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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.

Abstract 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.

Abstract 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.

Abstract 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.

Abstract 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.

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.

Background: Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells). Design: The R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor. Participants: Synovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population. Main outcome measures: The primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of

Summary: Background: Primary HPV screening, due to its low specificity, requires an additional liquid-based cytology (LBC) triage test. However, even with LBC triage there has been a near doubling in the number of patients referred for colposcopy in recent years, the majority having low-grade disease. Methods: To counter this, a triage test that generates a spatial map of the cervical surface at a molecular level has been developed which removes the subjectivity associated with LBC by facilitating identification of lesions in their entirety. 50 patients attending colposcopy were recruited to participate in a pilot study to evaluate the test. For each patient, cells were lifted from the cervix onto a membrane (cervical cell lift, CCL) and immunostained with a biomarker of precancerous cells, generating molecular maps of the cervical surface. These maps were analysed to detect high-grade lesions, and the results compared to the final histological diagnosis. Findings: We demonstrated that spatial molecular mapping of the cervix has a sensitivity of 90% (95% CI 69-98) (positive predictive value 81% (95% CI 60-92)) for the detection of high-grade disease, and that AI-based analysis could aid disease detection through automated flagging of biomarker-positive cells. Interpretation: Spatial molecular mapping of the CCL improved the rate of detection of high-grade disease in comparison to LBC, suggesting that this method has the potential to decisively identify patients with clinically relevant disease that requires excisional treatment. Funding: CRUK Early Detection Project award, Jordan-Singer BSCCP award, Addenbrooke's Charitable Trust, UK-MRC, Janssen Pharmaceuticals/Advanced Sterilisation Products, and NWO.

Abstract Background There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. Methods Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. Results 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21–2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, p

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

All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.

Background: Esophageal adenocarcinoma has a very poor prognosis unless detected early. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett esophagus, a precursor of esophageal adenocarcinoma. Randomised controlled trial data from the BEST3 trial has shown that an offer of Cytosponge-TFF3 in the primary care setting in England to individuals on medication for acid reflux increases detection of Barrett esophagus 10-fold over a year compared with standard care. This is an economic evaluation of Cytosponge-TFF3 screening versus usual care using data from the BEST3 trial which took place between 20th March 2017 and 21st March 2019. Methods: A Markov model with a one-year cycle-length and a lifetime time horizon was created, adapting previous modeling work on Cytosponge screening. The impact of one round of Cytosponge screening was modelled in patients with a median age of 69 years (based on BEST3 trial population). Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted on model parameters. Findings: Per person, one round of Cytosponge-TFF3 screening, including confirmatory endoscopy and treatment, in the intervention arm costed £82 more than usual care and generated an additional 0.015 quality-adjusted life-years (QALYs) at an ICER of £5,500 per QALY gained. Probabilistic sensitivity analysis gave an ICER of £5,405 (95% CI -£6,791 to £17,600). The average QALY gain per person is small because the majority of patients in the model will not develop BE and therefore will have no resulting change in their utility, however the small proportion of patients who are identified with BE dysplasia or cancer derive large benefit. At a willingness-to-pay threshold of £20,000 per QALY, the probability that Cytosponge-TFF3 was cost-effective was over 90%. Interpretation: Using data from a pragmatic randomised trial, one-off Cytosponge-TFF3 screen is cost-effective relative to usual care for patients with gastro-esophageal reflux disease, despite relatively low uptake and an older population in this trial setting than previously modelled. Improving Cytosponge-TFF3 uptake and targeting younger patients is likely to further improve cost-effectiveness.

Abstract Background A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible. Methods The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1–5), rate of recruitment (R1–2), and DLT events timing (DT1–4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD. Results The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric. Conclusion When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario. Trial registration Clinical Trials NCT03307148 (11 October 2017).

