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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Use of a Cytosponge biomarker panel to prioritise endoscopic Barrett's oesophagus surveillance: a cross-sectional study followed by a real-world prospective pilot.

BACKGROUND: Endoscopic surveillance is recommended for patients with Barrett's oesophagus because, although the progression risk is low, endoscopic intervention is highly effective for high-grade dysplasia and cancer. However, repeated endoscopy has associated harms and access has been limited during the COVID-19 pandemic. We aimed to evaluate the role of a non-endoscopic device (Cytosponge) coupled with laboratory biomarkers and clinical factors to prioritise endoscopy for Barrett's oesophagus. METHODS: We first conducted a retrospective, multicentre, cross-sectional study in patients older than 18 years who were having endoscopic surveillance for Barrett's oesophagus (with intestinal metaplasia confirmed by TFF3 and a minimum Barrett's segment length of 1 cm [circumferential or tongues by the Prague C and M criteria]). All patients had received the Cytosponge and confirmatory endoscopy during the BEST2 (ISRCTN12730505) and BEST3 (ISRCTN68382401) clinical trials, from July 7, 2011, to April 1, 2019 (UK Clinical Research Network Study Portfolio 9461). Participants were divided into training (n=557) and validation (n=334) cohorts to identify optimal risk groups. The biomarkers evaluated were overexpression of p53, cellular atypia, and 17 clinical demographic variables. Endoscopic biopsy diagnosis of high-grade dysplasia or cancer was the primary endpoint. Clinical feasibility of a decision tree for Cytosponge triage was evaluated in a real-world prospective cohort from Aug 27, 2020 (DELTA; ISRCTN91655550; n=223), in response to COVID-19 and the need to provide an alternative to endoscopic surveillance. FINDINGS: The prevalence of high-grade dysplasia or cancer determined by the current gold standard of endoscopic biopsy was 17% (92 of 557 patients) in the training cohort and 10% (35 of 344) in the validation cohort. From the new biomarker analysis, three risk groups were identified: high risk, defined as atypia or p53 overexpression or both on Cytosponge; moderate risk, defined by the presence of a clinical risk factor (age, sex, and segment length); and low risk, defined as Cytosponge-negative and no clinical risk factors. The risk of high-grade dysplasia or intramucosal cancer in the high-risk group was 52% (68 of 132 patients) in the training cohort and 41% (31 of 75) in the validation cohort, compared with 2% (five of 210) and 1% (two of 185) in the low-risk group, respectively. In the real-world setting, Cytosponge results prospectively identified 39 (17%) of 223 patients as high risk (atypia or p53 overexpression, or both) requiring endoscopy, among whom the positive predictive value was 31% (12 of 39 patients) for high-grade dysplasia or intramucosal cancer and 44% (17 of 39) for any grade of dysplasia. INTERPRETATION: Cytosponge atypia, p53 overexpression, and clinical risk factors (age, sex, and segment length) could be used to prioritise patients for endoscopy. Further investigation could validate their use in clinical practice and lead to a substantial reduction in endoscopy procedures compared with current surveillance pathways. FUNDING: Medical Research Council, Cancer Research UK, Innovate UK.

The influence of postscreening follow-up time and participant characteristics on estimates of overdiagnosis from lung cancer screening trials.

We aimed to explore the underlying reasons that estimates of overdiagnosis vary across and within low-dose computed tomography (LDCT) lung cancer screening trials. We conducted a systematic review to identify estimates of overdiagnosis from randomised controlled trials of LDCT screening. We then analysed the association of Ps (the excess incidence of lung cancer as a proportion of screen-detected cases) with postscreening follow-up time using a linear random effects meta-regression model. Separately, we analysed annual Ps estimates from the US National Lung Screening Trial (NLST) and German Lung Cancer Screening Intervention Trial (LUSI) using exponential decay models with asymptotes. We conducted stratified analyses to investigate participant characteristics associated with Ps using the extended follow-up data from NLST. Among 12 overdiagnosis estimates from 8 trials, the postscreening follow-up ranged from 3.8 to 9.3 years, and Ps ranged from -27.0% (ITALUNG, 8.3 years follow-up) to 67.2% (DLCST, 5.0 years follow-up). Across trials, 39.1% of the variation in Ps was explained by postscreening follow-up time. The annual changes in Ps were -3.5% and -3.9% in the NLST and LUSI trials, respectively. Ps was predicted to plateau at 2.2% for NLST and 9.2% for LUSI with hypothetical infinite follow-up. In NLST, Ps increased with age from -14.9% (55-59 years) to 21.7% (70-74 years), and time trends in Ps varied by histological type. The findings suggest that differences in postscreening follow-up time partially explain variation in overdiagnosis estimates across lung cancer screening trials. Estimates of overdiagnosis should be interpreted in the context of postscreening follow-up and population characteristics.

