3 procedure, with a subsequent endoscopy if the procedure identified TFF3-positive cells (intervention group). The primary outcome was the diagnosis of Barrett's oesophagus at 12 months after enrolment, expressed as a rate per 1000 person-years, in all participants in the intervention group (regardless of whether they had accepted the offer of the Cytosponge-TFF3 procedure) compared with all participants in the usual care group. Analyses were intention-to-treat. The trial is registered with the ISRCTN registry, ISRCTN68382401, and is completed., Findings: Between March 20, 2017, and March 21, 2019, 113 general practice clinics were enrolled, but four clinics dropped out shortly after randomisation. Using an automated search of the electronic prescribing records of the remaining 109 clinics, we identified 13 657 eligible patients who were sent an introductory letter with 14 days to opt out. 13 514 of these patients were randomly assigned (per practice or at the individual patient level) to the usual care group (n=6531) or the intervention group (n=6983). Following randomisation, 149 (2%) of 6983 participants in the intervention group and 143 (2%) of 6531 participants in the usual care group, on further scrutiny, did not meet all eligibility criteria or withdrew from the study. Of the remaining 6834 participants in the intervention group, 2679 (39%) expressed an interest in undergoing the Cytosponge-TFF3 procedure. Of these, 1750 (65%) met all of the eligibility criteria on telephone screening and underwent the procedure. Most of these participants (1654 [95%]; median age 69 years) swallowed the Cytosponge successfully and produced a sample. 231 (3%) of 6834 participants had a positive Cytosponge-TFF3 result and were referred for an endoscopy. Patients who declined the offer of the Cytosponge-TFF3 procedure and all participants in the usual care group only had an endoscopy if deemed necessary by their general practitioner. During an average of 12 months of follow-up, 140 (2%) of 6834 participants in the intervention group and 13 (<1%) of 6388 participants in the usual care group were diagnosed with Barrett's oesophagus (absolute difference 18·3 per 1000 person-years [95% CI 14·8-21·8]; rate ratio adjusted for cluster randomisation 10·6 [95% CI 6·0-18·8], p<0·0001). Nine (<1%) of 6834 participants were diagnosed with dysplastic Barrett's oesophagus (n=4) or stage I oesophago-gastric cancer (n=5) in the intervention group, whereas no participants were diagnosed with dysplastic Barrett's oesophagus or stage I gastro-oesophageal junction cancer in the usual care group. Among 1654 participants in the intervention group who swallowed the Cytosponge device successfully, 221 (13%) underwent endoscopy after testing positive for TFF3 and 131 (8%, corresponding to 59% of those having an endoscopy) were diagnosed with Barrett's oesophagus or cancer. One patient had a detachment of the Cytosponge from the thread requiring endoscopic removal, and the most common side-effect was a sore throat in 63 (4%) of 1654 participants., Interpretation: In patients with gastro-oesophageal reflux, the offer of Cytosponge-TFF3 testing results in improved detection of Barrett's oesophagus. Cytosponge-TFF3 testing could also lead to the diagnosis of treatable dysplasia and early cancer. This strategy will lead to additional endoscopies with some false positive results., Funding: Cancer Research UK, National Institute for Health Research, the UK National Health Service, Medtronic, and the Medical Research Council., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In 2012, the Euroscreen project published a review of incidence-based mortality evaluations of breast cancer screening programmes. In this paper, we update this review to October 2019 and expand its scope from Europe to worldwide. We carried out a systematic review of incidence-based mortality studies of breast cancer screening programmes, and a meta-analysis of the estimated effects of both invitation to screening and attendance at screening, with adjustment for self-selection bias, on incidence-based mortality from breast cancer. We found 27 valid studies. The results of the meta-analysis showed a significant 22% reduction in breast cancer mortality with invitation to screening, with a relative risk of 0.78 (95% CI 0.75-0.82), and a significant 33% reduction with actual attendance at screening (RR 0.67, 95% CI 0.61-0.75). Breast cancer screening in the routine healthcare setting continues to confer a substantial reduction in mortality from breast cancer.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations., Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status., Design, Setting, and Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy., Outcome Measurements and Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians., Results and Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65)., Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers., Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Early detection of oesophageal cancer improves outcomes; however, the optimal strategy for identifying patients at increased risk from the pre-cancerous lesion Barrett's oesophagus (BE) is not clear. The Cytosponge, a novel non-endoscopic sponge device, combined with the biomarker Trefoil Factor 3 (TFF3) has been tested in four clinical studies. It was found to be safe, accurate and acceptable to patients. The aim of the BEST3 trial is to evaluate if the offer of a Cytosponge-TFF3 test in primary care for patients on long term acid suppressants leads to an increase in the number of patients diagnosed with BE., Methods: The BEST3 trial is a pragmatic multi-site cluster-randomised controlled trial set in primary care in England. Approximately 120 practices will be randomised 1:1 to either the intervention arm, invitation to a Cytosponge-TFF3 test, or the control arm usual care. Inclusion criteria are men and women aged 50 or over with records of at least 6 months of prescriptions for acid-suppressants in the last year. Patients in the intervention arm will receive an invitation to have a Cytosponge-TFF3 test in their general practice. Patients with a positive TFF3 test will receive an invitation for an upper gastro-intestinal endoscopy at their local hospital-based endoscopy clinic to test for BE. The primary objective is to compare histologically confirmed BE diagnosis between the intervention and control arms to determine whether the offer of the Cytosponge-TFF3 test in primary care results in an increase in BE diagnosis within 12 months of study entry., Discussion: The BEST3 trial is a well-powered pragmatic trial testing the use of the Cytosponge-TFF3 test in the same population that we envisage it being used in clinical practice. The data generated from this trial will enable NICE and other clinical bodies to decide whether this test is suitable for routine clinical use., Trial Registration: This trial was prospectively registered with the ISRCTN Registry on 19/01/2017, trial number ISRCTN68382401 .

