Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

Urine high-risk human papillomavirus testing as an alternative to routine cervical screening: A comparative diagnostic accuracy study of two urine collection devices using a randomised study design trial.

OBJECTIVE: To evaluate the sensitivity of human papillomavirus (HPV) tested urine to detect high-grade cervical precancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) using two urine collection devices. DESIGN: Randomised controlled trial. SETTING: St Mary's Hospital, Manchester, UK. POPULATION: Colposcopy attendees with abnormal cervical screening; a total of 480 participants were randomised. Matched urine and cervical samples were available for 235 and 230 participants using a first-void urine (FVU)-collection device and standard pot, respectively. METHODS: Urine was self-collected and mixed with preservative - randomised 1:1 to FVU-collection device (Novosanis Colli-pee® 10 mL with urine conservation medium [UCM]) or standard pot. Matched clinician-collected cervical samples were taken before colposcopy. HPV testing used Roche cobas® 8800. A questionnaire evaluated urine self-sampling acceptability. MAIN OUTCOME MEASURES: The primary outcome measured sensitivity of HPV-tested urine (FVU-collection device and standard pot) for CIN2+ detection. Secondary outcomes compared HPV-tested cervical and urine samples for CIN2+ and evaluated the acceptability of urine self-sampling. RESULTS: Urine HPV test sensitivity for CIN2+ was higher with the FVU-collection device (90.3%, 95% CI 83.7%-94.9%, 112/124) than the standard pot (73.4%, 95% CI 64.7%-80.9%, 91/124, p = 0.0005). The relative sensitivity of FVU-device-collected urine was 0.92 (95% CI 0.87-0.97, pMcN = 0.004) compared with cervical, considering that all women were referred after a positive cervical HPV test. Urine-based sampling was acceptable to colposcopy attendees. CONCLUSIONS: Testing of FVU-device-collected urine for HPV was superior to standard-pot-collected urine in colposcopy attendees and has promising sensitivity for CIN2+ detection. General population HPV testing of FVU-device-collected urine will establish its clinical performance and acceptability as an alternative to routine cervical screening.

Optimising brain age estimation through transfer learning: A suite of pre-trained foundation models for improved performance and generalisability in a clinical setting.

Estimated age from brain MRI data has emerged as a promising biomarker of neurological health. However, the absence of large, diverse, and clinically representative training datasets, along with the complexity of managing heterogeneous MRI data, presents significant barriers to the development of accurate and generalisable models appropriate for clinical use. Here, we present a deep learning framework trained on routine clinical data (N up to 18,890, age range 18-96 years). We trained five separate models for accurate brain age prediction (all with mean absolute error ≤4.0 years, R2 ≥ .86) across five different MRI sequences (T2 -weighted, T2 -FLAIR, T1 -weighted, diffusion-weighted, and gradient-recalled echo T2 *-weighted). Our trained models offer dual functionality. First, they have the potential to be directly employed on clinical data. Second, they can be used as foundation models for further refinement to accommodate a range of other MRI sequences (and therefore a range of clinical scenarios which employ such sequences). This adaptation process, enabled by transfer learning, proved effective in our study across a range of MRI sequences and scan orientations, including those which differed considerably from the original training datasets. Crucially, our findings suggest that this approach remains viable even with limited data availability (as low as N = 25 for fine-tuning), thus broadening the application of brain age estimation to more diverse clinical contexts and patient populations. By making these models publicly available, we aim to provide the scientific community with a versatile toolkit, promoting further research in brain age prediction and related areas.

Safety of e-cigarettes and nicotine patches as stop-smoking aids in pregnancy: Secondary analysis of the Pregnancy Trial of E-cigarettes and Patches (PREP) randomized controlled trial.