Background: There remains disagreement on the long-term effect of mammographic screening in women aged 40–49 years. Objectives: The long-term follow-up of a randomised controlled trial that offered annual mammography to women aged 40–49 years. The estimation of the effect of these mammograms on breast cancer and other-cause mortality, and the effect on incidence, with implications for overdiagnosis. Design: An individually randomised controlled trial comparing offering annual mammography with offering usual care in those aged 40–48 years, and thus evaluating the effect of annual screening entirely taking place before the age of 50 years. There was follow-up for an average of 23 years for breast cancer incidence, breast cancer death and death from other causes. We analysed the mortality and incidence data by Poisson regression and estimated overdiagnosis formally using Markov process models. Setting: Twenty-three screening units in England, Wales and Scotland within the NHS Breast Screening Programme. Participants: Women aged 39–41 years were recruited between 1990 and 1997. After exclusions, a total of 53,883 women were randomised to undergo screening (the intervention group) and 106,953 women were randomised to have usual care (the control group). Interventions: The intervention group was invited to an annual breast screen with film mammography, two view at first screen and single view thereafter, up to and including the calendar year of their 48th birthday. The control group received no intervention. Both groups were invited to the National Programme from the age of 50 years, when screening is offered to all women in the UK. Main outcome measures: The main outcome measures were mortality from breast cancers diagnosed during the intervention phase of the trial (i.e. before the first National Programme screen at 50 years), mortality from all breast cancers diagnosed after randomisation, all-cause mortality, mortality from causes other than breast cancer, and the incidence of breast cancer. Results: There was a statistically significant 25% reduction in mortality from breast cancers diagnosed during the intervention phase at 10 years’ follow-up (relative rate 0.75, 95% confidence interval 0.58 to 0.97; p = 0.03). No reduction was observed thereafter (relative rate 0.98, 95% confidence interval 0.79 to 1.22). Overall, there was a statistically non-significant 12% reduction (relative rate 0.88, 95% confidence interval 0.74 to 1.03; p = 0.1). The absolute benefit remained approximately constant over time, at one death prevented per 1000 women screened. There was no effect of intervention on other-cause mortality (relative rate 1.02, 95% confidence interval 0.97 to 1.07; p = 0.4). The intervention group had a higher incidence of breast cancer than the control group during the intervention phase of the trial, but incidence equalised immediately on the first National Programme screen at the age of 50–52 years. Limitations: There was 31% average non-compliance with screening and three centres had to cease screening for resource and capacity reasons. Conclusions: Annual mammographic screening at the age of 40–49 years resulted in a relative reduction in mortality, which was attenuated after 10 years. It is likely that digital mammography with two views at all screens, as practised now, could improve this further. There was no evidence of overdiagnosis in addition to that which already results from the National Programme carried out at later ages. Future work: There is a need for research on the effects of modern mammographic protocols and additional imaging in this age group. Trial registration: Current Controlled Trials ISRCTN24647151. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 55. See the NIHR Journals Library website for further project information. Other funding in the past has been received from the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, the US National Cancer Institute and the American Cancer Society.

The COVID-19 epidemic can probably be ended and normal life restored, perhaps quite quickly, by weekly SARS-CoV-2 RNA testing together with household quarantine and systematic contact tracing. Isolated outbreaks could then be contained by contact tracing, supplemented if necessary by temporary local reintroduction of population testing or lockdown. Leading public health experts have recommended that this should be tried in a demonstration project in which a medium-sized city introduces weekly testing and lifts lockdown completely. The idea was not considered by the groups whose predictions have guided UK policy, so we have examined the statistical case for such a study. The combination of regular testing with strict household quarantine, which was not analysed in their models, has remarkable power to reduce transmission to the community from other household members as well as providing earlier diagnosis and facilitating rapid contact tracing.