Background: The aim of this study was to assess the incidence and trends of oesophageal adenocarcinomas (OACs) and squamous cell carcinomas (OSCCs) in England from 1971 to 2037., Methods: Data on 220,026 oesophageal cancers diagnosed in England between 1971 and 2013 were extracted. Multiple imputation was used to predict morphology data were missing. Incidence rates were modelled and extrapolated to 2037 using age-period-cohort models., Results: The OAC age-standardised incidence rate (ASRs) increase was greatest from 1972 to 1992 (from 4.8 to 12.3 for men and 1.1 to 3 per 100,000 for women) and slowed from 1992 to 2012 (with an increase to 17 for men and 3.8 per 100,000 for women). OSCCs rates decreased from 7.5 to 4.9 from 1972 to 2012 for men. For women, ASRs increased from 5.5 to 5.9 between 1972 and 1992 and then decreased to 4.7 per 100,000 until 2012. Rates until 2032 are predicted to stay stable for OACs and further decrease for OSCCs., Conclusions: Imputing missing morphology allowed accurate and up-to-date estimates of trends and projections. We observed a slowing down of the increase in OAC ASRs and an overall decrease in OSCC ASRs.

Barrett's esophagus (BE) predisposes patients to esophageal adenocarcinoma. 3 to 6% of individuals with gastro-esophageal reflux disease are estimated to have BE but only 20 to 25% of BE patients are currently diagnosed. The current gold standard for diagnosis of BE is per-oral upper GI endoscopy. As this is not suitable for large-scale screening, a number of alternative methods are currently being investigated: transnasal and video capsule endoscopy, endomicroscopy, cell collection devices like the cytosponge and biomarkers. Some of these are promising, however, well powered studies carried out in relevant screening populations are needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: In England, participation in breast cancer screening has been decreasing in the past 10 years, approaching the national minimum standard of 70%. Interventions aimed at improving participation need to be investigated and put into practice to stop this downward trend. We assessed the effect on participation of sending invitations for breast screening with a timed appointment to women who did not attend their first offered appointment within the NHS Breast Screening Programme (NHSBSP)., Methods: In this open, randomised controlled trial, women in six centres in the NHSBSP in England who were invited for routine breast cancer screening were randomly assigned (1:1) to receive an invitation to a second appointment with fixed date and time (intervention) or an invitation letter with a telephone number to call to book their new screening appointment (control) in the event of non-attendance at the first offered appointment. Randomisation was by SX number, a sequential unique identifier of each woman within the NHSBSP, and at the beginning of the study a coin toss decided whether women with odd or even SX numbers would be allocated to the intervention group. Women aged 50-70 years who did not attend their first offered appointment were eligible for the analysis. The primary endpoint was participation (ie, attendance at breast cancer screening) within 90 days of the date of the first offered appointment; we used Poisson regression to compare the proportion of women who participated in screening in the study groups. All analyses were by intention to treat. This trial is registered with Barts Health, number 009304QM., Findings: We obtained 33 146 records of women invited for breast cancer screening at the six centres between June 2, 2014, and Sept 30, 2015, who did not attend their first offered appointment. 26 054 women were eligible for this analysis (12 807 in the intervention group and 13 247 in the control group). Participation within 90 days of the first offered appointment was significantly higher in the intervention group (2861 [22%] of 12 807) than in the control group (1632 [12%] of 13 247); relative risk of participation 1·81 (95% CI 1·70-1·93; p<0·0001)., Interpretation: These findings show that a policy of second appointments with fixed date and time for non-attenders of breast screening is effective in improving participation. This strategy can be easily implemented by the screening sites and, if combined with simple interventions, could further increase participation and ensure an upward shift in the participation trend nationally. Whether the policy should vary by time since last attended screen will have to be considered., Funding: National Health Service Cancer Screening Programmes and Department of Health Policy Research Programme., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Lung cancer survival is low and comparatively poor in the UK. Patients with symptoms suggestive of lung cancer commonly consult primary care, but it is unclear how general practitioners (GPs) distinguish which patients require further investigation. This study examined how patients' clinical and sociodemographic characteristics influence GPs' decisions to initiate lung cancer investigations., Methods: A factorial experiment was conducted among a national sample of 227 English GPs