AIMS: The aim of this study was to examine the safety of e-cigarettes (EC) and nicotine patches (NRT) when used to help pregnant smokers quit. DESIGN: A recent trial of EC versus NRT reported safety outcomes in the randomized arms. We conducted a further analysis based on product use. SETTING: Twenty-three hospitals in England and a stop-smoking service in Scotland took part. PARTICIPANTS: The participants comprised 1140 pregnant smokers. INTERVENTIONS: We compared women using and not using EC and NRT regularly during pregnancy. MEASUREMENTS: Measurements included nicotine intake compared with baseline, birth weight, other pregnancy outcomes, adverse events, maternal respiratory symptoms and relapse in early abstainers. FINDINGS: Use of EC was more common than use of NRT (47.3% vs 21.6%, P < 0.001). Women who stopped smoking (abstainers) and used EC at the end-of-pregnancy (EOP) reduced their salivary cotinine by 45% [49.3 ng/ml, 95% confidence interval (CI) = -79.8 to -10]. Only one abstainer used NRT at EOP. In dual users, cotinine increased by 19% (24 ng/ml, 95% CI = 3.5-68). In women reporting a reduction of at least 50% in cigarette consumption, cotinine levels increased by 10% in those using nicotine products and by 9% in those who did not. Birth weights in dual users and exclusive smokers were the same (3.1 kg). Birth weight in abstainers using either nicotine product was higher than in smokers [3.3 kg, standard deviation (SD) = 0.7] versus 3.1 kg, SD = 0.6; difference = 0.15 kg, 95% CI = 0.05-0.25) and not different from abstainers not using nicotine products (3.1 kg, SD = 0.8). Abstainers and smokers using nicotine products had no worse pregnancy outcomes or more adverse events than abstainers and smokers not using them. EC users reported more improvements than non-users in cough [adjusted relative risk (aRR) = 0.59, 95% CI = 0.37-0.93] and phlegm (aRR = 0.53, 95% CI = 0.31-0.92), controlling for smoking status. EC or NRT use had no association with relapse. CONCLUSIONS: Regular use of e-cigarettes or nicotine patches by pregnant smokers does not appear to be associated with any adverse outcomes.

The cost-effectiveness of risk-stratified breast cancer screening in the UK.

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.

Helping pregnant smokers quit: a multi-centre randomised controlled trial of electronic cigarettes versus nicotine replacement therapy.

Background: Some pregnant smokers try e-cigarettes, but effectiveness and safety of such use are unknown. Objectives: To compare effectiveness and safety of nicotine patches and e-cigarettes in pregnancy. Design: A pragmatic multi-centre randomised controlled trial. Setting: Twenty-three hospitals across England, and a Stop Smoking Service in Scotland. Participants: One thousand one hundred and forty pregnant daily smokers (12-24 weeks' gestation) motivated to stop smoking, with no strong preference for using nicotine patches or e-cigarettes. Interventions: Participants in the e-cigarette arm were posted a refillable e-cigarette device with two 10 ml bottles of tobacco-flavoured e-liquid (18 mg nicotine). Participants in the nicotine patches arm were posted a 2-week supply of 15 mg/16-hour nicotine patches. Supplies were provided for up to 8 weeks. Participants sourced further supplies themselves as needed. Participants in both arms received support calls prior to their target quit date, on the quit date, and weekly for the next 4 weeks. Outcome measures: The primary outcome was validated prolonged abstinence at the end of pregnancy. Participants lost to follow-up or not providing biochemical validation were included as non-abstainers. Secondary outcomes included self-reported abstinence at different time points, treatment adherence and safety outcomes. Results: Only 55% of self-reported abstainers mailed back useable saliva samples. Due to this, validated sustained abstinence rates were low (6.8% vs. 4.4% in the e-cigarettes and nicotine patches arms, respectively, risk ratio = 1.55, 95% confidence interval 0.95 to 2.53; Bayes factor = 2.7). In a pre-specified sensitivity analysis that excluded abstainers using non-allocated products, the difference became significant (6.8% vs. 3.6%, risk ratio = 1.93, 95% confidence interval 1.14 to 3.26; Bayes factor = 10). Almost a third of the sample did not set a target quit date and the uptake of support calls was low, as was the initial product use. At end of pregnancy, 33.8% versus 5.6% of participants were using their allocated product in the e-cigarettes versus nicotine patches arm (risk ratio = 6.01, 95% confidence interval 4.21 to 8.58). Regular use of e-cigarettes in the nicotine patches arm was more common than use of nicotine replacement products in the e-cigarette arm (17.8% vs. 2.8%). Rates of adverse events and adverse birth outcomes were similar in the two study arms, apart from participants in the e-cigarette arm having fewer infants with low birthweight (<2500 g) (9.6% vs. 14.8%, risk ratio = 0.65, 95% confidence interval 0.47 to 0.90; Bayes factor = 10.3). Limitations: Low rates of validation reduced the study power. A substantial proportion of participants did not use the support on offer sufficiently to test its benefits. Sample size may have been too small to detect differences in less frequent adverse effects. Conclusions: E-cigarettes were not significantly more effective than nicotine patches in the primary analysis, but when e-cigarettes use in the nicotine patches arm was accounted for, e-cigarettes were almost twice as effective as patches in all abstinence outcomes. In pregnant smokers seeking help, compared to nicotine patches, e-cigarettes are probably more effective, do not pose more risks to birth outcomes assessed in this study and may reduce the incidence of low birthweight. Future work: Routine monitoring of smoking cessation and birth outcomes in pregnant women using nicotine patches and e-cigarettes and further studies are needed to confirm these results. Trial registration: This trial is registered as ISRCTN62025374 and Eudract 2017-001237-65. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 13. See the NIHR Journals Library website for further project information.