Background: Randomised controlled trials demonstrating improved longevity are needed to justify high-dose vitamin D supplementation for older populations. Objectives: To demonstrate the feasibility of a large trial (n ≈ 20,000) of high-dose vitamin D in people aged 65–84 years through general practitioner (GP) practices, and to cluster randomise participating practices between open-label and double-blind randomisation to compare effects on recruitment, compliance and contamination. Design: Twenty GP practices were randomised in matched pairs between open-label and double-blind allocation. Within each practice, patients were individually randomised to vitamin D or control (i.e. no treatment or placebo). Participants were invited to attend their GP practice to provide a blood sample and complete a lifestyle questionnaire at recruitment and again at 2 years. Randomisation by telephone followed receipt of a serum corrected calcium assay confirming eligibility ( 400 IU vitamin D per day at 2 years was 5.0% in open practices and 4.8% in double-blind practices. Mean serum 25(OH)D concentration was 51.5 nmol/l [95% confidence interval (CI) 50.2 to 52.8 nmol/l] with 82.6% of participants

Summary: Background: Screening for Barrett's oesophagus relies on endoscopy, which is invasive and few who undergo the procedure are found to have the condition. We aimed to use machine learning techniques to develop and externally validate a simple risk prediction panel to screen individuals for Barrett's oesophagus. Methods: In this prospective study, machine learning risk prediction in Barrett's oesophagus (MARK-BE), we used data from two case-control studies, BEST2 and BOOST, to compile training and validation datasets. From the BEST2 study, we analysed questionnaires from 1299 patients, of whom 880 (67·7%) had Barrett's oesophagus, including 40 with invasive oesophageal adenocarcinoma, and 419 (32·3%) were controls. We randomly split (6:4) the cohort using a computer algorithm into a training dataset of 776 patients and a testing dataset of 523 patients. We compiled an external validation cohort from the BOOST study, which included 398 patients, comprising 198 patients with Barrett's oesophagus (23 with oesophageal adenocarcinoma) and 200 controls. We identified independently important diagnostic features of Barrett's oesophagus using the machine learning techniques information gain and correlation-based feature selection. We assessed multiple classification tools to create a multivariable risk prediction model. Internal validation of the model using the BEST2 testing dataset was followed by external validation using the BOOST external validation dataset. From these data we created a prediction panel to identify at-risk individuals. Findings: The BEST2 study included 40 diagnostic features. Of these, 19 added information gain but after correlation-based feature selection only eight showed independent diagnostic value including age, sex, cigarette smoking, waist circumference, frequency of stomach pain, duration of heartburn and acidic taste, and taking antireflux medication, of which all were associated with increased risk of Barrett's oesophagus, except frequency of stomach pain, with was inversely associated in a case-control population. Logistic regression offered the highest prediction quality with an area under the receiver-operator curve (AUC) of 0·87 (95% CI 0·84–0·90; sensitivity set at 90%; specificity of 68%). In the testing dataset, AUC was 0·86 (0·83–0·89; sensitivity set at 90%; specificity of 65%). In the external validation dataset, the AUC was 0·81 (0·74–0·84; sensitivity set at 90%; specificity of 58%). Interpretation: Our diagnostic model offers valid predictions of diagnosis of Barrett's oesophagus in patients with symptomatic gastro-oesophageal reflux disease, assisting in identifying who should go forward to invasive confirmatory testing. Our predictive panel suggests that overweight men who have been taking antireflux medication for a long time might merit particular consideration for further testing. Our risk prediction panel is quick and simple to administer but will need further calibration and validation in a prospective study in primary care. Funding: Charles Wolfson Charitable Trust and Guts UK.

Abstract 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.

Abstract Background High resolution anoscopy (HRA) examination is regarded as the best method for the management of anal high grade squamous intraepithelial lesions to prevent anal squamous carcinoma. However, little is known about the acceptability of this procedure. This analysis looks at patient experience of HRA examination and ablative treatment under local anaesthetic. Methods Patients took part in anonymised feedback of their experience immediately after their HRA examinations and/or treatments. A standard questionnaire was used that included assessment of pain and overall satisfaction scores as well as willingness to undergo future HRA examinations. Results Four hundred four (89.4%) responses were received and all responses were analysed. The group consisted of 119 females (29.4%) and 261 males (64.6%) with median age of 45 years (IQR = 19) and 45 years (IQR = 21) respectively, and included 58 new cases, 53 treatment cases and 202 surveillance cases. 158 patients (39.1%) had at least one biopsy during their visits. The median pain score was 2 [Inter Quartile Range (IQR) 3] on a visual analogue scale of 0 to 10, where 0 indicated no pain / discomfort and 10 indicated severe pain. The median pain score was 2 (IQR 2) in men and 4 (IQR = 3) in women [Dunn’s Test = 4.3, p