Interpreting the results of noninferiority trials-a review.

Noninferiority trials are becoming increasing common, but are often poorly reported and misunderstood. A better understanding of the new components of a noninferiority trial and their interpretation is needed. Noninferiority trials are an extension of conventional superiority trials, which provide a basis for determining if a new treatment, which may have advantages other than efficacy, has sufficient efficacy to be useful in certain situations. A key feature is the need to specify a clinical noninferiority margin above which the lower boundary of the confidence interval for the difference between the new treatment and the conventional treatment must lie. In most cases a nontreated control arm is not included, and when the efficacy of the new treatment is less than that of the standard treatment, determining its efficacy versus no treatment can be a major challenge. Treatments meeting a clinical noninferiority requirement can be statistically significantly superior to standard treatment, of similar efficacy (i.e., no significant difference), or even significantly inferior in a conventional analysis. Noninferiority comparisons are an important addition to the reporting of clinical trials, but require prior consideration of several factors that conventional superiority analyses do not address.

Impact of changes to the interscreening interval and faecal immunochemical test threshold in the national bowel cancer screening programme in England: results from the FIT pilot study.

INTRODUCTION: The NHS Bowel Cancer Screening Programme (BCSP) faces endoscopy capacity challenges from the COVID-19 pandemic and plans to lower the screening starting age. This may necessitate modifying the interscreening interval or threshold. METHODS: We analysed data from the English Faecal Immunochemical Testing (FIT) pilot, comprising 27,238 individuals aged 59-75, screened for colorectal cancer (CRC) using FIT. We estimated screening sensitivity to CRC, adenomas, advanced adenomas (AA) and mean sojourn time of each pathology by faecal haemoglobin (f-Hb) thresholds, then predicted the detection of these abnormalities by interscreening interval and f-Hb threshold. RESULTS: Current 2-yearly screening with a f-Hb threshold of 120 µg/g was estimated to generate 16,092 colonoscopies, prevent 186 CRCs, detect 1142 CRCs, 7086 adenomas and 4259 AAs per 100,000 screened over 15 years. A higher threshold at 180 µg/g would reduce required colonoscopies to 11,500, prevent 131 CRCs, detect 1077 CRCs, 4961 adenomas and 3184 AAs. A longer interscreening interval of 3 years would reduce required colonoscopies to 10,283, prevent 126 and detect 909 CRCs, 4796 adenomas and 2986 AAs. CONCLUSION: Increasing the f-Hb threshold was estimated to be more efficient than increasing the interscreening interval regarding overall colonoscopies per screen-benefited cancer. Increasing the interval was more efficient regarding colonoscopies per cancer prevented.

The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.

BACKGROUND: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12-13 years with a catch-up programme for females aged 14-18 years in 2008-10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations. METHODS: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20-64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders. FINDINGS: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25-41) for age 16-18 years (school year 12-13), 62% (52-71) for age 14-16 years (school year 10-11), and 87% (72-94) for age 12-13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36-41) for those offered at age 16-18 years, 75% (72-77) for age 14-16 years, and 97% (96-98) for age 12-13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339-556) fewer than expected cervical cancers and 17 235 (15 919-18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England. INTERPRETATION: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12-13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995. FUNDING: Cancer Research UK.

Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.

BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.

A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy.

BACKGROUND: E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited regarding their effectiveness as compared with that of nicotine products approved as smoking-cessation treatments. METHODS: We randomly assigned adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, including product combinations, provided for up to 3 months, or an e-cigarette starter pack (a second-generation refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength of their choice. Treatment included weekly behavioral support for at least 4 weeks. The primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included participant-reported treatment usage and respiratory symptoms. RESULTS: A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath. CONCLUSIONS: E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support. (Funded by the National Institute for Health Research and Cancer Research UK; Current Controlled Trials number, ISRCTN60477608 .).