using vignettes presented as simulated consultations. A multimedia-interactive website simulated key features of consultations using actors ('patients'). GP participants made management decisions online for six 'patients', whose sociodemographic characteristics systematically varied across three levels of cancer risk. In low-risk vignettes, investigation (ie, chest X-ray ordered, computerised tomography scan or respiratory consultant referral) was not indicated; in medium-risk vignettes, investigation could be appropriate; in high-risk vignettes, investigation was definitely indicated. Each 'patient' had two lung cancer-related symptoms: one volunteered and another elicited if GPs asked. Variations in investigation likelihood were examined using multilevel logistic regression., Results: GPs decided to investigate lung cancer in 74% (1000/1348) of vignettes. Investigation likelihood did not increase with cancer risk. Investigations were more likely when GPs requested information on symptoms that 'patients' had but did not volunteer (adjusted OR (AOR)=3.18; 95% CI 2.27 to 4.70). However, GPs omitted to seek this information in 42% (570/1348) of cases. GPs were less likely to investigate older than younger 'patients' (AOR=0.52; 95% CI 0.39 to 0.7) and black 'patients' than white (AOR=0.68; 95% CI 0.48 to 0.95)., Conclusions: GPs were not more likely to investigate 'patients' with high-risk than low-risk cancer symptoms. Furthermore, they did not investigate everyone with the same symptoms equally. Insufficient data gathering could be responsible for missed opportunities in diagnosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: To investigate the acceptability of the Cytosponge, a novel sampling device to detect Barrett's oesophagus (BE), a precursor to oesophageal adenocarcinoma (EAC), among people with risk factors for this condition., Design: A qualitative study using semistructured interviews and focus group discussions. Data were explored by three researchers using thematic analysis., Setting: Community setting in London, UK., Participants: A recruitment company identified 33 adults (17 men, 16 women) aged 50-69 years with gastro-oesophageal reflux disease (GERD), a risk factor for BE. The majority of participants were white British (73%). The focus groups were stratified by gender and education. 10 individuals were interviewed and 23 participated in four focus groups., Results: 3 key themes emerged from the data: the anticipated physical experience, preferences for the content of information materials and comparisons with the current gold-standard test. Overall acceptability was high, but there was initial concern about the physical experience of taking the test, including swallowing and extracting the Cytosponge. These worries were reduced after handling the device and a video demonstration of the procedure. Knowledge of the relationship between GERD, BE and EAC was poor, and some suggested they would prefer not to know about the link when being offered the Cytosponge. Participants perceived the Cytosponge to be more comfortable, practical and economical than endoscopy., Conclusions: These qualitative data suggest the Cytosponge was acceptable to the majority of participants with risk factors for BE, and could be used as a first-line test to investigate GERD symptoms. Concerns about the physical experience of the test were alleviated through multimedia resources. The development of patient information materials is an important next step to ensuring patients are adequately informed and reassured about the procedure. Patient stakeholders should be involved in this process to ensure their concerns and preferences are considered., Trial Registration Number: ISRCTN68382401; pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Some women make an informed choice not to attend breast screening, whereas others may have forgotten about the appointment. We report on a randomised trial that investigates whether a reminder letter affects attendance., Methods: Women scheduled for a breast screening appointment were randomised to either receive a reminder letter a few days before their breast screening appointment in addition to the standard invitation letter (intervention) or not (control). The primary outcome was attendance within 30 days of the first offered appointment. Secondary outcomes were attendance within 90 and 180 days., Results: In all, 11,383 (49.9%) women were randomised to the intervention and 11,445 (50.1%) to the control. In the intervention arm, 7759 (68.2%) attended within 30 days of the first offered appointment compared with 7349 (64.2%) in the control arm. This difference was significant (P<0.001). The odds ratio (OR) (95% confidence interval) for the primary end point was 1.19 (1.13-1.26). This was not significantly affected by age, socioeconomic status or type of screen (prevalent or incident). Secondary endpoint analyses supported these results. Results did differ, however, between the different centres studied., Conclusions: This study found that postal reminders increase breast screening uptake, and could be practicable to implement in the NHS Breast Screening Programme.