Purpose: To assess the sensitivity of cervical cytology to cancer by pooling individual patient cytology results from cancers diagnosed in studies that assessed cervical screening in low- and middle-income countries. Methods: Two authors reviewed studies identified through PubMed and Embase databases. We included studies that reported cervical cytology in which at least one woman was diagnosed with cervical cancer and in which abnormal cytology results were investigated at colposcopy and through a histologic sample (if appropriate). When cytology results were not reported in the manuscript, authors were contacted. Stratified analyses and meta-regression were performed to assess sources of heterogeneity between studies. Results: We included 717 cancers from 23 studies. The pooled sensitivity of cytology to cancer at a cutoff of a high-grade squamous intraepithelial lesion (HSIL) or worse was 79.4% (95% CI, 67.7% to 86.0%). Results from stratified analyses did not differ significantly, except among studies that recruited symptomatic women or women referred because of abnormal cytology, when the sensitivity of cytology was much higher (95.9%; 95% CI, 86.5% to 99.9%). The cutoff of an HSIL or worse detected 85% of the cancers that would have been detected at a cutoff of atypical squamous cells of undetermined significance or worse (relative sensitivity, 85.2%; 95% CI, 80.7% to 89.7%). Conclusion: Cytology at a high cutoff could be an excellent tool for targeted screening of populations at high risk of cervical cancer with a view to diagnose cancer at an earlier stage.

Purpose: To provide resource-stratified, evidence-based recommendations on the secondary prevention of cervical cancer globally. Methods: ASCO convened a multidisciplinary, multinational panel of oncology, primary care, epidemiology, health economic, cancer control, public health, and patient advocacy experts to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, a formal consensus-based process, and a modified ADAPTE process to adapt existing guidelines were conducted. Other experts participated in formal consensus. Results: Seven existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Four systematic reviews plus cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. Recommendations: Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies by setting are as follows: maximal: ages 25 to 65, every 5 years; enhanced: ages 30 to 65, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: ages 30 to 49, every 10 years; and basic: ages 30 to 49, one to three times per lifetime. For basic settings, visual assessment is recommended as triage; in other settings, genotyping and/or cytology are recommended. For basic settings, treatment is recommended if abnormal triage results are present; in other settings, colposcopy is recommended for abnormal triage results. For basic settings, treatment options are cryotherapy or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure (or ablation) is recommended. Twelve-month post-treatment follow-up is recommended in all settings. Women who are HIV positive should be screened with HPV testing after diagnosis and screened twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.Additional information can be found at www.asco.org/rs-cervical-cancer-secondary-prev-guideline and www.asco.org/guidelineswiki.It is the view of of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement, but not replace, local guidelines.