Exploring the utility and acceptability of Faecal immunochemical testing (FIT) as a novel intervention for the improvement of colorectal Cancer (CRC) surveillance in individuals with lynch syndrome (FIT for lynch study): a single-arm, prospective, multi-centre, non-randomised study.

BACKGROUND: Lynch Syndrome (LS) is an inherited cancer predisposition syndrome defined by pathogenic variants in the mismatch repair (MMR) or EPCAM genes. In the United Kingdom, people with LS are advised to undergo biennial colonoscopy from as early as 25 until 75 years of age to mitigate a high lifetime colorectal cancer (CRC) risk, though the consideration of additional surveillance intervention(s) through the application of non-invasive diagnostic devices has yet to be longitudinally observed in LS patients. In this study, we will examine the role of annual faecal immunochemical testing (FIT) alongside biennial colonoscopy for CRC surveillance in people with LS. METHODS/DESIGN: In this single-arm, prospective, non-randomised study, 400 LS patients will be recruited across 11 National Health Service (NHS) Trusts throughout the United Kingdom. Study inclusion requires a LS diagnosis, between 25 and 73 years old, and a routine surveillance colonoscopy scheduled during the recruitment period. Eligible patients will receive a baseline OC-Sensor™ FIT kit ahead of their colonoscopy, and annually for 3 years thereafter. A pre-paid envelope addressed to the central lab will be included within all patient mailings for the return of FIT kits and relevant study documents. A questionnaire assessing attitudes and perception of FIT will also be included at baseline. All study samples received by the central lab will be assayed on an OC-Sensor™ PLEDIA Analyser. Patients with FIT results of ≥6 µg of Haemoglobin per gram of faeces (f-Hb) at Years 1 and/or 3 will be referred for colonoscopy via an urgent colonoscopy triage pathway. 16S rRNA gene V4 amplicon sequencing will be carried out on residual faecal DNA of eligible archived FIT samples to characterise the faecal microbiome. DISCUSSION: FIT may have clinical utility alongside colonoscopic surveillance in people with LS. We have designed a longitudinal study to examine the efficacy of FIT as a non-invasive modality. Potential limitations of this method will be assessed, including false negative or false positive FIT results related to specific morphological features of LS neoplasia or the presence of post-resection anastomotic inflammation. The potential for additional colonoscopies in a subset of participants may also impact on colonoscopic resources and patient acceptability. TRIAL REGISTRATION: Trial Registration: ISRCTN, ISRCTN15740250 . Registered 13 July 2021.

Recovery strategies following COVID-19 disruption to cervical cancer screening and their impact on excess diagnoses.

BACKGROUND: The COVID-19 pandemic has disrupted cervical cancer screening services. Assuming increases to screening capacity are unrealistic, we propose two recovery strategies: one extends the screening interval by 6 months for all and the other extends the interval by 36/60 months, but only for women who have already missed being screened. METHODS: Using routine statistics from England we estimate the number of women affected by delays to screening. We used published research to estimate the proportion of screening age women with high-grade cervical intraepithelial neoplasia and progression rates to cancer. Under two recovery scenarios, we estimate the impact of COVID-19 on cervical cancer over one screening cycle (3 years at ages 25-49 and 5 years at ages 50-64 years). The duration of disruption in both scenarios is 6 months. In the first scenario, 10.7 million women have their screening interval extended by 6 months. In the second, 1.5 million women (those due to be screened during the disruption) miss one screening cycle, but most women have no delay. RESULTS: Both scenarios result in similar numbers of excess cervical cancers: 630 vs. 632 (both 4.3 per 100,000 women in the population). However, the scenario in which some women miss one screening cycle creates inequalities-they would have much higher rates of excess cancer: 41.5 per 100,000 delayed for screened women compared to those with a 6-month delay (5.9 per 100,000). CONCLUSION: To ensure equity for those affected by COVID-19 related screening delays additional screening capacity will need to be paired with prioritising the screening of overdue women.