Like many other smokers in the UK, some pregnant smokers try to limit or stop smoking with the help of e-cigarettes. It is not known whether this helps with stopping smoking and whether using e-cigarettes has any bad effects on the baby. We recruited 1140 pregnant smokers who wanted to quit. A random half were given nicotine patches, which are commonly used to help smokers quit. The other half were given an e-cigarette. They also received six weekly phone calls to support them in stopping smoking. We then looked at how many in each group stopped smoking by the end of pregnancy. More women stopped smoking in the group that was given an e-cigarette, but the difference was small and could be due to chance. However, some of the women in the nicotine patch group who had successfully stopped smoking were using e-cigarettes rather than patches. When these (and women in the e-cigarette group who used patches) were not counted, e-cigarettes helped almost twice as many women stop smoking than patches. E-cigarettes were better than patches in preventing low birthweight (having babies who weigh less than 2.5 kg). Otherwise, women given patches and those given e-cigarettes (and their babies) had similar numbers of medical complications. For pregnant women who smoke and need help to quit, e-cigarettes are probably more helpful than nicotine patches, and do not pose any additional risks to women or their babies.

Risk-stratified faecal immunochemical testing (FIT) for urgent colonoscopy in Lynch syndrome during the COVID-19 pandemic.

BACKGROUND: Lynch syndrome is a hereditary cancer disease resulting in an increased risk of colorectal cancer. Herein, findings are reported from an emergency clinical service implemented during the COVID-19 pandemic utilizing faecal immunochemical testing ('FIT') in Lynch syndrome patients to prioritize colonoscopy while endoscopy services were limited. METHODS: An emergency service protocol was designed to improve colonoscopic surveillance access throughout the COVID-19 pandemic in England for people with Lynch syndrome when services were extremely restricted (1 March 2020 to 31 March 2021) and promoted by the English National Health Service. Requests for faecal immunochemical testing from participating centres were sent to the National Health Service Bowel Cancer Screening South of England Hub and a faecal immunochemical testing kit, faecal immunochemical testing instructions, paper-based survey, and pre-paid return envelope were sent to patients. Reports with faecal haemoglobin results were returned electronically for clinical action. Risk stratification for colonoscopy was as follows: faecal haemoglobin less than 10 µg of haemoglobin/g of faeces (µg/g)-scheduled within 6-12 weeks; and faecal haemoglobin greater than or equal to 10 µg/g-triaged via an urgent suspected cancer clinical pathway. Primary outcomes of interest included the identification of highest-risk Lynch syndrome patients and determining the impact of faecal immunochemical testing in risk-stratified colonoscopic surveillance. RESULTS: Fifteen centres participated from June 2020 to March 2021. Uptake was 68.8 per cent amongst 558 patients invited. For 339 eligible participants analysed, 279 (82.3 per cent) had faecal haemoglobin less than 10 µg/g and 60 (17.7 per cent) had faecal haemoglobin greater than or equal to 10 µg/g. In the latter group, the diagnostic accuracy of faecal immunochemical testing was 65.9 per cent and escalation to colonoscopy was facilitated (median 49 versus 122 days, χ2 = 0.0003, P < 0.001). CONCLUSION: Faecal immunochemical testing demonstrated clinical value for Lynch syndrome patients requiring colorectal cancer surveillance during the pandemic in this descriptive report of an emergency COVID-19 response service. Further longitudinal investigation on faecal immunochemical testing efficacy in Lynch syndrome is warranted and will be examined under the 'FIT for Lynch' study (ISRCTN15740250).

audit_cc: A Stata command for the analysis of matched case-control audits of cervical cancer screening.