Background: The value of screen detection and treatment of ductal carcinoma in situ (DCIS) is a matter of controversy. At present, the extent to which the diagnosis and treatment of DCIS could prevent the occurrence of invasive breast cancer in the future is not clear. We sought to estimate the association between detection of DCIS at screening and invasive interval cancers subsequent to the relevant screen., Methods: We obtained aggregate data for screen-detected cancers from 84 local screening units within 11 regional Quality Assurance Reference Centres in England, Wales, and Northern Ireland from the National Health Service Breast Screening Programme. Data for DCIS diagnoses were obtained for women aged 50-64 years who were invited to and attended mammographic breast screening from April 1, 2003, to March 31, 2007 (4 screening years). Patient-level data for interval cancer arising in the 36 months after each of these were analysed by Poisson regression with invasive interval cancer screen detection rate as the outcome variable; DCIS detection frequencies were fitted first as a continuous and then as a categorical variable. We repeated this analysis after adjustment with both small size and high-grade invasive screen-detected cancers., Findings: We analysed data for 5,243,658 women and on interval cancers occurring in the 36 months after the relevant screen. The average frequency of DCIS detected at screening was 1·60 per 1000 women screened (median 1·50 [unit range 0·54-3·56] [corrected to] per 1000 women). There was a significant negative association of screen-detected DCIS cases with the rate of invasive interval cancers (Poisson regression coefficient -0·084 [95% CI -0·13 to -0·03]; p=0·002). 90% of units had a DCIS detection frequency within the range of 1·00 to 2·22 per 1000 women; in these units, for every three screen-detected cases of DCIS, there was one fewer invasive interval cancer in the next 3 years. This association remained after adjustment for numbers of small screen-detected invasive cancers and for numbers of grade 3 invasive screen-detected cancers., Interpretation: The association between screen-detected DCIS and subsequent invasive interval cancers suggests that detection and treatment of DCIS is worthwhile in prevention of future invasive disease., Funding: UK Department of Health Policy Research Programme and NHS Cancer Screening Programmes., (Copyright © 2016 Duffy et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

DNA replication stress is a source of genomic instability. Here we identify changed mutation rate 1 (Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that Cmr1--together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins--define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to Cmr1, its human orthologue WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that Cmr1/WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins.