Background: Over the past few years, a large number of smokers in the UK have stopped smoking with the help of e-cigarettes. So far, UK Stop Smoking Services (SSSs) have been reluctant to include e-cigarettes among their treatment options because data on their efficacy compared with the licensed medications are lacking. Objective: The objective was to compare the efficacy of refillable e-cigarettes and nicotine replacement therapy (NRT) products, when accompanied by weekly behavioural support. Design: A randomised controlled trial comparing e-cigarettes and NRT. Setting: Three sites that provide local SSSs. Participants: The participants were 886 smokers seeking help to quit smoking, aged ≥ 18 years, not pregnant or breastfeeding, with no strong preference to use or not to use NRT or e-cigarettes in their quit attempt, and currently not using NRT or e-cigarettes. A total of 886 participants were randomised but two died during the study (one in each study arm) and were not included in the analysis. Interventions: The NRT arm (n = 446) received NRT of their choice (single or combination), provided for up to 12 weeks. The e-cigarette arm (n = 438) received an e-cigarette starter pack and were encouraged to buy addtional e-liquids and e-cigarette products of their choice. Both arms received the same standard behavioural support. Participants attended weekly sessions at their SSS and provided outcome data at 4 weeks. They were then followed up by telephone at 6 and 12 months. Participants reporting abstinence or at least 50% reduction in cigarette consumption at 12 months were invited to attend for carbon monoxide (CO) validation. Participants/researchers could not be blinded to the intervention. Main outcome measures: The primary outcome was CO-validated sustained abstinence rates at 52 weeks. Participants lost to follow-up or not providing biochemical validation were included as non-abstainers. Secondary outcomes included abstinence at other time points, reduction in smoke intake, treatment adherence and ratings, elicited adverse reactions, and changes in self-reported respiratory health. A cost-efficacy analysis of the intervention was also conducted. Results: The 1-year quit rate was 9.9% in the NRT arm and 18.0% in the e-cigarette arm (risk ratio 1.83, 95% confidence interval 1.30 to 2.58; p

ABSTRACT Human papillomavirus (HPV) vaccination elicits high-titer genotype-specific antibody responses that are associated with a reduced risk of cervical disease caused by vaccine-incorporated genotypes. Our objective was to evaluate dried blood spots (DBSs) and oral mucosal transudate (OMT) as alternative samples to serum to confirm HPV vaccine antibody status. A study was carried out to evaluate the feasibility of detecting HPV16 and HPV18 antibodies in OMT, DBSs, and sera among women who self-reported being unvaccinated or fully vaccinated with the HPV vaccine. Serum had the highest sensitivity (100%) for detection of antibodies against both HPV16 and HPV18 but the lowest specificity, due to the detection of natural infection antibodies in 16% of unvaccinated women. Conversely, DBSs and OMT had lower sensitivity (96% and 82%, respectively) but high specificity (98%). We confirmed that these antibodies were functional (i.e., neutralizing) and that their detection was quantitatively reproducible and well correlated between sample types when normalized to IgG content. DBSs and OMT are appropriate alternative sample types for HPV vaccine surveillance. These alternative sample types warrant consideration for the purposes of cervical screening, diagnosis, and management, but more work will be needed to establish the stringent parameters required for such application. IMPORTANCE Human papillomavirus (HPV) is the causative agent of cervical and other anogenital cancers. HPV vaccination, primarily targeted at young girls before the age of sexual debut, is starting to demonstrate population-level declines in HPV infection and early disease associated with vaccine-incorporated genotypes. Monitoring young women for vaccine-specific antibody is important for vaccine surveillance and may be useful as an adjunct test within a cervical screening context. We evaluated serum, dried blood spots, and oral fluid as potential samples for such applications and report robust measures of diagnostic accuracy. This is the first time a direct comparison of alternative sample types has been made between vaccinated and unvaccinated women for the detection and quantitation of HPV antibodies.

Background Food frequency questionnaires (FFQs) are essential tools to investigate the relationship between peanut consumption and the development of peanut allergy. The aim was to validate a 50-item FFQ for use in peanut protein sensitization studies.Methods There were 38 mother-child pairs visiting a pediatric clinic of a London hospital included. Mothers recorded their own and their child's diet, using a 7 day food diary (7DFDR), completed prospectively over week. Six months later, they tried to recall the consumption of food items for the index week on a FFQ.Results Of these, 33 out of 38 mothers completed both the 7DFDR and the recall FFQ. Although there was considerable variation at the individual level between the 2 tools, there was extremely close agreement between the mean 7DFDR response and the FFQ when considering groups of fives with similar FFQ levels. Agreement was apparent on both peanut and other control foods consumption patterns.Conclusion The FFQ will reliably divide the population into groups with markedly different peanut consumption levels. It accurately reflects true adults and children peanut consumption, especially at low levels of peanut consumption, as it was validated against the gold standard, the 7DFDR. It also provides a good measure of other foods consumption. Keywords: validation, food frequency questionnaire, recall, children