Background and objectives: Cervical screening programmes are crucial for the early diagnosis and prevention of cancer of the cervix. Regular auditing is vital for ensuring that these programmes achieve their full potential and meet their objectives in practice. Unfortunately, the time and skills required for the statistical analysis of the data collected are often important limiting factors. Comparisons across countries and over time have also been particularly difficult due to a lack of standardized definitions and methodology. We aimed to overcome these problems. Methods: Using the statistical software Stata, we developed a new command called audit_cc for the analysis of matched case-control audits of cervical cancer screening. Analyses are reported for two measures of screening history: time since last test and time since last negative test. Results: The command carries out the data manipulation which is required for the analysis and allows to save the resulting data set in an external file for further investigations. It promotes consistent evaluations of screening programmes over time and across studies and facilitates the creation of automatic publication-quality reports, which are especially useful in the context of routine audits. Conclusions: audit_cc is a valid tool that not only simplifies the analysis and reporting of cervical screening audits but also allows meaningful international comparisons. Although it is specific for cervical cancer, it can be seen as an example of how the standardisation of exposure definitions and key methodological issues can enable consistent and comparable evaluations of screening programmes across different countries and settings.

Years of life lost due to cancer in the United Kingdom from 1988 to 2017.

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.

Protocol for the YORKSURe prospective multistage study testing the feasibility for early detection of bladder cancer in populations with high disease-specific mortality risk.

INTRODUCTION: Around 25% of patients with bladder cancer (BCa) present with invasive disease. Non-randomised studies of population-based screening have suggested reductions in BCa-specific mortality are possible through earlier detection. The low prevalence of lethal disease in the general population means screening is not cost-effective and there is no consensus on the best strategy. Yorkshire has some of the highest mortality rates from BCa in England. We aim to test whether population screening in a region of high mortality risk will lead to a downward stage-migration of aggressive BCa, improved survival and is cost-effective. METHODS AND ANALYSIS: YORKSURe is a tiered, randomised, multicohort study to test the feasibility of a large BCa screening randomised controlled trial. In three parallel cohorts, participants will self-test urine (at home) up to six times. Results are submitted via a mobile app or freephone. Those with a positive result will be invited for further investigation at community-based early detection clinics or within usual National Health Service (NHS) pathways. In Cohort 1, we will post self-testing kits to research engaged participants (n=2000) embedded within the Yorkshire Lung Screening Trial. In Cohort 2, we will post self-testing kits to 3000 invitees. Cohort 2 participants will be randomised between haematuria and glycosuria testing using a reveal/conceal design. In Cohort 3, we will post self-testing kits to 500 patients within the NHS pathway for investigation of haematuria. Our primary outcomes are rates of recruitment and randomisation, rates of positive test and acceptability of the design. The study is currently recruiting and scheduled to finish in June 2023. ETHICS AND DISSEMINATION: The study has received the following approvals: London Riverside Research Ethics Committee (22/LO/0018) and Health Research Authority Confidentiality Advisory Group (20/CAG/0009). Results will be made available to providers and researchers via publicly accessible scientific journals. TRIAL REGISTRATION NUMBER: ISRCTN34273159.