Mutations in three of the genes encoding the XPB, XPD and TTDA components of transcription factor TFIIH can result in the clinical phenotype of trichothiodystrophy (TTD). Different mutations in XPB and XPD can instead cause xeroderma pigmentosum (XP). The completely different features of these disorders have been attributed to TTD being a transcription syndrome. In order to detect transcriptional differences between TTD and XP cells from the XP-D complementation group, we have compared gene expression profiles in cultured fibroblasts from normal, XP and TTD donors. Although we detected transcriptional differences between individual cell strains, using an algorithm of moderate stringency, we did not identify any genes whose expression was reproducibly different in proliferating fibroblasts from each type of donor. Following UV-irradiation, many genes were up- and down-regulated in all three cell types. The microarray analysis indicated some apparent differences between the different donor types, but on more detailed inspection, these turned out to be false positives. We conclude that there are minimal differences in gene expression in proliferating fibroblasts from TTD, XP-D and normal donors.

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder whose defining feature is brittle hair. Associated clinical symptoms include physical and mental retardation of different severity, ichthyosis, premature aging, and, in half of the patients, photosensitivity. Recently, C7orf11 (TTDN1) was identified as the first disease gene for the nonphotosensitive form of TTD, being mutated in two unrelated cases and in an Amish kindred. We have evaluated the involvement of TTDN1 in 44 unrelated nonphotosensitive TTD cases of different geographic origin and with different disease severity. Mutations were found in six patients, five of whom are homozygous and one of whom is a compound heterozygote. All five identified mutations are deletions that have not been described before. Three are deletions of a few bases, resulting in frameshifts and premature termination codons. The other two include the whole TTDN1 gene, suggesting that TTDN1 is not essential for cell proliferation and viability. The severity of the clinical features does not correlate with the type of mutation, indicating that other factors besides TTDN1 mutations influence the severity of the disorder. Since only a small proportion of the analyzed cases were mutated in TTDN1, the nonphotosensitive form of TTD is genetically heterogeneous. Mutations in TTDN1 do not affect the response to ultraviolet (UV) light or the steady state level of the repair/transcription factor IIH (TFIIH), which is central to the onset of the photosensitive form of TTD., ((c) 2006 Wiley-Liss, Inc.)

Microsatellite instability (MSI) in tumors is diagnostic for inactive DNA mismatch repair. It is widespread among some tumor types, such as colorectal or endometrial carcinoma, but is rarely found in leukemia. Therapy-related acute myeloid leukemia/myelodysplastic syndrome (tAML/MDS) is an exception, and MSI is frequent in tAML/MDS following cancer chemotherapy or organ transplantation. The development of MSI+ tumors is associated with an accumulation of insertion/deletion mutations in repetitive sequences. These events can cause inactivating frameshifts or loss of expression of key growth control proteins. We examined established MSI+ cell lines and tAML/MDS cases for frameshift-like mutations of repetitive sequences in several genes that have known, or suspected, relevance to leukemia. CASPASE-5, an acknowledged frameshift target in MSI+ gastrointestinal tract tumors, was frequently mutated in MSI+ cell lines (67%) and in tAML/MDS (29%). Frameshift-like mutations were also observed in the NF1 and FANCD2 genes that are associated with genetic conditions conferring a predisposition to leukemia. Both genes were frequent targets for mutation in MSI+ cell lines and colorectal carcinomas. FANCD2 mutations were also common in MSI+ tAML/MDS, although NF1 mutations were not observed. A novel FANCD2 polymorphism was also identified.

Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.

DNA mismatch repair (MMR) is an important replication error avoidance mechanism that prevents mutation. The association of defective MMR with familial and sporadic gastrointestinal and endometrial cancer has been acknowledged for some years. More recently, it has become apparent that MMR defects are common in acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS) that follows successful chemotherapy for a primary malignancy. Therapy-related haematological malignancies are often associated with treatment with alkylating agents. Their frequency is increasing and they now account for at least 10% of all AML cases. There is also evidence for an association between MMR deficient AML/MDS and immunosuppressive treatment with thiopurine drugs. Here we review how MMR interacts with alkylating agent and thiopurine-induced DNA damage and suggest possible ways in which MMR defects may arise in therapy-related AML/MDS.