Conventional cytology (Pap) and visual inspection after the application of acetic acid (VIA) are currently used in primary screening in Peru. Studies suggest that the quality of VIA is highly variable. Over 36 000 women were screened with Pap and VIA in the TATI (Tamizaje y Tratamiento Inmediato de Lesiones Cervico-uterinas) project conducted in Amazonian Peru. Within a nested study to compare several screening techniques (C-TATI), a total of 5435 women were additionally screened with liquid-based cytology (LBC) and high-risk human papillomavirus testing (HR-HPV). We investigate the variation of positivity rates of VIA, Pap, LBC and HR-HPV in C-TATI and of VIA in the full TATI intervention.At the screening visit, midwives collected three cervical samples for Pap, LBC and HC2 before performing VIA. The dispersion factor "D" (D = Pearson chi-square value/degrees-of-freedom) was used to measure the variability of tests results. Within C-TATI, the variability of positivity rates of VIA, Pap, LBC and HR-HPV was also graphically assessed with box- and scatter plots by midwife and month of screening. Funnel plots and smoothed scatter plots were used to correlate the variation of VIA by the number of examinations performed by each midwife over the full TATI intervention.Consistently over TATI, VIA results were highly variable, independently of the examiner, the time when the test was performed and the number of tests the examiner performed (D>6, p-values25, p-values0.05 for HR-HPV). No evidence for correlation between the number of VIAs done per midwife and the variability of VIA results was observed.The lack of over-dispersion for HR-HPV detection suggests that the variable VIA results do not reflect true variation in underlying disease, but a lack of consistency in human judgement.

BackgroundThere is little consensus, and minimal evidence, regarding the age at which to stop cervical screening. We studied the association between screening at age 50-64 y and cervical cancer at age 65-83 y.Methods and findingsCases were women (n = 1,341) diagnosed with cervical cancer at age 65-83 y between 1 April 2007 and 31 March 2012 in England and Wales; age-matched controls (n = 2,646) were randomly selected from population registers. Screening details from 1988 onwards were extracted from national databases. We calculated the odds ratios (OR) for different screening histories and subsequent cervical cancer. Women with adequate negative screening at age 65 y (288 cases, 1,395 controls) were at lowest risk of cervical cancer (20-y risk: 8 cancers per 10,000 women) compared with those (532 cases, 429 controls) not screened at age 50-64 y (20-y risk: 49 cancers per 10,000 women, with OR = 0.16, 95% CI 0.13-0.19). ORs depended on the age mix of women because of the weakening association with time since last screen: OR = 0.11, 95% CI 0.08-0.14 at 2.5 to 7.5 y since last screen; OR = 0.27, 95% CI 0.20-0.36 at 12.5 to 17.5 y since last screen. Screening at least every 5.5 y between the ages 50 and 64 y was associated with a 75% lower risk of cervical cancer between the ages 65 and 79 y (OR = 0.25, 95% CI 0.21-0.30), and the attributable risk was such that in the absence of screening, cervical cancer rates in women aged 65+ would have been 2.4 (95% CI 2.1-2.7) times higher. In women aged 80-83 y the association was weaker (OR = 0.49, 95% CI 0.28-0.83) than in those aged 65-69 y (OR = 0.12, 95% CI 0.09-0.17). This study was limited by an absence of data on confounding factors; additionally, findings based on cytology may not generalise to human papillomavirus testing.ConclusionsWomen with adequate negative screening at age 50-64 y had one-sixth of the risk of cervical cancer at age 65-83 y compared with women who were not screened. Stopping screening between ages 60 and 69 y in women with adequate negative screening seems sensible, but further screening may be justifiable as life expectancy increases.