Modelled mortality benefits of multi-cancer early detection screening in England.

BACKGROUND: Screening programmes utilising blood-based multi-cancer early detection (MCED) tests, which can detect a shared cancer signal from any site in the body with a single, low false-positive rate, could reduce cancer burden through early diagnosis. METHODS: A natural history ('interception') model of cancer was previously used to characterise potential benefits of MCED screening (based on published performance of an MCED test). We built upon this using a two-population survival model to account for an increased risk of death from cfDNA-detectable cancers relative to cfDNA-non-detectable cancers. We developed another model allowing some cancers to metastasise directly from stage I, bypassing intermediate tumour stages. We used incidence and survival-by-stage data from the National Cancer Registration and Analysis Service in England to estimate longer-term benefits to a cohort screened between ages 50-79 years. RESULTS: Estimated late-stage and mortality reductions were robust to a range of assumptions. With the least favourable dwell (sojourn) time and cfDNA status hazard ratio assumptions, we estimated, among 100,000 screened individuals, 67 (17%) fewer cancer deaths per year corresponding to 2029 fewer deaths in those screened between ages 50-79 years. CONCLUSION: Realising the potential benefits of MCED tests could substantially reduce late-stage cancer diagnoses and mortality.

Dynamic data-enabled stratified sampling for trial invitations with application in NHS-Galleri.

BACKGROUND: Participants of health research studies such as cancer screening trials usually have better health than the target population. Data-enabled recruitment strategies might be used to help minimise healthy volunteer effects on study power and improve equity. METHODS: A computer algorithm was developed to help target trial invitations. It assumes participants are recruited from distinct sites (such as different physical locations or periods in time) that are served by clusters (such as general practitioners in England, or geographical areas), and the population may be split into defined groups (such as age and sex bands). The problem is to decide the number of people to invite from each group, such that all recruitment slots are filled, healthy volunteer effects are accounted for, and equity is achieved through representation in sufficient numbers of all major societal and ethnic groups. A linear programme was formulated for this problem. RESULTS: The optimisation problem was solved dynamically for invitations to the NHS-Galleri trial (ISRCTN91431511). This multi-cancer screening trial aimed to recruit 140,000 participants from areas in England over 10 months. Public data sources were used for objective function weights, and constraints. Invitations were sent by sampling according to lists generated by the algorithm. To help achieve equity the algorithm tilts the invitation sampling distribution towards groups that are less likely to join. To mitigate healthy volunteer effects, it requires a minimum expected event rate of the primary outcome in the trial. CONCLUSION: Our invitation algorithm is a novel data-enabled approach to recruitment that is designed to address healthy volunteer effects and inequity in health research studies. It could be adapted for use in other trials or research studies.

Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response. METHODS: We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment. RESULTS: We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone. CONCLUSION: While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response.

Managing an extension of screening intervals: Avoiding boom and bust in health care workloads.

Extending screening intervals in ongoing cancer screening programmes can lead to challenging year-on-year variations in the number of screening tests. We explored how such variation could be diminished with a managed transition to the extended interval. We defined three extension scenarios: immediate extension for the entire target population; stepped transition by birth cohort; and gradual transition by reducing the number of available screening appointments. These were compared to a situation in which the interval remains unchanged in a demographic model covering a 15-year period. The model was populated with observed parameters from England, a real-world setting recommending cervical screening with 3-year intervals at age 25-49 and 5-year intervals at age 50-64. Informed by typical changes currently considered by several European programmes including the programme in England, we explored the effect on screening test numbers of an extension of the 3-year interval to 5 years for women younger than 50. All three extension scenarios resulted in similar cumulative numbers of screening tests, which were about 30% lower compared to a situation in which the interval would remain unchanged. However, the year-on-year variation in the number of screening tests varied between the scenarios. This variation was around 4-fold for the immediate scenario. In the stepped scenario, the yearly numbers could differ by around 20%, whereas in the gradual scenario they were virtually constant. A managed interval extension, transitioning different groups of the target population at different times, can substantially reduce the yearly variation in screening workload without increasing the total number of screening tests in the long term.

Predictors of the experience of a Cytosponge test: analysis of patient survey data from the BEST3 trial.

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.

Diagnosis, treatment and survival from bladder, upper urinary tract, and urethral cancers: real-world findings from NHS England between 2013 and 2019.

OBJECTIVE: We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. MATERIALS AND METHODS: Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. RESULTS: Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7-34.3 for BC, 3.9-4.2 for UTUC and 0.6-0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7-42.0%]) were referred outside the 2-week-wait pathway and 15 340 (mean [range] 12.2% [11.7-12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97-0.97) at 2 years in contrast to other cancers. CONCLUSION: The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete.

A case-control study to evaluate the impact of the breast screening programme on breast cancer incidence in England.

BACKGROUND: There is uncertainty about overdiagnosis in mammography screening. METHODS: We aimed to estimate the effect of screening on breast cancer incidence and overdiagnosis in the NHS Breast Screening Programme in England. The study included 57,493 cases and 105,653 controls, with cases defined as women diagnosed at ages 47-89 with primary breast cancer, invasive or ductal carcinoma in situ, in 2010 or 2011. Where possible, two controls were selected per case, matched on date of birth and screening area. Conditional logistic regression was used to estimate the effect of screening on breast cancer risk, with adjustment for potential self-selection bias. Results were combined with national incidence data to estimate absolute rates of overdiagnosis. Overdiagnosis was calculated as the cumulative excess of cancers diagnosed in the age group 50-77 in a woman attending three-yearly screening between ages 50 and 70 compared with a woman attending no screens. RESULTS: The estimated number of cases overdiagnosed in women attending all screens in the programme was 679.3 per 100,000 without adjustment for self-selection bias and 261.2 per 100,000 with adjustment. These corresponded to an estimated 9.5% of screen-detected cancers overdiagnosed without adjustment and 3.7% with adjustment for self-selection. CONCLUSIONS: The NHS Breast Screening Programme in England confers at worst modest levels of overdiagnosis.

Overcoming challenges of translating deep-learning models for glioblastoma: the ZGBM consortium.

OBJECTIVE: To report imaging protocol and scheduling variance in routine care of glioblastoma patients in order to demonstrate challenges of integrating deep-learning models in glioblastoma care pathways. Additionally, to understand the most common imaging studies and image contrasts to inform the development of potentially robust deep-learning models. METHODS: MR imaging data were analysed from a random sample of five patients from the prospective cohort across five participating sites of the ZGBM consortium. Reported clinical and treatment data alongside DICOM header information were analysed to understand treatment pathway imaging schedules. RESULTS: All sites perform all structural imaging at every stage in the pathway except for the presurgical study, where in some sites only contrast-enhanced T1-weighted imaging is performed. Diffusion MRI is the most common non-structural imaging type, performed at every site. CONCLUSION: The imaging protocol and scheduling varies across the UK, making it challenging to develop machine-learning models that could perform robustly at other centres. Structural imaging is performed most consistently across all centres. ADVANCES IN KNOWLEDGE: Successful translation of deep-learning models will likely be based on structural post-treatment imaging unless there is significant effort made to standardise non-structural or peri-operative imaging protocols and schedules.

International burden of cancer deaths and years of life lost from cancer attributable to four major risk factors: a population-based study in Brazil, Russia, India, China, South Africa, the United Kingdom, and United States.

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.